Canine and Feline Endocrinology PDF

CONVERSION TO SYSTEME INTERNATIONAL (SI) UNITS
FOR HORMONE ASSAYS
Measurement SI Unit Common Unit Common SI* SI Common*

Aldosterone pmol/L ng/dL 27.7 0.036
Corticotropin (ACTH) pmol/L pg/mL 0.220 4.51
Cortisol nmol/L g/dL 27.59 0.036
C-peptide nmol/L ng/mL 0.331 3.02
-Endorphin pmol/L pg/mL 0.292 3.43
Epinephrine pmol/L pg/mL 5.46 0.183
Estrogen (estradiol) pmol/L pg/mL 3.67 0.273
Gastrin ng/L pg/mL 1.00 1.00
Gastrointestinal polypeptide pmol/L pg/mL 0.201 4.98
Glucagon ng/L pg/mL 1.00 1.00
Growth hormone g/L ng/mL 1.00 1.00
Insulin pmol/L U/mL 7.18 0.139
Metanephrine pmol/L pg/mL 5.07 0.197
MSH pmol/L pg/mL 0.601 1.66
Norepinephrine pmol/L pg/mL 5.91 0.169
Normetanephrine pmol/L pg/mL 5.46 0.183
Pancreatic polypeptide mmol/L mg/dL 0.239 4.18
Parathyroid hormone (PTH) pmol/L pg/mL 0.11 9.1
Progesterone nmol/L ng/mL 3.18 0.315
Prolactin g/L ng/mL 1.00 1.00
Renin ng/L/s ng/mL/hr 0.278 3.60
Somatostatin pmol/L pg/mL 0.611 1.64
Testosterone nmol/L ng/mL 3.47 0.288
Thyroxine (T4) nmol/L g/dL 12.87 0.078
Free Thyroxine (fT4) pmol/L ng/dL 12.87 0.078
Triiodothyronine (T3) nmol/L g/dL 0.0154 64.9
Vasoactive intestinal polypeptide pmol/L pg/mL 0.301 3.33
*Factor to multiply to convert from one unit to other.

CONVERSION TO SYSTEME INTERNATIONAL (SI) UNITS
FOR COMMON SERUM CHEMISTRY DATA
Measurement SI Unit Common Unit Common SI* SI Common*

Albumin g/L g/dL 10.0 0.100
Bile acids mol/L mg/L 2.55 0.392
Bilirubin mol/L mg/dL 17.10 0.058
Calcium mmol/L mg/dL 0.250 4.00
Carbon dioxide content mmol/L mEq/L 1.00 1.00
Cholesterol mmol/L mg/dL 0.026 38.7
Chloride mmol/L mEq/L 1.00 1.00
Creatinine mol/L mg/dL 88.40 0.011
Creatinine clearance mL/s mL/min 0.017 60.0
Glucose mmol/L mg/dL 0.056 18.0
Inorganic phosphorus nmol/L mg/dL 0.323 3.10
Magnesium mmol/L mg/dL 0.41 2.44
Osmolality nmol/kg mOsm/kg 1.00 1.00
Potassium mmol/L mEq/L 1.00 1.00
Protein, total g/L g/dL 10.0 0.100
Sodium mmol/L mEq/L 1.00 1.00
Triglycerides mmol/L mg/dL 0.01 10.0
Urea nitrogen mmol/L mg/dL 0.357 2.8

*Factor to multiply to convert from one unit to other.
Canine & Feline
ENDOCRINOLOGY
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Fourth Edition
Canine& Feline
ENDOCRINOLOGY
Edward C. Feldman, DVM, DACVIM (Internal Medicine)
Professor, Department of Medicine and Epidemiology
School of Veterinary Medicine
University of California, Davis
Davis, California
Richard W. Nelson, DVM, DACVIM (Internal Medicine)

Professor, Department of Medicine and Epidemiology
School of Veterinary Medicine
University of California, Davis
Davis, California
Claudia E. Reusch, DVM, DECVIM-CA

Professor
Clinic for Small Animal Internal Medicine
Vetsuisse Faculty
University of Zurich
Zurich, Switzerland
J. Catharine R. Scott-Moncrieff, MA, Vet MB, MS, DACVIM (Small Animal Internal Medicine),
DSAM, DECVIM-CA
Professor, Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Purdue University
West Lafayette, Indiana
CONTRIBUTING AUTHOR
Ellen N. Behrend, VMD, PhD, DACVIM (Small Animal Internal Medicine)

Joezy Griffin Professor, Department of Clinical Sciences
Auburn University
Auburn, Alabama
3251 Riverport Lane
St. Louis, Missouri 63043
CANINE AND FELINE ENDOCRINOLOGY, EDITION 4 ISBN: 978-1-4557-4456-5

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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using
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Library of Congress Cataloging-in-Publication Data

Feldman, Edward C., author.
[Canine and feline endocrinology and reproduction]
Canine and feline endocrinology / Edward C. Feldman, Richard W. Nelson, Claudia E. Reusch, J. Catharine R.
Scott-Moncrieff. -- Fourth edition.
pages ; cm
Preceded by Canine and feline endocrinology and reproduction / Edward C. Feldman, Richard W. Nelson.
3rd ed. c2004.
Includes bibliographical references and index.
ISBN 978-1-4557-4456-5 (hardcover : alk. paper) 1. Dogs--Diseases. 2. Cats--Diseases. 3. Dogs--Endocrinology.
4. Cats--Endocrinology. 5. Dogs--Reproduction. 6. Cats--Reproduction. I. Nelson, Richard W. (Richard William),
author. II. Reusch, Claudia, author. III. Scott-Moncrieff, J. Catharine R., author. IV. Title.
[DNLM: 1. Dog Diseases. 2. Endocrine System Diseases--veterinary. 3. Cat Diseases. 4. Genital Diseases,
Female--veterinary. 5. Genital Diseases, Male--veterinary. SF 992.E53]
SF992.E53F45 2015
636.708964--dc23
2014034827
Vice President and Publisher: Loren Wilson

Content Strategy Director: Penny Rudolph
Content Development Specialist: Brandi Graham
Publishing Services Manager: Deborah Vogel
Senior Project Manager: Brandilyn Flagg
Designer: Ashley Miner
Printed in the United States of America
Last digit is the print number: 987654321

Editors
Edward C. Feldman, DVM, DACVIM (Internal Medicine), is a Professor of

Small Animal Internal Medicine in the Department of Medicine & Epidemiol-
ogy, School of Veterinary Medicine, University of California, Davis. Dr. Feld-
man earned his DVM from the University of California in 1973. He joined the
Davis faculty in 1979 after an internship at the Animal Medical Center in New
York City, a residency with Dr. Stephen Ettinger in the worlds first referral-only
private-veterinary-practice in Berkeley California, a year in general practice, and
another 2 years on faculty at the University of Saskatchewan in Canada. Dr. Feld-
man has authored more than 160 peer-reviewed scientific publications, 110 sci-
entific abstracts, and 75 book chapters. He is co-editor with Dr. Ettinger of the
Textbook of Veterinary Internal Medicine, now in its 7th edition and translated into
six foreign languages. He has also served as co-author with Dr. Nelson on the first
three editions of this book, which have been translated into five foreign languages. Dr. Feldman has lectured
in more than 40 of the 50 United States and 25 countries. He has served on the Board of Directors for Guide
Dogs for the Blind and on the Board of Directors for the Western Veterinary Conference (one of the two largest
veterinary conferences in the United States), and he is a member of the Scientific Advisory Board of the Annette
Funicello Foundation for Multiple Sclerosis. He is a co-founder and two-term past-president of the Society for
Comparative Endocrinology. Dr. Feldmans teaching awards include the Faculty Teacher of the Year Award from
the University of Saskatchewan Western College of Veterinary Medicine, the UC Davis Norden Distinguished
Teaching Award, the North American Veterinary Conference Speaker of the Year Award, and the California Acad-
emy of Veterinary Medicines Award for Excellence in Continuing Education. Dr. Feldman has been honored
with several research awards, including the Ralston Purina Small Animal Research Award, the American Association
of Feline Practitioners Research Award, the SmithKline Beecham Award for Research Excellence, eight Daniels /
Oxford Laboratory Awards for authoring one of the two or three best clinical veterinary endocrine research pub-
lications for a given year, and the American Veterinary Medical Foundation / AKC Career Achievement Award in
Canine Research. Additional recognitions received by Dr. Feldman include the FIDO Award from the American
Veterinary Medical Association, the Distinguished Alumnus Award from the Animal Medical Center in New York
City, and the UC Davis Alumni Achievement Award.
Richard W. Nelson, DVM, DACVIM (Internal Medicine), is a Professor in

the Department of Medicine & Epidemiology, School of Veterinary Medi-
cine, University of California, Davis. Dr. Nelson received his DVM degree
from the University of Minnesota in 1979. After graduation he completed
an internship at Washington State University and a medicine residency at the
University of California, Davis. In 1982 he joined the small animal medicine
faculty at Purdue University. In 1989 he moved to the University of Califor-
nia, Davis, where he is currently a professor in small animal internal medi-
cine. Dr. Nelsons interest lies in clinical endocrinology, with an emphasis on
disorders of the endocrine pancreas, thyroid gland, and adrenal gland. Dr.
Nelson has authored numerous scientific publications and book chapters; has
co-authored two textbooks, Canine and Feline Endocrinology and Reproduction
with Dr. Feldman and Small Animal Internal Medicine with Dr. Guillermo Couto; and has lectured exten-
sively nationally and internationally. He was an associate editor for the Journal of Veterinary Internal Medicine
and serves as a reviewer for several veterinary journals. Dr. Nelson is a co-founder and member of the Society
for Comparative Endocrinology and a member of the European Society of Veterinary Endocrinology. Dr.
Nelson has served as Chair of the Department of Medicine and Epidemiology and as Director of the Small
Animal Clinic at UC Davis. Dr. Nelson has received the N orden Distinguished Teaching Award, the BSAVA
Bourgelat Award, and the ACVIM Robert W. Kirk Award for Professional Excellence.
v
vi EDITORS
Claudia E. Reusch, DVM, J. Catharine R. Scott-Moncrieff,

DECVIM-CA, Professor, Clinic MA, Vet MB, MS, DACVIM
for Small Animal Internal Medi- (Small Animal Internal Medicine),
cine, Vetsuisse Faculty, University DSAM, DECVIM (Companion
of Zurich, Switzerland. After grad- Animal), Professor, Department
uation Claudia Reusch worked in of Veterinary Clinical Sciences,
private small animal clinics for College of Veterinary Medicine,
several years before moving to the Purdue University, West Lafay-
University of Munich, where she ette, Indiana. C atharine Scott-
became Professor for Small Animal Moncrieff received her veterinary
Internal Medicine in 1992. Since degree from the University of
1996 she has been the director of Cambridge in 1985. She com-
the Clinic for Small Animal Internal Medicine at the University of pleted an internship in small animal medicine and surgery at
Zurich in Switzerland. She is founding member of the European the University of Saskatchewan, Canada, and a residency and
Society of Veterinary Endocrinology (ESVE) and was its president Master of Science degree in internal medicine at Purdue Univer-
from 2001 to 2003. From 2003 to 2006 she was president of the sity. In 1989 she joined the faculty of Purdue University, where
European College of Veterinary Internal Medicine-Companion she is currently Professor of small animal internal medicine and
Animals (ECVIM-CA). Since 2011 she has been a member of Head of the Department of Veterinary Clinical Sciences. She
the University Council of the University of Veterinary Medicine is a Diplomate of the American College of Veterinary Internal
in Vienna, Austria, and since 2013 she has been a member of the Medicine (small animal) and the European College of Veterinary
Scientific Advisory Board of the same university. In 2014 she was Internal Medicine (companion animal), and has a diploma in
given the Bourgelat Award by the British Small Animal Veterinary Small Animal Medicine from the Royal College of Veterinary
Association (BSAVA) for outstanding international contributions Surgeons. She is a past president of the Socety for Compara-
to the field of small animal practice. Her research focus is on clini- tive Endocrinology and has lectured extensively nationally and
cal endocrinology in dogs and cats. internationally. Her research focus is clinical endocrinology of
the dog and cat with an emphasis on disorders of the thyroid and
adrenal glands. She has authored numerous scientific publica-
tions and lectured extensively both nationally and internation-
ally. She served as Associate Editor of the Journal of Veterinary
Internal from 2002 to 2010 and is a member and past president
of the Society of Comparative Endocrinology. She has received
the Daniels Award for Excellence in Small Animal Endocrinol-
ogy on three occasions.
CONTRIBUTING AUTHOR
Ellen N. Behrend, VMD, PhD, DACVIM (Small Animal Internal Medicine), Joezy
Griffin Professor, Department of Clinical Sciences, Auburn University, Auburn, Ala-
bama. Dr. Behrend received her VMD degree from the University of Pennsylvania in
1988 and her PhD from Auburn University in 2001. Dr. Behrends research interest
lies in clinical endocrinology with an emphasis on diagnostic testing and diseases of the
canine adrenal glands. She has authored numerous scientific publications and book
chapters, served as Endocrine section editor for editions of Consultations in Feline Inter-
nal Medicine and Kirks Current Veterinary Therapy, and was the editor for the canine
chapters of Clinical Endocrinology of Companion Animals. Dr. Behrend has been on the
review board for two journals and is currently serving on the Small Animal Advisory
Panel for Morris Animal Foundation and holds a position on the ACVIM Board of
Regents. She has provided numerous continuing education lectures at national and
international conferences. Dr. Behrend has received the Daniels Award for Excellence in Small Animal Endocrinology
and has twice won the Norden Distinguished Teaching Award.
Preface
The goal of the fourth edition of our textbook on canine and and algorithms. Diagnostic strategies are presented with the intent
feline endocrinology is similar to that of the first three editions: to of making them practical, cost-effective, and expedient while
provide veterinarians and readers of this textbook with a concise ensuring they represent standard of care backed by research and
but complete source of information on pathophysiology, clini- experience. Treatment recommendations were also consistently
cal signs, diagnosis, and treatment of endocrine disorders in dogs developed with practicality, cost-effectiveness, and compassionate
and cats. Because of the tremendous expansion of information on care in mind, backed by research and experience.
these disorders since publication of the last edition more than a The development of this textbook provided us with a challeng-
decade ago, the fourth edition required a complete overhaul of ing, informative, and laborious but rewarding task. We are confi-
the previous edition. To help accomplish this, we brought three dent this textbook provides the reader with complete, current, and
additional world-renowned clinical endocrinologists on board, applicable information on endocrine disorders of dogs and cats
Claudia Reusch, Catharine Scott-Moncrieff, and Ellen Behrend, and will help veterinary students, practitioners, interns, residents,
whom are superb clinician scientists; all are actively involved in and owners. We do not claim that the information is presented
patient care, clinical investigative studies, and publications in the completely without bias. Indeed, our extensive clinical experience
field of small animal endocrinology. creates bias, which we are convinced provides a positive and well-
The fourth edition has significant changes starting with the established foundation to our recommendations on diagnostic
removal of the reproduction section, thereby allowing us to focus and treatment strategies. We hope you will find our textbook a
entirely on our primary passion: endocrine disorders of dogs valuable resource for information on endocrine disorders of dogs
and cats. There are many additions to this book we believe will and cats.
enhance the clinical usefulness of this resource. All chapters have
undergone extensive rewriting and updating of material, provision Edward C. Feldman
of new or updated tables, and addition of new or updated figures Richard W. Nelson
vii

To our colleagues and clients who have provided us with cases
and supported our work through the years.
To Claudia, Catharine, and Ellen for their willingness to become involved
in this project and for their hard work and dedication.
To Penny Rudolph, Brandi Graham, Brandi Flagg, Katie Stark,
and many others at Elsevier for their commitment, patience, and latitude
in the development of this textbook.
Also, with special thanks to our residents, technicians, and students who have
helped perform much of our clinical research and who refuse to allow
us to stop searching for answers.
ECF & RWN
To our students, interns, residents, staff members, referring veterinarians,

pet owners, and colleagues: thank you for asking the questions whose answers
would improve the quality of life for our patients. To the late Ruth Johnston, whose contributions
allowed us to complete so many clinical research studies. Regarding both veterinary
medicine and ourselves: we have learned much, we have much to learn.
ECF
To my soul mate Kay who has been with me for 40 years and has had
to endure all of the trials and tribulations affiliated with all of my publication
endeavors; it would not have been possible without you.
RWN
To my family for their love and continuous support.

CER
To my husband Wallace who has supported all my endeavors. To the students,

interns, residents, and colleagues who have asked thought provoking questions
about endocrinology and the pets and pet owners who have helped answer
some of those questions.
CSM
To my parents, Erika and Stephen, who gave me immeasurable support and

the drive to ask questions, to learn, and to succeed. To Charles, for continuing
their tradition.
ENB

Contents
SECTION 1 SECTION 4
THE PITUITARY GLAND, 1 THE ADRENAL GLAND, 377
1 Water Metabolism and Diabetes Insipidus, 1 10 Canine Hyperadrenocorticism, 377
Richard W. Nelson Ellen N. Behrend
2 Disorders of Growth Hormone, 37 11 Hyperadrenocorticism in Cats, 452

Claudia E. Reusch Edward C. Feldman
SECTION 2 12 Hypoadrenocorticism, 485

THE THYROID GLAND, 77 J. Catharine Scott-Moncrieff
3 Hypothyroidism, 77 13 Pheochromocytoma and Multiple Endocrine

J. Catharine Scott-Moncrieff Neoplasia, 521
Claudia E. Reusch
4 Feline Hyperthyroidism, 136
J. Catharine Scott-Moncrieff 14 Glucocorticoid Therapy, 555
Claudia E. Reusch
5 Canine Thyroid Tumors and Hyperthyroidism, 196
J. Catharine Scott-Moncrieff SECTION 5
PARATHYROID GLAND, 579
SECTION 3
THE ENDOCRINE PANCREAS, 213 15 Hypercalcemia and Primary Hyperparathyroidism, 579
Edward C. Feldman
6 Canine Diabetes Mellitus, 213
Richard W. Nelson 16 Hypocalcemia and Primary Hypoparathyroidism, 625
Edward C. Feldman
7 Feline Diabetes Mellitus, 258
Claudia E. Reusch
8 Diabetic Ketoacidosis, 315

Richard W. Nelson
9 Beta-Cell Neoplasia: Insulinoma, 348

Richard W. Nelson
xi

SECTION 1 THE PITUITARY GLAND
CHAPTER 1 Water Metabolism and Diabetes Insipidus

Richard W. Nelson
CHAPTER CONTENTS Confirming the Diagnosis of Diabetes Insipidus, 17

Physiology of Water Metabolism, 2 Response to Trial Therapy with Desmopressin Acetate, 17
The Neurohypophysis, 2 Modified Water Deprivation Test, 17
Vasopressin: Biosynthesis, Transport, and Metabolism, 2 Principle of the Test, 17
Actions of Vasopressin, 3 Protocol, 18
Thirst, 5 Responses to the Modied Water Deprivation Test, 19
Differential Diagnoses for Polydipsia and Polyuria, 6 Misdiagnosis (Inaccuracies) Using the Modied Water Deprivation Test, 22
Osmotic Diuresis, 6 Approach If the Dog or Cat Is Brought into the Hospital Dehydrated, 23
Primary Pituitary (Central) Diabetes Insipidus, 7 Complications of the Modied Water Deprivation Test: Hypertonic Dehydration
Primary Nephrogenic Diabetes Insipidus, 7 and Hypernatremia, 24
Acquired (Secondary) Nephrogenic Diabetes Insipidus, 7 Plasma Vasopressin Determinations, 26
Primary and Psychogenic Polydipsia, 9 Random Plasma Osmolality as a Diagnostic Tool, 28
Iatrogenic (Drug-Induced) Causes of Polydipsia and Polyuria, 9 Additional Diagnostic Tests: Computed Tomography and Magnetic
Renal Medullary Solute Washout, 9 Resonance Imaging, 28
Diagnostic Approach to Polyuria and Polydipsia, 9 Treatment, 29
Etiology of Diabetes Insipidus and Primary Polydipsia, 12 Vasopressin Analogues (Used in Central Diabetes Insipidus and Partial
Vasopressin DeciencyCentral Diabetes Insipidus, 12 Central Diabetes Insipidus), 29
Primary Nephrogenic Diabetes Insipidus, 14 Oral Agents (Used in Central Diabetes Insipidus, Partial Central Diabetes
Primary or Psychogenic Polydipsia, 14 Insipidus, Nephrogenic Diabetes Insipidus, and Primary Polydipsia), 30
Clinical Features of Diabetes Insipidus and Psychogenic Polydipsia, 14 No Treatment, 31
Signalment, 14 Behavior Modication (Used in Psychogenic Polydipsia), 31
Clinical Signs, 15 Prognosis, 31
Physical Examination, 16 Syndrome of Inappropriate Vasopressin Secretion: Excess Vasopressin, 31
Clinical Pathology Abnormalities, 16 Hypodipsic Hypernatremia, 34
Water consumption and urine production are controlled by com- Diabetes insipidus results from deciencies in secretion of
plex interactions between plasma osmolality, fluid volume in the vasopressin or in its ability to interact normally with receptors
vascular compartment, the thirst center, the kidney, the pituitary located in the distal and collecting tubular cells of the kidney.
gland, and the hypothalamus. Dysfunction in any of these areas The result of either disorder is impaired ability to conserve water
results in the clinical signs of polyuria and polydipsia. Arginine and concentrate urine, with production of large volumes of
vasopressin (AVP) plays a key role in the control of renal water hypotonic dilute urine and compensatory often severe polydipsia
resorption, urine production and concentration, and water bal- to minimize dehydration. Because of the dramatic polyuria and
ance. In the presence of vasopressin and dehydration, the average polydipsia associated with diabetes mellitus and diabetes insipi-
dog and cat can produce urine concentrated to or above 2300 dus, the term diabetes (secretion of a large volume of urine) was
mOsm/kg of H2O. In the absence of vasopressin or vasopressin historically used for both conditions. However, the urine is taste-
action on the kidneys, the urine may be as dilute as 20 mOsm/ less (insipid) with diabetes insipidus because, unlike in diabetes
kg of H2O. mellitus (in which the urine is sweet from sugar), polyuria in
1
2 SECTION 1 THE PITUITARY GLAND
2% increase in 10% decrease in

ECF osmolality blood volume
CNS osmoreceptor Baroreceptor
AVP release Angiotensin II
Thirst Magnocellular
neurosecretory
cells
Hypothalamus
Water conservation Water acquisition
Optic
chiasm Posterior
Increased blood volume lobe of
Decreased ECF osmolality pituitary
FIGURE 1-1Schematic illustration of the primary mechanisms involved in

maintenance of water balance. Solid lines indicate osmotically stimulated path-
ways, and dashed lines indicate volume stimulated pathways. (Adapted from
Reeves WB, Andreoli TE: The posterior pituitary and water metabolism. In Wilson
JD, Foster DW, editors: Williams textbook of endocrinology, ed 8, Philadelphia,
Anterior lobe
1992, WB Saunders, p. 311.) AVP, Arginine vasopressin; CNS, central nervous of pituitary Capillary bed
system; ECF, extracellular fluid.
FIGURE 1-2 Midsagittal view of the hypothalamus and pituitary gland illustrating
the cell bodies of the magnocellular neurons in the hypothalamus and extension
diabetes insipidus is not the result of a glucose-induced osmotic of their axons into the pituitary gland where vasopressin and oxytocin are secreted
diuresis. directly into capillaries in the posterior lobe of the pituitary gland. (From Bear MF,
etal.: Neuroscience: exploring the brain, ed 3, Baltimore, 2007, Lippincott Williams
PHYSIOLOGY OF WATER METABOLISM & Wilkins, p. 486.)
Plasma osmolality and its principal determinant, the plasma sodium

concentration, are normally maintained within remarkably narrow located in the carotid sinus and aortic arch and low-pressure vol-
ranges. This stability is achieved largely by adjusting total body ume receptors located in the atria and pulmonary venous system
water to keep it in balance with the serum sodium concentration. (Thrasher, 1994). Baroreceptors and volume receptors normally
Water balance is controlled by an integrated system that involves inhibit the magnocellular neurons, and decreases in this tonic inhi-
regulation of water intake by the thirst center and control of urine bition result in the release of vasopressin. Arterial and venous con-
volume by plasma vasopressin (Fig. 1-1). The physiologic regulation striction induced by vasopressin action on V1a receptors on blood
of vasopressin synthesis and secretion involves two systems: extracel- vessels contracts the vessels around the existing plasma volume to
lular fluid (ECF) osmolality and blood pressure and volume. Vaso- effectively increase plasma volume and reestablish the inhibition
pressin is the main hormone involved in the regulation of water of secretion of vasopressin (Robinson and Verbalis, 2011). Vaso-
homeostasis and osmolality and the renin-angiotensin-aldosterone pressins action at the kidney to retain water does help replace vol-
system (RASS) is mainly responsible for regulation of blood pres- ume, but the major hormonal regulation to control blood volume
sure and volume (Robinson and Verbalis, 2011). Regarding osmo- is the RAAS, which stimulates sodium reabsorption in the kidney.
regulation, vasopressin secretion is relatively uncomplicated, with
small increases in osmolality producing a parallel increase in vaso- Vasopressin: Biosynthesis, Transport, and Metabolism
pressin secretion and small decreases in osmolality causing a parallel
decrease in vasopressin secretion. Vasopressin and oxytocin are nonapeptides composed of a six-
membered disulde ring and a three-membered tail on which the
terminal carboxyl group is amidated (Fig. 1-3). AVP is the antidi-
The Neurohypophysis
uretic hormone in all mammals except swine and other members
The neurohypophysis consists of a set of hypothalamic nuclei of the suborder Suina, in which lysine vasopressin is synthesized
(supraoptic and paraventricular) containing magnocellular neurons (Reeves et al, 1998). Vasopressin differs from oxytocin in most
responsible for the synthesis of oxytocin and vasopressin; the axo- mammals only in the substitution of phenylalanine for isoleucine
nal processes of these cells, which form the supraopticohypophysial in the ring and arginine for leucine in the tail. The ratio of antidi-
tract; and the termini of these cells within the posterior lobe of the uretic to pressor effects of vasopressin is increased markedly by sub-
pituitary (Fig. 1-2; Reeves etal, 1998). The magnocellular neurons stituting d-arginine for l-arginine at position 8. This modication,
in the paraventricular and supraoptic nuclei secrete vasopressin or as well as removal of the terminal amino group from cysteine,
oxytocin in response to appropriate stimuli. The magnocellular yields desmopressin acetate (DDAVP), a synthetic commercially
neurons producing vasopressin receive neurogenic input from vari- available product (see Fig. 1-3). DDAVP is a clinically useful ana-
ous sensor elements, including high-pressure arterial baroreceptors logue with prolonged and enhanced antidiuretic activity that does
|
CHAPTER 1 Water Metabolism and Diabetes Insipidus 3
Position Oxytocin Vasopressin DDAVP
NH2 NH2
1 Cysteine Cysteine Cysteine
2 Tyrosine Tyrosine Tyrosine

S S S
3 Isoleucine Phenylalanine Phenylalanine
4 Glutamine Glutamine Glutamine

S S S
5 Asparagine Asparagine Asparagine
6 Cysteine Cysteine Cysteine
7 Proline Proline Proline
8 Leucine Arginine D-arginine
9 Glycinamide Glycinamide Glycinamide

FIGURE 1-3 The chemical structures of oxytocin, vasopressin, and 1 desmopressin acetate (DDAVP).
not require injection to be effective and is commonly used to treat vasculosum of the lamina terminalis and in areas of the adjacent
central diabetes insipidus (CDI) in dogs and cats. anterior hypothalamus near the anterior wall of the third cerebral
The production of vasopressin and oxytocin is associated with syn- ventricle (Robinson and Verbalis, 2011). Because cells in these
thesis of specic binding proteins called neurophysins. One molecule areas are perfused by fenestrated capillaries, the blood brain barrier
of neurophysin I binds one molecule of oxytocin and one molecule is deficient, the cells are influenced by the composition of plasma
of neurophysin II binds one molecule of vasopressin (Reeves et al, rather than cerebrospinal fluid (CSF) and are able to invoke a
1998). The neurophysin peptide combination, often referred to as rapid change in vasopressin secretion in response to changes in
neurosecretory material, is transported along the axons of the hypothal- plasma osmolality. As little as a 1% increase or decrease in plasma
amo-neurohypophyseal nerve tract and stored in granules in the nerve osmolality causes a rapid increase or decrease of vasopressin from
terminals located in the posterior pituitary gland (see Fig. 1-2). Release the store of hormone in the posterior pituitary. Rapid metabolism
of vasopressin into the bloodstream occurs following electrical activa- of vasopressin (half-life of approximately 15 minutes) also allows
tion of the magnocellular neurons containing AVP. Secretion proceeds rapid changes in the concentration of vasopressin in plasma.
by a process of exocytosis, with release of vasopressin and neurophy- In the kidney, water is conserved by the combined functions
sin II into the bloodstream. In plasma, the neurophysin-vasopressin of the loop of Henle and the collecting duct. The loop of Henle
combination dissociates to release free vasopressin. Nearly all of the generates a high osmolality in the renal medulla by means of the
hormone in plasma exists in an unbound form, which because of countercurrent multiplier system. Vasopressin acts to increase
its relatively low molecular weight, readily permeates peripheral and the water permeability of the collecting duct, thereby allow-
glomerular capillaries. Metabolic degradation of AVP appears to be ing osmotic equilibration between the urine and the hypertonic
mediated through binding of AVP to specic receptors, with subse- medullary interstitium. The effects of AVP are mediated primar-
quent proteolytic cleavage of the peptide (Reeves etal, 1998). Renal ily by the intracellular second messenger cyclic adenosine mono-
excretion is the second method for elimination of circulating AVP and phosphate (cAMP) (Fig. 1-4). AVP binds to the V2 receptors
accounts for about one-fourth of total metabolic clearance. of hormone-responsive epithelial cells and activates membrane-
associated adenylate cyclase to catalyze cAMP generation from
adenosine triphosphate (ATP). cAMP-dependent activation of
Actions of Vasopressin
protein kinase A leads to an increase in water permeability of
AVP binds to cellular receptors at the end organs of response. The the luminal membrane of the cell as a result of insertion of aqua-
antidiuretic action of AVP is mediated through V2 cyclic adenos- porin-2 water channels into the apical membrane of the epithe-
ine monophosphate (AMP)-dependent receptors on renal collect- lial cell. Transmembrane water movement occurs through these
ing duct epithelia, whereas its vasoconstrictive action is mediated water channels, rather than by diffusion across the lipid bilayer
through V1a phosphatidylinositol dependent receptors on blood or through junctional complexes (Fig. 1-5; Robben etal, 2006).
vessels. A third receptor (V3 or V1b) is responsible for the nontra- In essence, AVP, working via cAMP and protein kinase A, alters
ditional biologic action of vasopressin to stimulate adrenocorti- water transport in hormone-responsive epithelia by causing the
cotropic hormone (ACTH) secretion from the anterior pituitary. microtubule-dependent insertion of specialized membrane units
V2 receptors also regulate the nontraditional action of vasopres- (aquaporin-2 water channels) into the apical plasma membranes
sin to stimulate production of factor VIII and von Willebrand of these cells. The increase in water permeability in these seg-
factor (Robinson and Verbalis, 2011). The vasopressin analogue, ments augments osmotic water flow from the tubular lumen into
DDAVP, which is commonly used for the treatment of CDI, has a a hypertonic medullary interstitium. Blood vessels in the intersti-
strong afnity for V2 receptors with minimal pressor (V1) activity. tium (i.e., vasa recta) distribute absorbed water into the systemic
The primary receptors for sensing changes in osmolality circulation, maintaining the hypertonicity of the medullary inter-
are located in the brain and, specifically cells in the organum stitium. The net effect of this process is to extract water from the
Demeclocycline Alpha adrenergic drugs

Halothane E. coli endotoxin
Barbiturates
Lithium Glucocorticoids
Beta adrenergic drugs
Methoxyflurane Hypercalcemia
Carbamazepine
Hypokalemia
Cholinergic drugs
Chlorpropamide
Clofibrate
Narcotics Chlorpropamide
Nicotine
Nitrous oxide
Tricyclic antidepressants 5' AMP
Vincristine
PDE
Protein
cAMP kinases
Neurohypophysis Vasopressin AC
H2O
ATP
Ethanol PGE Collecting
Glucocorticoids
duct cell
Phenytoin Luminal AA
Chlorpropamide membrane
Basolateral
membrane
AA PGE
Nonsteroidal
Renal anti-inflammatory
Medullary drugs
Interstitial
Cell
FIGURE 1-4 Effects of selected drugs and electrolytes on vasopressin release and action. (From DeBartola SP: Dis-
orders of sodium and water: hypernatremia and hyponatremia. In DiBartola SP, editor: Fluid therapy in small animal
practice, ed 2, Philadelphia, 2000, WB Saunders, p. 52.) 5AMP, 5-adenosine monophosphate, AA, arachidonic
acid; AC, adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PDE, phosphodies-
terase; PGE, prostaglandin E.
urine, resulting in increased urine concentration and decreased concentrate urine; thus desert rodents with extremely concen-
urine volume. Dissociation of AVP from the V2 receptor allows trated medullary interstitium can produce urine more concen-
intracellular cAMP levels to decrease and the water channels are trated than that of dogs and are remarkably capable of conserving
then reinternalized, terminating the increased water permeability. fluid. Conversely, loss of the renal medullary hypertonicity may
The primary effect of AVP is to conserve body fluid by reduc- inhibit vasopressins antidiuretic activity (see Fig. 1-5). Decreased
ing the volume of urine production (Table 1-1). This antidiuretic medullary hypertonicity (or lack thereof ) can result from various
action is achieved by promoting the reabsorption of solute free causes, such as chronic water diuresis or reduced medullary blood
water in the distal and/or collecting tubules of the kidney. In the flow. However, because a majority of fluid flowing from the loop
absence of AVP, the membranes lining this portion of the nephron of Henle can still be reabsorbed isotonically in the distal convo-
are uniquely resistant to the diffusion of both water and solutes. luted tubule and proximal collecting duct, loss of the hypertonic
Hence the hypotonic ltrate formed in the more proximal por- medullary concentration gradient alone rarely results in marked
tion of the nephron passes unmodied through the distal tubule polyuria (Robertson, 1981).
and collecting duct. In this condition, referred to as water diuresis, It should be noted that 85% to 90% of the fluid ltered by the
urine osmolality is low and urine volume is great (see Fig. 1-5). glomerulus is reabsorbed isosmotically with sodium and glucose
The amount of water reabsorbed in the distal nephron depends in the proximal portion of the nephron. Sodium is then selectively
on the plasma AVP concentration and the existence of a signicant reabsorbed from the remaining fluid, making the fluid hypotonic
osmotic gradient in the renal interstitium. Vasopressin does not as it reaches the distal nephron. An additional 90% of this remain-
cause an active (i.e., energy-requiring) reabsorption of solute ing fluid can be reabsorbed under the influence of AVP (Robert-
free water. It merely opens the water channels in the luminal son, 1981). However, if the oral intake of salt is high or if a poorly
membrane to allow water to flow in the direction of the higher reabsorbed solute such as mannitol, urea, or glucose is present in
osmolality (along the osmotic gradient). In the normal animal, the the glomerular ltrate, fluid resorption from the proximal tubule
osmolality of the ltrate entering the distal tubule is low, whereas is impaired. The resultant increase in fluid volume presented to
that of the renal interstitium is high, promoting reabsorption of the distal nephron may overwhelm its limited capacity to reabsorb
water when the pores are open. Increasing the renal medullary water. As a consequence, urine osmolality decreases and volume
interstitial osmolality increases the ability to reabsorb water and increases, even in the presence of large amounts of vasopressin.
|
AVP +AVP
OSMOLARITY
mOsm/kg
290
Na Na
H2O
120 120
K K
H2O
Na Na
H2O H2O
H2O
290
14 16 16 CORTEX 24 16 2.5 H2O
300 MEDULLA
Na H2O
H2O H2O
600 Na
Na
H2O
900 H2O Na
H2O
1200
H2O
16 0.6
FIGURE 1-5 Schematic representation of the effect of vasopressin on the formation of urine by the human nephron. The
osmotic pressure of tissue and tubular fluid is indicated by the density of the shading. The numbers within the lumen of the
nephron indicate typical rates of flow in milliliters per minute. Arrows indicate reabsorption of sodium (Na) or water (H2O)
by active (solid arrows) or passive (broken arrows) processes. Note that vasopressin acts only on the distal nephron, where
it increases the hydro-osmotic permeability of tubular membranes. The fluid that reaches this part of the nephron normally
amounts to between 10% and 15% of the total filtrate and is hypotonic owing to selective reabsorption of sodium in the
ascending limb of the loop of Henle. In the absence of vasopressin, the membranes of the distal nephron remain relatively
impermeable to water, as well as to solute, and the fluid issuing from the loop of Henle is excreted essentially unmodified
as urine. With maximum vasopressin action, all but 5% to 10% of the water in this fluid is reabsorbed passively down the
osmotic gradient that normally exists with the surrounding tissue. Remember that the concentration of the canine renal
medullary interstitial fluid can be greater than 2500 mOsm/kg. (Reprinted with permission from Robertson GL: Posterior
pituitary. In Felig P, et al. (eds): Endocrinology and metabolism, ed 2, New York, 1987, McGraw Hill Book Co, p. 351.)
TABLE 1-1 ACTIONS OF VASOPRESSIN This type of polyuria is referred to as solute diuresis to distinguish
it from that due to a deciency of vasopressin action.
TYPE OF
TARGET ORGAN RECEPTOR ACTION Thirst
Kidney
Consumption of water to preserve body fluid tonicity is governed
Cortical and medullary V2 Enhances water permeability by the sense of thirst, which in turn is regulated by many of the
collecting ducts same factors that determine AVP release (Fig. 1-6). Thirst can be
Thick ascending limb of V2 Enhances Na2+, Cl-, K+ stimulated by increases in ECF osmolality and by decreases in
the loop of Henle reabsorption intravascular volume. Osmoreceptors in the anterior hypothalamus
Juxtaglomerular cells V1 Suppresses renin release and low- and high-pressure baroreceptors in the thorax mediate
Cardiovascular system the thirst stimulus. Circulating angiotensin II may also stimulate
thirst when hypovolemia and hypotension are severe (Stocker etal,
Arterioles V1 Vasoconstriction 2000). Studies in humans using quantitative estimates of subjec-
Coagulation system V2 Stimulate von Willebrand tive symptoms of thirst have confirmed that increases in plasma
factor osmolality of 2% to 3% are necessary to produce an unequivocal
Stimulate antihemophiliac sensation of thirst (Baylis and Thompson, 1988).
factors
Satiation of Thirst
Pituitary gland V3 Stimulate ACTH secretion
Dehydrated animals have a remarkable capacity to consume
ACTH, Adrenocorticotropic hormone. the appropriate volume of water to repair a decit. It has been
25 A variety of metabolic disturbances can cause polydipsia and poly-

Pressure uria (Table 1-2). Primary polyuric disorders can be classified on the
basis of the underlying pathophysiology into primary pituitary and
20
Plasma vasopressin (pg/mL)
nephrogenic diabetes insipidus (NDI), secondary NDI, osmotic

diuresis-induced polyuria, and interference with the hypothalamic-
Volume
15 Osmolality pituitary secretion of AVP. The most common form of diabetes
insipidus is acquired secondary NDI. This form includes a variety
of renal and metabolic disorders in which the renal tubules lose the
10 ability to respond adequately to AVP. Most of these acquired forms
are potentially reversible after elimination of the underlying illness.
Secondary NDI results from interference with the normal inter-
5
action of AVP and renal tubular AVP receptors, problems with the
generation of intracellular cAMP, problems with renal tubular cell
0 function, or loss of the renal medullary interstitial concentration
gradient. Primary polydipsic disorders occur in dogs and usually
0 10 20 30 (Osmolality)
have a psychogenic or behavioral basis for the compulsive water
0 10 20 30 (Pressure consumption.
or volume)
Percent change
FIGURE 1-6The relationship between plasma osmolality and plasma Osmotic Diuresis
vasopressin level. (Adapted from Robertson GL, Berl T: Water metabolism.
Diabetes Mellitus
In Brenner BM, Rector FC Jr, editors: The kidney, ed 3, Philadelphia,1986,
WB Saunders, p. 385.) Diabetes mellitus is one of the most common endocrinopathies
in the dog and cat. As glucose utilization diminishes as a result of
relative or absolute insulin deciencies, glucose accumulates in the
blood. When the rising blood glucose concentration exceeds the
demonstrated that dogs deprived of water for various periods of renal tubular capacity for glucose reabsorption, glucose appears in
time drink just the volume of water needed to meet the decit the urine and acts as an osmotic diuretic, causing increased water
within 5 minutes. All animals have this capacity, although some loss into the urine. The water loss results in hypovolemia, which in
species take longer to ingest the required amount of fluid. Sati- turn stimulates increased water intake. Urinalysis and fasting blood
ation of thirst in dogs and cats requires restoration of normal glucose measurement are usually sufcient screening tests for diag-
plasma osmolality and blood volume, with correction of plasma nosing diabetes mellitus.
osmolality playing the major role. In dogs with hypertonic vol-
ume depletion, restoration of osmolality in the carotid circulation Primary Renal Glycosuria
without correcting osmolality outside the central nervous system This uncommon disorder is seen primarily in the Basenji and
(CNS) caused a 70% decrease in drinking (Reeves etal, 1998). Norwegian Elkhound. Primary renal glycosuria is a congenital
Restoration of blood volume in these dogs without ameliorat- renal tubular disorder resulting in an inability to reabsorb glucose
ing plasma hypertonicity reduced drinking by about 30%. Addi- from the ultraltrate in the nephron. In some dogs and cats, renal
tional mechanisms may also play a minor role, including gastric glycosuria may also be a component of a Fanconi-like syndrome,
distention and perhaps the participation of receptors in the liver. in which phosphate, potassium, uric acid, amino acids, sodium,
Similar inhibitory influences affect vasopressin secretion. Follow- and/or bicarbonate may also be inadequately reabsorbed from the
ing voluntary rehydration in dehydrated animals, plasma vaso- ultraltrate. As in diabetes mellitus, glucose appears in the urine
pressin secretion returns to normal before redilution of the body and acts as an osmotic diuretic, causing polyuria and, in turn,
fluids has been completed. polydipsia. Primary renal glycosuria should be suspected in a dog
with polyuria and polydipsia, persistent glycosuria, and normal
DIFFERENTIAL DIAGNOSES FOR POLYDIPSIA blood glucose and serum fructosamine concentrations. Urinaly-
AND POLYURIA sis and fasting blood glucose measurement are sufcient initial
screening tests for this disorder.
Increased thirst (polydipsia) and urine production (polyuria) are
common owner concerns in small animal veterinary practice. In Chronic Renal Failure
dogs, normal water intake is usually less than 80 mL/kg of body Chronic renal failure is a syndrome in which the number of func-
weight/24 h. Water intake between 80 and 100 mL/kg/24 h is sug- tioning nephrons progressively decreases as a result of structural
gestive of polydipsia but may be normal in some dogs. Water intake damage to the kidney, as occurs with chronic interstitial nephritis,
greater than 100 mL/kg/24 h confirms polydipsia. Similar values medullary interstitial amyloidosis, and chronic pyelonephritis. A
are used for cats, although most cats drink considerably less than compensatory increase is seen in glomerular ltration rate (GFR)
these amounts. Normal urine output varies between 20 and 45 mL/ per surviving nephron, but the amount of fluid presented to the
kg/24 h (1 to 2 mL/kg/h; Barsanti etal, 2000). Polyuria in the dog distal renal tubules is increased. Increased tubular flow rate causes
and cat has been defined as urine production greater than 50 mL/ less urea, sodium, and other substances to be reabsorbed. The result
kg/24 h, respectively, although it is possible for urine production to is an osmotic diuresis that is further complicated by a reduced renal
be abnormal within the limits of these normal v alues in individual medullary concentration gradient. These factors contribute to poly-
dogs and cats. Polyuria and polydipsia usually exist concurrently, uria. The water loss results in hypovolemia, which causes compensa-
and determining the primary component of the syndrome is one of tory polydipsia. Findings on routine blood and urine tests include
the initial diagnostic considerations when approaching the problem increased blood urea nitrogen (BUN), creatinine, and inorganic
of polydipsia and polyuria (see Diagnostic Approach to Polyuria phosphorus concentrations, nonregenerative anemia and isosthenu-
and Polydipsia later in this chapter). ric urine (urine specic gravity of 1.008 to 1.015).
|
TABLE 1-2 DIFFERENTIAL DIAGNOSIS FOR POLYDIPSIA AND POLYURIA AND USEFUL DIAGNOSTIC TESTS
DISORDER DIAGNOSTIC AIDS

Diabetes mellitus Fasting blood glucose, urinalysis
Renal glycosuria Fasting blood glucose, urinalysis
Chronic renal failure History, physical exam, BUN, creatinine, Ca:P, urinalysis
Polyuric acute renal failure History, physical exam, BUN, creatinine, Ca:P, urinalysis
Postobstructive diuresis History, monitoring urine output
Pyometra History of recent estrus, CBC, abdominal radiography, abdominal ultrasonography
Escherichia coli and septicemia Blood cultures
Hypercalcemia Serum calcium
Hepatic insufficiency Biochemistry panel, bile acids, ammonia tolerance test, abdominal radiography and ultrasonography
Hyperadrenocorticism Physical exam, chemistry panel, abdominal ultrasonography, urine cortisol/creatinine ratio, low-dose dexamethasone
suppression test
Primary hyperaldosteronism Serum sodium and potassium, blood pressure, abdominal ultrasonography, baseline plasma aldosterone
Bacterial pyelonephritis Urine culture, abdominal ultrasonography, excretory urography
Hypokalemia Serum potassium
Hyponatremia Serum sodium
Hypoadrenocorticism Na:K, baseline serum cortisol, ACTH stimulation test
Hyperthyroidism Serum T4 and TSH
Diabetes insipidus Modified water deprivation test, response to DDAVP
Psychogenic polydipsia Modified water deprivation test, response to gradual water restriction
Renal medullary solute washout Response to gradual water restriction
Polycythemia CBC
Acromegaly Physical exam, serum GH and IGF-I, CT scan
Paraneoplastic Disorders
Intestinal leiomyosarcoma Abdominal ultrasonography, biopsy
Iatrogenic; medications History
Very low protein diet History
ACTH, Adrenocorticotropic hormone; BUN, blood urea nitrogen; Ca:P, calcium:phosphorus; CBC, complete blood count; CT, computed tomography; DDAVP, desmopressin acetate; GH, growth
hormone; IGF-I, insulin-like growth factor-I; T4, thyroxine; TSH, thyroid stimulating hormone.
Postobstructive Diuresis Primary NDI results from a congenital defect involving the cellu-
Postobstructive diuresis may occur in any animal but is most com- lar mechanisms responsible for opening the water channels that
mon after urethral obstruction by a urolith or urethral plug is allow water to be absorbed from the renal tubular ultraltrate.
relieved in male cats with feline lower urinary tract disease (e.g., This syndrome is discussed in subsequent sections (see Primary
feline interstitial cystitis). Obstructed male cats often develop Nephrogenic Diabetes Insipidus).
postrenal azotemia and electrolyte and acid-base disturbances that
can be severe. A marked osmotic diuresis usually occurs once the Acquired (Secondary) Nephrogenic Diabetes Insipidus
obstruction is relieved. The veterinarian must be aware of this prob-
lem and maintain the animals hydration through frequent adjust- Several disorders may interfere with the normal interaction between
ments in intravenous (IV) fluid administration aimed at matching AVP and its renal tubular AVP receptors, affect the generation of
urine production. Postobstructive diuresis is self-limiting and the intracellular cAMP, create problems with renal tubular cell function,
rate of fluid administration should be slowly decreased over several or result in loss of the hypertonic renal medullary interstitial gradi-
days as the uremia resolves and the osmotic diuresis declines. ent. Polyuria with a compensatory polydipsia results and can be quite
severe. These disorders resemble primary NDI but are referred to as
acquired or secondary because AVP, AVP receptor sites, and postre-
Primary Pituitary (Central) Diabetes Insipidus
ceptor mechanisms responsible for water absorption are present.
Partial or complete lack of vasopressin production by the mag-
nocellular neurons located in the supraoptic and paraventricular Bacterial Endotoxins (Pyometra)
nuclei in the hypothalamus is called primary CDI. This syndrome Bacterial endotoxins, especially those associated with Escherichia
is discussed in subsequent sections. coli, may compete with AVP for its binding sites on the renal
tubular membrane, causing a potentially reversible renal tubular
insensitivity to AVP, interference with the insertion of aquapo-
Primary Nephrogenic Diabetes Insipidus
rin-2 water channels in renal tubular cells or reversible renal tubu-
A partial or complete lack of response of the renal tubule to the lar cell lesions (Heiene etal, 2004). The kidneys have an impaired
actions of AVP is called nephrogenic diabetes insipidus (NDI). ability to concentrate urine and conserve water, and polyuria with
compensatory polydipsia develops. Pyometra is the most common Primary Hyperaldosteronism

infectious disorder associated with the development of polyuria Polyuria and polydipsia have been reported in cats and dogs with pri-
and polydipsia, although it has also been reported with prostatic mary hyperaldosteronism. The mechanism for polyuria and polydip-
abscessation, pyelonephritis, and septicemia (Barsanti etal, 2000). sia is not clear, although mineralocorticoid-induced renal resistance
Affected bitches and queens may produce extremely dilute urine, to the actions of AVP and disturbed osmoregulation of AVP release
causing fluid depletion and compensatory polydipsia. Normal have been documented in a dog with primary hyperaldosteronism
urine-concentrating ability usually returns within days of success- (Rijnberk et al, 2001). Similar abnormalities have been identied
fully eliminating the source of the infection. in dogs with glucocorticoid excess, suggesting similar mechanisms
of action for the polyuria and polydipsia in hyperaldosteronism and
Hypercalcemia hyperadrenocorticism. Hyperaldosteronism-induced hypokalemia
Increases in serum calcium concentration are associated with down- may also result in downregulation of aquaporin-2 water channels and
regulation of aquaporin-2 water channels and decreased function of urea transporters, thereby interfering with the ability to concentrate
AVP by inhibiting binding of AVP to its receptor site, damage to AVP urine (Robben etal, 2006; Sands and Bichet, 2006). Baseline plasma
receptors in the renal tubules, inactivation of adenylate cyclase, or aldosterone concentrations are markedly increased, and plasma renin
decreased transport of sodium and chloride into the renal medullary activity is suppressed (see Chapters 10 and 11).
interstitium (Sands and Bichet, 2006; Robben etal, 2006). Polydipsia
and polyuria are common early signs of hypercalcemia, which is easily Pyelonephritis
diagnosed with a serum biochemistry panel. Once hypercalcemia is Infection and inflammation of the renal pelvis can destroy the
identied, the clinician must undertake an often extensive diagnostic countercurrent mechanism in the renal medulla and the collecting
evaluation to determine its cause (see Chapter 15). ducts, resulting in isosthenuria, polyuria, polydipsia, and eventually
renal failure. Bacterial endotoxins, especially those associated with
Hepatic Insufficiency and Portosystemic Shunts E. coli, can also compete with AVP for its binding sites on the renal
Liver insufciency and portosystemic shunts are recognized tubular membrane, causing a potentially reversible renal tubular
causes of polyuria and polydipsia. Many of the metabolic causes insensitivity to AVP. A dog or cat with acute bacterial pyelonephri-
of polyuria and polydipsia (e.g., diabetes mellitus, hyperadreno- tis may develop nonspecic systemic signs of lethargy, anorexia,
corticism, hypercalcemia) secondarily affect the liver, making it and fever, and a neutrophilic leukocytosis may be identied on a
difcult to determine the role of the liver in causing polyuria CBC. Systemic signs are usually not present with chronic pyelo-
and polydipsia. The exact cause of the polyuria is not known nephritis. Pyelonephritis should also be suspected in a patient with
but may involve loss of medullary hypertonicity secondary to recurring urinary tract infection. Urinalysis may reveal white blood
impaired urea nitrogen production or altered renal blood flow, cells and white blood cell casts, bacteria, and occasionally red blood
increased GFR and ultrafiltrate volume, hypokalemia, impaired cells. Culture of urine obtained by antepubic cystocentesis should
metabolism of cortisol, and primary polydipsia (Deppe et al, be positive for bacterial growth. Abdominal ultrasonography and
1999). Urea nitrogen is a major constituent in the establishment excretory urography may reveal abnormalities consistent with
and maintenance of the renal medullary concentration gradi- pyelonephritis (e.g., renal pelvis dilatation).
ent. Without urea nitrogen, the kidney loses the ability to con-
centrate urine, causing polyuria and compensatory polydipsia. Hypokalemia
Hepatic insufciency and portosystemic shunts are usually sus- Hypokalemia is believed to render the terminal portion of the
pected after evaluation of a complete blood count (CBC), serum nephron less responsive to AVP by causing downregulation of
biochemistry panel, urinalysis, and abdominal ultrasonography; aquaporin-2 water channels, thereby interfering with the ability to
these causes are conrmed with a liver function test (e.g., pre- concentrate urine (Robben etal, 2006; Sands and Bichet, 2006).
and postprandial bile acids), specialized diagnostic imaging (e.g., Hypokalemia may also alter the hypertonic medullary interstitial
positive contrast portogram, technetium scan) and histologic gradient by causing downregulation of urea transporters and inter-
evaluation of a hepatic biopsy. fering with solute accumulation and may interfere with release of
AVP from the pituitary. Polyuria and polydipsia are not common
Hyperadrenocorticism (Cushings Syndrome) clinical signs of hypokalemia. The most common clinical signs
Polyuria and polydipsia are common clinical signs of hyperadre- are related to neuromuscular dysfunction of skeletal, cardiac, and
nocorticism. Glucocorticoids inhibit AVP release by a direct effect smooth muscle (e.g., weakness, cervical ventriflexion). Hypoka-
within the hypothalamus and/or neurohypophysis (Papanek and lemia usually develops secondary to another disorder, many of
Raff, 1994; Papanek et al, 1997). This inhibition of AVP release which also cause polyuria and polydipsia.
is characterized by both an increase in osmotic threshold and a
decrease in the sensitivity of the AVP response to increasing osmo- Hypoadrenocorticism (Addisons Disease)
lality (Biewenga etal, 1991). Glucocorticoids also increase glomeru- Adrenocortical insufciency results in impaired ability to concen-
lar filtration rate, proximal tubular epithelial sodium transport, and trate urine (see Chapter 12). Despite normal kidney function and
free water clearance and cause resistance to the effect of AVP in severe hypovolemia, many dogs with hypoadrenocorticism have a
the kidney, possibly through interference with the action of AVP at urine specic gravity of less than 1.030 and in some dogs urine
the level of the renal collecting tubules or direct depression of renal specific gravity is in the isosthenuric range. Mineralocorticoid
tubular permeability to water (Marver, 1984; Quinkler and Stewart, deciency results in chronic sodium wasting, renal medullary sol-
2003). In a few patients, a deciency in AVP may result from direct ute washout, and loss of the medullary hypertonic gradient. Adre-
compression of magnocellular neurons by a pituitary macrotumor nalectomy in rats also decreases AVP-stimulated activation of renal
that has extended beyond the sella. Suspicion of hyperadrenocorti- medullary adenylate cyclase, primarily because of impairment in the
cism is usually aroused after careful review of the history, physical coupling between the AVP receptor complex and adenylate cyclase.
examination, and results of CBC, serum biochemistry panel, and Treatment with dexamethasone corrects the defect. Hypercalcemia
urinalysis. Conrmation requires appropriate pituitary adrenocorti- occurs in some patients with hypoadrenocorticism and may also
cal function tests (see Chapter 10). play a role in the generation of polyuria and polydipsia.
|
Polyuria and polydipsia typically develop early in the course of

the disease and are quickly overshadowed by the more worrisome BOX 1-1 D
rugs and Hormones Causing Polyuria
and obvious vomiting, diarrhea, anorexia, weakness, and lethargy and Polydipsia in Dogs and Cats
seen in these patients, although occasionally polyuria and poly-
dipsia are the primary owner complaints. The polyuria of hypoad- Anticonvulsants*
renocorticism can be difcult to differentiate from primary renal Phenobarbital
failure unless specic tests of the pituitary adrenocortical axis (e.g., Primidone
ACTH stimulation test) are performed. Initial suspicion for hypo- Dilantin
adrenocorticism usually follows evaluation of serum electrolytes, Glucocorticoids*
although hyperkalemia and hyponatremia can also occur with Desoxycorticosterone pivalate (DOCP)*
renal insufciency. Diuretics*
Hyperthyroidism. Polyuria and polydipsia are common ndings Mannitol
in cats and dogs with hyperthyroidism. The exact mechanism for Synthetic thyroid hormone supplements
the polyuria and polydipsia is not clear. Increased renal medul- Amphotericin B
lary blood flow may decrease medullary hypertonicity and impair Lithium
water resorption from the distal portion of the nephron. Psycho- Methoxyflurane
genic polydipsia secondary to thyrotoxicosis and, in some patients, Sodium bicarbonate
concurrent renal insufciency may also contribute to the polyuria Salt Supplementation*
and polydipsia. The tentative diagnosis of hyperthyroidism is usu- Vitamin D (toxicity)
ally based on clinical signs, palpation of an enlarged thyroid lobe *Common cause
or lobes (i.e., goiter), and measurement of serum thyroxine (T4)
concentration.
Acromegaly is discussed in more detail in subsequent sections (see Primary or

Excessive secretion of growth hormone (GH) in the adult dog Psychogenic Polydipsia later in this chapter).
or cat results in acromegaly (see Chapter 2). Acromegaly causes
carbohydrate intolerance and the eventual development of overt
Iatrogenic (Drug-Induced) Causes of Polydipsia
diabetes mellitus. In most cats and dogs with acromegaly, the
and Polyuria
polyuria is assumed to be caused by an osmotic diuresis induced
by glycosuria. Renal insufciency from a diabetic or GH-induced Several drugs have the potential to cause polyuria and polydipsia
glomerulonephropathy may also play a role (Peterson etal, 1990). (Box 1-1). The most commonly encountered in small animal vet-
erinary practice are glucocorticoids, diuretics, anticonvulsants (e.g.,
Polycythemia phenobarbital), synthetic levothyroxine, and salt supplementation.
Polyuria and polydipsia may occur with polycythemia. Studies Drug-induced polyuria and polydipsia do not usually pose a diagnos-
in two dogs with secondary polycythemia identied an increased tic challenge. The polyuria and polydipsia should resolve following
osmotic threshold for AVP release, resulting in a delayed AVP discontinuation of the drug; the time to resolution being dependent
response to increasing plasma osmolality (van Vonderen et al, on the duration of action of the drug (e.g., prednisone versus long-
1997a). The authors attributed the abnormal AVP response to acting depot glucocorticoid preparation). If polyuria and polydip-
increased blood volume and hyperviscosity, which stimulate atrial sia persist, a concurrent disorder causing polyuria and polydipsia or
natriuretic peptide (ANP) secretion and atrial and carotid bifur- renal medullary solute washout should be considered.
cation baroreceptors. ANP inhibits AVP release from the pitu-
itary gland and the renal collecting ducts responsiveness to AVP
Renal Medullary Solute Washout
(Dillingham and Anderson, 1986; Lee etal, 1987).
Loss of renal medullary solutes, most notably sodium and urea, results
Primary and Psychogenic Polydipsia in loss of medullary hypertonicity and impaired ability of the neph-
ron to concentrate the ultraltrate. Renal medullary solute washout
Primary polydipsia is dened as a marked increase in water intake is usually caused by one of the disorders previously described. It has
that cannot be explained as a compensatory mechanism for exces- also been associated with chronic diuretic therapy and abnormali-
sive fluid loss. In humans, primary polydipsia results from a defect ties in circulation, such as hyperviscosity syndromes (polycythemia,
in the thirst center or may be associated with mental illness (Reeves hyperproteinemia), renal lymphatic obstruction (lymphosarcoma,
etal, 1998). Primary dysfunction of the thirst center resulting in lymphangiectasia), and systemic vasculitis (septicemia, systemic lupus
compulsive water consumption has not been reported in the dog erythematosus). Perhaps the most important clinical ramication of
or cat, although an abnormal vasopressin response to hypertonic renal medullary solute washout is its potential to interfere with results
saline infusion has been reported in dogs with suspected primary of the modied water deprivation test (see Misdiagnosis [Inaccura-
polydipsia (van Vonderen etal, 1999). A psychogenic or behav- cies] Using the Modied Water Deprivation Test). Hypertonicity of
ioral basis for compulsive water consumption does occur in the the renal medulla is usually restored once the underlying cause of the
dog but has not been reported in the cat. Psychogenic polydipsia polyuria and polydipsia is corrected.
may be induced by concurrent disease (e.g., hepatic insufciency,
hyperthyroidism) or may represent a learned behavior following
DIAGNOSTIC APPROACH TO POLYURIA
a change in the pets environment. Polyuria is compensatory to
AND POLYDIPSIA
prevent overhydration. Psychogenic polydipsia is diagnosed by
exclusion of other causes of polyuria and polydipsia and by dem- Depending on the cause, the cost and time expenditure for evalu-
onstrating that the dog or cat can concentrate urine to a specic ating a dog or cat with polyuria and polydipsia may be brief and
gravity in excess of 1.030 after water deprivation. This syndrome inexpensive (e.g., diabetes mellitus) or time-consuming and costly
TABLE 1-3 URINALYSIS RESULTS IN DOGS WITH SELECTED DISORDERS CAUSING POLYURIA AND POLYDIPSIA
Urine Specific Gravity

DISORDER NUMBER OF DOGS MEAN RANGE PROTEINURIA WBC (> 5/HPF)
CDI 20 1.005 1.001-1.012 5% 0%
Psychogenic polydipsia 18 1.011 1.003-1.023 0% 0%
Hyperadrenocorticism 20 1.012 1.001-1.027 48% 0%
Renal insufficiency 20 1.011 1.008-1.016 90% 25%
Pyelonephritis 20 1.019 1.007-1.045 70% 75%
CDI, Central diabetes insipidus; HPF, high power field; WBC, white blood count.
(e.g., partial CDI). Therefore, the clinician should be reasonably common being diabetes insipidus. An animal with a history of
sure that polyuria and polydipsia exist, preferably based on a com- severe polyuria and polydipsia should be thoroughly evaluated
bination of history, multiple random urine specic gravity deter- for other causes of polyuria and polydipsia prior to performing
minations, and if necessary, quantitation of water consumption specic diagnostic procedures for diabetes insipidus or psycho-
over several days with the dog or cat in the home environment. In genic polydipsia (Fig. 1-7). Our diagnostic approach to the ani-
dogs, normal water intake is usually less than 80 mL/kg of body mal with polyuria and polydipsia is initially to rule out the more
weight/24 h. Water intake between 80 and 100 mL/kg/24 h is common causes. In the dog, these include chronic renal failure,
suggestive of polydipsia but may be normal in some dogs. Water diabetes mellitus, hyperadrenocorticism, liver insufficiency, and
intake greater than 100 mL/kg/24 h confirms polydipsia. Similar hypercalcemia. In the cat, these include chronic renal failure,
values are used for cats, although most cats drink considerably diabetes mellitus, and hyperthyroidism. Recommended initial
less than these amounts. If an owner knows the volume of water diagnostic studies include a CBC, serum biochemistry panel, and
the pet is consuming in an average 24-hour period and if that urinalysis with bacterial culture of urine obtained by antepubic
amount exceeds the upper limit of normal, a diagnostic evalua- cystocentesis. A serum T4 concentration should be measured in
tion to determine the cause is warranted. If 24-hour water intake older cats. Depending on the history and physical examination
is normal, pathologic polyuria and polydipsia are unlikely and ndings, abdominal ultrasonography may be warranted to evalu-
another inciting factor (e.g., hot weather) should be sought, or ate the liver, kidneys, adrenal glands, and uterus or uterine stump
misinterpretation of polyuria (e.g., pollakiuria instead of polyuria) in the female dog. Careful evaluation of the history, physical
should be considered. If the owner is certain that a change in the examination ndings, and results of initial blood, urine, and diag-
volume of water consumption or urination exists, even though nostic imaging results usually provides the diagnosis outright (e.g.,
water consumption is still in the normal range, a diagnostic evalu- diabetes mellitus, pyometra) or offers clues that allow the clinician
ation may still be warranted. to focus on the underlying cause (e.g., increased serum alkaline
Assessment of urine specic gravity may be helpful in identify- phosphatase and cholesterol in hyperadrenocorticism, hypercalce-
ing polyuria and polydipsia and may provide clues to the under- mia of malignancy).
lying diagnosis, especially if multiple urine specic gravities are Occasionally, the physical examination and initial data base
evaluated (Table 1-3). Urine specic gravity varies widely among are normal in the dog and, less commonly, the cat with polyuria
healthy dogs and, in some dogs, can range from 1.006 to greater and polydipsia. Viable possibilities in these dogs include diabe-
than 1.040 within a 24-hour period (van Vonderen etal, 1997b). tes insipidus, psychogenic water consumption, hyperadrenocor-
Wide fluctuations in urine specic gravity have not been reported ticism, renal insufciency without azotemia, and possibly mild
in healthy cats. hepatic insufciency and the early stages of hypoadrenocorticism.
We prefer to have the owner collect several urine samples at dif- Viable possibilities in cats include renal insufficiency without azo-
ferent times of the day for 2 to 3 days, storing the urine samples in temia, mild hepatic insufficiency, and diabetes insipidus. Hyper-
the refrigerator until they can be brought to the veterinary hospi- adrenocorticism, renal insufciency, and hepatic insufciency
tal for determination of urine specic gravity. Urine specic gravi- should be ruled out before performing tests to establish a diag-
ties measured from multiple urine samples that are consistently nosis of diabetes insipidus or psychogenic polydipsia. Diagnostic
less than 1.020 support the presence of polyuria and polydipsia tests to consider include tests of the pituitary adrenocortical axis,
and the need for a diagnostic evaluation to determine the cause; liver function tests (e.g., pre- and postprandial bile acids), urine
the lower the urine specific gravities, the stronger the support for protein-to-creatinine ratio, endogenous or exogenous creatinine
the existence of a polyuria/polydipsia disorder. Identication of clearance studies, contrast imaging of the kidney, and, if indi-
one or more urine specic gravities greater than 1.030 supports cated, renal biopsy.
normal urine concentrating ability and an intact, functioning Careful evaluation of urine specic gravity and urine protein loss
pituitary vasopressin-renal tubular cell axis. Dogs and cats may may provide clues to the underlying diagnosis (see Table 1-3). For
still have polyuria and polydipsia despite identication of con- example, if the urine specic gravity measured on multiple urine
centrated urine; possible differential diagnoses include disorders samples is consistently in the isosthenuric range (1.008 to 1.015),
causing an osmotic diuresis (e.g., diabetes mellitus), psychogenic renal insufciency should be considered the primary differential
polydipsia, and disorders in the regulation of AVP secretion (van diagnosis, especially if the BUN and serum creatinine concentra-
Vonderen etal, 1999). tion are high normal or increased (i.e., 25 mg/dL and 1.6
Many potential causes exist for the development of polyuria mg/dL, respectively) and proteinuria is present. Although isosthe-
and polydipsia in dogs and cats (see Table 1-2), one of the least nuria is relatively common in dogs with hyperadrenocorticism,
|
Step 1 Verification
a) Water consumption >100 mL/kg body weight/day
b) Urine production >50 mL/kg body weight/day
c) Random urine specific gravity 1.012
Step 2 History and physical examination
a. Intact female: b. Lymphadenopathy: c. Weight loss, polyphagia, d. Symmetrical alopecia, e. Medications: f. Normal
R/O pyometra R/O hypercalcemia restlessness, tachycardia: Pot-bellied appearance, R/O Glucocorticoids
R/O Hyperthyroidism calcinosis cutis, R/O Diuretics
R/O Diabetes mellitus thin skin, muscle weakness R/O Primidone
Hepatomegaly, etc.: R/O Salt supplementation
R/O Hyperadrenocorticism
Step 3 Urinalysis
a. Glycosuria b. Pyuria, bacteriuria c. Significant proteinuria d. Normal

R/O Pyelonephritis R/O Renal disease
Blood glucose R/O Hyperadrenocorticism R/O Pyometra
R/O Pyometra
Euglycemia Hyperglycemia
R/O Primary renal (>200 mg/dL)
Glucosuria R/O Diabetes mellitus
Step 4 Evaluation of urine specific gravity

a. If SG <1.006 b. If SG >1.030 c. If urine SG 1.007-1.030
candidate for CDI, patient may have psychogenic polydipsia
NDI, PP, Cushing's
Step 5 Obtain data base

a. Hemogram b. Biochemistry panel c. Electrolytes d. Serum T4 (cat) e. Abdominal radiographs/
R/O Pyelonephritis R/O Renal failure R/O Hypoadrenocorticism R/O Hyperthyroidism ultrasonography
R/O Pyometra R/O Hyperadrenocorticism R/O Hypokalemia R/O Pyometra
R/O Hypercalcemia R/O Hyperadrenocorticism
R/O Hepatic insufficiency R/O Hepatic insufficiency
R/O Chronic renal failure
Step 6
a. Suggestive of Cushing's b. Suggestive of another diagnosis c. Normal
1. UCCR
2. Dexamethasone screening
Step 7 Modified water deprivation test or trial DDAVP therapy

R/O Pituitary diabetes insipidus
R/O Nephrogenic diabetes insipidus
R/O Primary polydipsia
FIGURE 1-7 The diagnostic plan in a dog or cat with severe polydipsia and polyuria. CDI, Central diabetes insipidus;
DDAVP, desmopressin acetate; NDI, nephrogenic diabetes insipidus; PP, primary (psychogenic) polydipsia; R/O, rule
out (a diagnosis); SG, specific gravity; T4, thyroxine; UCCR, urinary cortisol creatinine ratio.
psychogenic water consumption, hepatic insufciency, pyelone- be considered the primary differential diagnoses. CDI and primary
phritis, and partial CDI with concurrent water restriction, urine NDI are ruled out if the urine specific gravity exceeds 1.025. Urine
specic gravities tend to fluctuate above (hyperadrenocorticism, specific gravities that range from less than 1.005 to greater than
hypoadrenocorticism, psychogenic water consumption, hepatic 1.030 are suggestive of psychogenic polydipsia.
insufciency, pyelonephritis) and below (hyperadrenocorticism, All realistic causes of secondary acquired NDI should be ruled
hepatic insufficiency, psychogenic water consumption, partial CDI) out before performing tests (especially the modied water depriva-
the isosthenuric range in these disorders. In contrast, if the urine tion test) to diagnose CDI, primary NDI and psychogenic poly-
specic gravity is consistently less than 1.006, renal insufciency dipsia. An index of suspicion for CDI and primary NDI versus
is ruled out and central and primary NDI, psychogenic water con- psychogenic polydipsia can often be gained after reviewing the
sumption, hyperadrenocorticism and hepatic insufficiency should history and findings on physical examination and routine blood
1.050
1.040
Urine (SD)
1.030
1.020
FIGURE 1-8Mean urine specific gravity obtained before

and for 3 months after hypophysectomy in four dogs treated 1.010
with intraoperative polyionic fluids (solid line) and four dogs
treated with intraoperative polyionic fluids and dexametha-
sone (dashed line). (From Lantz GC, etal: Transsphenoidal 1
Before 1 2 3 4 5 6 7 8 9 10 11 12
hypophysectomy in the clinically normal dog, Am J Vet Res surgery
49[7]:1134-1142, 1988.) Time after surgery (weeks)
and urine tests. CDI and primary NDI are polyuric disorders with Pathophysiology
compensatory polydipsia to minimize dehydration. The presence Destruction of the production sites for vasopressinthe supraoptic
of neurologic signs, serum sodium concentrations at the upper and paraventricular nuclei of the hypothalamusand/or loss of the
limit of the reference range, urine specific gravities consistently major ducts (axons) that carry AVP to the storage and release depots
in the hyposthenuric range, and rapid onset of dehydration with in the posterior pituitary (see Fig. 1-2) result in CDI. Permanent CDI
water restriction support the presence of CDI or primary NDI. requires an injury that is sufciently high in the neurohypophyseal
In contrast, psychogenic polydipsia is a polydipsic disorder with tract to cause bilateral neuronal degeneration in the supraoptic and
compensatory polyuria to prevent water intoxication. The iden- paraventricular nuclei. Transection of the hypothalamic hypophyseal
tification of behavioral issues in the dog, serum sodium concen- tract below the median eminence or removal of the posterior lobe of
trations at the lower limit of the reference range, urine specific the pituitary usually causes transient (albeit severe) CDI and poly-
gravities that fluctuate below and above the isosthenuric range, uria because sufcient hormone can be released from bers ending
and a relatively prolonged time interval to develop dehydration in the median eminence and pituitary stalk to prevent occurrence of
after water restriction support the presence of psychogenic poly- permanent diabetes insipidus (Fig. 1-8; Ramsay, 1983).
dipsia. The definitive diagnosis of CDI, primary NDI and psy-
chogenic water consumption should be based on results of the Etiology
modied water deprivation test, measurement of plasma osmolal- CDI may result from any condition that damages the neurohy-
ity, and response to synthetic vasopressin therapy (see Conrming pophyseal system. Recognized causes for CDI in the dog and cat
the Diagnosis of Diabetes Insipidus). are listed in Box 1-2. Idiopathic cases of CDI are the most com-
mon, appearing at any age in any breed in either gender. Nec-
ETIOLOGY OF DIABETES INSIPIDUS ropsies performed in dogs and cats with idiopathic CDI fail to
AND PRIMARY POLYDIPSIA identify an underlying reason for the AVP deciency.
Autoimmune hypothalamitis has been suggested as a possible
Vasopressin DeciencyCentral Diabetes Insipidus cause of idiopathic CDI in humans (Salvi etal, 1988). Circulat-
ing AVP cell antibodies, which bind to cell membranes of hypo-
Definition thalamic preparations, have been identied in some humans with
CDI is a polyuric syndrome that results from a lack of sufcient CDI (Scherbaum, 1987). AVP cell antibodies have been identied
AVP to concentrate the urine for water conservation. This prior to the development of CDI, and titers of AVP cell antibod-
deciency may be absolute or partial. An absolute deciency of ies decline eventually to negative values with increasing duration
AVP causes persistent hyposthenuria and severe diuresis. Urine of the disease (Bhan and OBrien, 1982; Scherbaum etal, 1986).
specic gravity in dogs and cats with complete lack of AVP remains These patients also show a signicant association with other endo-
hyposthenuric ( 1.006), even with severe dehydration. A partial crine disorders (e.g., immune thyroiditis, Addisons disease), sug-
deciency of AVP, referred to as a partial CDI, also causes persis- gesting that, at least in some cases, polyendocrine autoimmunity
tent hyposthenuria and a marked diuresis as long as the dog or may also involve the hypothalamus (see Chapter 3). A similar
cat has unlimited access to water. During periods of water restric- association between CDI and other endocrinopathies has not
tion, however, dogs and cats with partial CDI can increase their been identied in dogs and cats. However, lymphocytic hypophy-
urine specic gravity into the isosthenuric range (1.008 to 1.015) sitis has been documented in a dog with CDI, an inflammatory
but cannot typically concentrate their urine above 1.015 to 1.020, mass compressing the hypothalamus, and marked lymphocytic
even with severe dehydration. For any dog or cat with partial infiltration of the adenohypophysis (Meij etal, 2012). In humans,
CDI, maximum urine-concentrating ability during dehydration is lymphocytic inflammation involving the posterior pituitary lobe
inversely related to the severity of the deciency in AVP secretion; and infundibulum is called lymphocytic infundibuloneurohypophy-
that is, the more severe the AVP deciency, the less concentrated sitis and humans typically develop acute onset of diabetes insipi-
the urine specic gravity during dehydration. dus with intracranial mass-effect symptoms (Abe, 2008).
|
BOX 1-2 R
ecognized Causes of Central Diabetes
Insipidus in Humans, Dogs, and Cats
Humans Dogs/Cats
Acquired Acquired
Idiopathic Idiopathic
Head trauma Head trauma
Neoplasia Neoplasia
Craniopharyngioma Craniopharyngioma
Germinoma Chromophobe adenoma and
A
Meningioma adenocarcinoma
Lymphoma Meningioma
Leukemia Metastases
Adenoma Hypothalamic/pituitary malforma-
Metastases tion
Granulomatous disease Cysts
Infectious Inflammation (lymphocytic hypophy-
Viral sitis)
Bacterial (abscess) Parasite migration
Vascular Transsphenoidal hypophysectomy
Sheehan syndrome
Familial (?)
Aneurysms B
Immune-mediated
FIGURE 1-9Transverse (A) and sagittal (B) magnetic resonance images of the
Lymphocytic infundibulohy-
pituitary region in a 12-year-old male Boxer with central diabetes insipidus (CDI),
pophysitis
hypothyroidism, and neurologic signs. A mass is evident in the region of the pitu-
Hypophysectomy
itary gland, hypothalamus, and rostral floor of the calvarium (arrows).
Familial
Neoplastic destruction of magnocellular neurons may also

The most common identiable causes for CDI in dogs and cats are cause CDI. However, 90% of the magnocellular neurons must
head trauma (accidental or neurosurgical), neoplasia, and hypotha- be destroyed to produce symptomatic diabetes insipidus. To pro-
lamic/pituitary malformations (e.g., cystic structures). Head trauma duce CDI, a mass lesion would have to destroy a large area of the
may cause transient or permanent CDI, depending on the viability hypothalamus or be located where the tracks of the nuclei con-
of the cells in the supraoptic and paraventricular nuclei. Trauma- verge at the base of the hypothalamus and the top of the pituitary
induced transection of the pituitary stalk often results in transient stalk (Robinson and Verbalis, 2011). Tumors confined to the sella
CDI, usually lasting 1 to 3 weeks (see Fig. 1-8; Lantz etal, 1988; do not cause CDI. Primary intracranial tumors associated with
Authement etal, 1989). The duration of diabetes insipidus depends diabetes insipidus in dogs and cats include craniopharyngioma,
on the location of the transection of the hypophyseal stalk relative to pituitary chromophobe adenoma, and pituitary chromophobe
the hypothalamus. Transection at more proximal levels, close to the adenocarcinoma (Fig. 1-9; Neer and Reavis, 1983; Goossens etal,
median eminence, is associated with a longer time for hypothalamic 1995; Harb etal, 1996). Tumor metastases to the hypothalamus
axons to undergo regeneration and secretion of AVP. Trauma-induced and pituitary gland can also cause CDI. In humans, metastatic
CDI should be suspected when severe polydipsia and polyuria tumors most often spread from the lung or breast (Reeves et al,
develop within 48 hours of head trauma or when hypernatremia, 1998). Metastatic mammary carcinoma, lymphoma, malignant
hyposthenuria, and hypertonic dehydration develop in a traumatized melanoma, and pancreatic carcinoma have been reported to cause
dog or cat that is being treated with IV fluids rather than water ad CDI by their presence in the pituitary gland and hypothalamus in
libitum (see Complications of the Modied Water Deprivation Test: dogs (Capen and Martin, 1983; Davenport etal, 1986). Metastatic
Hypertonic Dehydration and Hypernatremia later in this chapter). neoplasia as a cause for CDI has not yet been reported in the cat.
Transient or permanent diabetes insipidus commonly occurs A rare, hereditary form of CDI occurs in humans, is transmit-
following transsphenoidal hypophysectomy for the treatment of ted as an autosomal dominant trait, has equal occurrence in males
pituitary-dependent hyperadrenocorticism in dogs. In one study and females, displays father-to-son transmission, and shows vari-
evaluating hypophysectomy in 127 dogs with pituitary-dependent able expression among affected individuals (Baylis and Robertson,
hyperadrenocorticism, postoperative CDI was transient in 78% of 1981). This condition is believed to result from a degenerative dis-
the dogs with DDAVP discontinued 2 weeks after surgery in 47% order affecting the magnocellular neurons (Kaplowitz etal, 1982).
and eventually discontinued in 31% a median of 133 days (range, Although CDI is well documented in kittens and puppies, heredi-
28 to 1329 days) postsurgery (Hanson etal, 2005). CDI was pres- tary CDI has not yet been documented. In one report, heredi-
ent until death or until latest available follow-up in 22% of the dogs. tary CDI was suggested in two sibling Afghan Hound pups that
In another study, the incidence of postoperative permanent CDI in developed CDI at younger than 4 months of age and were from
dogs undergoing transsphenoidal surgery for Cushings disease was a bitch suffering from polyuria and polydipsia all her life (Post
strongly influenced by the size of the pituitary tumor; the larger the etal, 1989). Necropsy of these puppies revealed vacuolated areas
tumor, the more likely CDI was permanent after surgery (Teshima in the neurohypophysis and hypothalamohypophysial tracts of the
etal, 2011). median eminence of the tuber cinereum, ndings that suggested
hypomyelination or demyelination. We have also diagnosed CDI

Primary and Psychogenic Polydipsia
in a litter of ve 8-week-old German Short-Haired Pointers and
three of ve 7-week-old Schnauzers, suggesting possible familial Primary polydipsia (compulsive water consumption) is a syn-
CDI in these dogs. drome characterized by ingestion of excess water resulting in
compensatory polyuria to prevent water intoxication. In humans,
Primary Nephrogenic Diabetes Insipidus primary polydipsia is most commonly found in individuals with
underlying psychiatric illness (Cronin, 1987; Victor etal, 1989)
Definition and rarely, in individuals with lesions involving the thirst center.
NDI is a polyuric disorder that results from impaired responsive- The cause of the polydipsia in individuals with psychiatric illness is
ness of the nephron to the actions of AVP. Plasma AVP concen- uncertain, and most patients have, in addition to polydipsia, some
trations are normal or increased in animals with this disorder. abnormality in water excretion, such as excessive AVP secretion
NDI is classied as primary or secondary (acquired). Secondary (Goldman etal, 1988).
or acquired NDI is common in dogs and cats and is discussed in Primary polydipsia caused by a hypothalamic lesion affecting
an earlier section (see Acquired [Secondary] Nephrogenic Diabetes the thirst center has not been reported in the dog or cat. A psy-
Insipidus). Primary NDI is a rare disorder in dogs and cats; poly- chogenic basis for compulsive water consumption occurs uncom-
dipsia and polyuria typically become apparent by the time the dog monly in the dog and has not been reported in the cat. Affected
or cat is 8 to 12 weeks of age suggesting that primary NDI may be animals are usually hyperactive dogs that are placed in exercise-
a congenital disorder. restrictive environments. Some of these dogs have had signicant
changes to their environment, resulting in unusual stress. In some
Etiology dogs, compulsive water consumption is a learned behavior to gain
Two types of congenital NDI have been identied in humans: muta- attention from the owner. Dogs with psychogenic water consump-
tions of the V2 receptor and mutations of the aquaporin-2 water tion can concentrate urine to greater than 1.030 during water
channels (van Lieburg etal, 1999; Bichet, 2006). More than 90% deprivation, although the latter may take hours because of con-
of cases of congenital NDI in humans are X-linked recessive disor- current renal medullary solute washout. Urine specic gravity may
ders in males who have one of more than 200 different mutations vary widely over time, and concentrated urine may be identied
of the V2 receptor (Spanakis etal, 2008). When congenital NDI is on random urine evaluation. Identication of concentrated urine
identified in a girl, it is likely that the defect is a mutation of the implies hypothalamic AVP production, pituitary AVP secretion,
aquaporin-2 water channel gene producing an autosomal recessive and renal tubular responsiveness to AVP.
disease (Sands and Bichet, 2006). For both disorders, clinical signs Abnormal AVP release in response to hypertonic saline stimu-
are apparent shortly after birth. The diagnosis of congenital NDI is lation was described in four dogs with suspected primary poly-
established by high concentrations of AVP in the presence of hypodipsia (van Vonderen etal, 1999). All dogs presented for polyuria
tonic polyuria and the lack of response to DDAVP administration. and polydipsia and had normal routine laboratory examinations
Only a few reports of primary NDI in dogs have appeared in except for hyposthenuria and concentrated urine during the
the veterinary literature (Breitschwerdt et al, 1981; Grunbaum water deprivation test. During serial measurements, urine osmo-
etal, 1990; Grunbaum and Moritz, 1991). Primary NDI has not lality spontaneously reached high concentrations (i.e., greater
yet been reported in the cat. The cause of primary NDI in dogs than 1000 mOsm/kg of H2O) in two dogs. During water depri-
and cats is unknown. Electron microscopic examination of the vation, plasma AVP concentrations remained relatively low in all
renal medulla in a Miniature Poodle with primary NDI revealed dogs. The AVP response to hypertonic saline infusion was abnor-
vacuoles in the cells of the Henle loops, blood vessels, and intersti- mal in all dogs, with an increased threshold value in three dogs,
tium, but the signicance of these lesions is not known. Necropsy an increased sensitivity in two dogs, and an exaggerated response
failed to identify any lesions in the kidney of a German Shepherd in one dog. These ndings suggested a primary disturbance in
dog with primary NDI. the regulation of AVP secretion, although chronic overhydra-
Familial NDI has been reported in a family of Huskies, in which tion may have caused downregulation of AVP release in response
the female parent was diagnosed as a carrier of the NDI gene, and to hypertonicity (Moses and Clayton, 1993). Subnormal AVP
three of four male puppies in her litter had NDI (Grunbaum etal, release during water deprivation and hypertonic stimulation has
1990). Affected puppies possessed normal V2 receptor numbers in been documented in humans with primary polydipsia (Zerbe and
the kidney inner medulla, but the receptors had a ten-fold lower Robertson, 1981); these individuals were subsequently classied
binding afnity for AVP than in normal dogs (Luzius etal, 1992). as having partial diabetes insipidus. It is not clear whether the
Adenylate cyclase stimulation by AVP was similarly reduced in a dogs described by van Vonderen, etal., (1999) represent a variant
dose-response manner; however, stimulation of adenylate cyclase or early stage of partial diabetes insipidus. They were classied as
by nonAVP-mediated chemicals was comparable for normal having primary polydipsia based on their ability to concentrate
and NDI-affected dogs, implying normal adenylate cyclase in the urine to a specic gravity greater than 1.030, but the identied
affected Huskies. The NDI-affected dogs also had antidiuretic abnormalities suggest a problem with AVP release rather than the
responses to high doses of DDAVP, consistent with their possess- thirst center, per se.
ing V2 receptors of lower binding afnity.
In an older dog and cat, primary NDI should only be considered if
CLINICAL FEATURES OF DIABETES INSIPIDUS
polyuria and polydipsia has been present the animals entire life. The
AND PSYCHOGENIC POLYDIPSIA
onset of polyuria and polydipsia later in life in a dog or cat suspected
to have NDI is suggestive of acquired NDI. A complete evaluation
Signalment
of the kidney, including creatinine clearance studies, IV pyelogram,
computed tomographic (CT) or magnetic resonance imaging (MRI) Central Diabetes Insipidus
scan, and kidney biopsy should be considered in these dogs and cats There is no apparent breed, gender, or age predilection for CDI
if another cause of for acquired NDI is not identified. (Fig. 1-10). Of 60 dogs diagnosed with CDI at University of
|
30 20
Number of dogs
25 15
Number of dogs
20 10
15 5
10 0
1 1week- 1-6 6-12 12
week 1 month months months months
5
FIGURE 1-11 Duration of polyuria and polydipsia in 38 dogs with central dia-
0 betes insipidus (CDI) before owners presented their pet to the veterinarian for
A M M/C F F/S examination.
30
Psychogenic Polydipsia
25 Psychogenic polydipsia can be diagnosed in dogs of any age, either
gender, and numerous breeds. Fifteen different breeds were repre-
Number of dogs
20 sented in 18 dogs diagnosed with psychogenic polydipsia at UC

Davis. Eleven dogs were female or female/spayed, and the age at
15 time of diagnosis ranged from 6 months to 11 years, with a mean
and median age of 4 and 4 years, respectively. Psychogenic poly-
10 dipsia has not yet been reported in the cat.
5 Clinical Signs
0 Polyuria and polydipsia are the hallmark clinical signs for dia-
B 1 1-3 4-5 6-10 10 betes insipidus and psychogenic polydipsia. Polyuria and poly-
dipsia can be quite severe, with 24-hour water intake exceeding
FIGURE 1-10Gender (A) and age (B) distribution of 60 dogs diagnosed with
200 mL/kg. Polyuria and polydipsia have usually been present
central diabetes insipidus (CDI). F, Female; F/S, female/spayed; M, male; M/C,
for 1 to 6 months before veterinary care is sought (Fig. 1-11).
male/castrated.
Many owners also report urinary incontinence, in part because
of the frequency of urination and loss of normal house broken
behavior and in part because of the inability to maintain con-
California, Davis, 25 different breeds were represented. The tinence because of the large volume of urine being produced,
Labrador Retriever (eight dogs), Boxer (ve dogs), and German especially when the dog or cat is sleeping. Owners of cats with
Shepherd (five dogs) were the breeds most commonly affected. diabetes insipidus also complain about the increased frequency
The age at time of diagnosis in these 60 dogs ranged from of changing the litter, which often needs to be done two or three
7 weeks to 14 years, with a median age of 6 years. Most dogs times a day. An insatiable desire for water may result in the con-
diagnosed with CDI were younger than 2 years or older than 5 sumption of any liquid, including ice, snow, and urine. Occa-
years of age. sionally, the afflicted pets strong desire for water overrides its
Twelve cats with CDI have been reported in the literature (Burnie normal appetite (i.e., they would rather drink than eat), result-
and Dunn, 1982; Winterbotham and Mason, 1983; Kraus, 1987; ing in weight loss.
Brown etal, 1993; Pittari, 1996; Aroch etal, 2005), and we have Additional clinical signs depend, in part, on the underlying
diagnosed an additional four cats at UC Davis. Thirteen of these cause. Other historical abnormalities (e.g., vomiting, diarrhea,
sixteen cats were Domestic Short- or Long-Haired, two were Per- coughing) are usually not present in dogs or cats with congeni-
sian, and one was an Abyssinian. Eight of the cats were female or tal, idiopathic, or trauma-induced forms of diabetes insipidus.
female/spayed, and eight were male or male/castrated. The age at These pets are typically alert and playful and have normal exer-
the time of diagnosis of CDI ranged from 8 weeks to 6 years, with cise tolerance. However, dogs with acquired CDI secondary to
a mean of 1 years. a growing pituitary or hypothalamic neoplasm may develop
additional signs related to the nervous system, including inap-
Primary Nephrogenic Diabetes Insipidus petence, stupor, disorientation, pacing, ataxia, seizures, and
Primary NDI is rare in dogs and cats. To date, primary NDI has tremors (Harb et al, 1996). Neurologic signs may be present
been reported in a 13-week-old male German Shepherd dog, an at the time CDI is diagnosed or, more typically, develop weeks
18-month-old male Miniature Poodle, an 18-month-old female to months after CDI is identied. In one study, 6 of 20 dogs
Boston Terrier, and a family of Huskies (Breitschwerdt et al, with CDI developed neurologic signs from 2 weeks to 5 months
1981; Grunbaum etal, 1990). We have also diagnosed NDI in a (median, 1 month) after CDI was diagnosed (Harb etal, 1996).
5-month-old Norwegian Elkhound and a 1-year-old Boston Ter- A tumor in the region of the hypothalamus and pituitary was
rier. Both dogs had polyuria and polydipsia since being acquired identied by CT scan or necropsy in all six dogs. Neurologic
by their owners at 6 to 8 weeks of age. Primary NDI has not yet signs may also develop secondary to hypertonic dehydration and
been reported in the cat. severe hypernatremia.
14
Physical Examination
As with the history, the abnormalities found during the physical 12
examination depend on the underlying cause. For most animals,
10
the physical examination is unremarkable, although some dogs
Number of dogs
tend to be thin. Abnormalities of the cardiovascular, respiratory, 8
gastrointestinal, and urogenital systems are usually absent. Ani-
mals with idiopathic or congenital diabetes insipidus are alert and 6
active. Typically, as long as access to water is not restricted, hydra-
tion, mucous membrane color, and capillary rell time remain 4
normal. The presence of neurologic abnormalities is variable in
dogs and cats with trauma-induced CDI or neoplastic destruc- 2
tion of the hypothalamus and/or pituitary gland. Many of these
0
animals have no perceptible neurologic alterations on physical 1.001 1.005 1.010 1.015
examination. A few show mild to severe neurologic signs, includ-
ing stupor, disorientation, ataxia, circling, and pacing. Urine specific gravity
FIGURE 1-12 Urine specific gravity measured in 49 dogs with central diabetes
insipidus (CDI) at the time of initial presentation to the veterinarian.
Clinical Pathology Abnormalities
Complete Blood Count
The CBC in dogs and cats with CDI or NDI is usually unremark- Serum Chemistries
able. The white blood cell count and differential are normal. The The serum biochemistry panel is normal in most dogs and cats
red blood cell count is normal or mildly increased. Polycythemia with diabetes insipidus and psychogenic polydipsia. The chronic
is not common and is the result of a mild, clinically imperceptible and severe diuresis associated with CDI, NDI, and psychogenic
state of dehydration. Diabetes insipidus is a primary polyuric dis- polydipsia causes excessive loss of urea via the kidneys and may
order with compensatory polydipsia, and affected dogs and cats cause a subsequent reduction of BUN to concentrations of 5 to
are chronically, albeit mildly, fluid-depleted to stimulate the com- 10 mg/dL. Ten of 40 dogs with CDI had a BUN less than 10 mg/
pensatory thirst response. Owners commonly tire of their pets dL at the time of initial presentation to UC Davis. Inadequate
polyuria and polydipsia and begin restricting access to water, fur- access to water can cause severe dehydration and prerenal azote-
ther exacerbating dehydration. Fluid depletion results in hemo- mia with hyposthenuria. The combination of prerenal azotemia,
concentration with a mild increase in hematocrit, red blood cell hypernatremia, and hyposthenuria was identified in 3 of our 40
count, and serum total protein concentration. The CBC in dogs dogs with CDI at the time of initial presentation to our hospital.
with psychogenic polydipsia is rarely abnormal. These clinicopathologic abnormalities resolved after allowing the
dogs to have access to water and initiating DDAVP therapy. Own-
Urinalysis ers had restricted access to water in all three dogs.
Random urinalysis in dogs and cats with CDI, NDI, or psy-
chogenic polydipsia typically reveals a urine specic gravity less Serum Electrolytes
than 1.006, with values of 1.001 and 1.002 occurring commonly Serum electrolytes are usually normal in dogs and cats with diabe-
(Fig. 1-12). The corresponding urine osmolality is usually less tes insipidus and psychogenic polydipsia. Mild hyponatremia and
than 300 mOsm/kg. A urine specic gravity in the isosthenuric hypokalemia have been identied in 20% of our dogs with CDI
range (1.008 to 1.015) does not rule out diabetes insipidus (see and psychogenic polydipsia. More important, severe hypernatre-
Fig. 1-12) or psychogenic polydipsia (see Table 1-3), especially mia (serum sodium, 159 to 165 mEq/L) and hyperkalemia (5.4 to
when the urine has been obtained after water is knowingly or 5.9 mEq/L) have been identied in 15% of our dogs with CDI,
inadvertently withheld (e.g., a long car ride and wait in the vet- abnormalities presumably developing secondary to water restric-
erinary ofce). Dogs and cats with partial diabetes insipidus can tion and dehydration. An intact renin-angiotensin-aldosterone
concentrate their urine into the isosthenuric range if dehydrated. axis succeeds in maintaining electrolyte homeostasis in most dogs
The remaining components of the urinalysis in these animals are and cats despite the remarkable urine output associated with CDI,
usually normal. NDI, and psychogenic polydipsia. Maintenance of fluid and elec-
Extremely dilute urine is not commonly seen in veterinary trolyte balance depends on functioning thirst and hunger centers
practice, being limited usually to animals with postobstructive in the hypothalamus. Water restriction can cause severe dehydra-
diuresis, excessive IV fluid administration, diuretic use, and tion in a matter of hours. Because free water diuresis continues
hyperadrenocorticism, as well as CDI, NDI, and psychogenic despite water restriction, vascular and systemic hyperosmolarity
polydipsia. Although numerous disorders can result in poly- develops. Increases in serum sodium contribute significantly to
dipsia and polyuria (see Table 1-2), most of these disorders do this hyperosmolarity. Hypertonic dehydration, severe hypernatre-
not cause the severe polyuria suggested by remarkable depres- mia, and neurologic signs may develop in a dog or cat with diabe-
sion in the specic gravity (< 1.005). Although we have seen tes insipidus that is unable to drink (e.g., posttraumatic episode) or
animals that were polyuric owing to hypercalcemia, hypokale- has restricted access to water (Reidarson etal, 1990). Severe hyper-
mia, pyometra, pyelonephritis, and other disorders, the degree natremia is associated with significant metabolic consequences and
of urine dilution is less dramatic and typically in the 1.006 to is a difficult therapeutic challenge. Water deprivation studies to
1.020 range. However, even mild disturbances in the ability to confirm the diagnosis of diabetes insipidus are not without com-
concentrate urine, resulting in urine specic gravities of 1.008 plications and require careful patient monitoring to avoid dan-
to 1.015, often alter behavior sufciently to allow an owner to gerous consequences (see Complications of the Modified Water
realize the change. Deprivation Test: Hypertonic Dehydration and Hypernatremia).
|
CONFIRMING THE DIAGNOSIS OF DIABETES response to water deprivation provides insight into the animals
INSIPIDUS ability to concentrate urine (i.e., can the patient concentrate urine
to a specic gravity above 1.030).
Diagnostic tests to confirm and differentiate among CDI, pri- A simpler approach that is especially appealing in a busy prac-
mary NDI, and psychogenic water consumption include the tice is the evaluation of response to trial therapy with DDAVP
modified water deprivation test, random plasma osmolality deter- and, if available, measurement of plasma osmolality obtained
mination, and the clinical response of the dog or cat to DDAVP while the dog or cat has free access to water (see Random Plasma
treatment. The results of these tests can be interpreted only after Osmolality as a Diagnostic Tool).
the causes for acquired NDI have been ruled out. Recommended
initial diagnostic studies to rule out acquired NDI include a
RESPONSE TO TRIAL THERAPY
CBC; serum biochemistry panel; serum T4 concentration (older
WITH DESMOPRESSIN ACETATE
cat); urinalysis with bacterial culture; abdominal ultrasonogra-
phy; a urine cortisol-to-creatinine ratio, low-dose dexamethasone CDI, primary NDI, and psychogenic polydipsia are uncommon
suppression test, or both in dogs; baseline serum cortisol concen- to rare causes of polyuria and polydipsia in dogs and cats; and
tration if hypoadrenocorticism is suspected (dogs); and pre- and of these three differential diagnoses, partial CDI and psychogenic
postprandial bile acids if hepatic insufficiency is suspected. Results polydipsia are the most common. Because CDI is treated with
of these screening tests are normal in dogs and cats with CDI, DDAVP, a viable approach to establishing the diagnosis is to eval-
primary NDI, and psychogenic water consumption, although a uate the animals response to trial therapy with DDAVP (Aventis
low-normal serum urea nitrogen concentration may be identified Pharmaceuticals). Oral DDAVP tablets or conjunctival drops of
in animals with unrestricted access to water and erythrocytosis, DDAVP nasal spray (see Treatment) should be administered every
hyperproteinemia, hypernatremia, and azotemia may be found if 12 hours for 7 days. The effect of DDAVP should not be critically
access to water has been restricted. evaluated until after 5 to 7 days of therapy because renal med-
Pituitary-dependent hyperadrenocorticism can mimic CDI in ullary solute washout may prevent a dog or cat with CDI from
the adult dog. Pituitary-dependent hyperadrenocorticism com- concentrating its urine and decreasing water intake after only 1
monly causes severe polyuria and polydipsia and occasionally dogs or 2 days of DDAVP treatment. Clients should notice a definite
have no other clinical signs, do not have the typical abnormalities improvement in the severity of polyuria and polydipsia by the end
(e.g., increased serum alkaline phosphatase activity, hypercholes- of the treatment period if the polyuria and polydipsia are caused
terolemia) associated with the disease, and adrenal gland size is by CDI. Urine specific gravity should be measured on several
at the upper end of the reference interval with ultrasonography. urine samples collected by the client on the last couple of days
Results of the modied water deprivation test in dogs with hyper- of trial therapy. An increase in urine specific gravity by 50% or
adrenocorticism are similar to results in dogs with partial CDI more, compared with pretreatment specific gravities, supports the
(see Fig. 1-18) and, sometimes, dogs with psychogenic polydipsia. diagnosis of CDI, especially if the urine specific gravity exceeds
Severity of polyuria and polydipsia may improve noticeably to the 1.030. There should be only minimal improvement in dogs and
owner after initiating treatment with DDAVP in these dogs but cats with primary NDI, although a response may be observed with
improvement tends to be transient, lasting only a few months, very high doses of DDAVP (Luzius etal, 1992). Dogs and cats
and the dog typically re-presents to the hospital with owner con- with psychogenic water consumption may exhibit a mild decline
cerns that the DDAVP is no longer working. For these reasons, in urine output and water intake because the chronically low
we always perform screening tests for hyperadrenocorticism (i.e., serum osmolality tends to depress AVP production. Theoretically,
urine cortisol-to-creatinine ratio on urine collected at home; low dogs with psychogenic polydipsia could develop clinical signs of
dose dexamethasone suppression test) in an adult dog in which hyponatremia during DDAVP therapy but we have not yet identi-
CDI and psychogenic polydipsia have risen to the top of the differ- fied this complication (see Syndrome of Inappropriate Vasopressin
ential diagnoses and always before initiating DDAVP treatment. Secretion: Excess Vasopressin). A thorough review of the diagnos-
An index of suspicion for CDI and primary NDI versus psychotic evaluation of the patient, owner compliance in treating the
genic polydipsia can often be gained after reviewing the history pet, and adjustments in the DDAVP treatment protocol should be
and findings on physical examination and routine blood and urine undertaken in dogs and cats that fail to respond to DDAVP before
tests. The presence of neurologic signs or behavioral issues, the considering the modified water deprivation test.
serum sodium concentration (i.e., upper versus lower limit of the
reference range), the consistency of hyposthenuric urine, and the
MODIFIED WATER DEPRIVATION TEST
dogs susceptibility to dehydration after water restriction provide
clues to the underlying diagnosis. The definitive diagnosis is based
Principle of the Test
on results of the modied water deprivation test, measurement
of plasma osmolality, measurement of plasma AVP concentration The modied water deprivation test is designed to determine
and response to synthetic vasopressin therapy. whether endogenous AVP is released in response to dehydration
Historically, the modied water deprivation test has been con- and whether the kidneys respond to this stimulus. The modified
sidered the best diagnostic test to differentiate between CDI, water deprivation test consists of two phases. In phase I the AVP
primary NDI and psychogenic polydipsia. However, the test can secretory capabilities and renal distal and collecting tubule respon-
be labor-intensive, time-consuming, and expensive, especially if siveness to AVP are evaluated by assessing the effects of dehydra-
urine and plasma osmolalities and plasma AVP concentrations are tion (i.e., water restriction until the animal loses 3% of its body
measured. Results of the test can also be confusing, especially with weight) on urine specific gravity. The normal dog and cat, as well
partial deciency syndromes. Currently, we consider performing as those with psychogenic water consumption, should be able to
a water deprivation test only in dogs (and rarely cats) that have concentrate urine to greater than 1.030 (1.035 in the cat) if dehy-
a poor response to trial DDAVP treatment and when we sus- drated. Dogs and cats with partial and complete CDI and primary
pect either partial CDI or psychogenic polydipsia. In these cases, NDI have an impaired ability to concentrate urine in the face
of dehydration (Table 1-4 and see Figure 1-17). Phase II of the 1.030
water deprivation test is indicated for dogs and cats that do not
concentrate urine to greater than 1.030 during phase I of the test. 1.025
Phase II determines the effect, if any, that exogenous AVP has on
Urine specific gravity

the renal tubular ability to concentrate urine in the face of dehy- 1.020
dration (see Fig. 1-19). This phase differentiates impaired AVP
secretion from impaired renal tubular responsiveness to AVP (see 1.015
Table 1-4). The modied water deprivation test is not indicated to
study the function of any organ system other than renal tubular 1.010
response to AVP. This protocol is specically contraindicated in
patients suspected or known to have renal disease, those that are 1.005
uremic owing to prerenal or primary renal disorders, and animals
with suspected or obvious dehydration (see Approach if the Dog
1.000
or Cat Is Brought into the Hospital Dehydrated). Pre 1 2 3 4 5 6 7 8 9 10
Time (hours)
Protocol FIGURE 1-13 Results of the modified water deprivation test in a 1-year-old Per-
sian cat with congenital central diabetes insipidus (CDI). Solid line, Initial water
See Box 1-3.
deprivation test results. Dotted line, Water deprivation test results after gradu-
Preparation for the Test ally restricting water consumption for 7 days prior to performing the test. Dashed
line, Water deprivation test results after gradual water restriction and twice-daily
The severity of renal medullary solute washout is a difcult vari-
injections of arginine vasopressin (AVP) for 7 days prior to performing the test.
able to evaluate in an animal with severe polydipsia and polyuria;
AVP injections were discontinued 24 hours prior to performing the test. , 5% loss
yet it may have an effect on test results. Theoretically, correction
of body weight and aqueous AVP injection.
of renal medullary solute washout improves renal tubular concen-
trating ability and the accuracy of the modied water deprivation
test in differentiating among CDI, primary NDI, and psycho-
genic polydipsia. However, in animals with CDI, water restriction At the start of the test, the dogs or cats bladder is emptied
alone may not improve renal medullary solute washout; only after by micturition (walking outside) or catheterization; then an exact
correction of polyuria and polydipsia with vasopressin therapy body weight is obtained and water is completely withheld from
can the capacity of the renal tubule to concentrate urine be fully the patient. Urine specic gravity and, if possible, osmolality
appreciated (Fig. 1-13). Nevertheless, we attempt to minimize the should be determined on a pretest urine sample. Periodic evalua-
effects of severe medullary washout on the results of the modied tion of BUN and serum sodium concentration, beginning at the
water deprivation test, using progressive water restriction before start of the test, is helpful in identifying the development of azote-
initiating total water deprivation. The goal is to decrease 24-hour mia or hypernatremia. The onset of azotemia or hypernatremia is
water intake to approximately 100 mL/kg the day prior to per- a criterion for ending the test.
forming the water deprivation test. This goal can be hard to attain, Although urine osmolality is more consistent and accurate
especially in dogs or cats with severe polyuria and polydipsia. Total than urine specic gravity, determination of urine specic gravity
water intake per 24 hours should be determined by the owner and allows differentiation between CDI, primary NDI and psycho-
based on unrestricted access to water. Water restriction is begun genic polydipsia in most situations, is readily available, inexpen-
once total 24-hour water intake has been quantied. We arbitrarily sive, and provides immediate information on urine concentration.
decrease daily water intake by 10% every 1 to 2 days and continue Prior to starting the modied water deprivation test, the clinician
until the goal of 100 mL/kg/24 h is attained, the animal becomes should check the accuracy of the refractometer by ensuring that
aggressive for water, or begins to develop clinical signs suggestive a reading of 1.000 is obtained with distilled water (Barsanti etal,
of hypertonic dehydration (e.g., change in mentation; see Com- 2000).
plications of the Modified Water Deprivation Test: Hypertonic
Dehydration and Hypernatremia). Each days 24-hour allotment During Phase I of the Test
of water should be divided into six to eight aliquots with the last The urinary bladder should be emptied by micturition or catheter-
aliquot given at bedtime. No food is given within 12 hours of ization every 1 to 2 hours. For cats, an indwelling urinary catheter
beginning the test or during the procedure. is usually required. The specic gravity should be determined on
each urine sample and an aliquot stored for osmolality determi-
Phase I of the Test nation, should it be desired at the end of the test. Most impor-
The water deprivation test should always be started at the begin- tant, the dog or cat must be carefully weighed at least once an
ning of the workday, because animals undergoing this test must hour. Phase I ends when 3% of body weight has been lost or urine
be observed and evaluated frequently. Most dogs and cats with specic gravity exceeds 1.030. Additionally, the dog or cat should
CDI or primary NDI dehydrate and lose 3% of their body weight be assessed for clinical evidence of dehydration and changes in
(end point for this phase of the test) within 3 to 10 hours (see mentation or behavior. Periodic evaluation of BUN and serum
Table 1-4). Withholding water and leaving the dog or cat with sodium concentration should also be done. The test should be
diabetes insipidus unattended for several hours or throughout halted if the dog or cat becomes azotemic, hypernatremic, or
the night may result in the development of severe complications severely dehydrated or develops changes in mentation or behavior.
and possibly death (see Complications of the Modied Water
Deprivation Test: Hypertonic Dehydration and Hypernatremia). End of Phase I
Frequent observation of the animal helps avoid complications or Maximal secretion of AVP and concentration of urine are achieved
severe dehydration. when an animal loses 3% of its body weight owing to loss of fluid
|
in the urine with simultaneous water deprivation. At that point Normal Dog
the urinary bladder should be completely emptied, the urine 2200
checked for specic gravity and osmolality, and phase II of the 10%
water deprivation test initiated (see Box 1-3). If available, a plasma 2000
vasopressin concentration obtained at this time is helpful in inter-
Urine osmolality (mOsm/kg)

preting the test (see Plasma Vasopressin Determinations). 1800
Normal dogs typically require more than 24 hours to lose 3% of
body weight following water deprivation. In contrast, water depri- 800
vation usually causes 3% or greater loss of body weight within
3 to 10 hours if the animal has CDI or primary NDI (see Table
600
1-4). Dogs or cats with partial CDI or psychogenic polydipsia
may require considerably longer than 10 hours to achieve 3% loss
of body weight. The clinician should always be prepared to con- 400
tinue the water deprivation test into the late evening hours. If this Plasma
is not possible and the dog or cat has not yet lost 3% body weight 200
or attained a urine specic gravity greater than 1.030 by the end of
the working hours, the dog or cat can be transferred to a veterinary 0
hospital with overnight care so the test can be continued. 0 1 2 3 4 5 6 18 24 36 48
Hours
Alternatively, the study can be stopped and water offered, ini-
tially in small amounts to prevent overzealous intake. The modied FIGURE 1-14 The effect of water deprivation on the urine osmolality of a normal
water deprivation test can then be repeated in a few days with the dog. represents an injection of aqueous vasopressin, which alters urine osmo-
following adjustments in protocol: body weight is measured and lality 10% or less.
water withheld beginning at midnight; the dog or cat is kept in a
cage (or at home) for the remainder of the night, ideally with peri-
odic visual assessment by individuals working at night (or by the
owner if the patient is at home); the urinary bladder is completely parameters, but monitoring cannot be considered as consistent
emptied rst thing in the morning and urine specic gravity and/ or informative as body weight and patient observation. One
or osmolality are measured; body weight is recorded; and phase I important aid during phase I of the modied water deprivation
is continued as previously discussed. With this modication, the test is the periodic check of the BUN and serum sodium concen-
clinician is already 6 to 8 hours into phase I of the test at the tration. Whenever the BUN rises above 30 mg/dL, the patient is
beginning of the workday. Complete CDI and primary NDI must azotemic and phase I should be ended; development of azotemia
be ruled out before this modication to the modied water depri- suggests occult renal disease. Azotemia developing during the
vation test is used; that is, the clinician must prove that the dog or modied water deprivation test has not resulted in problems in
cat requires at least 10 hours of water deprivation before 3% loss dogs and cats monitored as suggested earlier. Similarly, hyperna-
of body weight occurs. The modication described here should tremia and increased plasma osmolality are potent stimulants of
never be incorporated into the initial modied water deprivation AVP secretion; when identied, these findings suggest that phase
test performed on the dog or cat. I of the water deprivation test be ended.
Serial evaluation of body weight is a simple, inexpensive, reli-
able, and readily available method to determine the end point Response to Exogenous Arginine Vasopressin (Phase II)
of phase I of the test. The goal is to lose 3% body weight during Phase I determines the effects of dehydration on endogenous
water deprivation. A 1% to 2% loss of weight due to dehydration AVP secretion and AVP action on the renal tubules. Phase II
may fail to maximally stimulate AVP secretion. False plateaus in determines what effect, if any, exogenous AVP has on renal tubu-
urine osmolality and urine specic gravity have been observed lar ability to concentrate urine in the face of dehydration. This
with weight loss in the range of 2%, which can be misleading. phase differentiates impaired AVP secretion from impaired renal
Other criteria have been used to determine whether and when tubular responsiveness to AVP. Synthetic aqueous vasopressin
maximal urinary concentration has been achieved through water (Pitressin) at a dosage of 0.2 to 0.4 U/kg up to a maximum of
deprivation. One method is recognition of a plateau, or lack 5U, is administered with a intramuscular (IM) injection, urine
of increase, in urine osmolalities. This criterion is based on the samples are obtained, and the bladder is emptied 30, 60 and 120
knowledge that after the maximal renal response to water depri- minutes following the injection. Alternatively, DDAVP injec-
vation is achieved, the urine osmolality becomes relatively con- tion may be administered at a dose of 5 g subcutaneously (SC)
stant. This plateau in urine concentration is dened as a change in and urine samples obtained and the bladder emptied 2 and 4
osmolality between three consecutive urine collection periods, 1 hours following injection. Specific gravity and/or urine osmolal-
hour apart, of less than 5% or 30 mOsm/kg of H2O. Monitoring ity are determined on these urine samples and the dog or cat
urine specic gravity in lieu of osmolality or body weight is less is offered small amounts of water over the next 2 hours. Ulti-
reliable because false plateaus in urine specic gravity are com- mately, the animal is returned to free-choice water. The water is
mon, even before 3% loss of body weight has occurred. Although initially offered in small amounts to prevent overzealous intake,
the ability to ascertain a specic gravity is readily available, it is not which could result in vomiting or water intoxication.
sufciently accurate to use as a criterion for ending phase I of the
study, unless the urine specic gravity exceeds 1.030. Responses to the Modied Water Deprivation Test
Monitoring skin turgidity and measuring the packed cell vol-
ume of blood have not proved to be reliable or consistent tools Normal Dogs
for recognizing dehydration. Measurement of total plasma pro- Normal dogs dehydrate quite slowly (Fig. 1-14). The secretion
tein concentration may be more reliable than the former two of AVP in the normal dog results in exquisite conservation
of fluid over long time periods. Random urine samples from Central Diabetes Insipidus
normal dogs with free access to water reveal a specic gravity 1400
of 1.006 to greater than 1.040 and an osmolality of 160 to
greater than 2500 mOsm/kg of H2O (uOsm; van Vonderen 1200
etal, 1997b). In a report on laboratory dogs, the range of values
was narrower and maximal urine concentration was achieved in
20 dogs after an average of approximately 40 hours of water

1000
deprivation (Hardy and Osborne, 1979). Maximal urine
osmolality ranged from 1700 to 2700 uOsm and specic
gravity from 1.050 to 1.075. Urine concentration indices 800
(specic gravity and osmolality) did not plateau after reaching
maximal values. Most dogs reached a peak in urine concen- 600
tration, followed by slight fluctuations below that value for
the remaining period of water deprivation. No difference in
testing parameters occurred between males and females. 400
Although not specically evaluated, similar ndings are Plasma
expected in the cat.
200
In a clinical setting, normal for the modied water depriva-
tion test is dened as a urine osmolality signicantly greater
than plasma osmolality. Normal dogs and cats have urine 0
that is typically greater than 1100 uOsm and a urine specic 0 1 2 3 4 5 6 7 8 9 10
Hours
gravity greater than 1.030 after dehydration. If urine osmolal-
ity and specic gravity exceed these values, pituitary AVP secre- FIGURE 1-15 The effect of water deprivation on the urine osmolality of a dog
tion and renal responsiveness to AVP are considered intact, with severe central diabetes insipidus (CDI). represents an injection of aqueous
and there is no need to evaluate renal responsiveness to exog- vasopressin administered after 5% or more body weight is lost, causing greater
enous AVP. than 50% increase in urine osmolality. Note how quickly these dogs lose 5% of
What happens if AVP is injected after maximal urine concen- their body weight.
tration is reached via water deprivation in normal dogs and cats?
As expected, such animals are experiencing maximal endogenous 700
AVP secretion, and no further urine concentration can occur.
Therefore, exogenous AVP should have little effect on urine con-
centration in these animals. After dehydration, changes in urine 600
concentration of 10% or less of preinjection levels are not con-
sidered signicant. Such lack of change is typical in dogs and cats
with normal AVP secretion rates and renal responsiveness to AVP 500
(see Fig. 1-14).
400
Increase in urine osmolality (%)
Central Diabetes Insipidus

Dogs and cats with severe (complete) CDI cannot concen-
trate urine to levels greater than plasma osmolality (280 to 300
310 mOsm/kg [pOms]), even with severe dehydration. In
fact, the parameters of urine concentration change little, if
any, with continuing water deprivation (Fig. 1-15). CDI may 200
be subdivided into severe or partial deciencies of AVP. The
modied water deprivation test has been used to help differ-
entiate between mild and severe forms of CDI. As previously 100
described, mild states of dehydration, resulting in a 1% to 2%
loss in body weight, cause sustained release of AVP in the nor-
50
mal subject. After maximal urine concentration occurs in the
normal animal, it does not increase more than an additional 40
10% with the injection of aqueous vasopressin. If the admin- 30
istration of AVP to a dehydrated dog or cat causes a signicant
20
increase in the concentration of the urine, endogenous AVP
production and/or secretion must be insufcient. In dogs and 10
cats with severe AVP deciency, the urine osmolalities do not 0
reach 300 mOsm/kg with dehydration; however, the increase Complete Partial Nephrogenic
in osmolality after administration of vasopressin ranges from central diabetes insipidus diabetes insipidus
50% to 600% greater than the preinjection level (Figs. 1-16 FIGURE 1-16 Increase in urine osmolality during phase III of the modified water
and 1-17). deprivation test, that is, after intramuscular (IM) administration of aqueous va-
Dogs and cats with partial AVP deciencies can increase their sopressin, in 22 dogs with complete central diabetes insipidus (CDI), 9 dogs with
urine osmolality above 300 mOsm/kg after dehydration, but partial CDI, and 7 dogs with primary nephrogenic diabetes insipidus (NDI). Note
they also experience a further 10% to 50% or greater increase the marked increase in urine osmolality after vasopressin administration with
in urine osmolality following administration of vasopressin complete CDI versus partial CDI or primary NDI.
|
1200 1.035
1.030
900
1.025
600

1.020
300
1.015
0 1.010
Hydrated 3% to 5% Post-AVP
dehydration administration
FIGURE 1-17 Urine osmolality in 10 dogs with complete central diabetes in-
sipidus (CDI; solid circle) and 7 dogs with partial CDI (open circle) at the begin- 1.005
ning (hydrated), end of phase II (3% to 5% dehydration), and end of phase III
(post-arginine vasopressin [AVP] administration) of the modified water depriva-
tion test. Note the relative failure of dogs with complete CDI to increase urine
0
osmolality with dehydration and the marked increase in urine osmolality after Hydrated 5% Post-AVP
aqueous vasopressin administration. The opposite occurred in the dogs with dehydration administration
partial CDI. FIGURE 1-19 Urine specific gravity in 7 dogs with complete central diabetes
insipidus (CDI; solid circle) and 13 dogs with partial CDI (open circle) at the
beginning (hydrated), end of phase II (5% dehydration), and end of phase III
(post-arginine vasopressin [AVP] administration) of the modified water depriva-
Hyperadrenocorticism or tion test. Note the similarity of response between urine specific gravity and urine
Partial Diabetes Insipidus osmolality (see Fig. 1-17).
1400
1200 (Fig. 1-18; see Fig. 1-17). Changes in urine specic gravity
often behave in a manner similar to changes in urine osmo-
lality (Fig. 1-19; see Table 1-4). However, in some dogs and
1000
cats, urine specic gravity is not as easy to interpret as is urine

osmolality (Fig. 1-20).
800
Primary Nephrogenic Diabetes Insipidus
Dogs, and presumably cats, afflicted with primary NDI cannot
600 concentrate urine to levels greater than plasma osmolality (280
to 300 pOsm), even after severe dehydration. As with CDI, the
parameters of urine concentration change little, if any, with con-
400 tinuing water deprivation (Fig. 1-21; see Table 1-4). Unlike CDI,
Plasma however, minimal to no increase in urine osmolality and urine
specic gravity occurs after administration of AVP (see Fig. 1-16).
200
Similar to dogs with severe CDI, dogs with primary NDI dehy-
drate quickly without water (see Table 1-4). The only difference
0 between primary NDI and severe CDI is the lack of response to
0 1 2 3 4 5 6 7 8 9 10 DDAVP seen in primary NDI versus the dramatic increase in
Hours urine concentration seen in CDI after DDAVP administration.
FIGURE 1-18The effect of water deprivation on the urine osmolal- Dogs with primary NDI are young and have a history of polyuria
ity of a dog afflicted with partial central diabetes insipidus (CDI) or canine and polydipsia their entire life. In contrast, dogs and cats with
hyperadrenocorticism. represents an injection of aqueous vasopressin admin- acquired NDI are usually adults with a concurrent illness that
istered after 5% or more body weight is lost owing to fluid loss via the urine. interferes with AVP action at the renal tubular level and have a his-
The urine osmolality did increase, but subnormally, in response to dehydration. tory of normal water intake and urination habits prior to the onset
Vasopressin results in a further 10% to 50% increase in urine osmolality. Note of polyuria and polydipsia. Acquired NDI patients are usually dif-
that the dog with partial CDI takes longer to dehydrate than one with severe CDI ferentiated from those with CDI or primary NDI after review of
(see Fig. 1-15). the history, physical examination, and results of routine blood and
urine tests and diagnostic imaging, eliminating the need for the of change reflects the competent AVP secretory response of the
modied water deprivation test. posterior pituitary to dehydration and a response to AVP by the
renal tubules.
Psychogenic Polydipsia
Dogs, and presumably cats, with psychogenic polydipsia have Misdiagnosis (Inaccuracies) Using the Modied Water
an intact hypothalamic pituitary renal tubular axis for control- Deprivation Test
ling fluid balance and variable severity of renal medullary sol-
ute washout. These dogs can concentrate urine to an osmolality The modied water deprivation test is an excellent study to dif-
above that of plasma with complete water deprivation and, given ferentiate primary NDI from CDI, but it may not differentiate
enough time, can attain urine specic gravities in excess of 1.030. partial CDI from psychogenic polydipsia with complete certainty
Depending on the severity of renal medullary solute washout, it (Fig. 1-23). Difculties in differentiating partial CDI from psy-
may take 24 hours or longer of water deprivation to attain concen- chogenic polydipsia may be explained by two associated changes
trated urine. The previously described progressive water restriction in the renal response to AVP. First is the reduction in maximal
procedure preceding the water deprivation test aids in reestablish- concentrating capacity resulting from chronic polyuria itself (i.e.,
ing the renal medullary concentration gradient in these dogs and renal medullary solute washout), which is manifested as subnor-
shortens the time to attain concentrated urine. Phase II (response mal urine concentrations in the presence of excess levels of plasma
to DDAVP administration) is rarely needed in dogs with psy- vasopressin. Second, there appears to be an enhanced antidi-
chogenic polydipsia. If phase II is performed, administration of uretic response to low levels of plasma AVP in patients with CDI;
DDAVP to a dehydrated dog with psychogenic polydipsia causes that is, these patients have a supersensitive response to the small
little change (< 10%) in urine osmolality (Fig. 1-22). This lack amount of AVP they secrete endogenously (Block et al, 1981).
TABLE 1-4 GUIDELINES FOR INTERPRETATION OF THE WATER DEPRIVATION TEST*
Urine Specific Gravity Time to 5% Dehydration (Hours)

DISORDER INITIALLY 5% DEHYDRATION POST-ADH MEAN RANGE
CDI
Complete < 1.006 < 1.006 > 1.010 4 3-7
Partial < 1.006 1.0081.020 > 1.015 8 6-11
Primary NDI < 1.006 < 1.006 < 1.006 5 3-9
Primary polydipsia 1.002-1.020 > 1.030 NA 13 8-20
ADH, Antidiuretic hormone; CDI, central diabetes insipidus; NA, not applicable; NDI, nephrogenic diabetes insipidus.
*Based on results from 20 dogs with CDI, 5 dogs with primary NDI, and 18 dogs with primary (psychogenic) polydipsia.
Nephrogenic Diabetes Insipidus

1400
Central Diabetes Insipidus

1400 1200
1200 1000
1000 800
800
600
600
400
1.018 Plasma
400
200
Plasma 1.012
200
1.006 0
0 1 2 3 4 5 6 7 8 9 10
Hours
0 1.000
0 1 2 3 4 5 6 7 8 9 10 FIGURE 1-21 The effect of water deprivation on the urine osmolality of a dog
Hours afflicted with primary nephrogenic diabetes insipidus (NDI). Vasopressin is ad-
FIGURE 1-20 Same dog as in Figure 1-15. Solid line, Urine osmolality; dashed ministered () after 5% or more of body weight is lost (in this dog, after only 4
line, increasing plasma osmolality caused by dehydrating a dog with central dia- hours). Note the rapid loss of weight and the absence of any increase in urine
betes insipidus (CDI); dotted line, urine specific gravity, illustrating why it is a concentration following 5% or more loss in body weight. The urine osmolality is
less precise and less obvious diagnostic marker with severe CDI (see Fig. 1-15). not increased by vasopressin administration (< 10% change).
|
The consequence of the enhanced antidiuretic effect is the ame- partially resistant to the antidiuretic effect of vasopressin and can
lioration of the urinary manifestations of partial AVP deciency. concentrate their urine to some degree if the plasma levels of the
Therefore, patients with partial CDI and those with psychogenic hormone are quite high (Robertson and Scheidler, 1981). Because
polydipsia (that have not attained 3% loss of body weight) may the standard diagnostic dose of aqueous AVP customarily pro-
respond to fluid deprivation with similar levels of urine concentra- duces marked hypervasopressinemia, patients with partial resis-
tion that cannot be increased further by injections of AVP (see Figs. tance may respond in this phase of the modied water deprivation
1-17 and 1-21). Thus neither the absolute level of urine osmolality test as though they had CDI (Zerbe and Robertson, 1981). Partial
achieved during fluid deprivation nor the percentage of increase resistance to the antidiuretic actions of vasopressin has been docu-
evoked by exogenous AVP consistently permits a clear distinction mented in Huskies with primary NDI (Luzius etal, 1992), raising
between the two disorders (Zerbe and Robertson, 1981). the possibility, albeit an uncommon one, that the modied water
The modied water deprivation test may also occasionally mis- deprivation test could misdiagnose primary NDI in dogs too.
diagnose human patients with congenital NDI. This inconsis- A number of humans have been incorrectly diagnosed as hav-
tency arises because a small percentage of these patients are only ing primary (psychogenic) polydipsia. The diagnosis was initially
based on results of a modied water deprivation test similar to that
1400
Psychogenic Polydipsia illustrated in Fig. 1-22. However, sophisticated studies have revealed
that some individuals have a metabolic explanation for such a test
result. These patients have an abnormal osmostat (i.e., an abnor-
1200 mally elevated set point in their osmoreceptors for stimulating
release of AVP). Therefore, at a relatively high plasma osmolality,
which should cause release of AVP, these individuals remain AVP
1000
free, polyuric, and thus polydipsic. Similarly, such patients may
have a lower than normal set point for thirst (i.e., thirst may be
800 stimulated at a plasma osmolality of 290 pOsm when it should not
be stimulated until the osmolality reaches 295 or 300 pOsm). A
similar phenomenon has been described in four dogs with suspected
600 primary polydipsia, in which the AVP response to hypertonic saline
infusion was abnormal and suggested a primary disturbance in the
400 regulation of AVP secretion (van Vonderen etal, 1999).
Plasma
200
Approach If the Dog or Cat Is Brought
into the Hospital Dehydrated
0 Occasionally, pets with severe polydipsia and polyuria appear

0 1 2 3 4 5 6 7 8 9 10 clinically dehydrated or have developed hypernatremia before the
Hours
modied water deprivation test can be undertaken. The most com-
FIGURE 1-22 The effect of water deprivation on the urine osmolality of a dog af- mon cause for this dehydration is the owners withholding of water
flicted with psychogenic polydipsia. Although these dogs are hormonally normal, in an attempt to reduce the likelihood of urination in the home.
the chronic diuresis may inhibit normal concentrating ability. represents an If the dehydrated dog or cat exhibits CNS signs, immediate fluid
injection of aqueous vasopressin administered after 5% or more body weight is therapy should be initiated. However, if the pet is in no appar-
lost as a result of the unabated diuresis. The urine does show mild concentrating ent distress, the bladder can be drained and the urine checked for
ability with dehydration, but less than 10% change in concentration following specic gravity and osmolality. A serum sample can be obtained to
vasopressin administration. assess BUN, sodium, osmolality, and vasopressin concentrations.
Severe
900 diabetes
% Change in urine osmolality after pitressin
insipidus
800 (error = 6%)
Diagnosis by
700 vasopressin assay
600 = Severe DI
= Partial DI
500
= Nephrogenic DI
400 = Normal function
300 (primary polydipsia)
200
Partial diabetes insipidus

100 (error = 59%) FIGURE 1-23 Relationship between maximum urine osmolality after de-
hydration and percentage of increase in urine osmolality after vasopres-
50
Nephro- sin administration in humans with central diabetes insipidus (CDI) and
0 genic
diabetes nephrogenic diabetes insipidus (NDI) and primary polydipsia. Note the
Normal vasopressin function
insipidus
(error = 35%) overlap in results between patients with partial CDI and patients with
(error = 0%)
normal vasopressin function (i.e., primary polydipsia). (From Robertson
0 200 400 600 800 1000 1200 GL: The Endocrine Society 41st postgraduate annual assembly syllabus,
Maximum urine osmolality after dehydration New Orleans, October, 1989, p. 25.)
BOX 1-3 Protocol for the Modified Water Deprivation Test
Preparation for the Test C . End of phase I

A . Determine total water intake per 24 hours based on unrestricted access to 1. If urine specific gravity exceeds 1.030
water 2. When dog is clinically dehydrated or appears ill
B. Several days prior to the test, gradually decrease total 24 hour water intake 3. When dog has lost 3% body weight
by approximately 10% every 1 to 2 days; continue until the goal of 100 mL/ a. Obtain plasma for vasopressin concentration if available
kg/24 h is attained or the animal becomes aggressive for water b. Empty bladder
C. Withhold food beginning 12 hours before the test c. Check urine specific gravity/osmolality
d. Check BUN and serum electrolytes
Phase I: Water Deprivation
e. Check serum osmolality
A. Prior to initiation
1. Withdraw food and all water Phase II: Response to Exogenous AVP
2. Empty bladder completely A. Administer aqueous vasopressin 0.2 to 0.4 U/kg (max, 5U) IM or desmo-
3. Obtain exact body weight pressin acetate injection 5 g SC
4. Check urine specific gravity and, if available, osmolality B. Continue withholding food and water
5. Obtain serum osmolality C. Monitor patient
6. Obtain BUN and serum electrolytes 1. Empty bladder every 30 minutes for 2 hours maximum (aqueous vaso-
7. Check hydration and CNS status pressin) or at 2 and 4 hours (desmopressin)
B. During the test 2. Check urine specific gravity/osmolality
1. Empty bladder every 60 to 120 min 3. Monitor hydration and CNS status
2. Check exact body weight every 60 min
At End of Test
3. Check urine specific gravity/osmolality at each interval
A. Introduce small amounts of water (10 to 20 mL/kg) every 30 minutes for
4. Check hydration and CNS status at each interval
2 hours and monitor patient
5. Periodically recheck BUN and serum electrolytes
B. If patient is well 2 hours after ending test, return to ad libitum water
AVP, Arginine vasopressin; BUN, blood urea nitrogen; CNS, central nervous system; IM, intramuscular; SC, subcutaneous.
The clinician can then proceed with the next phase of the modied Intracellular fluid Extracellular fluid
water deprivation test (phase II; see Box 1-3) if the urine present in (2/3 TBW) (1/3 TBW)
the bladder has a specic gravity of less than 1.030 (osmolality <
1100 uOsm) and the dog or cat is not uremic or hypernatremic. If Interstitial
the urine is more concentrated than 1.030 (1100 uOsm), a normal fluid
pituitary-renal tubular concentrating axis probably exists. If the ani- (1/4 TBW)
(1/12 TBW)
mal is truly polyuric/polydipsic, psychogenic polydipsia and hyper-
adrenocorticism remain possible diagnoses. If the urine is dilute,
response to exogenous vasopressin administration should help to
establish the diagnosis.
280-310 280-310
mOsm/kg mOsm/kg
Complications of the Modied Water Deprivation Test:
Plasma volume
Hypertonic Dehydration and Hypernatremia
An adult dog or cat is composed of 60% water. This water is sub-
divided into an intracellular compartment, which accounts for
two-thirds of the total, and an extracellular compartment, which
is one-third (Fig. 1-24). Movement of solutes that readily diffuse
across all membranes (e.g., urea) is not accompanied by apprecia-
ble fluid shifts, because these solutes generate equal osmotic forces FIGURE 1-24 In the hydrated state, uniform total body water (TBW) distribution
on either side of the cell membrane. Increased concentration of is maintained between the intracellular fluid (ICF) and extracellular fluid (ECF)
these solutes creates hyperosmolality in all fluid compartments compartments by osmotic forces (normal range, 280 to 310 mOsm/kg; average,
because of a lack of water redistribution. 295 mOsm/kg) generated by solutes. (From Edwards DF, etal.: Hypernatremic,
Solutes that are less permeable across cell membranes by hypertonic dehydration in the dog with diabetes insipidus and gastric dilatation
virtue of molecular size, electrical charge, or active membrane volvulus, J Am Vet Med Assoc 182[9]:973-977, 1983.)
pumps create an effective osmotic force. Intracellular solutes of
this kind include potassium, phosphate, glucose and protein.
Sodium and its anions serve the same purpose in the extracellu- movement of water, causing both hypovolemia and cellular
lar fluid (ECF). Increased concentrations of such solutes in the overhydration (Edwards etal, 1983).
ECF produce hyperosmolality and hypertonicity. The osmotic Three chemically distinct forms of dehydration (isotonic, hypo-
gradient that is formed results in movement of intracellular tonic, and hypertonic) occur in veterinary practice. Isotonic dehy-
fluid (ICF) into the extracellular space. Therefore, extracellular dration is produced by proportional loss of water and electrolytes
volume increases at the expense of cellular hydration. Alterna- (solutes) (Fig. 1-25, A). Protracted vomiting and diarrhea are one
tively, decreased concentrations of extracellular solutes produce cause of isotonic dehydration, in which water and electrolyte losses
a hyposmotic, hypotonic ECF that necessitates intracellular occur predominantly from the ECF compartment to the external
|
ICF ECF ICF ECF
295
(mOsm/kg)
>310
(mOsm/kg)
295 295 295 <280

(mOsm/kg) (mOsm/kg) (mOsm/kg) (mOsm/kg)
A B
ICF ECF
<280
(mOsm/kg)
295 >310
(mOsm/kg) (mOsm/kg)
C
FIGURE 1-25 A, Isotonic dehydration results from extracellular fluid (ECF) loss of water and electrolytes isosmotic
(295 mOsm/kg) to total body water (TBW). Because compartmental osmolality and tonicity remain unchanged (295
mOsm/kg), no major shift of intracellular fluid (ICF) occurs. B, Hypotonic dehydration results from ECF loss of water
and electrolytes hyperosmotic (> 310 mOsm/kg) to TBW. The ECF becomes hypo-osmolar and hypotonic (< 280 mOsm/
kg) to ICF. The intracellular movement of ECF reestablishes compartmental equilibrium at a lower osmotic pressure
(<295 mOsm/kg) and minimizes fluid loss from the ICF space. C, Hypertonic dehydration results from ECF loss of
water and electrolytes hyposmotic (< 280 mOsm/kg) to TBW. The ECF becomes hyperosmolar and hypertonic (> 310
mOsm/kg) and minimizes fluid loss from the ECF space. (From Edwards DF, etal.: Hypernatremic, hypertonic dehydra-
tion in the dog with diabetes insipidus and gastric dilatation volvulus, J Am Vet Med Assoc 182[9]:973-977, 1983.)
environment. Serum sodium concentrations are generally normal, lack of skin turgidity/elasticity, decreased pulse pressure, and
and clinical signs (e.g., skin turgidity/elasticity) are proportional decreased vascular volume are not detected until severe dehy-
to the degree of hypovolemia. dration is present. Weight loss is consistently seen much sooner
Hypotonic dehydration is produced by loss of electrolytes in and further emphasizes the importance of monitoring body
excess of water, as is seen in hypoadrenocorticism. In this example, weight during a water deprivation test.
excessive sodium is lost in the urine and gastrointestinal tract, creat- Severe hypernatremia with hyposthenuria are classic markers for
ing a hypotonic extracellular compartment that loses water to both hypertonic dehydration in the dog or cat with CDI or primary
the external environment and the intracellular space. Serum sodium NDI. Other causes of hypernatremia are not typically associated
values are generally low in this condition, prerenal a zotemia is com- with hyposthenuria (Box 1-4). The predominant clinical signs
mon, and these animals exhibit more obvious signs of hypovolemia associated with hypertonic dehydration result from CNS dysfunc-
than those with isotonic dehydration (Fig. 1-25,B). tion. The initial critical signs include irritability, weakness, and
Hypertonic dehydration is produced by loss of water in ataxia; as the hypernatremia worsens, stupor progresses to coma
excess of electrolytes and is the major concern after water and seizures. The progression and severity of these signs depend
deprivation in a dog or cat with CDI, primary NDI, or psy- on the rate of onset, degree, and duration of hypernatremia.
chogenic polydipsia and in dogs and cats with inadequate fluid Sodium has limited access to brain cells and is slow to equilibrate
intake following the onset of trauma-induced CDI (Fig. 1-25, with the CSF. Rapidly developing severe hypernatremia results in
C). The hypertonic extracellular compartment preserves vol- a shift of water from the intracellular to the extracellular space and
ume by dehydrating the intracellular compartment. The total forces reduction in CSF volume as water crosses into the hyper-
water decit is shared by fluid compartments in proportion osmotic fluid outside the CSF, causing shrinkage of the brain.
to their normal content of water (Edwards et al, 1983). The Reduction in brain size leads to tearing of veins, subdural hemor-
cells, which contain two-thirds of the total body water, lose rhage, and venous thrombosis. The brain synthesizes intracellular
substantially more fluid than does the extracellular compart- cerebral osmolar active substances (i.e., polyols) to compensate for
ment. Plasma volume, constituting only one-twelfth of the the hyperosmolar ECF and to minimize the shift of fluid into the
total body water, is relatively well preserved under these cir- extracellular space. Osmolytes are produced in the brain begin-
cumstances. Thus hypertonic dehydration results in few of ning within 1 hour after induction of persistent hyperosmolality
the expected signs of severe fluid depletion. Tachycardia, of ECF (Pollock and Arieff, 1980).
to correct hypovolemia. Serum sodium concentration should be

BOX 1-4 Causes of Hypernatremia in Dogs and Cats measured frequently (every 4 to 6 hours) to assess response to
treatment and status of the CNS evaluated frequently for change
Caused by Pure Water Loss in clinical signs. Worsening neurologic status or sudden onset of
Central diabetes insipidus (CDI)* seizures during fluid therapy is generally indicative of cerebral
Nephrogenic diabetes insipidus (NDI)* edema and the need for hypertonic saline solution or mannitol
Hypodipsia-adipsia therapy.
Neurologic disease Once ECF decits have been replaced, the serum sodium con-
Abnormal thirst mechanism centration should be reevaluated and water decits corrected if
Defective osmoregulation of vasopressin release hypernatremia persists. An approximation of the free water decit
Inadequate access to water in liters may be calculated using the following formula:
High environmental temperature (heat stroke)
Fever ( [ ] [ ] )
current Na + normal Na + 1 (0.6 body weight in kg)2
Hypotonic Fluid Loss
Gastrointestinal fluid loss* Oral fluid administration is preferable for correcting water
Vomiting deficits, with fluid administered through an IV route if oral
Diarrhea administration is not possible. Maintenance crystalloid solutions
Chronic renal failure* (e.g., half-strength [0.45%] saline solution with 2.5% dextrose
Polyuric acute renal failure* or half-strength lactated Ringers solution with 2.5% dextrose)
Osmotic diuresis should be used to correct the water deficit in hypernatremic ani-
Diabetes mellitus mals with normal perfusion and hydration and should also be
Mannitol infusion used in dehydrated animals with persistent hypernatremia after
Diuretic administration the correction of fluid deficits. Dextrose 5% in water (D5W)
Postobstructive diuresis solution can be substituted for maintenance crystalloid solutions
Cutaneous burns if the hypernatremia does not abate after 12 to 24 hours of fluid
Third-space loss therapy.
Pancreatitis The water deficit should be replaced slowly. Approximately
Peritonitis 50% of the water deficit should be corrected in the first 24
hours, with the remainder corrected over the ensuing 24 to 48
Excess Sodium Retention
hours. The serum sodium concentration should decline slowly,
Primary hyperaldosteronism
preferably at a rate of less than 1 mEq/L/hr. The rate of fluid
Iatrogenic
administration should be adjusted as needed to ensure an appro-
Salt poisoning
priate decrease in the serum sodium concentration. A gradual
Hypertonic saline infusion
reduction in the serum sodium concentration minimizes the
Sodium bicarbonate therapy
fluid shift from the extracellular to the intracellular compart-
Sodium phosphate enemas
ment, thereby minimizing neuronal cell swelling and cerebral
Parenteral nutrition*
edema and increasing intracranial pressure. A deterioration in
Modified from DiBartola SP: Disorders of sodium and water: hypernatremia and CNS status after the start of fluid therapy indicates the presence
hyponatremia. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders in of cerebral edema and the immediate need to reduce the rate of
small animal practice, ed 3, St Louis, 2006, Saunders/Elsevier. fluid administration. Frequent monitoring of serum electrolyte
*Common causes. concentrations, with appropriate adjustments in the type of fluid
administered and rate of fluid administration, is important in
the successful management of hypernatremia. It is much simpler
The goal in treating hypernatremic, hypertonic dehydration is to avoid these complications by careful monitoring during water
to restore the ECF volume to normal and correct water decits deprivation.
at a fluid rate that avoids signicant complications. Because the
brain adjusts to hypertonicity by increasing the intracellular sol- Plasma Vasopressin Determinations
ute content via the accumulation of idiogenic osmoles, the rapid
repletion of body water with ECF dilution causes translocation The direct assay of plasma AVP substantially improves the accuracy
of water into cells and can cause cerebral edema (Edwards etal, of conventional tests used in the differential diagnosis of polyuria in
1983; Reeves etal, 1998). If slower water repletion is undertaken humans (Zerbe and Robertson, 1981). The modied water depri-
brain cells lose the accumulated intracellular solutes and osmotic vation test alone is consistently correct in establishing a diagnosis
equilibration can occur without cell swelling. of severe CDI, because direct measure of AVP concentrations does
The initial priority is to restore the ECF volume to normal. not alter the results of tests in which a patient did not concentrate
The choice of fluid to be administered depends on whether cir- urine during dehydration. However, inaccuracies may occur in dif-
culatory collapse is present, the rate at which hypernatremia ferentiating patients with partial CDI from those with primary poly-
developed, and the magnitude of the hypernatremia. In patients dipsia and primary NDI; incorporating plasma AVP determinations
with modest volume contraction (e.g., tachycardia, dry mucous into the modied water deprivation test helps differentiate these
membranes, slow skin turgor), fluid decits should be corrected disorders.
with 0.9% saline supplemented with an appropriate amount of Reports incorporating plasma AVP measurements into the
potassium. In replacing decits, rapid administration of fluids is modied water deprivation test are sporadic in the veterinary lit-
contraindicated unless there are signs of signicant hypovolemia. erature. Plasma AVP concentrations failed to increase after 5%
Any fluid should be administered in a volume only large enough loss of body weight by water deprivation in two dogs with primary
|
15 Dehydration Pitressin
+ +
1200
10
9 +
1000
+
+
Urine osmolality mOsm/kg

8
Plasma vasopressin pg/mL
+
800
7
6 +
600
5
+ 400
4
+
3 200
+
2
1 0.5 1 5 10 50 >50
LD Plasma vasopressin pg/mL
280 290 300 310 = Severe diabetes insipidus = Nephrogenic diabetes insipidus
= Partial diabetes insipidus = Primary polydipsia
Plasma osmolality + = Normal subjects
mOsm/kg
FIGURE 1-27 Relationship of urine osmolality to plasma vasopressin in human
= Severe diabetes insipidus beings with diabetes insipidus and primary polydipsia. Note that values obtained
= Partial diabetes insipidus during dehydration in humans with central diabetes insipidus (CDI) almost al-
= Nephrogenic diabetes insipidus
= Primary polydipsia ways fall within or above the normal range, whereas those from patients with
+ = Normal subjects nephrogenic diabetes insipidus (NDI) fall uniformly below normal. Values in most
FIGURE 1-26Relationship of plasma arginine vasopressin (AVP) to plasma osmo- humans with primary polydipsia are normal, but a few may be subnormal, pre-
lality after dehydration in human beings with diabetes insipidus and primary polydip- sumably as a consequence of washout of the medullary concentration gradient.
sia. Note that values from patients with central diabetes insipidus (CDI) fall below the (From Robertson GL: Posterior pituitary. In Felig P, etal., editors: Endocrinology
normal range (shaded area), whereas those from patients with nephrogenic diabetes and metabolism, ed 2, New York, 1987, McGraw Hill, p. 338.)
insipidus (NDI) and primary polydipsia are almost always within or above the normal
range. (From Robertson GL: Posterior pituitary. In Felig P, etal., editors: Endocrinology
and metabolism, ed 2, New York, 1987, McGraw Hill, p. 338.) LD, Limit of detection. In humans, the plasma AVP value is interpreted in conjunc-
tion with the concurrent plasma and urine osmolality. When
evaluating plasma AVP and plasma osmolality concurrently after
CDI compared with normal dogs (Post etal, 1989). Plasma AVP dehydration, values from humans with severe or partial CDI fall
concentration was 3.3 and 3.7 pg/mL in these two dogs versus below the normal range, whereas those from humans with NDI
a mean of 31.3 pg/mL in three healthy dogs after water depri- or primary polydipsia are almost always within or above the nor-
vation. A similar deciency in plasma AVP after water depriva- mal range (Fig. 1-26; Robertson, 1988). When plasma AVP and
tion was identied in a cat with CDI (plasma AVP, 1.3 pg/mL urine osmolality are evaluated concurrently after dehydration, val-
versus a mean of 84.6 pg/mL in eight healthy cats) (Brown etal, ues from humans with severe or partial CDI almost always fall
1993). Plasma AVP concentrations remained within or below the within or above the normal range, whereas those from humans
reference range (i.e., less than 7 pg/mL) during water deprivation with NDI fall uniformly below normal (Fig. 1-27). In most cases,
in four dogs with suspected primary polydipsia that were subse- the values from humans with primary polydipsia are normal, but
quently identied with a disturbance in the regulation of AVP a few may be subnormal, presumably as a consequence of renal
secretion (van Vonderen etal, 1999). medullary solute washout. The AVP response to IV infusion of
When measurement of plasma AVP is incorporated into the 20% saline was evaluated in conjunction with plasma and urine
modied water deprivation test, plasma for AVP determina- osmolality and results did not consistently distinguish between
tion should be obtained after 3% loss of body weight is caused CDI, NDI, and primary polydipsia in 18 young dogs with poly-
by water deprivation but before exogenous AVP is administered uria and polydipsia suspected to have one of the these three dis-
(i.e., at the end of phase I). Plasma for AVP determination can orders (van Vonderen etal, 2004). The authors speculated that
also be obtained prior to water deprivation, although this may the results of the study raise doubt about the generally accepted
not be necessary. Commercially available canine and feline plasma notion that AVP measurements during hypertonic saline infu-
AVP assays are not widely available in the United States, but this sion are the gold standard for the diagnostic interpretation of
may change in the near future. Recently a commercially available polyuria in dogs.
human enzyme immunoassay kit for measurement of plasma AVP Until more extensive studies have been completed, we inter-
concentration was validated for use in dogs and the plasma con- pret plasma AVP concentrations after dehydration as follows:
centration of AVP was significantly higher in dogs with congestive patients with severe or partial CDI should have AVP deciencies,
heart failure, compared with healthy dogs; results that suggest the and those with primary NDI or primary/psychogenic polydipsia
assay may be diagnostically useful in dogs with suspected diabetes should have normal or excessive concentrations of AVP in the face
insipidus (Scollan etal, 2013). of dehydration and subnormal urine osmolality (Table 1-5).
TABLE 1-5 R
ESULTS OF DIAGNOSTIC STUDIES IN DOGS WITH CENTRAL DIABETES INSIPIDUS, NEPHROGENIC
DIABETES INSIPIDUS, AND PSYCHOGENIC POLYDIPSIA
TEST CENTRAL DIABETES INSIPIDUS NEPHROGENIC DIABETES INSIPIDUS PSYCHOGENIC POLYDIPSIA

Random plasma osmolality Normal or Normal or Normal or
Random urine osmolality
Urine osmolality after water deprivation No change No change
( 3% loss of body weight)
Urine osmolality during hypertonic saline No change No change
infusion
Urine osmolality after vasopressin administration No change No change or mild
Plasma vasopressin after water deprivation Low Normal or high Normal or high
( 3% loss of body weight)
350 excessively because they drink excessively. In these dogs, uncon-

trollable fluid intake raises blood volume and decreases plasma
340 osmolality, which in turn causes decreased secretion of AVP and
a decreased renal medullary concentration gradient, resulting in
large urine volumes. Dogs with psychogenic polydipsia, in theory,
330
Plasma osmolality (mOsm/kg)
should have plasma osmolalities on the low end of or below the

reference interval.
320 It should be pointed out that the above discussion applies to
the classic situation. Unfortunately, nature rarely provides us
310 with classic patients. This is illustrated in a study of polyuric
humans, in whom the serum osmolality varied from 281 to 298
sOsm in CDI, 285 to 292 in NDI, and 275 to 291 in primary
300
polydipsia (Zerbe and Robertson, 1981). In our series of dogs, as
well as those reported in the literature, plasma osmolality varied
290 from 281 to 339 pOsm in CDI, 283 to 340 in NDI, and 274
to 304 in psychogenic polydipsia (see Fig. 1-28). Based on our
280 experiences, a random plasma osmolality of less than 280 pOsm
obtained while the dog or cat has free access to water suggests
primary or psychogenic polydipsia, whereas a plasma osmolality
270
Complete Partial Nephrogenic Psychogenic greater than 280 pOsm is consistent with CDI, NDI, or psycho-
central diabetes insipidus diabetes polydipsia genic polydipsia.
insipidus
FIGURE 1-28 Random plasma osmolality in 19 dogs with complete central dia-
ADDITIONAL DIAGNOSTIC TESTS: COMPUTED
betes insipidus (CDI), 12 dogs with partial CDI, 9 dogs with primary nephrogenic
TOMOGRAPHY AND MAGNETIC RESONANCE
diabetes insipidus (NDI), and 11 dogs with primary (psychogenic) polydipsia.
IMAGING
Note the overlap in values between groups of dogs.
Neoplasia in the region of the pituitary and hypothalamus should
be considered in the older dog or cat in which CDI develops. A
complete neurologic evaluation, including CT or MRI may be
warranted before idiopathic CDI is arbitrarily diagnosed, espe-
RANDOM PLASMA OSMOLALITY
cially if the client is willing to consider radiation therapy or che-
AS A DIAGNOSTIC TOOL
motherapy should a tumor be identified (see Fig. 1-9).
Measurement of random plasma osmolality may help identify pri- MRI has been used to identify the presence of vasopressin in
mary or psychogenic polydipsia and should be done while the dog the posterior pituitary in humans. On T1-weighted images, MRI
or cat has unrestricted access to water. Plasma osmolality in nor- produces a bright spot in the sella caused by stored hormone in
mal dogs and cats is approximately 280 to 300 pOsm. Dogs and the neurosecretory granules in the posterior pituitary (Moses
cats with CDI and NDI have a primary polyuric disorder with etal, 1992; Kurokawa etal, 1998). The bright spot is present in
secondary compensatory polydipsia; that is, they drink excessively approximately 80% of normal humans and is absent in patients
because they urinate excessively. The stimulation for water intake with CDI, although some studies have identified a bright spot
in CDI and NDI is loss of free water through the kidneys, result- in patients with clinical evidence of CDI (Maghnie et al., 1997;
ing in decreased blood volume and increased serum osmolality. Saeki et al., 2003). The bright spot decreases with a prolonged
Thus, patients with CDI and NDI should have high normal or stimulus for vasopressin secretion and has been variably reported
high plasma osmolalities (Fig. 1-28). In contrast, dogs with pri- in other polyuric disorders (Fujisawa etal, 2004). A bright spot in
mary or psychogenic polydipsia have a primary polydipsic disor- the region of the posterior pituitary has also been identified in dogs
der with secondary compensatory polyuria; that is, they urinate and presumably represents vasopressin stored in neurosecretory
|
BOX 1-5 T
herapies Available for Polydipsic/Polyuric Dogs
with Central Diabetes Insipidus, Nephrogenic
Diabetes Insipidus, or Primary (Psychogenic)
Polydipsia
A. CDI (severe)
1. DDAVP
a. Effective
b. Expensive
c. Oral tablets or drops of nasal solution in conjunctival sac
d. DDAVP injection SC once or twice a day
2. LVP (lypressin [Diapid])
a. Short duration of action; less potent than DDAVP
b. Expensive
c. Requires drops into nose or conjunctival sac
3. No treatmentprovide continuous source of water
B. CDI (partial)
1. DDAVP
2. LVP
3. Chlorpropamide
FIGURE 1-29 Magnetic resonance imaging (MRI) T1-weighted transverse image
a. 30% to 70% effective
of the pituitary gland in a healthy adult dog illustrating the hyperintense bright
b. Inexpensive
spot (arrow) in the sella. In humans, the bright spot is caused by stored argi-
c. Pill form
nine vasopressin (AVP) in the neurosecretory granules in the posterior pituitary.
d. Takes 1 to 2 weeks to obtain effect of drug
Presumably the same is true in dogs.
e. May cause hypoglycemia
4. Thiazide diuretics
a. Mildly effective
granules (Fig. 1-29). Studies evaluating changes in the presence b. Inexpensive
and intensity of the bright spot in dogs with polyuric disorders c. Pill form
have not yet been reported. d. Should be used with low-sodium diet
5. Low-sodium diet
TREATMENT C. NDI
Therapeutic options for dogs and cats with diabetes insipidus are 1. Thiazide diureticsas described earlier
listed in Box 1-5. 2. Low sodium diet
D. Primary (psychogenic) polydipsia
Vasopressin Analogues (Used in Central Diabetes 1. Water restriction at times
Insipidus and Partial Central Diabetes Insipidus) 2. Water limitation
The synthetic analogue of vasopressin, DDAVP (see Fig. 1-1), is the 3. Behavior modification
standard therapy for CDI. DDAVP has almost three times the a. Change environment
antidiuretic action of AVP with minimal-to-no vasopressor or b. Change in daily routine
oxytocic activity (Robinson, 1976). Several extrarenal actions of c. Increase daily exercise
DDAVP have also been described: release of two coagulation fac- d. Increase contact with humans or dogs
tors (Factor VIIIc and von Willebrand factor (Richardson and CDI, Central diabetes insipidus; DDAVP, desmopressin acetate; LVP, lysine vaso-
Robinson, 1985); a decrease in blood pressure and peripheral pressin; NDI, nephrogenic diabetes insipidus; SC, subcutaneous.
resistance; and an increase in plasma renin activity (Schwartz etal,
1985).
The metabolism of DDAVP in humans follows a bi-exponential transferred to a sterile eye dropper bottle and drops placed into
curve with rst and second half-lives of 7.8 and 75.5 minutes, the conjunctival sac of the dog or cat. Although the solution is
respectively. Similar ndings are noted in experiments with nor- acidic, ocular irritation rarely occurs. One drop of DDAVP nasal
mal dogs (Ferring, 1985) and in spontaneous canine cases of CDI. contains 1.5 to 4 g of DDAVP, and a dosage of one to two drops
Additionally, blood chemistry studies and necropsies on treated administered once or twice daily controls signs of CDI in most
dogs (Ferring, 1985) and clinical experience in dogs and cats with dogs and cats.
CDI (Kraus, 1987; Harb etal, 1996; Oliveira etal, 2013) indicate Because of the expense of DDAVP nasal and loss of DDAVP
that the drug is safe for use in dogs and cats. drops from the conjunctival sac with head shaking, blinking, and
The intranasal DDAVP preparation (DDAVP nasal, 2.5- and inadvertent application of excessive amounts, our preference is to
5.0-mL bottles containing 100 g DDAVP/mL) is used most initially use DDAVP tablets (0.1 and 0.2 mg) when using response
commonly for treating CDI in humans and is effective for the to DDAVP to establish the diagnosis of CDI and for long-term
treatment of CDI in dogs and cats (Harb et al, 1996). Admin- treatment of CDI. Clinical response in humans is variable, in part,
istration of DDAVP nasal to dogs and cats via the intranasal because the bioavailability of DDAVP tablets is approximately 5%
route is possible but not recommended. DDAVP nasal should be to 15% of the intranasal dose in humans. Similar information is
not available for dogs and cats. Our initial dose for DDAVP tablets is associated with a proportional rise in urine osmolality, correction
is 0.05 mg for dogs weighing less than 5 kg and for cats, 0.1 mg of dehydration, and a reduction in fluid consumption similar to
for dogs weighing 5 to 20 kg, and 0.2 mg for dogs weighing more that observed with small doses of vasopressin (Robertson, 1981).
than 20 kg given every 12 hours. The frequency of administration The exact mechanism of the potentiating effect of chlorprop-
is increased to every 8 hours if unacceptable polyuria and polydip- amide on the action of AVP in the kidney is not known. Chlor-
sia persist 1 week after therapy is initiated. Treatment should be propamide may enhance AVP stimulation of renal medullary
switched to DDAVP nasal if there is minimal to no response to oral cAMP by augmenting adenylate cyclase sensitivity to AVP or by
DDAVP administered three times a day. Decreasing the frequency inhibiting phosphodiesterase (Reeves et al, 1998). Inhibition of
of administration of the tablets, decreasing the dose of DDAVP, or prostaglandin E2 (PGE2) synthesis, thereby removing an antago-
both can be tried once clinical response has been documented. To nist of AVP, has also been proposed as a mechanism for chlor-
date, most dogs and cats have required 0.1 to 0.2 mg and 0.025 to propamide potentiation. Finally, chlorpropamide treatment may
0.05 mg, respectively, of oral DDAVP two to three times a day to augment AVP dependent NaCl absorption by the medullary thick
control polyuria and polydipsia (Aroch etal, 2005). ascending loop of Henle, thereby increasing the driving force
DDAVP parenteral (2 mL vials containing 4 g/mL) can be for water absorption in collecting ducts (Kusano et al, 1983).
used in lieu of the nasal formulation or oral tablets. In humans, Like DDAVP, chlorpropamide is ineffective in treating patients
parenteral administration of DDAVP is 5 to 20 times as potent with NDI. Other drugs of the sulfonylurea class do not have a
as DDAVP nasal (Richardson and Robinson, 1985). The initial signicant antidiuretic effect in CDI and, in some humans, may
parenteral dosage of DDAVP is 0.5 to 1.0 g administered SC actually be mildly diuretic.
once a day. Subsequent adjustments in the dose and frequency of The effectiveness of chlorpropamide in the treatment of canine
administration are based on improvement in polyuria and poly- CDI is a matter unresolved in the literature. As in humans, use of
dipsia, duration of clinical response, and changes in serum sodium the drug in dogs requires the presence of some endogenous AVP.
concentration. Hyponatremia is more apt to develop with paren- Some veterinarians have had little or no success using chlorprop-
teral DDAVP than with tablets or nasal spray and can mimic the amide, citing a reduction in urine volume of only 18% during
syndrome of inappropriate vasopressin secretion. 7 days of therapy (Schwartz Porsche, 1980). Other veterinarians
In humans with CDI, a decrease in urine volume usually occurs have claimed a 50% reduction in urine volume after 5 days of
within 2 hours after administration of DDAVP, regardless of the therapy. The drug has also had mixed results when used in cats
route of administration, and the total duration of action varies with CDI (Kraus, 1987).
from 6 to 18 hours (Lam etal, 1996). Larger doses of DDAVP An effective dosage of chlorpropamide for the treatment of par-
appear both to increase its antidiuretic effects and to prolong its tial CDI has not been determined in the dog or cat, although
duration of action; however, expense becomes a limiting factor. 10 to 40 mg/kg/day has been suggested (Hardy, 1982). The dose
The medication may be administered exclusively in the evening as of chlorpropamide used in the unsuccessful study in dogs was
insurance against nocturia. 250 mg twice daily (Schwartz Porsche, 1980) and was approxi-
We have had excellent results in dogs and cats receiving daily mately 30 mg/kg/day in one cat that failed to respond (Kraus,
medication for longer than 5 years. Owners of dogs and cats with 1987). The dosage was not mentioned in the dog study and was
CDI have reported that their pets become accustomed to receiv- approximately 10 mg/kg/day in one cat in which chlorpropamide
ing eye drops, mentioning eye or conjunctival irritation as an improved polyuria and polydipsia.
infrequent complication. If polyuria and polydipsia recur despite The primary adverse effect of chlorpropamide is hypoglycemia
DDAVP therapy, several possibilities should be considered, caused by chlorpropamide-induced insulin secretion. Regular
including problems with owner compliance or administration feeding schedules should be adhered to if hypoglycemic prob-
technique, inadequate dose, outdated or inactivated DDAVP, or lems are to be avoided. We have had little experience with chlor-
development of a concurrent disorder causing polyuria and poly- propamide simply because our success with DDAVP has been
dipsia. Hyperadrenocorticism is the primary differential diagnosis excellent, and our owners have accepted the cost and difculties
when polyuria and polydipsia recur despite DDAVP treatment in encountered in treating their pets with this drug. If successful in
a dog with CDI. a trial administration period, chlorpropamide may prove to be a
DDAVP was effective in Husky puppies with familial NDI valid alternative in treating partial CDI.
caused by a defect in V2 receptor binding afnity for AVP (Luz-
ius et al, 1992). However, extremely high dosages (0.33 U/kg Thiazide Diuretics
body weight intramuscularly three times a day) of DDAVP were The thiazide diuretics may reduce the polyuria in animals with
required to obtain improvement in polyuria and polydipsia, dos- diabetes insipidus (Breitschwerdt etal, 1981). This seemingly par-
ages that most owners would consider cost-prohibitive. For prac- adoxic effect is seen in NDI, as well as in CDI, suggesting that this
tical purposes, DDAVP is considered ineffective in the treatment therapeutic agent has a mode of action distinct from that of chlor-
of NDI. propamide. By inhibiting sodium reabsorption in the ascending
limb of the loop of Henle, the thiazides reduce total body sodium
concentrations, thus contracting the ECF volume and increasing
Oral Agents (Used in Central Diabetes Insipidus,
salt and water resorption in the proximal renal tubule. This results
Partial Central Diabetes Insipidus, Nephrogenic
in lower sodium concentrations in the distal renal tubule and less
Diabetes Insipidus, and Primary Polydipsia)
osmotic effect to maintain tubular volume, resulting in a reduc-
Chlorpropamide tion in urine volume. The net effect in diabetes insipidus is to
Chlorpropamide (Diabinese) is an oral sulfonylurea drug used for cause a slight rise in urine osmolality and a proportionate reduc-
the treatment of hyperglycemia in humans. Largely by chance, tion in urine volume. Depending on sodium intake, polyuria can
chlorpropamide has also been found to be efcacious in treating be reduced 30% to 50% in humans with NDI or CDI. Apart
humans with CDI and has been found to reduce urine output from occasional hypokalemia, signicant side effects are uncom-
30% to 70% in humans afflicted with partial CDI. This reduction mon. The thiazides reduce the ability to excrete a water load and,
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if given to a patient with primary polydipsia, may precipitate

PROGNOSIS
water intoxication (Robertson, 1981).
Chlorothiazides are recommended at a dose of 20 to 40 mg/ Dogs and cats with idiopathic or congenital CDI usually become
kg twice daily, in concert with low-sodium diets. Periodic serum asymptomatic with appropriate therapy, and with proper care
electrolyte determinations (every 2 to 3 months) should aid in these animals have an excellent life expectancy. Unfortunately,
avoiding iatrogenic problems. many owners discontinue DDAVP therapy or elect euthanasia of
their pet after a few months because of the expense of DDAVP.
Sodium Chloride (Salt) Restriction Without therapy, these animals often lead acceptable lives as long
Restricting salt intake, as the sole therapy in diabetes insipidus, as water is constantly provided and they are housed in an environ-
reduces urine output by increasing the volume of ltrate absorbed ment that cannot be damaged by severe polyuria. However, the
isosmotically in the proximal nephron. This simple therapy may untreated animal is always at risk for developing life-threatening
be helpful in the treatment of both CDI and NDI. Salt content dehydration if water is withdrawn for longer than a few hours.
of commercial dog and cat foods is quite variable, ranging from Additionally, even mild illness that causes vomiting or reduces
0.14 to 3.27 g Na/Mcal for dog foods and 0.3 to 4.0 g Na/Mcal water intake can develop into one associated with severe dehydra-
for cat foods. In general, diets considered lower in sodium content tion. Thus, untreated dogs and cats carry a guarded prognosis.
contain less than 1.0 g Na/Mcal. In one study, long-term follow-up of 19 dogs with CDI found
7 of 19 dogs still alive a mean of 29 months (median, 30 months)
No Treatment from the time of diagnosis of CDI (Harb etal, 1996). Six of these
seven dogs were 3 years of age or younger at the time CDI was
Therapy for diabetes insipidus (CDI and NDI) and primary diagnosed. Of the original 19 dogs, 12 had died within an average
polydipsia is not mandatory as long as the dog or cat has unlim- of 6 months (median, 2 months) after diagnosis of CDI. Three
ited access to water and is maintained in an environment where dogs died from unrelated or unknown causes, two dogs were
polyuria does not create problems. In most instances, untreated euthanized shortly after the diagnosis of CDI was established,
pets are outdoor animals. Some of our owners have elected not and seven dogs died or were euthanized because of development
to treat their pets after the diagnosis is established. More com- of neurologic disease. In these later seven dogs, neurologic signs
monly, owners have discontinued DDAVP treatment after 1 or 2 developed 2 months (median, 1 month; range, 0.5 to 5 months)
months of therapy, primarily because of the expense. Still others and the dogs were dead 3.3 months (median, 1.5 months; range,
treat their pet with DDAVP periodically, when it is undesirable 1 to 7 months) after CDI was diagnosed (Harb etal, 1996). A
for the dog or cat to be exhibiting severe polyuria and polydipsia mass in the region of the pituitary gland was identied by CT scan
(e.g., relatives staying at the house). If an owner elects not to treat or at necropsy in six of the dogs in which these procedures were
his or her pet, it is imperative that the dog or cat have access to performed. The seven dogs that developed neurologic signs were
a constant water supply because relatively short periods of water older than 6 years of age.
restriction can have catastrophic results, such as the development Obviously, dogs with aggressive hypothalamic or pituitary
of hypernatremic, hypertonic dehydration, and neurologic signs; problems, such as a growing tumor, have a grave prognosis. Treat-
a complication that would occur with CDI and primary NDI but ment of tumors in the region of the hypothalamus and pituitary,
not psychogenic polydipsia. using either irradiation (see Chapter 10) or chemotherapy (e.g.,
bis-chloroethylnitrosourea [BCNU]), can be tried; however,
Behavior Modication (Used in Psychogenic Polydipsia) results are unpredictable. Polyuria and polydipsia typically persists
despite radiation therapy, in part, because clinical signs of CDI do
Water Restriction not develop until 90% of the magnocellular neurons are destroyed
Gradually limiting water intake to amounts in the high normal (Robinson and Verbalis, 2011). Based on experience with pitu-
range (60 to 80 mL/kg/24 h) improves and may resolve polyuria itary macrotumors, successful response to radiation therapy is
and polydipsia in dogs with psychogenic polydipsia. In some dogs, more likely when the tumor is small and before neurologic clinical
rapid water restriction results in bizarre behavior, excessive bark- signs develop. CT or MRI scan is warranted at the time of diagno-
ing, urine consumption, and dehydration. Therefore, we prefer to sis of CDI, especially when CDI is acquired in an older dog or cat.
have the owner rst calculate the dogs approximate water intake The prognosis for dogs and cats with primary NDI is guarded
per 24 hours while free-choice water is allowed. This volume of to poor because of limited therapeutic options, the generally poor
water is then reduced by 10% per week until water volumes of 60 response to therapy, and the risk for developing severe dehydration
to 80 mL/kg/24 h are reached. The total 24-hour volume of water and hypernatremia. The prognosis with acquired NDI depends on
should be divided into several aliquots, with the last aliquot given the prognosis of the primary problem.
at bedtime. Oral salt (1 g/30 kg twice a day) and/or oral sodium The prognosis in psychogenic polydipsia is usually excellent.
bicarbonate (0.6 g/30 kg twice a day) may also be administered for Water restriction and some form of behavior modication help
3 to 5 days, to reestablish the medullary concentration gradient. most of these animals to become asymptomatic, although relapses
We have had excellent success with gradual water restriction and do occur.
do not routinely use oral salt or sodium bicarbonate.
Change in Environment SYNDROME OF INAPPROPRIATE VASOPRESSIN

SECRETION: EXCESS VASOPRESSIN
Changes in the dogs environment or daily routine should also be
considered for dogs with psychogenic polydipsia, such as initiat- A primary excess of AVP occurs in two clinical settingsin the
ing a daily exercise routine, bringing a second pet into the home, syndrome of inappropriate antidiuretic hormone (SIADH) and
providing some distraction (e.g., a radio playing when the clients as a consequence of drugs that stimulate AVP secretion, acti-
are not home), or moving the dog to an area with an increased vate renal V2 receptors, or potentiate the antidiuretic effect of
amount of contact with humans. AVP (Box 1-6). In SIADH, sustained release of AVP occurs in
BOX 1-6 D
rugs and Hormones Reported to Affect BOX 1-7 C
onditions Associated with Syndrome of
Vasopressin Secretion or Action Inappropriate Antidiuretic Hormone in Humans
Secretion Malignant Neoplasia

Stimulate AVP release Inhibit AVP release Carcinoma; bronchogenic, pancreatic, prostatic, bladder
Acetylcholine -Adrenergic drugs Lymphoma and leukemia
Anesthetic agents ANP Thymoma and mesothelioma
Angiotensin II Glucocorticoids
Drug-Induced
Apomorphine Haloperidol
ACE inhibitors
-Adrenergic drugs Oxilorphan
Chlorpropamide
Barbiturates Phenytoin
Clofibrate
Carbamazepine Promethazine
Clozapine
Clofibrate
Cyclophosphamide
Cyclophosphamide
Omeprazole
Histamine
Serotonin reuptake inhibitors
Insulin
Thiazides
Metoclopramide
Vincristine
Morphine and narcotic analogues
Others
PGE2
Vincristine Central Nervous System Disorders
Degenerative/demyelinating diseases
Renal Head trauma
Potentiate AVP action Inhibit AVP action Infection
Aspirin -Adrenergic drugs Inflammatory diseases
Carbamazepine ANP Porphyria
Chlorpropamide Barbiturates Tumors
Nonsteroidal anti-inflammatory agents Demeclocycline
Endocrine Diseases
Thiazides Glucocorticoids
Adrenal insufficiency
Hypercalcemia
Pituitary insufficiency
Hypokalemia
Hypothyroidism
Methoxyflurane
PGE2 Pulmonary Disorders
Protein kinase C Acute respiratory failure
Tetracyclines Aspergillosis
Vinca alkaloids Bacterial and viral pneumonia
Tuberculosis
ANP, Atrial natriuretic peptide; AVP, arginine vasopressin; PGE2, prostaglandin E2.
Adapted from Ramsay DJ: Posterior pituitary gland. In Greenspan FS, Fosham
PH, editors: Basic and clinical endocrinology, Los Altos, CA, 1983, Lange Medical
Publications, p. 120.
the absence of either osmotic or nonosmotic stimuli. In humans, ACE, Angiotensin converting enzyme.
SIADH has been observed in a variety of disorders, particularly
pulmonary, CNS, and neoplastic disorders (Box 1-7) (Robinson
and Verbalis, 2011). The most common association of SIADH is ascites), plasma hyposmolality (< 275 pOsm), urine osmolality
with tumors, most notably bronchogenic carcinomas. Vasopressin greater than that appropriate for the concomitant osmolality of
or a peptide having comparable biologic activity is produced by plasma, and increased renal sodium excretion despite hyponatre-
tumors. SIADH is rare in the dog and cat and has been reported mia. A similar clinical picture can be produced experimentally by
in one dog with heartworm disease, one dog with liver disease, one giving high doses of AVP to a normal subject who receives a nor-
dog with an undifferentiated carcinoma, one dog with a tumor mal to increased fluid intake, with subcutaneous administration
in the region of the hypothalamus, one cat following anesthesia, of high doses of parenteral DDAVP to dogs with CDI, and theo-
laparoscopy and metoclopramide treatment, and was considered retically with administration of DDAVP to dogs with psychogenic
idiopathic in two dogs (Rijnberk etal, 1988; Houston etal, 1989; polydipsia. Water restriction results in the plasma osmolality and
Cameron and Gallagher, 2010; Kang and Park, 2012). serum sodium concentrations returning to normal (Aron et al,
As a result of sustained release of AVP or AVP-like peptides, 2001; Cameron and Gallagher, 2010).
patients retain ingested water and become hyponatremic and Four patterns of plasma AVP secretion have been described in
modestly volume-expanded and generally gain body weight humans with SIADH, suggesting four patterns of osmoregula-
(Robinson and Verbalis, 2011). This volume expansion results in tory defects in this syndrome. The most common derangement
reduced rates of proximal tubular sodium absorption and, con- is random hypersecretion of AVP independent of osmotic and
sequently, natriuresis. Increased levels of ANP also contribute nonosmotic control (Robinson and Verbalis, 2011). This erratic
to the natriuresis. The diagnostic features that characterize this and irregular secretion of AVP can be associated with both malig-
syndrome include hyponatremia, clinical euvolemia as defined nant and nonmalignant disease. Others include a reset osmostat
by the absence of signs of hypovolemia (e.g., decreased skin tur- system in which the threshold for AVP secretion is abnormally
gor, tachycardia) and hypervolemia (e.g., subcutaneous edema, low but there is an appropriate response to changes in osmolality,
|
an AVP leak pattern characterized by inappropriate nonsup-

pressible basal AVP secretion but normal secretion in response to
osmolar changes above plasma osmolality, and low to undetect- 11
able AVP concentrations despite classic clinical characteristics of 10
Plasma vasopressin pg/mL

SIADH. The pattern of SIADH that occurs without measureable 9
AVP secretion may represent increased renal sensitivity to low 8
circulating AVP concentrations, which is possibly a result of an 7 Normal
activating mutation of the V2 receptor (Kamoi, 1997; Feldman 6 range
etal, 2005). Thus far, it has not been possible to correlate the pat- 5
tern of AVP abnormality with the pathology of the syndrome. The 4
threshold and sensitivity of vasopressin secretion were studied by 3
infusion of hypertonic saline in two dogs with idiopathic SIADH 2
(Rijnberk etal, 1988). One dog demonstrated a pattern of reset
1
osmostat and the other, a pattern consistent with vasopressin leak.
0
Clinical signs of hyponatremia include lethargy, anorexia, vom-
iting, weakness, muscle fasciculations, obtundation, disorien- 230 240 250 260 270 280 290 300 310
tation, seizures, and coma. CNS signs are the most worrisome,
Plasma osmolality mOsm/kg
occur when hyponatremia is severe (< 120 mEq/L), and develop
as changes in plasma osmolality cause fluid to shift from the extra- FIGURE 1-30 Plasma arginine vasopressin (AVP) levels in patients with the syn-
cellular to the intracellular space, resulting in neuronal swelling drome of inappropriate antidiuretic hormone (SIADH) secretion as a function of
and lysis. The onset and severity of clinical signs depend on the plasma osmolality. Each point depicts one patient at a single point in time. The
rapidity with which the hyponatremia develops as well as on the shaded area represents AVP levels in normal subjects over physiologic ranges
degree of hyponatremia. The more chronic the hyponatremia and of plasma osmolality. (Modified from Zerbe RL, Stropes L, Robertson GL: Vaso-
the more slowly it develops, the more capable the brain is of com- pressin function in the syndrome of inappropriate antidiuresis, Annu Rev Med
pensating for changes in osmolality through the loss of potassium 31:315-327, 1980. In Robertson GL, et al: Neurogenic disorders of osmoregula-
and organic osmolytes from cells. Clinical signs develop when the tion, Am J Med 72: 339, 1982.)
decrease in plasma osmolality occurs faster than the brains defense
mechanisms can counter the influx of water into neurons.
The diagnosis of SIADH is made by excluding other causes of sodium concentration rapidly to greater than 125 mEq/L can cause
hyponatremia (see Chapter 12) and meeting the following criteria: demyelination in the CNS (Ayus etal, 1987; Sterns etal, 1994).
hyponatremia with plasma hyposmolality; inappropriately high Humans and presumably dogs and cats with SIADH are assumed
urine osmolality in the presence of plasma hyposmolality; normal to have chronic hyponatremia, arbitrarily defined as the presence
renal and adrenal function; presence of natriuresis despite hypo- of hyponatremia of less than 130 mEq/L for 48 hours or longer.
natremia; no evidence of hypovolemia (e.g., decreased skin turgor, The current recommendation for correcting severe chronic hypo-
tachycardia), ascites or edema; and correction of hyponatremia natremia is to increase the serum sodium concentration slowly at
with fluid restriction (Reeves etal, 1998). Another supportive cri- a rate of approximately 0.5 to 1.0 mEq/L per hour using intrave-
terion is an inappropriately increased plasma AVP concentration nously administered normal (0.9%) or hypertonic (3% to 5%)
in relation to plasma osmolality. However, plasma AVP concentra- saline. Adjustments in the rate of fluid administration or composi-
tions are often in the reference range in humans with SIADH and tion of the fluid should be based on results of frequent assessment
are abnormal only in relation to plasma osmolality (Fig. 1-30), of serum electrolyte concentrations and the patients CNS status.
some patients do not have measurably increased plasma AVP Once the serum sodium concentration is greater than 125 mEq/L,
concentrations, and most disorders causing solute and volume further correction of hyponatremia is accomplished by restricting
depletion are associated with appropriately increased plasma AVP water intake. Reduction of fluid intake to the point at which uri-
concentrations (Robinson and Verbalis, 2011). nary and insensible losses induce a negative water balance leads
Treatment is directed toward alleviation of hyponatremia and to restoration of normal body fluid volume, reduction in urinary
elimination of the underlying disease causing SIADH. The goal sodium excretion, and increased serum sodium concentration.
of treatment directed at the hyponatremia is to correct body water Long term treatment of SIADH includes discontinuation of
osmolality and restore cell volume to normal by raising the ratio any drugs known to be associated with SIADH and daily restric-
of sodium to water in ECF using IV fluid therapy, water restriction of water intake. The approach to water restriction is simi-
tion, or both. The increase in ECF osmolality draws water from lar to that used to treat dogs with psychogenic polydipsia (see
cells and therefore reduces their volume. Rapid correction of severe Psychogenic Polydipsia under Responses to the Modied Water
hyponatremia can result in demyelination in white matter areas of Deprivation Test earlier in this chapter). However, the goal of
the brain, a syndrome referred to as osmotic demyelination syn- water restriction for SIADH is to identify a daily water intake that
drome, and must be avoided (Verbalis and Martinez, 1991). This maintains the serum sodium concentration near the lower end of
pathologic disorder is believed to be precipitated by brain dehydra- the reference range. Additional treatments for SIADH in humans
tion that occurs after correction of serum sodium concentration include agents that interfere with AVP signaling (e.g., demeclocy-
towards normal (Sterns et al, 1989). Because loss of brain idio- cline) and AVP receptor antagonists (e.g., tolvaptan). There are no
genic osmoles represents one of the compensatory mechanisms for reports on the use of demeclocycline for SIADH in dogs or cats.
preserving brain cell volume during dilutional states, an increase Treatment of a dog with SIADH with tolvaptan (Otsuka Pharma-
in serum sodium concentration toward normal (greater than 140 ceuticals) at a dose of 3 mg/kg orally every 12 hours resulted in a
mEq/L) is relatively hypertonic to brain cells that are partially marked increase in free-water excretion and signicant palliation
depleted of idiogenic osmoles as a result of hyponatremia (Sterns of clinical signs with no discernible side effects detected over a
etal, 1989; Sterns etal, 1993). Consequently, raising the serum 3-year treatment period (Fleeman etal, 2000).
HYPODIPSIC HYPERNATREMIA Interestingly, congenital hypodipsic hypernatremia has been iden-

tified most commonly in Miniature Schnauzers.
Hypodipsic hypernatremia is a neurologic disorder causing Dogs and cats typically present to the veterinarian with signs
diminished sensation of thirst and diminished release of AVP in related to hypernatremia (i.e., lethargy, inappetence, weakness,
response to osmotic stimulation. Hypodipsic hypernatremia is neurologic signs). Consistent ndings on physical examination
characterized by chronic hypernatremia in a setting of euvolemia, and initial clinical pathology include dehydration, hypernatremia,
normal renal function, decreased thirst perception, and a normal hyperchloridemia, prerenal azotemia, and urine specic gravities
renal response to exogenous AVP (Reeves et al, 1998). Despite greater than 1.030. Serum sodium concentrations ranged from
elevations of serum sodium concentration and ECF osmolalities, 168 to 215 mEq/L; consequently, serum osmolalities were mark-
affected patients exhibit hypodipsia and an inappropriately dilute edly increased. The dogs and cat were conscious and adipsic or
urine for the corresponding plasma osmolality. The primary defect hypodipsic despite severe hypernatremia and hyperosmolality,
in human patients with hypodipsic hypernatremia appears to be ndings that strongly support the diagnosis of hypodipsic hyper-
an insensitivity of thirst centers and osmoreceptors to osmotic natremia. The diagnosis was conrmed in one dog by documenting
stimuli. Affected patients have a normal response of AVP release, lack of endogenous AVP secretion with worsening hyperosmolal-
measured either as a rise in urine osmolality or as an increase in ity induced by hypertonic saline infusion and marked AVP secre-
plasma AVP levels, to baroreceptor stimulation following volume tion in response to conjunctival administration of apomorphine
contraction. (DiBartola etal, 1994).
Given the association of a diminished sensation of thirst and Treatment is directed toward alleviation of the hypernatremia
a diminished release of AVP in response to osmotic stimulation, and, if possible, elimination of the underlying disease. Rapid cor-
it is likely that hypodipsic hypernatremia represents a more or rection of hypernatremia by administration of hypotonic fluids
less specic ablation of hypothalamic osmoreceptor function. In intravenously is not recommended, because hypernatremia typi-
humans, hypodipsic hypernatremia has been reported in children cally has been developing for more than a week and intracellular
as a congenital disease and in adults in association with CNS his- idiogenic osmoles have been produced within neurons in response
tiocytosis, pineal tumors, surgery for craniopharyngioma, head to the increased osmolality of the ECF. Rapid reduction of plasma
trauma, and vascular disturbances (e.g., ischemia, hemorrhage). osmolality can result in an intracellular influx of water into neu-
Necropsy has been performed in six dogs with hypodipsic hyper- rons, thereby worsening neurologic signs (see Complications of
natremia and revealed hypothalamic dysplasia in a 4-month- the Modified Water Deprivation Test: Hypertonic Dehydration
old Dalmatian (Bagley et al, 1993); hydrocephalus in an adult and Hypernatremia). Forced oral hydration is recommended in
mixed-breed dog (DiBartola etal, 1994); astrogliosis and neuronal humans, but it does not consistently correct the hypernatremia.
degeneration in the region of the hypothalamus and thalamus in a Addition of water to the food in excess of maintenance require-
7-month-old Miniature Schnauzer (Crawford etal, 1984); focal, ments and/or forced oral administration of water was benecial in
severe meningoencephalitis in the hypothalamus in a 7-year-old most, but not all, dogs and the cat with hypodipsic hypernatremia.
Doberman Pinscher (Mackay and Curtis, 1999); lobar holopros- One dog was clinically healthy 3 years after establishing the diag-
encephaly in a 9-month-old Miniature Schnauzer (Sullivan etal, nosis and initiating water supplementation with food (Miyama
2003); and no identiable lesions in the anterior, third cerebral etal, 2009). Chlorpropamide, a sulfonylurea drug that augments
ventricular area, hypothalamus or pituitary gland in a 5-month- the antidiuretic effect of low levels of circulating AVP (see Chlor-
old Great Dane (Hawks etal, 1991). Results of an MRI of the CNS propamide under Oral Agents (Used in Central Diabetes Insipi-
in a 6-month-old Miniature Schnauzer with hypodipsic hyper- dus, Partial Central Diabetes Insipidus, Nephrogenic Diabetes
natremia revealed dysgenesis of the corpus callosum and other Insipidus, and Primary Polydipsia earlier in this chapter), has been
forebrain structures (Miyama et al, 2009). Hypodipsic hyper- useful in restoring osmotic homeostasis in humans with hypodip-
natremia has also been described in a 14-month-old Miniature sic hypernatremia (Reeves etal, 1998). Chlorpropamide (33 mg/
Schnauzer (Hoskins and Rothschmitt, 1984), but the dog was still kg/day for 2 weeks) was ineffective in stimulating thirst or correct-
alive at the time of the report. Hypodipsic h
ypernatremia was also ing hypernatremia in one dog (Crawford etal, 1984). Patients with
reported in a 7-month-old Domestic Short-Haired cat in which neurologic signs induced by severe hypernatremia may require
hydrocephalus was identied with CT imaging (Dow etal, 1987). intensive fluid therapy to initially control the hypernatremia.
REFERENCES
Abe T: Lymphocytic infundibulo-neurohypoph- Ayus JC, etal.: Treatment of symptomatic Baylis PH, Thompson CJ: Osmoregulation of
ysitis infundibulopanhypophysitis regarded hyponatremia and its relation to brain vasopressin secretion and thirst in health
as lymphocytic hypophysitis variant, Brain damage: a prospective study, N Engl J Med and disease, Clin Endocrinol 29(5):549,
Tumour Pathol 25(2):59, 2008. 317:1190, 1987. 1988.
Aroch I, etal.: Central diabetes insipidus in Bagley RS, etal.: Hypernatremia, adipsia, and Bhan GL, OBrien TD: Autoimmune endocri-
five cats: clinical presentation, diagnosis diabetes insipidus in a dog with hypotha- nopathy associated with diabetes
and oral desmopressin therapy, J Fel Med lamic dysplasia, JAAHA 29:267, 1993. insipidus, Postgrad Med J 58:165,
Surg 7:333, 2005. Barsanti JA, etal.: Diagnostic approach to 1982.
Aron DC, etal.: Hypothalamus and pituitary. In polyuria and polydipsia. In Bonagura JD, Bichet DG: Nephrogenic diabetes insipidus,
Greenspan FS, Gardner DG, editors: Basic editor: Current veterinary therapy XIII, Semin Nephrol 26:224, 2006.
and clinical endocrinology, New York, Philadelphia, 2000, WB Saunders, Biewenga WJ, etal.: Osmoregulation of sys-
2001, McGraw Hill, p 100. p 831. temic vasopressin release during long-term
Authement JM, etal.: Transient, traumatically Baylis PH, Robertson GL: Vasopressin function glucocorticoid excess: a study in dogs with
induced, central diabetes insipidus in a in familial cranial diabetes insipidus, hyperadrenocorticism, Acta Endocrinol
dog, J Am Vet Med Assoc 194:683, 1989. Postgrad Med J 57:36, 1981. 124:583, 1991.
|
Block LH, etal.: Changes in tissue sensitiv- Goossens MMC, etal.: Central diabetes insipi- Lam KS, etal.: Pharmacokinetics, pharmaco-
ity to vasopressin in hereditary hypotha- dus in a dog with a pro-opiomelanocortin- dynamics, long-term efficacy and safety of
lamic diabetes insipidus, Klin Wochenschr producing pituitary tumor not causing oral 1-deamino-8-D-arginine vasopressin in
59:831, 1981. hyperadrenocorticism, J Vet Int Med adult patients with central diabetes insipi-
Breitschwerdt EB, etal.: Nephrogenic diabetes 9:361, 1995. dus, Br J Clin Pharmacol 42(3):379, 1996.
insipidus in three dogs, J Am Vet Med As- Grunbaum EG, Moritz A: Zur diagnostik des Lantz GC, etal.: Transsphenoidal hypophysec-
soc 179:235, 1981. diabetes insipidus renalis beim hund, tomy in the clinically normal dog, Am J Vet
Brown BA, etal.: Evaluation of the plasma vaso- Tierarztliche Praxis 19:539, 1991. Res 49:1134, 1988.
pressin, plasma sodium, and urine osmolal- Grunbaum EG, et al.: Genetisch bedingter Lee J, etal.: Atrial natriuretic factor inhibits
ity response to water restriction in normal diabetes insipidus renalis beim hund. 35th vasopressin secretion in conscious sheep,
cats and a cat with diabetes insipidus Annual Meeting, Deutsche Veterinarmed- Proc Soc Exp Biol Med 185:272, 1987.
[abstract], J Vet Intern Med 7:113, 1993. izinische Gesellschaft DVG, Fachgeruppe Luzius H, etal.: A low afnity vasopressin V2
Burnie AG, Dunn JK: A case of central diabetes Kleintierkrankheiten (ed. DVG), DVG, receptor in inherited nephrogenic diabetes
insipidus in the cat: diagnosis and treat- GieBen FRG, 1990, p. 126. insipidus, J Receptor Res 12:351, 1992.
ment, J Small Anim Pract 23:237, 1982. Hanson JM, etal.: Efficacy of transsphenoidal Mackay BM, Curtis N: Adipsia and hyperna-
Cameron K, Gallagher A: Syndrome of inappro- hypophysectomy in treatment of dogs with tremia in a dog with focal hypothalamic
priate antidiuretic hormone secretion in a pituitary-dependent hyperadrenocorticism, granulomatous meningoencephalitis, Aust
cat, J Am Anim Hosp Assoc 46:425, 2010. J Vet Intern Med 19: 687, 2005. Vet J 77:14, 1999.
Capen CC, Martin SL: Diseases of the pituitary Harb M, etal.: Central diabetes insipidus: 20 Maghnie M, etal.: Persistent high MR signal of
gland. In Ettinger SJ, editor: Textbook of dogs (1986-1995), J Am Vet Med Assoc the posterior pituitary gland in central dia-
veterinary internal medicine, ed 2, Phila- 209:1884, 1996. betes insipidus, J Neuroradiol 18:1749,
delphia, 1983, WB Saunders, p 1523. Hardy RM: Disorders of water metabolism, 1997.
Crawford MA, etal.: Hypernatremia and adipsia Vet Clin North Am Small Anim Pract Marver D: Evidence of corticosteroid ac-
in a dog, J Am Vet Med Assoc 184:818, 12(3):353, 1982. tion along the nephron, Am J Physiol
1984. Hardy RM, Osborne CA: Water deprivation test 246:F111, 1984.
Cronin RE: Psychogenic polydipsia with hy- in the dog: maximal normal values, J Am Meij BP, etal.: Lymphocytic hypophysitis in a
ponatremia: report of eleven cases, Am J Vet Med Assoc 174:479, 1979. dog with diabetes insipidus, J Comp Path
Kidney Dis 4:410, 1987. Hawks D, etal.: Essential hypernatremia in a 147:503, 2012.
Davenport DJ, etal.: Diabetes insipidus associ- young dog, J Small Anim Pract 32:420, Miyama TS, etal.: Magnetic resonance imag-
ated with metastatic pancreatic carcinoma 1991. ing and clinical findings in a Miniature
in a dog, J Am Vet Med Assoc 189:204, Heiene R, etal.: Vasopressin secretion in re- Schnauzer with hypodipsic hypernatremia,
1986. sponse to osmotic stimulation and effects J Vet Med Sci 71:1387, 2009.
Deppe TA, etal.: Glomerular ltration rate of desmopressin on urinary concentrating Moses AM, Clayton B: Impairment of osmoti-
and renal volume in dogs with congenital capacity in dogs with pyometra, Am J Vet cally stimulated AVP release in patients
portosystemic vascular anomalies before Res 65(4):404, 2004. with primary polydipsia, Am J Physiol
and after surgical ligation, J Vet Int Med Hoskins JD, Rothschmitt J: Hypernatremic 265:R1247, 1993.
13:465, 1999. thirst deciency in a dog, Vet Med 79:489, Moses AM, etal.: Use of T1-weighted MR
DiBartola SP, etal.: Hypodipsic hypernatremia 1984. imaging to differentiate between primary
in a dog with defective osmoregulation of Houston DM, etal.: Syndrome of inappropriate polydipsia and central diabetes insipidus,
antidiuretic hormone, J Am Vet Med Assoc antidiuretic hormone secretion in a dog, Am J Neuroradiol 13(5):1373, 1992.
204:922, 1994. Can Vet J 30:423, 1989. Neer TM, Reavis DU: Craniopharyngioma and
Dillingham MA, Anderson RJ: Inhibition of va- Kamoi K: Syndrome of inappropriate antidiure- associated central diabetes insipidus and
sopressin action by atrial natriuretic factor, sis without involving inappropriate secre- hypothyroidism in a dog, J Am Vet Med
Science 231:1572, 1986. tion of vasopressin in an elderly woman: Assoc 182:519, 1983.
Dow SW, etal.: Hypodipsic hypernatremia and effect of intravenous administration of Oliveira KM, etal.: Head trauma as a possible
associated myopathy in a hydrocephalic the nonpeptide vasopressin V2 receptor cause of central diabetes insipidus in a
cat with transient hypopituitarism, J Am antagonist OPC-31260, Nephron 76:111, cat, J Fel Med Surg 15:155, 2013.
Vet Med Assoc 191:217, 1987. 1997. Papanek PE, Raff H: Chronic physiological
Edwards DF, etal.: Hypernatremic, hypertonic Kang MH, Park HM: Syndrome of inappropriate increases in cortisol inhibit the vasopres-
dehydration in the dog with diabetes in- antidiuretic hormone secretion concurrent sin response to hypertonicity in conscious
sipidus and gastric dilatation volvulus, with liver disease in a dog, J Vet Med Sci dogs, Am J Physiol 267:R1342, 1994.
J Am Vet Med Assoc 182:973, 1983. 74:645, 2012. Papanek PE, etal.: Corticosterone inhibition
Feldman BJ, etal.: Nephrogenic syndrome of Kaplowitz PB, etal.: Radioimmunoassay of of osmotically stimulated vasopressin from
inappropriate antidiuresis, N Engl J Med vasopressin in familial central diabetes hypothalamic-neurohypophysial explants,
352:1884, 2005. insipidus, J Pediatr 100:76, 1982. Am J Physiol 272:R158, 1997.
Ferring AB: Product Information, DDAVP, Kraus KH: The use of desmopressin in diag- Peterson ME, etal.: Acromegaly in 14 cats,
Malmo, 1985, Sweden. nosis and treatment of diabetes insipidus J Vet Intern Med 4:192, 1990.
Fleeman LM, etal.: Effects of an oral vasopres- in cats, Compend Cont Educ Small Anim Pittari JM: Central diabetes insipidus in a cat,
sin receptor antagonist (OPC-31260) in Pract 9:752, 1987. Feline Pract 24:18, 1996.
a dog with syndrome of inappropriate Kurokawa H, etal.: Postserior lobe of the Pollock AS, Arieff AI: Abnormalities of cell
secretion of antidiuretic hormone, Aust Vet pituitary gland: correlation between signal volume and their functional consequence,
J 78:825, 2000. intensity on T1-weighted M images and Am J Physiol 239:F195, 1980.
Fujisawa I: Magnetic resonance imaging of the vasopressin concentration, Radiology Post K, etal.: Congenital central diabetes in-
hypothalamic-neurohypophyseal system, J 207:79, 1998. sipidus in two sibling Afghan Hound pups,
Neuroendocrinol 16:297, 2004. Kusano E, etal.: Chlorpropamide action on J Am Vet Med Assoc 194:1086, 1989.
Goldman MB, etal.: Mechanisms of altered renal concentrating mechanism in rats Quinkler M, Stewart PM: Hypertension and the
water metabolism in psychotic patients with hypothalamic diabetes insipidus, cortisol-cortisone shuttle, J Clin Endocrinol
with polydipsia and hyponatremia, N Engl J Clin Invest 72:1298, 1983. Metab 88:2384, 2003.
J Med 318:397, 1988.
Ramsay DJ: Posterior pituitary gland. In Salvi M, etal.: Role of autoantibodies in the Teshima T, etal.: Central diabetes insipidus
Greenspan FS, Forsham PH, editors: Basic pathogenesis and association of endocrine after transsphenoidal surgery in dogs with
and clinical endocrinology, Los Altos, CA, autoimmune disorders, Endocr Rev 9:450, Cushings disease, J Vet Med Sci 73:33,
1983, Lange Medical Publications, p 120. 1988. 2011.
Reeves WB, etal.: The posterior pituitary and Sands JM, Bichet DG: Neprogenic diabetes in- Thrasher TN: Baroreceptor regulation of vaso-
water metabolism. In Wilson JD, Foster sipidus, Ann Intern Med 144:186, 2006. pressin and renin secretion: low-pressure
DW, Kronenberg HM, Larsen PR, editors: Scherbaum WA: Role of autoimmunity in versus high-pressure receptors, Front
Williams textbook of endocrinology, ed 9, hypothalamic disorders, Baillieres Clin Neuroendocrinol 15(2):157, 1994.
Philadelphia, 1998, WB Saunders, p 341. Immunol 1:237, 1987. van Lieburg AF, etal.: Clinical presentation
Reidarson TH, etal.: Extreme hypernatremia Scherbaum WA, etal.: Autoimmune cranial and follow-up of 30 patients with congeni-
in a dog with central diabetes insipidus: a diabetes insipidus: its association with tal nephrogenic diabetes insipidus, J Am
case report, JAAHA 26:89, 1990. other endocrine diseases and with histiocy- Soc Nephrol 10:1958, 1999.
Richardson DW, Robinson AG: Desmopressin, tosis X, Clin Endocrinol 25:411, 1986. van Vonderen IK, etal.: Polyuria and polydipsia
Ann Intern Med 103:228, 1985. Schwartz J, etal.: Hemodynamic effects of and disturbed vasopressin release in two
Rijnberk A, etal.: Inappropriate vasopressin neurohypophyseal peptides with an- dogs with secondary polycythemia, J Vet
secretion in two dogs, Acta Endocrinol tidiuretic activity in dogs, Am J Physiol Int Med 11:300, 1997a.
117:59, 1988. 249:H1001, 1985. van Vonderen IK, etal.: Intra- and interindivid-
Rijnberk A, etal.: Aldosteronoma in a dog with Schwartz Porsche D: Diabetes insipidus. In Kirk ual variation in urine osmolality and urine
polyuria as the leading symptom, Domest RW, editor: Current veterinary therapy VII, specic gravity in healthy pet dogs of vari-
Anim Endocrinol 20:227, 2001. Philadelphia, 1980, WB Saunders, p 1005. ous ages, J Vet Int Med 11:30, 1997b.
Robben JH, etal.: Cell biological aspects of Scollan KF, etal.: Validation of a commercially van Vonderen IK, etal.: Disturbed vasopres-
the vasopressin type-2 receptor and aqua- available enzyme immunoassay for mea- sin release in four dogs with so-called
porin 2 channel in nephrogenic diabetes surement of plasma antidiuretic hormone primary polydipsia, J Vet Int Med
insipidus, Am J Physiol Renal Physiol concentration in healthy dogs and assess- 13:419, 1999.
291:F257, 2006. ment of plasma antidiuretic hormone con- van Vonderen IK, etal.: Vasopressin response
Robertson GL: Diseases of the posterior pituitary. centration in dogs with congestive heart to osmotic stimulation in 18 young dogs
In Felig P, etal.: Endocrinology and metabo- failure, Am J Vet Res 74:1206, 2013. with polyuria and polydipsia, J Vet Intern
lism, New York, 1981, McGraw Hill, p 251. Spanakis E, etal.: AVPR2 variants and muta- Med 18:800, 2004.
Robertson GL: Differential diagnosis of poly- tions in nephrogenic diabetes insipidus: re- Verbalis JG, Martinez AJ: Neurological and
uria, Ann Rev Med 39:425, 1988. view and missense mutation significance, J neuropathological sequelae of correc-
Robertson GL, Scheidler JA: A newly rec- Cell Physiol 217:605, 2008. tion of chronic hyponatremia, Kidney Int
ognized variant of familial nephrogenic Sterns RH, etal.: Brain dehydration and neuro- 39:1274, 1991.
diabetes insipidus distinguished by partial logic deterioration after rapid correction of Victor W, etal.: Failure of antipsychotic drug
resistance to vasopressin (type 2) [ab- hyponatremia, Kidney Int 35:69, 1989. dose to explain abnormal diurnal weight
stract], Clin Res 29:555A, 1981. Sterns RH, etal.: Organic osmolytes in acute hy- gain among 129 chronically psychotic
Robinson AG: DDAVP in the treatment of ponatremia, Am J Physiol 264:F833, 1993. inpatients, Prog Neuropsychopharmacol
central diabetes insipidus, N Engl J Med Sterns RH, etal.: Neurologic sequelae after Biol Psychiatry 13:709, 1989.
294:507, 1976. treatment of severe hyponatremia: a Winterbotham J, Mason KV: Congenital dia-
Robinson AG, Verbalis G: Posterior pituitary. In multicenter perspective, J Am Soc Nephrol betes insipidus in a kitten, J Small Anim
Melmed S, Polonsky K, Larsen PR, Kro- 4:1522, 1994. Pract 24:569, 1983.
nenberg HM, editors: Williams textbook of Stocker SD, etal.: Role of renin-angiotensin Zerbe RL, Robertson GL: A comparison of
endocrinology, ed 12, Philadelphia, 2011, system in hypotension-evoked thirst: stud- plasma vasopressin measurements with
Elsevier, p 291. ies with hydralazine, Am J Physiol Regul a standard indirect test in the differen-
Saeki N, etal.: MRI of ectopic posterior Integr Comp Physiol 279:R576, 2000. tial diagnosis of polyuria, N Engl J Med
pituitary bright spot with large adenomas: Sullivan SA, etal.: Lobar holoprosencephaly 305:1539, 1981.
appearances and relationship to transient in a Miniature Schnauzer with hypodip-
postoperative diabetes insipidus, Neurora- sic hypernatremia, J Am Vet Med Assoc
diology 45:713, 2003. 223:1783, 2003.
CHAPTER 2 Disorders of Growth Hormone
Claudia E. Reusch
CHAPTER CONTENTS PITUITARY DEVELOPMENT

Pituitary Development, 37
Biosynthesis of Growth Hormone and Insulin-Like Growth Factor-1, 39 The pituitary gland plays a central role in the regulation of growth.
Pituitary Growth Hormone and Insulin-Like Growth Factor-1, 39 The organ is composed of two main parts, the adenohypophysis
Mammary Growth Hormone, 40 and the neurohypophysis, which have different embryonic origin.
Regulation of Growth Hormone Secretion from the Pituitary Gland, 41 The adenohypophysis, which is also known as the anterior lobe
Metabolic Actions of Growth Hormone and Insulin-Like Growth Factor-1, 42 of the pituitary, consists of the pars distalis, the pars intermedia,
Causes of Growth Failure, 43 and the pars infundibularis. The structure, which gives rise to the
Humans, 43 adenohypophysis, was first described by Rathke, a German anato-
Dogs and Cats, 44 mist, embryologist, and zoologist in 1838 and was named after
Congenital Hyposomatotropism (Pituitary Dwarfism) in Dogs and Cats, 44 him. During embryogenesis the adenohypophysis develops from
Etiopathogenesis, 44 Rathkes pouch, which is an upward protuberance of a single-cell-
Signalment, 47 thick layer of ectoderm of the roof of the primitive mouth. This
Clinical Manifestations, 47 layer migrates to join the neuroectoderm of the primordium of the
Clinical Pathology, 48 ventral hypothalamus; the contact is important, because inductive
Dermatohistopathology, 48 signals from the hypothalamus are essential for normal develop-
Differential Diagnosis, 49 ment of the anterior pituitary gland. Subsequently, Rathkes pouch
Endocrinological Evaluation and Diagnosis, 49 separates by constriction from the oral cavity, and the anterior
Treatment, 52 wall thickens and forms the pars distalis of the adenohypophysis.
Prognosis, 54 The posterior wall of Rathkes pouch forms the pars intermedia,
Acquired Hyposomatotropism, 54 which remains separated from the pars distalis by the hypophyseal
Humans, 54 cleft, the former lumen of Rathkes pouch. The neurohypophy-
Dogs and Cats, 54 sis originates of the neural ectoderm as extension of the ventral
Hypersomatotropism (Acromegaly) in Humans, 55 hypothalamus. In the dog and cat, the adenohypophysis forms a
Hypersomatotropism (Acromegaly) in Cats, 56 collar around the proximal neurohypophysis and also surrounds
Prevalence and Etiology, 56 part of the median eminence (Meij, 1997; Kooistra, 2000; Meij
Pathophysiology, 57 etal, 2010a; Fig. 2-1).
Signalment, 57 The development of the pituitary gland and the determination
Clinical Manifestations, 57 of the specific cell types from common primordial cells follow a
Clinical Pathology, 59 distinct, well-regulated order. These processes are under the con-
Diagnostic Imaging, 59 trol of a complex cascade of transcription factors and signaling
Hormonal Evaluation, 60 molecules. After proliferation, the different cell types arise in a
Establishing the Diagnosis, 64 temporal and spatial manner and undergo a highly selective dif-
Treatment, 65 ferentiation. The corticotrophs are the first distinct cell type in the
Histopathology, 67 maturating anterior pituitary gland (Kooistra et al, 2000a; Kel-
Prognosis, 68 berman etal, 2009; Javorsky etal, 2011; Fig. 2-2). In humans,
Hypersomatotropism (Acromegaly) in Dogs, 68 abnormalities in these processes and pathways are associated with
Etiology, 68 a large spectrum of diseases, and the topic is an area of intensive
Pathophysiology, 69 research; in dogs and cats, exploration of potential mutations has
Signalment, 69 only recently begun.
Clinical Manifestations, 69 The cells of the anterior lobe were originally described by
Clinical Pathology, 70 their reactions with different colored stains as acidophils, baso-
Diagnostic Imaging, 70 phils, and chromophobes. Today, immunolabeling techniques
Hormonal Evaluation, 70 allow us to classify pituitary cells by their specific secretory
Establishing the Diagnosis, 71 products (Childs, 2009). There are five distinct types of endo-
Treatment, 71 crine cells: corticotrophs (secreting adrenocorticotropic hor-
Prognosis, 72 mone [ACTH] and related peptides), thyrotrophs (secreting
37
Diencephalon III ventricle

Pars
intermedia
Anterior
lobe
Rathke pouch Neurohypophysis
Rathke cleft
FIGURE 2-1 Simplified illustration of the pituitary ontogenesis. (Reproduced with permission from Meij BP, etal.:
Hypothalamus-pituitary system. In Rijnberk A, Kooistra HS, editors: Clinical endocrinology of dogs and cats, ed 2,
Hannover, 2010, Schltersche.)
TSH
GH
Pou1f1
LHX3
LHX4 Prop1 PRL
Rpp
Tbx19 Nr5a1
Gata2
POMC
ACTH
MSH LH
FSH
FIGURE 2-2Simplified, schematic representation of the differentiation of pituitary cell lineages. The final
endocrine cell types are labeled with the hormone synthesized by them. Various transcription factors are involved
in the process of cellular differentiation. Some of the best known factors are given. (Redrawn and modified from
Kelberman D, etal.: Genetic regulation of pituitary gland development in human and mouse, Endocr Rev 30[7]:790-
829, 2009; and Metherell LA, etal.: Genetic defects of the human somatotropic axis. In Wass JAH, Stewart PM, Amiel
SA, Davies MJ, editors: Oxford textbook of endocrinology and diabetes, ed 2, Oxford, 2011, Oxford University Press.)
ACTH, Adrenocorticotropic hormone; FSH, follicle-stimulating hormone; Gata2, gata binding protein 2; GH, growth
hormone; LH, luteinizing hormone; LHX3/LHX4, LIM-domain transcription factor ; MSH, melanocyte-stimulating
hormone; Nr5a1, nuclear receptor subfamily 5, group A, member 1 (also termed steroidogenic factor-1 [SF1]);
POMC, proopiomelanocortin; Pou1f1 (also termed PIT1), pituitary-specific positive transcription factor 1; PRL,
prolactin; Prop1, prophet of PIT1 transcription factor; Rpp, Rathke pouch progenitor; Tbx19; T-box transcription
factor 19 (previously termed T-box pituitary transcription factor [TPIT]), TSH, thyroid-stimulating hormone.
thyroid-stimulating hormone [TSH]), gonadotrophs (secreting to the pars intermedia (Meij etal, 2010b). During the last two
luteinizing hormone [LH] and follicle-stimulating hormone decades, however, it has become obvious that the traditional con-
[FSH]), somatotrophs (secreting growth hormone [GH]) and cept that each cell type in the pituitary stores and secretes only
lactotrophs (secreting prolactin). Somatotrophs and lactotrophs a single hormone and is regulated by its specific hypothalamic
are acidophil-staining cells, and thyrotrophs and gonadotrophs releasing factor, is too narrow and that additional mechanisms
are basophil-staining cells. Chromophobic cells include corti- exist (Childs, 2009; Meij et al, 2010b). There are subpopula-
cotrophs, nonsecretory follicular (stellate) cells, degranulated tions within the same endocrine cell type that synthesize several
chromophils, and undifferentiated stem cells (Capen, 2007). hormones and that may be activated by several releasing hor-
Somatotrophs are the most abundant cells and account for mones. Examples are mammosomatotropes that can store and
approximately 50% of the cells of the anterior lobe. The per- release GH and prolactin, somatogonadotropes that can store
centage of the other cell types ranges between 10% and 15%. and release GH and LH/FSH, thyrosomatotropes that contain
The distribution of the different cell types is not random, but it TSH and GH. Those cells may undergo a phenotypic switch
follows a topological and numeric organization. Somatotrophs between the two respective mature cell types depending on the
are mostly located in the dorsal region of the pars distalis close bodys need, which is a phenomenon called transdifferentiation
|
CHAPTER 2 Disorders of Growth Hormone 39
(Kineman etal, 1992; Childs, 2000; Vidal etal, 2000; Villalo- pulses is lower during times when plasma progesterone concentra-
bos etal, 2004; Childs, 2009). Most of the studies have been tion is high. This has been explained by the partial suppression
performed in experimental animals, cell cultures, or in biopsy of pituitary GH secretion by progesterone-induced GH synthesis
specimens from humans, and knowledge on potential transdif- in the mammary gland (see later) (Kooistra et al, 2000b). Sys-
ferentiation of pituitary cells in dogs and cats is scarce. A recent tematic evaluation of GH secretion patterns in cats has not yet
study suggests, however, the existence of similar mechanisms. A been performed. In the circulation, GH is to some extent bound
group of Beagle dogs was followed for 3 years after the induction to GH-binding proteins, which reduces fluctuations in GH levels
of primary hypothyroidism. Basal plasma GH levels increased and prolongs plasma half-life. The canine GH receptor has been
during this time, and there was a paradoxical hyperresponsive- characterized at a molecular level and its coding sequence shows
ness to thyrotropin-releasing hormone (TRH) stimulation. extensive homology with the GH receptor of several other species.
Histomorphology and immunohistochemistry of the pituitary After binding GH, the receptor dimerizes and activates cytosolic
gland revealed thyrotroph hyperplasia, large vacuolated thyroid tyrosine kinases of the Janus kinases (Jak) family (van Garderen
deficiency cells, and pituitary cells that double stained for both etal, 1999).
GH and TSH, the latter being indicative for transdifferentiation Originally, it was believed that the actions of GH are mediated
of somatotrophs into thyrotrophs (Diaz-Espieira etal, 2008). by the direct effect of the hormone on tissues. In 1957, growth
factors, which were termed sulfation factors, were discovered by
BIOSYNTHESIS OF GROWTH HORMONE AND Salmon and Daughaday and were renamed to somatomedins by
INSULIN-LIKE GROWTH FACTOR-1 Daughaday et al. (1972). After their isolation by Rinderknecht
and Humble (1978a, b), they were then called insulin-like growth
Pituitary Growth Hormone and Insulin-like Growth factors (IGFs), a term that is used today. There are two main IGFs,
Factor-1 IGF-1 (previously somatomedin-C) being the most important and
IGF-2. Initially it was proposed that GH induces IGF-1 synthesis
GH, also known as somatotropin, is a rather large, single chain in the liver, which then acts on target tissues to promote growth.
polypeptide. The hormone has a molecular weight of approxi- Currently, it is supposed that GH and IGF-1 act in fact in concert
mately 22 kDa and contains 191 amino acids with two intra- as well as independently to stimulate pathways that lead to growth
chain disulfide bridges. It is produced in the somatotropic cells, and that regulate many metabolic processes. It has also become
which represent the most abundant cells of the anterior pituitary clear that IGF-1 is not only produced in the liver, but in almost
(Rijnberk, 1995; Javorsky etal, 2011). The amino acid sequence all tissues of the body where it acts in an autocrine/paracrine man-
of canine GH is identical to the sequence of porcine GH; feline ner. Circulating IGF-1 levels, which are mainly derived from the
GH differs from canine GH by only one amino acid. GH of liver, parallel those of GH (i.e., in conditions in which GH is
humans (and other primates) differs considerably (i.e., there is a low, IGF-1 levels are also reduced and vice versa) (Le Roith etal,
difference of approximately 33%) (Ascacio-Martnez and Barrera- 2001). Liver disease also has an influence on IGF-1, because its
Saldaa, 1994; Castro-Peralta and Barrera-Saldaa, 1995; Warren level decreases with decreasing functional liver mass (Styne, 2011).
etal, 1996; Liu etal, 2001; Wallis, 2008). IGF-1 is a basic, single chain polypeptide of 70 amino acids
In most mammalian species, GH is encoded by a single gene, with three intrachain disulfide bridges and a molecular weight of
in humans (and other primates), a cluster of five genes encode approximately 7.5 kDa. Its structure displays substantial homol-
pituitary GH and human chorionic somatomammotropin (GH- ogy to proinsulin (Rinderknecht and Humble, 1978a; Cooke
hCs cluster). The hGH-N gene codes for the 22 kDa (191 amino et al, 2011; Frystyk, 2012). The IGF-1 molecule seems to be
acids) protein, and transcription is selectively in the somatotrophs well conserved between species, including dog and cat (Zangger
of the pituitary. Other genes are expressed in various structures of etal, 1987; Delafontaine etal, 1993). Different to insulin, IGF-1
the placenta. In humans, it is known that the pituitary somato- is bound by a group of six high-affinity proteins (IGF-binding
trophs secrete a mixture of several different forms of GH, which protein-1 [IGFBP-1] to IGFPB-6), and less than 1% of the circu-
derive from the 22 kDa form by posttranslational modifications. lating IGF-1 is present as free form. IGFBP-3 is the most impor-
The normal 22 kDa, 191 amino acid protein is the major physi- tant binding protein that binds most of the IGF-1 (approximately
ological form and accounts for 75% of the pituitary GH secretion 80% to 85%) in conjunction with an acid-labile subunit (ALS).
(Melmed etal, 2011; Barret etal, 2012). A similar, less abundant complex is also formed with IGFBP-5.
GH is secreted in a pulsatile fashion in mammalians, as are the These three molecules (IGF-1, IGFBP-3/IGFBP-5, ALS) form
other hormones of the anterior pituitary gland. The pulses are large 150 kDa ternary complexes. (Le Roith etal, 2001; Cooke
mainly induced by the effect of GH-releasing hormone (GHRH), et al, 2011). ALS is an 85 kDa glycoprotein, almost exclusively
whereas the intervening troughs are primarily generated by soma- produced in the liver under the control of GH, from where it is
tostatin (Melmed etal, 2011). The number of GH pulses dem- secreted into the circulation. Its main function is to prolong the
onstrated in healthy dogs differs slightly between studies: 1 to 3 half-life of the ternary complexes, which cannot cross the vascular
pulses/6 h, 1 pulse/4.5 h, 2 to 7 pulses/12 h (Cowan etal, 1984; endothelium. This is in contrast to the small amount of IGF-1
French etal, 1987; Beijerink etal, 2011). In humans, the onset of that binds to the other IGFBPs, resulting in 50 kDa binary com-
sleep is a strong stimulus for GF secretion. In dogs, however, no plexes, and that may cross the endothelial barrier more easily. The
difference was found between awake or asleep phases (French etal, half-life of free IGF-1 is approximately 10 minutes, and it extends
1987). In various mammalian species, age and gender-related dif- to more than 12 hours in case of the ternary complexes. Half-
ferences in GH secretion have been demonstrated. In dogs, how- life of the binary complexes has been described to be 30 min-
ever, GH secretion does not differ between females (in anestrus) utes (Guler etal, 1989a; Boisclair etal, 2001; Cooke etal, 2011).
and males; aging, however, is associated with a reduction in GH The binding of most of the IGF-1 in the large ternary complexes
secretion in dogs (Gobello et al, 2002; Lee, 2004). GH secre- allows storage of high concentrations of IGF-1 in the circulation
tion in intact female dogs changes during the luteal phase of the by preventing their insulin-like activity, which would otherwise
cycle, because basal GH secretion is higher and GH secretion in cause hypoglycemia (Zapf et al, 1995). In sum, IGFBPs can be
acromegalic features, glucose intolerance, and mammary tumors

IGFBP in dogs (Sloan and Oliver, 1975; Owen and Briggs, 1976; Grf
and El Etreby, 1979). Subsequent investigations revealed that
the phenomenon was due to the induction of high amounts of
IGF-1 IGFBP proteolyzed
fragments GH by the progestagens (Concannon etal, 1980; Rijnberk etal,
1980; Eigenmann and Rijnberk, 1981; Eigenmann and Eigen-
IGF-1 mann, 1981a).The increase in GH was higher when the bitches
were estradiol-primed before the administration of progestagens
(Eigenmann and Eigenmann, 1981b), and the increase was more
pronounced in older than in younger bitches (McCann et al,
1987). At that time it was also realized that GH excess and acro-
megaly as well as diabetes mellitus do not only develop after the
exposure to exogenous progestagens but may also occasionally
occur in middle-aged to elderly bitches during the luteal phase
Plasma membrane of the estrus cycle (i.e., when endogenous progestagen levels are
high) (Eigenmann etal, 1983). GH overproduction, acromegalic
features as well as diabetes mellitus were shown to be reversible
after withdrawal of exogenous progesterone or ovariohysterec-
tomy, respectively (Rijnberk etal, 1980; Eigenmann etal, 1983).
IGF-1 receptor The GH excess was associated with marked increase in IGF-1,
FIGURE 2-3 Simplified, schematic representation of the dissociation of insulin- which also declined after treatment (Eigenmann, 1984). It was
like growth factor-1 (IGF-1) from IGF-binding protein (IGFBP) and the binding of recognized thereafter, that progestagen-induced GH does not
free IGF-1 to its receptor. (Redrawn and modified from Cooke DW, etal.: Normal and show a pulsatile secretion pattern and is unresponsive to the
aberrant growth. In Melmed S, Polonsky KS, Larsen PR, Kronenberger HM, editors: stimulation with GHRH or clonidine and to the suppression
Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders/Elsevier.) with a somatostatin analogue (Rutteman et al, 1987; Watson
etal, 1987; Selman etal, 1991). The additional discovery that
hypophysectomy did not lead to a significant decrease in GH
regarded as carrier proteins for IGF-1 and as regulators of IGF-1 levels gave rise to the assumption that progestagen-induced GH
actions by modulating IGF-1 availability. Interestingly, IGFBPs is produced at an extra-pituitary site. The analysis of homog-
may also have intrinsic bioactivity independent of IGF-1 (Firth enates of various tissues from progestagen-treated dogs revealed
and Baxter, 2002). IGF-1 dissociates from IGFBP by proteolysis, that GH immunoreactivity was by far highest in the mammary
mass action, or other so far unknown mechanisms; thereafter, free gland. GH immunoreactivity was localized primarily in hyper-
IGF-1 binds and activates its ubiquitously expressed cell surface plastic ductular epithelium, as well as in ductular epithelium of
receptor (Fig. 2-3). The IGF-1 receptor is very similar to the insu- mammary adenomas that had developed in some dogs during
lin receptor; both belong to the transmembrane tyrosine kinase treatment. Mammary gland origin of the GH excess was con-
family. Structurally, they are tetramers consisting of two extracel- firmed by the finding that GH levels normalized within 2 hours
lular -subunits with binding sites for the ligand and two mainly after complete mammectomy (Selman et al, 1994a). Sequence
intracellular -subunits. The latter contains the tyrosine kinase analysis revealed 100% homology between the mammary- and
activity that upon activation of the receptor initiates multiple sig- the pituitary-expressed GH gene (Mol etal, 1995). Different to
naling pathways (Le Roith etal, 2001; Cooke etal, 2011; Frystyk, pituitary GH, however, mammary GH expression takes place
2012). The IGF-1 receptor binds IGF-1 with high affinity; it also in the absence of the transcription factor Pou1f1, previously
binds insulin, however, with hundredfold less affinity. IGF-1 may known as pituitary-specific positive transcription factor (PIT-1)
bind to the insulin receptor as well, however, with low affinity (Lantinga-van Leeuwen et al, 1999; see Fig. 2-2). Abnormally
(Cooke et al, 2011; Bach et al, 2013). In dogs, IGFBP profiles increased secretion of mammary GH occurs after prolonged expo-
have been shown to be similar to other species and IGFBP-3 also sure to exogenous progestagens or endogenously in some elderly
is the most abundant binding protein (Maxwell etal, 1998). Cats to old intact bitches. However, GH secretion from the mammary
seem to have less IGFBP-3 ternary complex formation, and it is gland is also a physiological event and occurs in all cyclic bitches.
suggested that ALS is the limiting factor (Lewitt etal, 2000). During the luteal phase in which plasma progesterone concen-
IGF-2 is a single chain polypeptide with 67 amino acids and tration is high, basal GH concentration is also increased and less
a molecular weight of approximately 7.5 kDa. Like IGF-1, it is GH is secreted in pulses compared to anestrus. As already men-
structurally similar to proinsulin, and it circulates in plasma com- tioned earlier, the loss of pulsatility is thought to be due to sup-
plexed to the six high-affinity IGFBP (Frystyk, 2012). However, pression of pituitary GH by the progestagen-induced mammary
the IGF-2 receptor has no structural homology with either the GH (Kooistra etal, 2000b). Mammary GH seems to act in an
IGF-1 receptor or the insulin receptor. Whereas the IGF-1 receptor autocrine and/or paracrine fashion and is important for normal
binds both IGFs with high affinity, the IGF-2 receptor binds only mammary gland development (van Garderen etal, 1997). The
IGF-2 with high affinity. IGF-1 binds to the IGF-2 receptor with growth-promoting effects are achieved by direct effects of GH
lower affinity, and insulin does not bind at all (Cooke etal, 2011). as well as indirectly by stimulating the synthesis of IGF-1. The
effects of the latter are modulated by the local production of
Mammary Growth Hormone IGF-binding proteins (Mol et al, 1997; Mol et al, 1999). The
progesterone-GH-IGF-1 system also seems to play an impor-
In dogs, circulating GH not only derives from the adenohypoph- tant role in mammary tumorigenesis. It is known that treatment
ysis but can also originate from the mammary gland. In the 1970s, of female dogs with progestagens leads to the development of
it was described that administration of progestagens could lead to mammary tumors in a dose-dependent manner. Many of those
|
tumors are benign; however, malignant tumors have also been Modulating factors
documented (Mol etal, 1995). Spontaneous mammary tumors
are also very common in dogs, and it is assumed that the long
exposure to high progesterone concentrations during the long Hypothalamus
luteal phase is a key factor in their formation (Rao etal, 2009).
The link seems to be the progesterone-induced local GH produc-

tion, because GH has been documented in the vast majority of Ghrelin GHRH Somatostatin
benign and malignant mammary tumors (Mol etal, 1995; van
Garderen etal, 1997). Tissue and plasma GH and IGF-1 are sig-
nificantly higher in malignant than in benign tumors (Queiroga
etal, 2008; Queiroga etal, 2010). Gene expression profiles of Pituitary
progestagen-induced mammary hyperplasia and spontaneous

mammary tumors of dogs identified altered expression of vari-
ous genes involved in tumor development and progression and GHBP GH
confirmed the role of progesterone in the process of cell prolif-
eration (Rao etal, 2009). In cats, the gene encoding GH is also IGFBP-1
IGFBP-2 Liver
expressed in the mammary gland. The highest expression was
IGFBP-3
demonstrated in fibroadenomatous hyperplasia induced by the IGFBP-4
administration of progestagens (Mol etal, 1995; Rijnberk and IGFBP-5
Mol, 1997). However, in cats, mammary GH does not seem to IGFBP-6 IGF-1
be secreted into the systemic circulation (Peterson, 1987). FIGURE 2-4Simplified, schematic representation of the hypothalamus-pitu-
itary-growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. See Box 2-1
REGULATION OF GROWTH HORMONE SECRETION for details on modulating factors. GHBP, Growth hormone-binding protein; GHRH,
FROM THE PITUITARY GLAND GH-releasing hormone; IGFBP, IGF-binding protein.
Synthesis and secretion of pituitary GH is regulated by a complex

network of stimulating and inhibiting factors. The integration of on other hormones (e.g., TSH, insulin glucagon, gastrin) and
all those factors results in the pulsatile release of GH from the on immune functions and tumor growth, and it has important
somatotropic cells of the anterior pituitary gland (Mol and Meij, impact on the gastrointestinal tract and other organ functions
2008). GHRH and somatostatin (also termed somatotropin-release (Reichlin, 1983; Giustina and Veldhuis, 1998). Somatostatin
inhibiting factor [SRIF]) thereby play a predominant role and are derives from prohormone cleavage, resulting in the generation of
the best known regulators. Both hormones derive from hypotha- the tetradecapeptide somatostatin 14 and a somatostatin molecule
lamic neurons, from where they are transported by nerve fibers to containing 28 amino acids, termed somatostatin 28. Somatostatin
the outer lamina of the median eminence. By subsequent release 14 is the major form in the brain, including the hypothalamus
into the capillaries of the hypothalamic-hypophyseal portal system, and is identical in all vertebrates; somatostatin 28 is the main
they reach the anterior pituitary gland (Meij etal, 2010a). GHRH form in the gastrointestinal tract (Low, 2011). Five somatostatin
is a peptide consisting of 44 amino acids and arises from post- receptors (SSTR1 to SSTR5) have been identified and all of
translational modification of a larger prohormone. Its structure them are expressed in the pituitary gland (Giustina and Veldhuis,
varies somewhat between species. The GHRH receptor belongs 1998). Binding to the somatostatin receptor leads to activation of
to a subfamily of G-protein coupled receptors and activates the membrane-bound inhibitory G-protein and inhibition of adenyl
somatotrophs through activation of the adenylate cyclase/cyclic cyclase activity and decrease of intracellular cAMP (Low, 2011).
adenosine monophosphate (cAMP) pathways. The activation of Half-life of somatostatin is approximately as short as of GHRH
the receptors leads to the release of preformed GH as well as to (Javorsky etal, 2011).
stimulation of gene transcription and synthesis of new GH (Mayo A complex interplay of feedback signals involves the four pep-
et al, 2000; Low, 2011). The pituitary actions of GHRH are tides GH, IGF-1, GHRH, and somatostatin (Fig. 2-4). GH itself
almost completely specific for GH secretion, and there appears stimulates hypothalamic somatostatin release, inhibits GHRH,
to be no relevant interaction between GHRH and other hypotha- and has a direct inhibitory effect on somatotropic cells. GHRH
lamic releasing hormones (Giustina and Veldhuis, 1998; Low, and somatostatin can each negatively regulate its own secretion and
2011). Half-life of GHRH is short (e.g., in humans between 2 to reciprocally controls secretion of its counterpart (Giustina and
4 minutes) (Javorsky etal, 2011). Veldhuis, 1998). IGF-1 inhibits GH secretion on the hypotha-
Somatostatin is a potent inhibitor of GH and suppresses both lamic levels by increasing somatostatin release as well as directly
basal and GHRH-stimulated pulse amplitude and frequency. It on the pituitary level (Melmed etal, 2011).
does not affect the synthesis of GH. Although many other factors The actions of GHRH and somatostatin do not completely
are involved, it is currently believed that GH pulses predominantly account for all pulses of GH secretion. A complex array of
reflect the pulsatile secretion of GHRH, whereas the GH external and internal stimuli (e.g., body composition and
troughs are mainly controlled by somatostatin. The high level of nutritional status, age, gender, sleep, exercise, fasting, genetic
somatostatin during a GH trough period probably primes the background, disease status, and many others) regulate GH
somatotropic cells to maximally respond to subsequent GHRH amplitude and frequency. The importance of those factors
pulses (Melmed et al, 2011). Somatostatin not only occurs in may differ between species; for instance GH secretion does
the hypothalamus, but in various other regions of the central not seem to be related to sleep or day-night cycles, and insu-
and peripheral nervous system as well as in the gastrointestinal lin-induced hypoglycemia does not consistently result in GH
tract, pancreas, and other tissues. Consequently, additionally to secretion in dogs (French etal, 1987; Bhatti etal, 2006a; Mol
its profound inhibition of GH, it also displays inhibitory effects and Meij, 2008; Box 2-1).
(GH secretagogues, GHS). After the identification of the GHS

BOX 2-1 F
actors Modulating Growth Hormone Release receptor (GHS-R), an active search for its endogenous ligand was
in Humans undertaken (Koijma etal, 1999; Sato etal, 2012).
Ghrelin acts directly at the level of the pituitary gland to stimu-
Stimulatory Factors Inhibitory Factors late the release of GH (see Fig. 2-4). The effect is greater invivo
Physiologic Physiologic than invitro, suggesting a synergistic action of ghrelin and GHRH
Sleep Postprandial hyperglycemia (i.e., GHRH is necessary to induce a maximal GH release) (Sato
Exercise Rise in free fatty acids etal, 2012). With regard to potency and effect on other pituitary
Stress Aging hormones, species specific differences have been demonstrated.
Postprandial decline of blood glucose In humans, GH release after ghrelin administration is more pro-
Pathologic Pathologic nounced than after GHRH administration, and the effect is not
Protein depletion Obesity absolutely specific, because ghrelin also increases the secretion of
Starvation Hypothyroidism prolactin, ACTH, and cortisol (Bhatti etal, 2006a). In dogs, ghrelin
Chronic renal failure Hyperthyroidism release appears to be age-related (Yokoyama etal, 2005; Bhatti etal,
Liver cirrhosis Hyperadrenocorticism 2006b). In young dogs (13 to 17 months), ghrelin exhibited more
Type 1 diabetes powerful GH-releasing effects than GHRH, whereas in older dogs
Interleukins 1,2,6 (7 to 12 years), GH secretion was significantly higher after GHRH
Pharmacologic Pharmacologic than after ghrelin application (Bhatti etal, 2006b). In dogs, ghrelin
Insulin-induced hypoglycemia Somatostatin neither activates the pituitary-adrenocortical axis nor stimulates the
Amino acid infusion (arginine, lysine) IGF-1, IGF-2 release of prolactin, TSH, and LH (Bhatti et al, 2002). In cats,
GHRH Glucocorticoids (chronic ghrelin also stimulates GH release in a dose-dependent manner
Ghrelin administration) (Ida, 2012). So far, its potency, age-dependency, and specificity for
ACTH, -MSH, vasopressin -adrenergic antagonists somatotrophs have not been evaluated in the cat. Ghrelin has vari-
Estrogen -adrenergic agonists ous additional physiological functions, such as appetite regulation
-adrenergic agonists (e.g., clonidine) Serotonin antagonists (induction of hunger), stimulation of gastric motility and gastric
-adrenergic antagonists Dopamine antagonists acid secretion, decrease of insulin secretion, and also has cardiovas-
Dopamine agonists cular and antiproliferative effects (Sato etal, 2012).
Serotonin precursors Finally, GH synthesis and release is modulated by other hor-
GABA agonists mones, such as thyroid hormones, glucocorticoids, and sex hor-
Potassium infusion mones. In humans, primary hypothyroidism is associated with
attenuated GH secretion. In hypothyroid dogs, however, basal
Modified from Javorsky BR, et al.: Hypothalamus and pituitary gland. In Gardner DG,
GH and IGF-1 concentrations are increased (Lee etal, 2001). In
Shoback D, editors: Greenspan's basic & clinical endocrinology, ed 9, San Francisco,
2011, McGraw Hill; and Low MJ: Neuroendocrinology. In Melmed S, Polonsky KS,
dogs with pituitary-dependent hyperadrenocorticism, basal GH
Larsen PR, Kronenberger HM, editors: Williams textbook of endocrinology, ed 12, concentrations are normal, but pulse frequency is lower and less
Philadelphia, 2011, Saunders Elsevier. GH is secreted in pulses. The inhibitory effect of prolonged gluco-
-MSH, -Melanocyte-stimulating hormone; ACTH, adrenocorticotropic hormone; corticoid excess is also seen in humans and may in part be medi-
GABA, gamma aminobutyric acid; GHRH, GH-releasing hormone; IGF, insulin-like ated by enhancement of somatostatin release (Lee etal, 2003).
growth factor.
Please note that there is variability between species, e.g., hypothyroidism in dogs is
associated with increased GH release and GH secretion in dogs does not seem to be
METABOLIC ACTIONS OF GROWTH HORMONE
related to sleep or day-night cycles. AND INSULIN-LIKE GROWTH FACTOR-1
The actions of GH and IGF-1 are usually described as separate
Approximately 15 years ago, ghrelin, another major factor in entities (i.e., rapid, direct actions are attributed to GH, and slow,
the complex regulation network, was identified (Kojima et al, indirect actions are attributed to IGF-1). However, understand-
1999). Ghre is the Indo-European root of the word grow, and relin ing has evolved, and it is now recognized that there is a tight and
means release (Bhatti et al, 2006a). Ghrelin is a 28-amino acid much more complex interplay between the two hormones. Several
peptide with a high degree of structural similarity between species. studies have shown the existence of so-called crosstalk between the
It circulates in the blood in a non-acylated and an acylated form; pathways activated by GH, IGF-1, and insulin (Vijayakumar etal,
acylation is mandatory for its biological effects (Nass etal, 2011). 2010). Roughly, GH exerts its effects by binding to the GH receptor,
The main site of ghrelin synthesis is the fundus of the stomach, which is expressed abundantly in the liver but also in other tissues.
but synthesis has also been demonstrated in the small intestinal Many of its effects are mediated through subsequent production
tract and many other tissues, including pancreas, pituitary, and of IGF-1 (Fig. 2-5). The liver is the predominant source of IGF-1,
hypothalamus (Nass etal, 2011; Sato etal, 2012). Ghrelin acts although it is also synthesized in many other tissues, where it acts in
through a receptor separate from the GHRH receptor, called the an autocrine/paracrine manner (Aragon-Alonso etal, 2011). Circu-
GH secretagogue receptor (GHS-R), or ghrelin receptor. It is a typical lating IGF-1 is stimulated by GH when nutrient intake is sufficient
G-protein coupled receptor and highly expressed in the anterior and insulin concentration in the portal vein is high, whereas IGF-1
pituitary gland, hypothalamus, hippocampus, and other areas in concentration decreases during fasting (Mller and Jrgensen,
the brain; its structure is well conserved across vertebrate species 2009). In adults, GH is a major metabolic hormone and functions
(Sato etal, 2012). Interestingly, the GHS-R was identified several by optimizing body composition and physical function as well as
years before the discovery of its natural ligand ghrelin and was by regulating energy and substrate metabolism. It interacts closely
therefore also called orphan GHS-R. Initially, it was found that with insulin to control fat, protein and carbohydrate metabolism
enkephalins reveal GH-releasing properties, which then lead to during fasting and fed states (Melmed etal, 2011). GH stimulates
the development of synthetic compounds inducing GH secretion lipolysis and fatty acid oxidation, which is of particular importance
|
GH etal, 1984c). Another study investigating a large number of dogs of

many different breeds confirmed the relation between IGF-1 and
body size, because IGF-1 increased with increasing weight (Greer
et al, 2011). Evaluation of young, growing dogs, however, raised
Insulin Lipolysis Protein Epiphyseal doubts on the assumption that the circulation level of IGF-1 is the
antagonism synthesis growth major determinant of body size in dogs (Rijnberk etal, 2003). Pro-
longed treatment of Toy Poodle puppies with recombinant human
IGF-1
IGF-1, although associated with substantial rise in circulating IGF-1
levels, did not increase body size in comparison to controls (Guler
etal, 1989b). No correlation was found between IGF-1 levels and
growth rate in Standard and Toy Poodle puppies (Brki, 2000).
Insulin-like Antilipolytic Protein Epiphyseal The issue of IGF-1 and body size was further investigated by
activity activity synthesis growth genetic studies. The IGF-1 gene, as a candidate gene for body size,
FIGURE 2-5 Simplified scheme of the major metabolic actions of growth hormone was shown to be a major gene to contribute to the size diversity in
(GH) and insulin-like growth factor-1 (IGF-1). dogs. The IGF-1 gene and the associated gene regions account for
approximately 50% of the genetic variations in dog size (Sutter etal,
2007; Boyko, 2011; Wayne and vonHoldt, 2012). Small breed dogs
in the fasted state to provide energy without protein degradation. have IGF-1 haplotypes that are closely related to those of wolves
The latter (protein-sparing) effect is an important mechanism by from the Middle East, suggesting an early evolution of small dog size
which GH promotes growth and development (Melmed et al, there (Gray etal, 2010; Wayne and vonHoldt, 2012). It is obvious
2011; Javorsky etal, 2011). GH also plays a role in adipocyte dif- that additional factors are involved, and it is likely that GH plays
ferentiation; the generation of large mature adipocytes is associated an important role. Basal GH concentrations as well as GH release
with an increased capacity to store triglyceride and higher lipophilic during pulses in Great Dane puppies were shown to be significantly
activity (Vijayakumar et al, 2010). GH increases protein synthe- higher than the corresponding levels of Beagles of the same age.
sis (directly and via IGF-1), by enhancing all facets of amino acid In the Beagles, GH decreased into the range of adults already by
uptake and incorporation into protein while suppressing proteoly- week 7, whereas the decrease was much slower in the Great Danes
sis. The carbohydrate metabolism is affected by GH both directly in which GH stayed elevated throughout the observation period of
and indirectly. The direct, anti-insulin actions of GH are of particu- 24 weeks. The authors therefore assumed that the different duration
lar importance during starvation and include decrease of glucose of GH elevation may be responsible for the differences in body size
uptake in extrahepatic tissues, increase in hepatic glucose output, between medium and large breed dogs (Favier etal, 2001).
and increase of plasma glucose concentration (Sjaastad etal, 2010;
Javorsky et al, 2011). IGF-1 has very different effects on carbo- CAUSES OF GROWTH FAILURE
hydrate metabolism. They are insulin-like and include increase of
glucose uptake in extrahepatic tissues, decrease of hepatic glucose Humans
output, and decrease of plasma glucose concentration (Mauras and
Haymond, 2005; Javorsky etal, 2011). In case of GH excess, its Decreased growth during childhood and short adult height may
anti-insulin or diabetogenic effect may lead to overt diabetes, be due to a large number of non-endocrine and endocrine causes.
which may become insulin-resistant. Non-endocrine causes include constitutional short stature (which is
In the growing individual, normal GH secretion and the func- not considered a disease but a variation from normal for the popula-
tional integrity of the GH-IGF-1 axis is mandatory for normal tion) as a familial pattern and as a characteristic pattern of various
linear growth and skeletal development. In human medicine, the syndromes (e.g. Turner syndrome). Malnutrition, severe chronic dis-
respective roles of GH, IGF-1, their binding proteins and receptors, eases and dysfunction of many organ systems are additional impor-
as well as the influence of other factors (e.g., cytokines) are an area tant causes. Main endocrine disorders include GH deficiency, GH
of intensive research, and an impressive number of genetic defects insensitivity, hypothyroidism, endogenous or exogenous glucocorti-
have so far been described (Savage et al, 2011). GH is thought coid excess, disorders of vitamin D metabolism and poorly-regulated
to act on the precursors of the growth plate to stimulate the dif- diabetes mellitus (Styne, 2011). GH deficiency in turn may be due
ferentiation of chondrocytes and stimulate local IGF-1 synthesis, to various abnormalities at the hypothalamic or pituitary level; addi-
which in turn acts in an autocrine/paracrine manner and induces tional defects are known at the level of IGF-1 and its receptor (Box
clonal expansion and hypertrophy of chondrocytes. GH may also 2-2). In cases of isolated GH deficiency at the pituitary level, often
have an additional direct effect on proliferation and hypertrophy of no cause can be identified (so-called idiopathic GH deficiency); how-
the chondrocytes (Zezulak and Green, 1986; Gevers etal, 2002). ever, there is increasing recognition of genetic defects (e.g., mutations
Part of the growth-promoting effect is also mediated by the circu- in the GHRH receptor gene or in the gene encoding GH, or syn-
lating, liver-derived IGF-1 (Stratikopoulos etal, 2008). thesis of mutant GH with reduced bioactivity) (Cooke, 2011). As
The dog is unique among mammalian species, because body discussed at the beginning of the chapter pituitary development and
weight at the opposite end of the scale (e.g., Chihuahua and St. the determination of specific cell types follows a distinct, well-regu-
Bernard) may differ nearly hundredfold (Favier et al, 2001; Rijn- lated order under the control of transcription factors and signaling
berk etal, 2003). Initial studies showed that circulating IGF-1 levels molecules (Kelberman etal, 2009; Javorsky etal, 2011; see Fig. 2-2).
were different between adult dogs of different breeds; smaller breed Multiple genetic defects have been identified within this complex cas-
dogs had lower IGF-1 levels than middle sized dogs, and the latter cade leading to combined pituitary hormone deficiencies. Mutations
had lower levels than large breed dogs (Eigenmann et al, 1984a). in the prophet of PIT1 (PROP1) gene result in GH, TSH, prolac-
Similarly, IGF-1 levels paralleled body size among genetic subgroups tin, FSH, and LH deficiencies. Mutations in the POU1F1 (or PIT1)
within one breed, because Standard Poodles had much higher IGF-1 gene lead to GH, TSH, and prolactin deficiencies (Kelberman etal,
levels than Toy Poodles, whereas GH levels were similar (Eigenmann 2009). In humans, mutations in the POU1F1 or PROP1 gene are
BOX 2-2 C
auses for Growth Hormone and Insulin-Like BOX 2-3 N
onendocrine and Endocrine Causes of Growth
Growth Factor-1 Deficiency in Humans Failure in Dogs and Cats
1. Hypothalamic dysfunction (GHRH deficiency) Non-Endocrine Causes of Growth Endocrine Causes of Growth
a) Congenital Failure Failure
b) Acquired (e.g., tumors, trauma, inflammation) Constitutional* GH/IGF-1 deficiency
2. Anterior pituitary dysfunction Familial* Hypothyroidism
a) Congenital Malnutrition Glucocorticoid excess
Isolated GH deficiency Any severe chronic disease including (endogenous and exogenous)
Combined pituitary hormone deficiency chronic infection Diabetes mellitus
b) Acquired (e.g., tumors, trauma, inflammation) Cardiac disorders (e.g., left-to-right shunt) Hypoadrenocorticism
3. GH dysfunction or GH insensitivity Pulmonary disorders Disorders of vitamin D
a) Defects of GH receptor or postreceptor signaling pathways (Laron Disorders of swallowing (e.g., vascular metabolism
syndrome and its variants) ring anomaly, megaesophagus)
4. Abnormalities of IGF-1 and IGF-1 receptor and signaling pathways Gastrointestinal and pancreatic disorders
(e.g., parasites, malabsorption, exocrine
Modified from Cooke DW, Divall SA, Radovick S: Normal and aberrant growth. In
pancreatic insufficiency)
Melmed S, Polonsky KS, Larsen PR, Kronenberger HM, editors: Williams textbook of
Hepatic disorders (e.g., portosystemic
endocrinology, ed 12, Philadelphia, 2011, Saunders Elsevier; and Styne D: Growth.
In Gardner DG, Shoback D, editors: Greenspan's basic & clinical endocrinology, ed 9, shunt, glycogen storage disease)
San Francisco, 2011, McGraw Hill. Hematological disorders
GH, Growth hormone; GHRH, GH-releasing hormone; IGF-1, insulin-like growth factor-1. Renal disorders
Immunological disorders
the most common causes for combined pituitary hormone deficiency. CNS disorders
LIM-domain transcription factor 3 (LHX3) belongs to a family of Abnormal bone growth
transcription factors that are essential for the development of the pitu- (e.g., chondrodystrophy)
itary gland and the nervous system. Mutations in the LHX3 gene Modified from Ihle SL: Failure to grow. In Ettinger SJ, Feldman EC, editors: Textbook
(recently shown to be associated with pituitary dwarfism in German of veterinary internal medicine, ed 7, St. Louis, 2010, Saunders Elsevier; and Styne
Shepherds) are a rare cause of hypopituitarism in humans; affected D: Growth. In Gardner DG, Shoback D, editors: Greenspan's basic & clinical endocri-
individuals have GH, TSH, prolactin, FSH, and LH deficiencies, nology, ed 9, San Francisco, 2011, McGraw Hill.
whereas ACTH synthesis is most often normal. The phenotypes with CNS, Central nervous system; GH, growth hormone; IGF-1, insulin-like growth factor-1.
LHX3 mutations are similar to those of the PROP1 defect; however, * Terms adapted from human medicine (Styne, 2011).
short rigid cervical spine with limited head rotation is an additional
feature. The genetic defects may be associated with structural defects
CONGENITAL HYPOSOMATOTROPISM (PITUITARY
of the pituitary and other parts of the brain as well as in other parts
DWARFISM) IN DOGS AND CATS
of the body (Kelberman etal, 2009; Cooke etal, 2011; Metherell
etal, 2011). Dysfunction of the GH-IGF-1 axis may also be caused
Etiopathogenesis
by GH insensitivity and IGF-1 associated abnormalities. GH insen-
sitivity, referred to as primary IGF-1 deficiency, comprises a variety Any defect in the hypothalamus-anterior pituitary axis and in
of genetic syndromes characterized by high GH levels and very low pituitary organogenesis may result in isolated or combined pituitary
IGF-1 levels. Those findings have been first described by Laron. The hormone deficiency. Congenital hyposomatotropism is certainly the
abnormalities are therefore also collectively known as Laron syndrome. most striking example of pituitary hormone deficiency (Kooistra,
The disorders reflect defects at the GH receptor or in postreceptor 2010). Congenital hyposomatotropism or pituitary dwarfism is long
signaling pathways (Cooke et al, 2011). For more details on tran- known as autosomal recessive disorder in the German Shepherd dog
scriptional control of pituitary development and genetic defects in and the Karelian Bear dog (Andresen and Willeberg, 1976 and 1977).
the human GF-IGF-1 axis, see Savage, etal. (2003), Kelberman, etal. Genealogical investigations by Andresen in 1978 indicated that the
(2009), and Savage, etal. (2011). mutation evolved around 1940 or even before. Several champion
dogs were shown to be carriers of the genetic defect, which was
Dogs and Cats certainly one of the reasons why the disease spread all around the
world (Andresen, 1978; Nicholas, 1978; Voorbij and Kooistra, 2009;
As in humans, failure to grow in dogs and cats may be caused by Kooistra, 2010). It is assumed that the genetic defect in the Karelian
non-endocrine and endocrine disorders (Box 2-3). Non-endocrine Bear dog is the same as in the German Shepherds, because both
causes comprise malnutrition, dysfunction of nearly any organ breeds were crossed in Finland in the 1940s (Andresen and Willeberg,
in the body, as well as any chronic disease. In dogs and cats, 1976). The situation is similar for the Saarloos Wolfhound and the
there is also a counterpart to human constitutional and familial Czechoslovakian Wolfdog, in which pituitary dwarfism is also known,
short stature, because individual dogs or cats may be somewhat and the German Shepherd has been used for breeding. It is possible
smaller than their littermates, and certain dog families within a that the defect is also present in other breeds in which a German
breed may also be smaller than other families of the same breed. Shepherd carrier has been used. For instance, GH deficiency was
Congenital hyposomatotropism and congenital hypothyroidism described in a litter of Weimaraner dogs; however, three generations
are endocrinopathies usually causing serious growth failure. Early previously, a mismating to a German Shepherd had occurred (Roth
development of other endocrinopathies such as diabetes mellitus, etal, 1980).
hyperadrenocorticism, hypoadrenocorticism, and disorders of Initially, it was assumed that the hormone deficiency was
vitamin D metabolism may also be associated with impaired growth. the result of pressure atrophy of the anterior pituitary gland by
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pituitary cysts. Those cysts may develop from remnants of the

distal craniopharyngeal duct (Rathke pouch), which normally
disappears at birth. Occasionally, they may become large, exert
pressure on the infundibular stalk, the hypophyseal portal system,
median eminence, or pars distalis and cause pituitary atrophy
due to compression and impaired blood supply. Rupture of
large cysts and escape of their proteinaceous content may lead to
inflammation, subsequent fibrosis, and reduced pituitary function.
Cystic remnants are relatively common and occur in many breeds.
Most often they are small and clinically insignificant (Capen,
2007). Further research indicated that the developmental defect in
German Shepherd dwarfs is different from those craniopharyngeal
remnants. Severe hypoplasia of the anterior pituitary has been
found in German Shepherds with very small cysts, which were
considered unlikely to be responsible for pressure atrophy. In
some dwarfs, there may even be no cysts at all (Kooistra et al, A
1998; Hamann etal, 1999; Kooistra etal, 2000a). According to
current knowledge, pituitary dwarfism in the German Shepherd
dog (and Karelian Bear dog and Saarloos Wolfhound) is caused
by a failure of the oropharyngeal ectoderm of the Rathke pouch
to differentiate into normal trophic-hormone-secreting cells of
the pars distalis. Accumulation of proteinaceous material may
follow, which may lead to cystic changes attracting water. This
assumption is compatible with the observation that cysts may
enlarge with time (Fig. 2-6). Cyst formation therefore is most
likely a consequence and not the cause of pituitary dwarfism
(Kooistra etal, 1998; Kooistra etal, 2000a; Capen, 2007).
In line with the assumption of complex failure of cell differ-
entiation is the finding that the secretory capacity of other pitu-
itary cells than the somatotrophs is also impaired. Kooistra, etal.
(2000a) studied the release of GH, TSH, prolactin, FSH, LH,
and ACTH in a combined pituitary function test using four
releasing hormones (GHRH, TRH, gonadotropin-releasing hor- B
mone [GnRH], and corticotropin-releasing hormone [CRH]) in FIGURE 2-6 A, Contrast-enhanced computed tomography (CT) images of a
a group of eight German Shepherd dwarfs. Basal GH, TSH, and 6-month-old German Shepherd dwarf with a pituitary of normal size (height 3.6
prolactin were significantly lower than those of healthy controls mm, width 4.3 mm) but having a radiolucent area due to a cyst (arrow). B, At
and did not respond to stimulation. Basal LH was not different the age of 3 years, the pituitary is enlarged (height 6.5 mm, width 5.4 mm), and
from basal LH of controls; however, stimulation was significantly the greater part of it lacks contrast enhancement due to the cyst. (Reproduced
less. With regard to FSH, a gender difference was obvious. In male with permission from Meij BP, etal.: Hypothalamus-pituitary system. In Rijnberk
dwarfs, basal and stimulated FSH concentrations were undetect- A, Kooistra HS, editors: Clinical endocrinology of dogs and cats, ed 2, Hannover,
ably low; in female dwarfs, basal FSH levels were measurable, 2010, Schltersche.)
however, somewhat lower than in age-matched female controls,
and there was only a slight increase after stimulation. Basal ACTH
and ACTH concentrations after stimulation were not different to in principle fit with the phenotype in German Shepherd dwarfs
controls (Fig. 2-7 and Fig. 2-8). In summary, German Shepherds because a defect results in combined deficiency of GH, TSH,
were shown to have a combined deficiency of GH, TSH, and pro- prolactin, LH, and FSH. However, PROP1 was also excluded as a
lactin, together with impaired release of gonadotropins. In con- candidate gene (Lantinga-van Leeuwen etal, 2000b). Thereafter,
trast, ACTH secretion is preserved (Kooistra etal, 2000a). factors acting at earlier stages of the pituitary development were
During the last decade, an extensive search was performed, mostly investigated. The LHX4 gene was also excluded as a candidate
at the University of Utrecht, to identify the causative defect. Please gene, as well as the leukemia inhibiting factor receptor gene.
see Fig. 2-2 for the differentiation of pituitary cell lineages and Leukemia inhibitor factor (LIF) is a pleiotropic cytokine that
the main important transcription factors involved. As mentioned plays an important role in the ontogeny of the anterior pituitary
earlier, mutations in the POU1F1 (or PIT1) and PROP1 genes gland (Van Oost etal, 2002; Hanson etal, 2006). More recently,
are the most common defects associated with pituitary hormone the search was successful, and the genetic defect could be located
deficiency in humans. It was, therefore, reasonable to explore in the LHX3 gene (Voorbij et al, 2011). LHX3 is a member
potential defects in those two genes also in the German Shepherd. of a family of transcription factors (the LIM homeodomain
However, the gene encoding for transcription factor POU1F1 family) that are critical for cell specialization during embryonic
(or PIT1) was the first one to be excluded as a candidate gene development and essential for the development of the pituitary
for pituitary dwarfism. This was in agreement with the hormone gland and the nervous system. In humans, defects in the LHX3
studies described earlier, because a defect in the POU1F1 gene gene are associated with combined pituitary hormone deficiency
would only cause GH, TSH, and prolactin deficiency, whereas LH, (usually ACTH secretion is preserved); this is very similar to the
FSH, and ACTH would not be affected (Lantinga-van Leeuwen findings in the German Shepherd dwarfs. A genetic test is now
etal, 2000a; Kooistra etal, 2000a). PROP1 gene mutation would available through the University of Utrecht and several other
20 40
15 30
Prolactin (g/L)
GH (g/L)
10 20
5 10
0 0
15 0 15 30 45 15 0 15 30 45
Time (min) Time (min)
1.20 30
1.00
0.80 20
TSH (g/L)
LH (g/L)
0.60
0.40 10
0.20
0.00 0
15 0 15 30 45 15 0 15 30 45
400
300
ACTH (ng/L)
200
100
0
15 0 15 30 45
Time (min)
FIGURE 2-7 Results of a combined pituitary anterior lobe function test (mean and standard error of the mean
[SEM]) in eight German Shepherd dogs with dwarfism ( ) and in eight adult healthy Beagle dogs (). The bars
indicating the SEM in the German Shepherd dwarfs are only depicted when they exceed the size of the sym-
bols. (Reproduced with permission from Kooistra HS, etal.: Combined pituitary hormone deficiency in German
Shepherd dogs with dwarfism, Domest Anim Endocrinol 19[3]:177-190, 2000.) ACTH, Adrenocorticotropic hormone;
GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
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30 30
Female dogs Male dogs
20 20
FSH (U/L)
FSH (U/L)
10 10
0 0
15 0 15 30 45 15 0 15 30 45
FIGURE 2-8 Basal and stimulated plasma follicle-stimulating hormone (FSH) concentrations in three female and
four male German Shepherd dogs with dwarfism ( ) and in two healthy female and two healthy male Beagle dogs of
the same age (). FSH, Follicle-stimulating hormone. (Reproduced with permission from Kooistra HS, etal.: Combined
pituitary hormone deficiency in German Shepherd dogs with dwarfism, Domest Anim Endocrinol 19[3]:177-190, 2000.)
laboratories, which enables the diagnosis of pituitary dwarfism and inheritance (Andresen and Willeberg, 1976 and 1977). Pituitary
the identification of carriers of the mutation. dwarfism has also been seen in the Weimaraner, Spitz, Miniature
There may be additional abnormalities in the GHRH-GH- Pinscher, Golden Retriever, Labrador Retriever, and cats. No
IGF-1 axis in dogs; however, no studies have been performed. studies with regard to genetic defects have been performed in
Randolph, et al. (1990) reported on two German Shepherd those breeds. There does not seem to be a gender predilection.
littermates showing stunted growth during the first weeks to
months but thereafter growing at steady rate and reaching normal
Clinical Manifestations
height at 1 year of age. Functional testing did not reveal any
hormonal abnormalities. Interestingly, two other littermates were The clinical manifestations of pituitary dwarfism are the result of
euthanized at early age, and hypoplasia of the anterior pituitary hormone deficiency, in particular lack of GH and TSH. Normal
gland as well as reduced number of cells was demonstrated. The GH levels (and normal IGF-1 levels) in concert with normal
authors hypothesized that the delayed growth of the two surviving thyroid function are essential for linear growth and physiological
dogs may represent one end of a clinical spectrum associated with bone development. Lack of gonadotropins leads to hypogonadism
pituitary dwarfism in German Shepherd dogs. Mller-Peddinghaus, and infertility.
etal. (1980) described a German Shepherd dwarf with high GH Pituitary dwarfs are most often presented to the veterinarian at
concentration and very low IGF-1 concentration, which is a the age of 3 to 5 months due to growth retardation and skin and
constellation typically seen in Laron disease (GH insensitivity) in hair coat abnormalities. During the first 1 to 2 months, the affected
humans. So far, similar cases have not been reported. animals are usually normal in size; thereafter, their growth rate is
Congenital hyposomatotropism has also been described in cats slower than that of their normal littermates. By the age of 3 to
(Donaldson etal, 2008); however, it seems to be extremely rare. 4 months, they are obviously undersized, and they usually never
attain full adult height (Feldman and Nelson, 2004). The growth
Signalment failure in pituitary dwarfism is proportionate (i.e., the patient has
normal body contour and just looks like the miniature version of
Pituitary dwarfism occurs primarily in the German Shepherd the same breed) (Fig. 2-9 and Fig. 2-10). In contrast, in congenital
dog, although it is also seen in the Karelian Bear dog, the Saarloos hypothyroidism growth failure is disproportionate (i.e., the affected
Wolfdog, and the Czechoslovakian Wolfdog. In the German animals have thick broad heads and short limbs). The pituitary
Shepherd dog the genetic defect has recently been identified dwarfs often have a pointed muzzle, resembling that of a fox (Meij
(Voorbij etal, 2011), and it seems that the defect is identical in et al, 2010a). Closure of the growth plates is usually delayed,
the Karelian Bear dog and the Wolfhound breeds in which the fontanelles of the skull may remain open, and there may be some
German Shepherd has been used for breeding. In the German delay in dental eruption, but dentition is otherwise normal.
Shepherd and the Karelian Bear dog, the disease has been known The most obvious dermatological sign is a soft and wooly hair coat
for many years to be transmitted through autosomal recessive because the puppy coat of secondary hairs is retained. Primary or
BOX 2-4 C
linical Signs Associated with Pituitary
Dwarfism
Musculoskeletal
Stunted growth (proportionate, normal body contours)
Fox-like facial features
Thin skeleton
Changes in ossification centers
Delayed closure of growth plates
Delayed dental eruption
Muscle atrophy
Dermatologic
Soft, wooly hair coat
Retention of secondary hair
FIGURE 2-9 A 12-month-old male German Shepherd with pituitary dwarfs. There Lack of primary, guard hair
is obvious growth failure with normal body contours, foxlike face expression, alo- Bilateral symmetrical alopecia (neck, trunk, proximal extremities)
pecia, and hyperpigmentation. Hyperpigmentation of skin
Thin, wrinkled skin
Scales
Comedones
Papules
Pyoderma
Reproduction
Uni-or bilateral cryptorchidism
Testicular atrophy
Flaccid penile sheath
Persistent anestrus
Other signs
Puppy-like, shrill bark
Lethargy
Listlessness
FIGURE 2-10 An 8-month-old male Domestic Short-Haired cat with pituitary Inappetence
dwarfism. The cats size was similar to that of an 8-week-old kitten; body con- Mental dullness
tours were normal. (Reproduced from Feldman EC, Nelson RW: Disorders of Signs of secondary hypothyroidism
growth hormone. In Feldman EC, Nelson RW, editors: Canine and feline endocri-
Modified from Feldman EC, Nelson RW: Disorders of growth hormone. In Feldman
nology and reproduction, St Louis, 2004, Saunders.)
EC, Nelson RW, editors: Canine and feline endocrinology and reproduction, St.
Louis, 2004, Saunders; and Voorbij AMWY, Kooistra HS: Pituitary dwarfism in
guard hair does not develop or is often only present on the face and German Shepherd dogs, J Vet Clin Sci 1:4, 2009.
distal extremities. The stagnant development of skin and hair coat
leads to increasing hair loss; initially, hair loss is confined to the areas of normal size. Likewise, the severity of the other clinical signs may
of wear, such as the neck (from collar) and posterolateral aspects of the also vary. The variation in severity as well as time of onset and rapid-
thighs (from sitting). With time, the entire trunk, neck, and proximal ity of deterioration is probably related to the degree of penetrance
limbs become alopecic with primary hairs remaining only on the of the defect. The degree to which the oropharyngeal ectoderm fails
face and distal extremities (Feldman and Nelson, 2004; Meij etal, to develop into normal trophic-hormone cells is variable, and the
2010a; Miller et al, 2013). The skin is initially normal, but it becomes rapidity with which the pituitary cysts enlarge and exert pressure
progressively hyperpigmented, scaly, thin and wrinkled; comedones, atrophy is also different between individuals (Capen, 2007).
papules, and pyoderma are common with increasing age (Feldman and
Nelson, 2004). In the male dwarf, uni- or bilateral cryptorchidism, Clinical Pathology
testicular atrophy, flaccid penile sheath, and azoospermia are typical
manifestations of the gonadotropin deficiency, which is part of the Results of hematology, serum biochemistry profile, and urinalysis are
combined pituitary deficiency. In the female dwarf, persistent anestrus often normal. There may be mild anemia, hypophosphatemia, and
is common, or estrus is irregular. Most dwarfs continue to have a hypoalbuminemia (Eigenmann, 1982a). Azotemia may be present as
puppy-like, shrill bark. They are usually lively and alert as long as they a result of abnormal glomerular development and decreased glomeru-
are young; however, at approximately 2 to 3 years of age, they start to lar filtration associated with GH and thyroid hormone deficiencies
become lethargic, inactive, dull, and lose appetite. These changes may (Kooistra, 2010). Hypercholesterolemia may be seen as a result of
reflect the deficiency of TSH (i.e., secondary hypothyroidism), the secondary hypothyroidism.
progressive enlargement of the pituitary cysts, and the development
of renal insufficiency (Andresen, 1978; Feldman and Nelson, 2004; Dermatohistopathology
Meij etal, 2010b; Box 2-4).
The degree of growth failure is variable. Adult dogs with pituitary The histopathological abnormalities in dogs with pituitary dwarfism
dwarfism may be as small as 2 kg of body weight or up to nearly half are consistent with an endocrine disorder and similar to findings
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in many other endocrinopathies. They include varying degrees of All German Shepherd dwarfs tested at the University of Utrecht
orthokeratotic hyperkeratosis, follicular hyperkeratosis, follicular during the last 3 years (i.e., since the availability of the genetic
dilatation, follicular atrophy, hair follicles predominantly in telogen test) had the LHX3 mutation (H.S. Kooistra, personal communi-
phase, excessive trichilemmal keratinization, sebaceous gland atrophy, cation, 2013). The test requires 2 mL of randomly sampled ethyl-
epidermal melanosis, and thinning of the dermis. A decreased enediaminetetraacetic acid (EDTA) plasma.
amount and size of dermal elastin fibers have been considered a Pituitary dwarfism in other breeds than the German Shepherd
highly suggestive finding; however, this issue is controversial. In case (and related breeds) and in cats is extremely rare. This means that
of secondary hypothyroidism, vacuolated or hypertrophied arrector in most cases the disease can be diagnosed by genetic testing. In
pili muscles may be present (Miller etal, 2013). the very few cases in which genetic testing is negative or testing is
inappropriate (e.g., cats) measurement of GH after stimulation with
Differential Diagnosis GHRH, clonidine, or xylazine is the test of choice. Unfortunately,
GH measurement is only done in very few laboratories (e.g., Univer-
Stunted growth may be due to various non-endocrine and sity of Utrecht). If GH measurement is unavailable, the veterinarian
endocrine disorders (see Box 2-3). The possibility should also should first exclude the various endocrine and non-endocrine causes
be considered that the patient is just a small individual within for growth failure (see Box 2-3). In disproportionate dwarfs, evalu-
the normal biological variation, or that the small stature is the ation of thyroid function should primarily be pursued (see Chapter
result of an unrecognized mating with a small sire (Meij et al, 3). Thereafter, measurement of IGF-1 may be pursued as a surro-
2010b). The cause of growth failure may also be feeding a low- gate for GH measurement. False positive results (i.e., low IGF-1 due
caloric or poorly composed diet, heavy intestinal parasitism, or to other reasons) may occur, and therefore test results need to be
the administration of glucocorticoids at an early age. A detailed interpreted with care (see Hormonal Evaluation).
history (including dietary history and deworming program),
physical examination, and routine laboratory evaluation Basal Growth Hormone
(hematology, serum biochemistry profile, urinalysis, and fecal Similar to the situation in many other endocrinopathies, measure-
evaluation for parasites) helps to narrow the list of differential ment of circulating basal hormone values is of little diagnostic rel-
diagnosis. Depending on the results, further step-by-step evance in the work-up of animals with suspected pituitary dwarfism.
work-up should be pursued, including tests such as liver function Various studies showed that random basal GH concentrations of
tests, measurement of circulating trypsinlike immunoreactivity pituitary dwarfs overlap largely with those of healthy dogs. Healthy
(TLI), radiology of skeletal abnormalities, ultrasonography, dogs may at times have low to undetectable GH levels, because GH
and echocardiography. Congenital hypothyroidism may be the is secreted in pulses and GH may be very low between the normal
most important differential diagnosis, although the dogs look pulses (Eigenmann, 1982b; Eigenmann etal, 1984d; Kooistra etal,
quite different. Congenital hyposomatotropism is associated 2000a; Bhatti etal, 2006c). Eigenmann, etal. (1984d) reported basal
with proportionate dwarfism, whereas animals with congenital GH levels of 0.48 0.09 g/L in German Shepherd dwarfs and of 1.5
hypothyroidism are disproportionate dwarfs. Usually, congenital 1.2 g/L in healthy dogs. In the study of Kooistra, etal. (2000a),
hypothyroidism is a primary thyroid disease (i.e., the defect lies basal GH levels ranged between 0.3 to 1.5 g/L (mean 0.5) in the
within the thyroid gland; e.g., thyroid dysgenesis, defective thyroid German Shepherd dwarfs and between 0.6 to 5.2 g/L (mean 1.8)
hormone synthesis) or is due to iodine deficiency. Secondary in healthy Beagle dogs. Bhatti, etal. (2006c) found basal GH levels
hypothyroidism (i.e., hypothyroidism due to TSH deficiency) has in German Shepherd dwarfs to be between 0.4 to 1.2 g/L (mean
been described, but it seems to be extremely rare. See Chapter 3 for 0.7) and 0.2 to 1.0 g/L (mean 0.6) in healthy Beagle dogs. Basal
further details on etiopathogenesis and diagnostic work-up. It is GH concentrations in healthy cats were reported to be 3.2 0.7 g/L
important to note that hyposecretion of TSH is usually part of the (Eigenmann etal, 1984b) and 1.2 1.0 g/L (Peterson etal, 1990).
combined pituitary hormone deficiency, which is typically seen in
pituitary dwarfism in the German Shepherd dog. In these dogs, Growth Hormone Stimulation Tests
the clinical manifestations of hypothyroidism are overshadowed A general rule for the work-up of endocrine disease is that the
by the pronounced deficiency of GH; this is in part because a confirmation of a hypofunctional state requires a stimulation test,
small but significant fraction of thyroid function is independent and confirmation of a hyperfunctional test requires a suppression
of TSH (Meij etal, 2010b; Brent and Davies, 2011). test (Eigenmann, 1982b). Consequently, confirmation of
hyposomatotropism requires the use of a stimulation test. Isolated
GH deficiency may be documented by a stimulation test using
Endocrinological Evaluation and Diagnosis
GHRH, clonidine, or xylazine. Stimulation with ghrelin has also
History and physical changes are often typical and highly suggestive been described (Table 2-1). For the diagnosis of combined pituitary
for pituitary dwarfism. As discussed earlier, pituitary dwarfism in the hormone deficiency, the combined pituitary function test, using
German Shepherd dog (and related breeds such as the Karelian Bear four releasing hormones, is an appropriate test. Circulating GH
dog, Saarloos Wolfhound, and Czechoslovakian Wolfdog) is due to concentrations are measured in blood samples taken at several
a mutation in the LHX3 gene (Voorbij etal, 2011). A dwarf with time points after the application of the stimulating substance. GH
this mutation has combined pituitary hormone deficiency, because deficiency is diagnosed if GH does not increase above a certain cut-off
this gene is important for the differentiation of all endocrine cells in value. A few important factors have to be considered with regard to test
the anterior pituitary, except for the corticotrophs. interpretation. First, GH deficiency may be complete or only partial.
In case of complete GH deficiency, there is absence of GH increase
Genetic Testing after stimulation. In case of partial GH deficiency, however, mild to
A genetic test for the LHX3 gene mutation is now available moderate response may be seen, which may overlap with the response
through the University of Utrecht and several other laboratories. If of healthy animals. The problem of overlapping GH levels also exists
a dwarf is tested positive for the mutation, further endocrinologi- in human medicine, where the cut-off between normal and abnormal
cal evaluations (including measurement of GH) are unnecessary. is matter of great debate and at least two provocative tests of assessing
TABLE 2-1 PROTOCOLS FOR GROWTH HORMONE STIMULATION TESTS
SUBSTANCE, DOSE, ROUTE TIME OF BLOOD SAMPLING

TEST OF ADMINISTRATION (MINUTES) NORMAL RESULTS ADVERSE REACTIONS
GHRH stimulation test Human GHRH, 1 g/kg, IV 0*, 5, 10, 20*, 30*, 45 GH > 5 g/L (poststimulation) None reported
Clonidine stimulation test Clonidine, 10 g/kg, IV 0*, 15*, 30*, 45, 60, 90 GH > 10 g/L (poststimulation) Sedation, bradycardia,
hypotension, dizziness,
aggressive behavior
Xylazine stimulation test Xylazine, 100 g/kg, IV 0*, 15*, 30*, 45, 60, 90 GH > 10 g/L (poststimulation) Sedation, bradycardia,
hypotension, dizziness,
aggressive behavior
Ghrelin stimulation test Human ghrelin, 2 g/kg, IV 0*, 5, 10, 20*, 30*, 45 GH > 5 g/L (poststimulation) None reported
GH, Growth hormone; GHRH, GH-releasing hormone; IV, intravenous. The reader should note that the original protocols include frequent blood sampling; not all of the blood samples are
required to decide if GH response is normal or insufficient. Blood samples should be taken at the time of peak GH response. Sampling may therefore be limited to times labeled with *.
Please see text for further details on handling of the blood samples. Also see text for discussion on the combined pituitary function test.
GH reserve are necessary before the diagnosis of GH deficiency 20

should be made (Cooke etal, 2011).
Secondly, availability of GH measurement in dogs is extremely
limited, because a species-specific, homologous assay has to be 15
used. Feline GH can reliably be measured in a radioimmunoassay
(RIA) developed for dogs (Kooistra, 2010). So far, no comparison
studies have been performed between different GH assays in GH (g/L) 10
veterinary medicine. In human medicine, one of the biggest
confounders in the evaluation of GH secretion is the variability
of the measured GH levels across different assays (Cooke et al, 5
2011). It is therefore of utmost importance that any GH assay
used in dogs (and cats) has been validated for the species and that
assay-specific reference ranges are available. 0
Thirdly, GH response to stimulation is known to be influenced by
30 15 0 15 30 45 60 75 90 105 120
various factors; their relevance, however, has not yet been thoroughly
investigated in dogs and cats. In humans (i.e., children with suspected
Time (min)
GH deficiency), GH stimulation tests should only be performed
after an overnight fast, because carbohydrates and fat suppress GH FIGURE 2-11 Plasma growth hormone (GH) response (mean standard error) in
secretion. Obesity also leads to an attenuated GH response. Testing eight healthy Beagle dogs after rapid (30-second) intravenous injection (arrow) of
should not be performed if the patient takes supraphysiological a combination of four hypothalamic releasing hormones () compared with single
doses of glucocorticoids, because these drugs suppress GH release stimulation with 1 g/kg GH-releasing hormone (GHRH) ( ). The area under the curve
(Cooke etal, 2011; Styne, 2011). Glucocorticoids are also known (AUC) and the increment (peak basal level at 0 min) in GH concentrations were not
to have a negative impact on GH release in dogs. In dogs with significantly different between combined and single stimulation test. (Reproduced
pituitary-dependent hyperadrenocorticism, GH release is suppressed with permission from Meij BP, etal.: Assessment of a combined anterior pituitary
after GHRH, clonidine, or xylazine (Peterson and Altszuler, 1981; function test in beagle dogs: rapid sequential intravenous administration of four
Regnier and Garnier, 1995; Meij etal, 1997). It appears likely, that hypothalamic releasing hormones, Domest Anim Endocrinol 13[2]:161-170, 1996).
GH response may also be impaired in animals receiving exogenous
glucocorticoids. Taken together, GH stimulation testing should 30 minutes), those samples are deemed unnecessary. Samples for GH
routinely be performed after an overnight fast in an otherwise measurement have to be handled carefully because rapid proteolytic
adequately nourished animal who has not received glucocorticoids. degradation of the hormone may occur. We routinely collect blood
None of the tests discussed below has been investigated in the cat. samples in EDTA-coated ice-chilled tubes and centrifuge them
immediately; the use of a cooled centrifuge is advantageous. Samples
GH-Releasing Hormone Test are stored at or below 20o C and are shipped to the laboratory on dry
The GHRH test using human GHRH has been shown to be a ice with express service (Rijnberk and Kooistra, 2010). There is a great
suitable test for the diagnosis of GH deficiency in dogs. Initial studies inter-individual variability of the normal GH response to GHRH.
in healthy dogs using varying doses of GHRH showed that GH rises Meij, etal. (1996a) investigated the GH response in eight healthy
within a few minutes after application of GHRH without any apparent Beagle dogs after the single administration of GH and compared it
clinical side effects. The use of 1 g/kg GHRH is similar effective as to the response after the combined administration of four releasing
the standard clonidine test (10 g/kg clonidine) (Abribat etal, 1989). hormones. Single GHRH application resulted in maximum GH
After collection of a zero blood sample, 1 g/kg of human GHRH is concentrations between 4.9 and 27.5 g/L (mean 14.7 3.7) after 10
injected intravenously and further blood samples are taken at 5, 10, minutes. Application of the combined stimulation test (see also later)
20, 30, and 45 minutes (Rijnberk and Kooistra, 2010). In some of leads to maximum GH concentrations of 5.4 to 24.8 g/L (12.6
the initial protocols, additional samples were taken after 60, 90, and 2.5) after 20 minutes. The GH responses did not differ between the
120 minutes; however, as the GH peak occurs early (between 10 and single and the combined test (Fig. 2-11). The study by Meij, etal.
|
(1996a) was performed in 1- to 6-year-old dogs (median 2 years). 45

In elderly Beagle dogs (7 to 12 years, median 10 years), the GH
response was considerably lower, confirming that GH responsiveness
to GHRH stimulation decreases with age (Bhatti etal, 2006b). In 40
German Shepherd dwarfs, basal GH was shown to be low and did
not respond to stimulation with GHRH (Hamann et al, 1999; 35
Kooistra etal, 2000a; see Fig. 2-7). As already mentioned earlier, it
may be difficult to differentiate partial GH deficiency from normal
because GH concentrations may overlap. A normal response would 30
Growth hormone (ng/mL)

be a poststimulation GH concentration above 5 g/L. GHRH may
not be available in some countries.
25
Stimulation with Ghrelin
Ghrelin is a GH secretogogue that stimulates GH release from 20
pituitary somatotrophs through the GHS-R. In contrast to
humans, administration of ghrelin does not stimulate the release
of other pituitary hormones in dogs (e.g., the effect is specific for 15
GH). GH responsiveness to ghrelin also decreases with age, which
is similar to the somatotrophic response to GHRH (Bhatti etal,
2002; Bhatti et al, 2006b). In eight healthy young Beagle dogs 10
Normal
(age 13 to 17 months, median 10), maximum GH concentration
after ghrelin ranged from 0.2 to 124 g/L (median 52). In six Ger-
5
man Shepherd dwarfs (age 9 to 21 months, median 12) maximum
GH increase after ghrelin was 0.7 to 4.1 g/L (median 1.9), which Dwarfs
was significantly lower compared to the healthy dogs. None of the 0
dwarfs had a GH release greater than 5 g/L; however, this was 0 15 30 45 60 90
also true for three of the healthy dogs (Bhatti etal, 2006c). Due to Time (min)
the relatively high number of false positive test results, the ghrelin FIGURE 2-12 Results of a clonidine stimulation test in normal dogs and nine
test appears to be inferior to the GHRH test and the clonidine or German Shepherd dogs with pituitary dwarfism. Clonidine, 10 g/kg body weight
xylazine test. was given intravenously at time 0. (Graph redrawn from data in Eigenmann
The ghrelin test was performed in all studies mentioned ear- JE, etal.: Growth hormone and insulin-like growth factor I in German Shepherd
lier by intravenous (IV) injection of 2 g/kg human ghrelin and dwarf dogs, Acta Endocrinol 105[3]:289-293, 1984. Reproduced from Feldman
sampling blood for GH measurement before injection and 5, 10, EC, Nelson RW: Disorders of growth hormone. In Feldman EC, Nelson RW, editors:
20, 30, and 45 minutes thereafter. Sample handling was done as Canine and feline endocrinology and reproduction, St Louis, 2004, Saunders.)
described for the GHRH test.
Clonidine Stimulation Test protocol as described by Eigenmann, etal. (1984d) includes the
Clonidine is a centrally-acting 2-adrenergic agonist that stimu- IV administration of 10 g/kg clonidine and sampling blood for
lates the release of GHRH and GH. The test was established for GH measurement before injection and 15, 30, 45, 60, and 90
use in dogs more than 30 years ago (Hampshire and Altszuler, minutes thereafter. Sample handling should be done as described
1981; Eigenmann and Eigenmann, 1981a). It can still be consid- for the GHRH test. An increase in GH above 10 g/L is considered
ered a suitable test for the diagnosis of GH deficiency. Clonidine a normal response (Eigenmann etal, 1984d).
doses ranging from 3 to 30 g/kg have been used by different
investigators. A dose of 10 g/kg is usually considered to be the Xylazine Stimulation Test
standard dose (Roth etal, 1980; Hampshire and Altszuler, 1981; Xylazine is a sedative analgesic that is structurally related to cloni-
Eigenmann and Eigenmann, 1981a; Feldman and Nelson, 2004). dine. Xylazine administration to healthy dogs results in GH release
GH increases within 10 to 15 minutes and reaches its peak 15 similar to the actions of clonidine (Hampshire and Altszuler,
to 30 minutes after the administration of clonidine; as seen after 1981), rendering the xylazine stimulation test a suitable test for
stimulation with GHRH, there is great inter-individual variability the diagnosis of GH deficiency. Adverse effects and their treat-
with regard to GH response. It is not clear if administration of ments are also similar to clonidine (see earlier). After taking a zero
clonidine to healthy dogs results in a more pronounced GH release sample, 100 g/kg xylazine are injected intravenously and further
than GHRH. Abribat, etal. (1989) found no difference between blood samples are taken as described for the clonidine stimulation
the GH response when 1 g/kg GHRH and 10 g/kg clonidine test. Test interpretation is similar to the clonidine stimulation test
were compared. Eigenmann, et al. (1984d) found a maximum (i.e., a GH increase greater than 10 g/L is considered a normal
GH release after clonidine of 44.4 13.9 g/L, whereas in a study response).
by Meij, etal. (1996a) GHRH resulted in a maximum GH release
of 14.7 3.7 g/L (see Fig. 2-11; Fig. 2-12). Adverse reactions to Combined Pituitary Function Testing and Evaluation of Thyroid
clonidine are possible, but they are more likely and more severe Function
with doses above 10 g/kg. They include sedation, bradycar- Lack of GH can occur as isolated GH deficiency, or in concert
dia, hypotension, dizziness, or aggressive behavior and may last with deficiencies of other pituitary hormones, called combined
15 to 60 minutes. If necessary, atropine can be used to combat pituitary hormone deficiency. The latter is present in the Ger-
bradycardia, IV fluids are indicated if hypotension is severe, and man Shepherd dwarfs (and related breeds) and includes a lack
yohimbine or atipamezole may be used as antagonists. The test of GH, TSH, and prolactin together with impaired release of
gonadotropins, whereas secretion of ACTH is preserved. The basal TSH concentrations were very low and did not increase
complexity of deficiencies was revealed by studies employing the after stimulation (Hamann etal, 1999; Kooistra etal, 2000a).
combined pituitary function test (Kooistra etal, 2000a). The dis- Corticotroph function is usually normal in pituitary dwarfism.
ease is due to a mutation in the LHX3 gene, and nowadays, a Performance of a CRH stimulation test with measurement of
genetic test replaces the combined pituitary function tests in the ACTH may be warranted in dwarfs that develop signs of corti-
German Shepherd (and related breeds). Pituitary dwarfism also sol deficiency (e.g., lethargy, inappetence, vomiting, weight loss)
occurs sporadically in other breeds, although very rarely. Because (Feldman and Nelson, 2004).
combined pituitary function tests have not been used in those
cases, it is not known how many of those have isolated GH defi- Growth Hormone Stimulation by Amino Acid Administration
ciency versus combined pituitary hormone deficiency. The origi- and Insulin-Induced Hypoglycemia
nal protocol of combined pituitary function tests consists of rapid In humans, administration of arginine or insulin-induced
(within 30 seconds) sequential IV injections of four releasing hor- hypoglycemia is used (amongst others) as tests to provoke GH
mones: CRH (1 g/kg), GHRH (1 g/kg), GnRH (10 g/kg) secretion. In dogs, however, the GH response after those stimuli
and TRH (10 g/kg). Blood samples are collected for the mea- is inconsistent, rendering the tests of limited use (Eigenmann
surement of ACTH, GH, LH, TSH, and prolactin prior to the and Eigenmann, 1981a).
administration and 5, 10, 20, 30, 45, 60, 90, and 120 min there-
after. Handling and storage of blood samples is done as described Measurement of Insulin-like Growth Factor-1 Concentration
with the GHRH test. When the combined test was compared with A deficiency in GH is associated with a low concentration of IGF-
the separate administration of the four releasing hormones, there 1. Different to GH concentrations, which rise and fall due to their
was no apparent inhibition or synergism with regard to ACTH, pulsatile secretion, circulating IGF-1 is stable throughout the day.
GH, and prolactin concentrations. LH and TSH responses were In human medicine, measurement of IGF-1 and IGF-binding pro-
less in the combined test; however, the difference in TSH secre- tein-3 (IGFBP-3) are used as additional tools to evaluate patients for
tion was minor. Adverse effects of the combined test included GH deficiency. The IGF-1 test, however, is known to have substan-
vomiting, hypersalivation, and restlessness in a few dogs, which tial limitations, because IGF-1 levels are influenced by various factors
disappeared within 5 minutes after the injection (Meij et al, including age, degree of sexual maturation, and nutritional status.
1996a; Meij etal, 1996b). The test has been modified slightly as Starvation lowers IGF-1 levels into ranges seen in children with GH
sampling at 60, 90, and 120 minutes was omitted (Kooistra etal, deficiency (Cooke etal, 2011). IGFBP-3 levels vary less with age and
2000a). Performance of the combined pituitary function test is are less dependent on nutritional status; however, sensitivity for GH
time consuming, expensive, and availability of some of the hor- deficiency in humans is only moderate (Styne, 2011). Eigenmann,
mone analysis is limited. To be considered normal, GH should et al. (1984d) reported mean IGF-1 levels in German Shepherd
increase above 5 g/L. However, this cut-off as well as the cut-offs dwarfs of 11 2 g/L, in healthy adult German Shepherds of 280
of the other hormones are assay-dependent. It should be noted 23 g/L, and in healthy immature German Shepherd of 345 50
that combined pituitary hormone deficiency is most likely more g/L. Very low IGF-1 levels in German Shepherd dwarfs were also
common than isolated GH deficiency. An alternative approach to found in other studies (Rijnberk etal, 1993; Kooistra etal, 1998;
the performance of the combined pituitary hormone deficiency Kooistra etal, 2000a; Knottenbelt and Herrtage, 2002). However,
would be to first document that the patient has GH deficiency by a low IGF-1 concentration should not be used as a sole criterion to
using one of the tests described earlier (stimulation with GHRH, diagnose GH deficiency. Starvation and illness may also lead to low
clonidine, or xylazine). Thereafter, a search for further hormone IGF-1 concentrations; and it should be remembered that specific
deficiencies may be limited to the evaluation of thyroid function. reference ranges are required because IGF-1 is age-dependent and
TSH deficiency is a common component of the combined pitu- correlates with body weight. Measurement of IGFBP-3 has not yet
itary hormone deficiency complex, and its documentation is of been described in pituitary dwarfs.
great importance, because normal thyroid function is required See the section Hypersomatotropism (Acromegaly) in Cats for
for physiological growth and development. Finding low basal more details on IGF-1 measurement.
thyroxine (T4) and free T4 concentrations, however, is not suf-
ficient to confirm that there is a lack of TSH. Basal T4 and free Diagnostic Imaging
T4 overlap between healthy and hypothyroid dogs, and low thy- Computed tomography (CT) or magnetic resonance imaging
roid hormone levels may be caused by various factors, such as (MRI) of the pituitary gland often reveals the presence of pitu-
nonthyroidal illness and drugs. Some dwarfs may have basal T4 itary cysts in dogs with pituitary dwarfism. In young dwarfs, the
in the lower range of normal and may even show some increase cysts are usually small; however, their size gradually increases with
when the TSH stimulation test is applied (Kooistra etal, 1998). age. Because healthy dogs may also have pituitary cysts, diagnosis
A low endogenous TSH level also does not confirm that there is a of pituitary dwarfism should not be based on pituitary imaging
lack of pituitary TSH production, because low levels are also seen (Kooistra, 2010).
in healthy dogs. For these reasons, evaluation of TSH deficiency
requires performance of the TRH stimulation test. For a com- Treatment
plete discussion of the TRH stimulation test, see Chapter 3. In
the study by Meij, etal. (1996b), basal TSH ranged between 0.07 In humans, GH of non-primate origin is not biologically active.
to 0.27 g/L in healthy dogs, and the injection of 10 g/kg TRH For many years, replacement therapy was therefore performed by
resulted in a rapid increase in plasma TSH levels. In the single using GH derived from human cadavers. In the 1980s distribu-
TRH test, maximum TSH concentration was 1.26 0.22 g/L at tion of human growth hormone (hGH) was ceased due to the
10 minutes. In the combined pituitary function test, maximum concern of a causal relationship with Creutzfeldt-Jakob disease. At
TSH was 0.85 0.17 g/L at 30 minutes. The TRH test should that time, recombinant human growth hormone (rhGH) became
be normal in cases with isolated GH deficiency. In the German available, which is now the accepted treatment for children with
Shepherd dwarfs with combined pituitary hormone deficiency, GH deficiency (Cooke et al, 2011). In dogs, the use of hGH,
|
rhGH, porcine, ovine, and bovine GH has been reported (Eigen- will be possible; usually, however, there is only a slight increase
mann, 1981a; Eigenmann and Patterson, 1984; Scott and Walton, in height. After a few months, the maximum possible treatment
1986; Schmeitzel and Lothrop, 1990; Van Herpen et al, 1994). success is usually achieved, allowing reduction in GH dose and fre-
The clinical response varied, which, however, may in several of quency of application. Long-term dose rates depend on the IGF-1
the cases not have been due to the substance itself, but due to levels, which should be maintained in the normal range for age
an erroneous assumption. Most of the studies were performed in and breed. Because GH is not only essential for linear growth but
dogs with adult onset alopecia, previously thought to be caused by is also important during adulthood, life-long treatment (albeit at a
acquired GH deficiency. However, there is now strong evidence lower dose) is recommended.
that the phenomenon in fact is not due to a lack in GH (see later). In children with GH deficiency, treatment is more successful
It is therefore not surprising that response to GH administration when the same weekly GH doses are administered in seven daily
was poor. Reports on GH treatment in congenital GH deficiency doses, instead of a 6 day/week or 3 day/week schedule (Cooke etal,
(i.e., in German Shepherds dwarfs) is limited to a low number 2011). A similar protocol has not been published for dogs yet.
of cases. In one study, use of rhGH had to be discontinued in a However, it may be a consideration to split the aforementioned
dwarf (and an adult Poodle with alopecia) after 1 month, because dose into smaller daily portions.
they collapsed and developed pale mucus membranes shortly The application of synthetic progesterone has been reported as
after the injection. Further investigations revealed the presence of an alternative treatment option to GH supplementation. In dogs,
antibodies to the human GH (Van Herpen etal, 1994). Porcine progesterone induces synthesis of GH in the mammary gland; as
GH is considered to be the better choice for treatment of con- discussed in Mammary Growth Hormone, this is a physiological
genital GH deficiency in dogs, because the amino acid sequences event in intact bitches and important for normal mammary
of porcine and canine GH are identical. Biosynthetic porcine gland development (van Garderen etal, 1997). Treatment of two
GH has been developed; however, at times availability may be a young German Shepherd dwarfs (one male, one female) with
problem. Due to the rarity of pituitary dwarfism, no studies have medroxyprogesterone acetate (MPA) was described by Kooistra,
been performed comparing different treatment regimens. The et al. (1998). The dogs were injected with 2.5 to 5.0 mg/kg
currently recommended initial dose for porcine GH is 0.1 IU/ MPA subcutaneously (starting dose of 5 mg/kg MPA), initially
kg body weight administered subcutaneously three times a week. at 3 week intervals and subsequently at 6 weeks interval. Primary
Dose adjustments should be based on clinical response and circu- hair started to grow after 9 weeks of treatment, and both dogs
lating IGF-1 levels. The goal is to have the IGF-1 levels increase developed a full hair coat within 6 months, body weight increased
into the normal range; because IGF-1 levels correlate with body substantially, and body size increased only slightly. Circulating GH
weight and are age-dependent, specific reference ranges have to and IGF-1 concentrations increased during treatment. Although
be used (Feldman and Nelson, 2004). GH administration may GH never exceeded the upper limit of the reference range, one of
lead to glucose intolerance and possibly to overt diabetes mellitus, the two dogs developed acromegalic features (soft tissue swelling
requiring cessation of treatment or dose reduction. Hypersensitiv- of the muzzle, the abdomen, and the feet), suggesting that there
ity reactions are also possible. Reevaluation of the patient should was an excessive exposure to GH. The most likely explanation is
be scheduled approximately every 4 to 6 weeks and should include that progesterone-induced GH secretion lacks the physiological
physical examination, measurement of blood glucose, and IGF-1 pulsatility of the pituitary GH. The daily secretion of GH may
concentrations; T4 concentrations should also be evaluated regu- have been too high despite normal plasma levels. Measurement
larly in dogs treated for secondary hypothyroidism. Improvement of circulating IGF-1 levels may be a better parameter to monitor
in hair coat and skin is usually seen within 6 to 8 weeks of treat- treatment and to assess if the dose of MPA is correct. Further
ment. Regrowth of secondary hair growth is relatively consistent, adverse effects were recurrent episodes of pruritic pyoderma in both
whereas regrowth of primary hair is more variable. Some dogs dogs and cystic endometrial hyperplasia with mucometra in the
develop a full hair coat (Fig. 2-13). The status of the growth plates female dog. The latter complication leads to the recommendation
at the time of initiation of GH therapy determines if linear growth that female dogs should be ovariohysterectomized before the start
of progestin treatment. The dogs stayed otherwise healthy for
at least 3 to 4 years (Kooistra et al, 1998). A similar approach
was taken by Knottenbelt and Herrtage (2002) who treated
three German Shepherd dwarfs (two female, one male) with
proligestone (PROL), 10 mg/kg every 3 weeks subcutaneously.
Two dwarfs were also supplemented with T4. Treatment resulted
in a substantial increase in IGF-1 levels, increase in body weight,
and development of a full hair coat in all three. Two of the dogs
developed acromegalic features, requiring temporary cessation of
PROL. Recurrent pyoderma and cystic endometrial hyperplasia
occurred in one dog each. None of the dogs in the two studies
developed hyperglycemia; it should, however, be kept in mind
that diabetes mellitus is a potential complication of progestin
(and GH) therapy. Development of mammary tumors is another
potential side-effect of progestin administration.
Treatment with progestins may be a suitable alternative to
porcine GH administration if the latter is unavailable. Both
FIGURE 2-13 The same German Shepherd dwarf as in Fig. 2-9 after 4 months of protocols certainly need refinement. As with GH treatment,
treatment with porcine growth hormone (GH) and thyroxine (T4). The dog developed regular reevaluations are mandatory, and they should at least
a full hair coat and the foxlike facial expression disappeared. Linear growth was include physical examination and measurement of blood glucose,
not achieved. IGF-1, and T4 concentrations.
German Shepherd dwarfs and dwarfs of related breeds suffer See the Consensus guidelines for the diagnosis and treatment of
from combined pituitary hormone deficiency. The lack of GH adults with GH deficiency for more details (Ho, 2007).
and TSH constitutes the biggest problem for normal growth and
development. In those dogs, treatment with GH or progestins
Dogs and Cats
should always be accompanied by life-long T4 administration.
The same accounts for dwarfs of other breeds with combined The categories listed in Box 2-5 as causes for acquired GH deficiency
pituitary hormone deficiency. Dwarfs with isolated GH deficiency in humans in principle also account for dogs and cats. It should be
(i.e., normal TSH response after TRH application) do not need noted, however, that knowledge on acquired GH deficiency in dogs
T4 supplementation. See Chapter 3 for details on dose and treat- and cats is extremely scarce.
ment monitoring. No treatment protocols have been described for Neoplastic, traumatic, vascular, inflammatory, and infectious
congenital hyposomatotropism in cats. disorders may result in pituitary destruction including the
somatotrophic cells. Depending on the extent of the destruction,
Prognosis other endocrine cell types of the pituitary gland may also be
involved, resulting in the deficiency of several pituitary hormones.
Dogs that are left untreated develop severe hair coat and skin In those cases, the clinical signs of GH deficiency are usually
abnormalities and become increasingly thin, lethargic, and dull. overshadowed by the signs caused by the deficiency of ACTH,
They usually die or are euthanized between 3 and 5 years of age. TSH, and vasopressin or by neurological dysfunction in case of
The poor condition is due to progressive loss of pituitary func- large masses. This statement is illustrated by two case reports on
tions, expansion of pituitary cysts, renal failure, or infections. lymphocytic and lymphoplasmacytic hypophysitis (Wolfesberger
Dogs that are treated with GH or progestins and T4 can live a etal, 2011; Meij etal, 2012a). One of the two dogs was presented
relatively healthy life for several years, provided that complications
(e.g., acromegaly, diabetes mellitus, pyometra, and pyoderma) are
avoided. The long-term prognosis, however, remains guarded; BOX 2-5 C
auses of Acquired Growth Hormone Deficiency
pituitary dwarfs usually do not have a normal life-expectancy in Adult Humans
(Feldman and Nelson, 2004; Meij etal, 2010b).
Traumatic
Surgical damage
ACQUIRED HYPOSOMATOTROPISM Radiation damage
Traumatic brain injury
Humans
Neoplastic
In humans, acquired GH deficiency is a well-recognized albeit Pituitary tumor
rare clinical entity. The partial or complete lack of GH has Craniopharyngioma
negative effects on multiple organs systems. The most important Hypothalamic tumor
of which are abnormal body composition (e.g., increased central Metastasis into pituitary
fat deposition, reduced skeletal muscle and lean body mass), Hematological malignancy
increase of cardiovascular risk factors (e.g., abnormal lipid profile, Parasellar mass (Rathke cyst, dermoid cyst, meningioma, and other brain
endothelial dysfunction, microvascular abnormalities, change in tumors)
cardiac size and function) and reduced bone mass. It also has
a negative impact on quality of life (i.e., due to a low energy Vascular
level and emotional liability) (Doga etal, 2006; Aragon-Alonso Subarachnoidal hemorrhage
etal, 2011; Melmed etal, 2011). The most common causes of Pregnancy-related
acquired GH deficiency are pituitary-hypothalamic tumors. In Aneurysm
affected patients, GH deficiency may develop either before or Apoplexy
after neurosurgery or radiation therapy. These scenarios account Arteritis
for more than 80% of cases. Other conditions associated with Inflammatory/Infiltrative
the risk of acquired GH deficiency are traumatic brain injury Primary hypophysitis (lymphocytic, granulomatous, xanthomatous)
and acute vascular injuries (e.g., subarachnoid hemorrhage and Secondary hypophysitis (sarcoidosis, histiocytosis X)
inflammatory/infectious disorders) (Ghigo etal, 2008; Melmed, Hemochromatosis
2013; Box 2-5). Acquired GH deficiency may occur as isolated Immune-mediated (Pit-1 antibodies)
deficit. It is, however, often associated with the failure of other cell
types in the anterior pituitary gland. Because somatotrophs are Infection
the most sensitive cells to pituitary insults, GH deficiency usually Tuberculosis
precedes the development of multiple failure (Melmed, 2013). Fungal (histoplasmosis, aspergillosis, pneumocystis)
There is some controversy on the topic of so-called idiopathic Parasitic (toxoplasmosis)
adult GH deficiency. The GH Deficiency Consensus Workshop Viral (cytomegalovirus)
states that idiopathic isolated GH deficiency is not a recognized Hormonal
diagnosed entity (Ho, 2007). Nevertheless, about 15% of Hyperparathyroidism
humans with adult GH deficiency are reported as suffering from Glucocorticoids
an idiopathic cause. Those patients, however, may at least in part Somatostatin analogs
reflect a group of individuals with unclear or incomplete medical
Idiopathic?
history (e.g., forgotten past sports head injury or car accident)
and incomplete work-up, inadequate biochemical testing, or Modified from: Melmed S: Update: idiopathic adult growth hormone deficiency, J Clin
with a yet to be defined occult defect (Melmed, 2013). Endocrin Metabol 98:2187, 2013.
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with progressive anorexia, weight loss, and cachexia. Histopathology The affected dogs are otherwise clinically unremarkable. Diagnosis
and immunohistochemistry of the pituitary gland revealed severe is by exclusion of endocrinopathies, such as hypercortisolism,
lymphoplasmacytic adenohypophysitis and marked reduction hypothyroidism, hyperestrogenism, hyperprogesteronism (a
of ACTH- and GH-positive cells, as well as some reduction of very rare event in some adrenocortical or testicular tumors), and
prolactin-positive cells. The zona fasciculata and reticularis of the conditions such as cyclic flank alopecia, follicular dysplasia, or
adrenal cortex were atrophied, and the dogs sudden death was sebaceous adenitis. Skin biopsies show changes typically seen in
attributed to secondary adrenocortical insufficiency resulting from endocrinopathies. A 100% reliable discrimination of Alopecia X
the ACTH deficiency (Wolfesberger et al, 2011). The other dog from the other disorders is not possible. However, so-called flame
suffered from polyuria and polydipsia, exercise intolerance, and a follicles appear to be more prominent and abundant than in the
dull hair coat. Central diabetes insipidus, secondary hypothyroidism, other dermatopathies. They are sometimes diffusely interspersed in
and hyposomatotropism were diagnosed during endocrinological a biopsy specimen. Flame follicles are characterized by large spikes
work-up. The dog was finally euthanized, and the histological of fused keratin appearing to protrude through the outer root sheath
diagnosis was lymphocytic hypophysitis (Meij et al, 2012a). It to the vitreous layer, creating a fiery effect (Gross etal, 2005).
remains unclear whether GH deficiency contributed to the clinical Various treatments have been used in those dogs, including
signs of lethargy and dull hair coat, because both symptoms may GH, castration, melatonin, mitotane, and trilostane. They are
have also been exclusively caused by secondary hypothyroidism. not always effective, and because hair cycle arrest is a cosmetic
Multiple hormone deficiency including lack of GH has disease, the risk of treatment has to weigh against the benefit. See
been demonstrated to occur in dogs after transsphenoidal the comprehensive review of Frank (2005) and the section on hair
hypophysectomy. Those dogs are cured from their pituitary- cycle arrest in the latest edition of Muller and Kirks Small Animal
dependent hypercortisolism (which was the reason for surgery) Dermatology (Miller etal, 2013) for more details, as well as the
and are supplemented with T4 and glucocorticoids; however, previous edition of this textbook for the references of the multiple
some of them do not regain normal liveliness, muscle mass, or studies performed on this topic. The earlier section is a summary
hair coat. It has been assumed, that these signs may reflect GH of the text of Frank (2005) and Miller, etal. (2013). The study
deficiency and that treatment with porcine GH or progestins of Cerundolo, etal. (2007) on assumed mild hypercortisolism as
may bring improvement (Meij et al, 2010a). The possibility of the cause of the disorder might also be interesting for the reader.
radiation therapy of pituitary masses leading to GH deficiency in The strong predilection and familial accumulation suggests a
dogs has not yet been investigated. hereditary background (Mausberg etal, 2007a). Genetic studies
For many years, veterinarians have hypothesized that in some have been initiated and a few candidate genes have already been
breeds acquired GH deficiency may be the cause of bilateral sym- excluded (Mausberg etal, 2007b; Mausberg etal, 2008).
metrical alopecia and hyperpigmentation. The affected breeds In summary, there is no evidence that the alopecic disorder in the
include those with double coat and dense undercoat, such as breeds listed earlier is due to acquired GH deficiency. Until further
Pomeranian, Alaskan Malamute, Chow Chow, and Keeshond. It studies bring light into the issue, the disorder might continue to be
has also been seen in Miniature and Toy Poodles. For some time, termed Alopecia X, which is a term used by many dermatologists.
imbalance within the steroid biosynthesis pathway in the adrenal
cortex (i.e., partial deficiency of the 21-hydroxylase enzyme) was
HYPERSOMATOTROPISM (ACROMEGALY) IN
favored as an alternative cause.
HUMANS
Over time, the disorder has been termed adult-onset GH
deficiency, GH-responsive alopecia, castration-responsive alopecia, In 1886, Pierre Marie, a French neurologist published the first
biopsy-responsive alopecia, black skin disease, and congenital adrenal description of GH excess and proposed the name acromegaly
hyperplasia-like syndrome. More recently, the term Alopecia X (Melmed and Kleinberg, 2011). The term derives from the Greek
was created, reflecting the mystery of the disease. The theory of words akron (extreme or extremity) and megas (large) and is used
an acquired GH deficiency was discarded when various studies until today to describe the disease in adults, in which there is local
revealed normal GH response after stimulation and normal IGF-1 overgrowth of bone. GH excess in childhood and adolescence
levels in many of the affected dogs. Similarly, abnormal adrenal leads to linear growth and large stature, which is termed gigantism.
steroid precursor or sex hormone production turned out to be Acromegaly was traditionally considered to be a rare disorder with
highly unlikely. The reason, why some of the affected dogs show an estimated prevalence of 30 to 40 individuals per million. More
suppressed GH response remains speculative. Glucocorticoids recently, it is assumed that the prevalence is much higher, ranging
are known to increase somatostatin release, thereby interfering between 100 to 130 cases or being even up to 1000 cases per million
with GH release. It may be that some of those dogs had received (Chanson et al, 2009). In more than 95% of affected humans,
exogenous glucocorticoids before referral for further work-up, the disease is due to a GH-producing adenoma in the anterior
in others, ACTH stimulation test and low-dose dexamethasone pituitary gland. Acromegaly may also be induced by extra-pituitary
(resulting in increased steroid concentrations) test may have been disorders, but these are rare events (Melmed and Kleinberg, 2011).
performed prior to GH testing. Recently, mild hypercortisolism has Approximately 60% of the pituitary adenomas are pure GH-secreting
been proposed as cause of the disease in Miniature Poodles and adenomas of the somatotrophic cells, which are histologically
Pomeranians. The age of onset of the disease is usually between 9 classified into two variants: they contain either densely granulated
months and 2 years; however, it may also occur much later in life. or sparsely granulated staining cytoplasmic GH vesicles. Biological
The initial signs are hair loss in areas of wear (collar, caudal thighs) behavior differs because sparsely granulated GH adenomas are
slowly progressing to nearly complete alopecia of the trunk, neck, more likely to be locally invasive and grow faster than their densely
and proximal legs, sparing head, distal legs, and distal tail. In some granulated counterpart; they also occur at younger age (Lopes, 2010).
animals, a sparse, wooly hair coat remains. An interesting finding Most of the remaining pituitary adenomas secrete GH and prolactin
is the very focal regrowth of hair after skin biopsy or focal trauma and occur as three different tumor types: mixed GH cell/prolactin
in some cases. Hyperpigmentation develops at the same time as cell adenoma, mammosomatotroph cell adenoma, and acidophilic
alopecia; however, it may be absent, in particular in white poodles. stem cell adenoma. Mixed GH cell/prolactin cell adenomas resemble
GH-secreting adenomas, but are bimorphous tumors with two separate

cell populations, GH cells and prolactin cells. Mammosomatotroph BOX 2-6 Causes of Acromegaly in Humans
adenomas contain monomorphous cell populations, and GH and
prolactin is present in the same tumor cell. Acidophilic stem cell Growth HormoneProducing Pituitary Tumor
adenomas are very rare and are composed of a single population of Adenoma
immature cells with features reminiscent of GH cells and prolactin GH-secreting (densely and parsley granulated)
cells. In affected patients, symptoms of hyperprolactinemia dominate Mixed GH cell/prolactin cell adenoma
the clinical picture (Lopes, 2010). Mixed GH- and TSH-secreting Mammosomatotroph adenoma
adenomas, or adenomas also secreting ACTH, are rare (Chanson Acidophilic stem cell adenoma
et al, 2009). The large majority of GH-producing tumors are GH-/TSH-secreting adenoma
adenomas. GH secreting pituitary carcinomas are the exception. The Other plurihormonal adenoma
origin of the somatotroph adenoma is not yet clear. The fact that the Carcinoma
adenomas are monoclonal in nature and usually do not relapse after Extra-Pituitary Growth HormoneProducing Tumor
surgical removal point to a pituitary etiology (Chanson etal, 2009). It Ectopic pituitary adenoma
is assumed, that they result from a multistep and multicausal process Peripheral tumor
in which a genetic disposition, endocrine factors, and specific somatic Islet cell tumor
mutations play a role (Lopes, 2010). The most common genetic Lymphoma
defect, found in approximately 40% of sporadic cases, is a mutation
Growth HormoneReleasing Hormone Hypersecretion
in the gene for the -subunit of the stimulatory G-protein (GNAS),
Hypothalamic tumor
which is a stimulatory protein of adenylate cyclase at the membrane
Gangliocytoma
level. The GNAS protein is coupled to the GHRH receptor, and
Hamartoma
the mutation mimics the effects of GHRH on hormone signaling
Choristoma
(Freda etal, 2007; Chanson etal, 2009; Lopes, 2010). Less than 5%
Glioma
of cases are due to extrapituitary acromegaly or are part of genetic
Peripheral tumor
syndromes. Extrapituitary GH excess can result from an ectopic
Bronchial carcinoid
pituitary adenoma (e.g., in sphenoidal sinus, nasopharyngeal cavity)
Islet cell tumor
or from peripheral tumors, such as islet cell tumors or lymphoma.
Adrenal adenoma
Another category of causes is hypersecretion of GHRH that leads to
Medullary thyroid carcinoma
hyperplasia of the somatotrophic cells and consequently GH excess.
Pheochromocytoma
GHRH hypersecretion either results from a hypothalamic tumor or
more often from peripheral tumors, including bronchial carcinoid, Genetic Syndromes Associated with Acromegaly
islet cell tumors, and various other endocrine tumors (Chanson etal, McCune-Albright syndrome
2009; Box 2-6). Carney complex
Multiple endocrine neoplasia type 1
Familial isolated pituitary adenoma
HYPERSOMATOTROPISM (ACROMEGALY) IN CATS
Modified from Melmed S, Kleinberg D: Pituitary masses and tumors. In Melmed S, Polon-
Prevalence and Etiology sky KS, Larsen PR, Kronenberger HM, editors: Williams textbook of endocrinology, ed 12,
Philadelphia, 2011, Saunders Elsevier.
In 1976, Gembardt and Loppnow described the first two cats with GH, Growth hormone; TSH, thyroid-stimulating hormone.
diabetes mellitus and acidophilic pituitary adenomas. Although
GH was not measured, the authors proposed that GH excess
from these tumors was responsible for the diabetes. During the in 334 of them (27.3%) (Niessen etal, 2013a). Similar screenings
following 30 years, further cases were only published sporadically in Switzerland and the Netherlands resulted in somewhat lower
or in a few case series, and feline acromegaly was considered a prevalence: 36 of 202 diabetic cats (17.8%) had IGF-1 levels less
rare disease. The rareness started to be questioned in 2007 when than 1000 ng/mL (Schfer et al, 2013). It is very important to
two larger studies accompanied by an editorial were published in note that a high IGF-1 level does not automatically mean that the
the same issue of the Journal of Veterinary Internal Medicine (Berg cat suffers from acromegaly. There are several reasons why IGF-1
et al, 2007; Niessen et al 2007a; Peterson, 2007). The study of may be falsely increased (e.g., methodological problems with the
Berg, et al. (2007), however, was not designed to evaluate the various IGF-1 assays). See the Hormonal Evaluation, Cats section
prevalence of acromegaly, but compared circulating IGF-1 levels later for more details. The studies mentioned earlier may also be
in diabetic cats known to have acromegaly with levels in cats confounded by selection bias. Poorly regulated diabetic cats (which
without acromegaly. Unfortunately, this study is often quoted in are more likely to harbor acromegaly) are usually presented to the
discussions on prevalence of feline acromegaly, something that veterinarian more often than well regulated cats and, therefore, the
seems inappropriate. Niessen, etal. (2007a) screened blood samples likelihood of sampling those cats is higher. On the other hand, it
from diabetic cats in the United Kingdom for the possible presence is possible that the IGF-1 cut-off value of 1000 ng/mL is too high
of acromegaly by measuring circulating IGF-1 levels. IGF-1 was and cats with acromegaly are missed (Niessen etal, 2013a). The
found to be markedly increased (> 1000 ng/mL, reference range definitive prevalence of acromegaly in diabetic cats is unknown so
208 to 443) in 59 of 184 (32%) variably controlled diabetic cats. far. In the authors hospital, screening for acromegaly is routinely
Further work-up was possible in 18 cats, and acromegaly was done in all diabetic cats for many years. From those data, it is
diagnosed in 17 of them. More recently, the same research group estimated, that the prevalence of acromegaly in the normal
confirmed the relatively high percentage of increased IGF-1 levels diabetic cat population is 10% to 15%; in the population of cats
in diabetic cats by doing an extensive screening project: IGF-1 that are difficult to regulate, the percentage is substantially higher
levels were measured in 1222 diabetic cats and found to be elevated and may be 30% or more.
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In the vast majority of cats, acromegaly is caused by a the section Metabolic Actions of Growth Hormone and Insulin-like
GH-producing acidophil pituitary adenoma. Capen (2007) Growth Factor 1 and Fig. 2-5 for more details. The growth promoting
mentions densely granulated and sparsely granulated cells in the effects of increased GH and IGF-1 result in the proliferation of bone,
adenomas; it is, however, unknown so far if those findings represent cartilage, soft tissues, and increase in size of various organs, leading to
different variants of the disease as known in humans (see earlier). It the characteristic physical (acral) changes of acromegaly. GH and
is also not yet known how many of those tumors exclusively secrete IGF-1 also have profound effects on carbohydrate metabolism. GH,
GH and how many are mixed or plurihormonal tumors. Such an IGF-1, and insulin can directly interact with each other by signaling
investigation would require immunohistochemical staining for crosstalk (Vijayakumar el at, 2010). Consequently, disturbance of the
the various pituitary hormones, which has only been reported for GH and IGF-1 system has impact on insulin action and vice versa.
a small number of cases (Middleton etal, 1985; Heinrichs etal, GH has anti-insulin actions that include increase in hepatic glucose
1989; Allgoewer etal, 1998; Meij etal, 2004; Meij etal 2010b; production and decrease of glucose uptake in extrahepatic tissues.
Sharman etal, 2013). The pituitary tumors of three acromegalic Chronic GH excess is associated with defects in both, hepatic and
cats only stained positive for GH (Heinrichs etal, 1989; Meij etal, extrahepatic insulin actions (Hansen et al, 1986). Recent studies
2004; Meij etal, 2010b), the tumors of three other cats mainly suggest that GH excess reduces insulin sensitivity by multiple
stained positive for GH, but also had some positive staining for mechanisms involving the insulin receptor as well as various steps in
prolactin, ACTH and prolactin, and -endorphin, FSH, and the postreceptor pathways (Dominici etal, 2005; Xu and Messina,
TSH respectively (Middleton etal, 1985; Allgoewer etal, 1998; 2009; Clemmons, 2012). In contrast to GH, IGF-1 enhances insulin
Sharman et al, 2013). Those mixed tumors, in which several sensitivity in hepatic and extrahepatic tissues. However, in acromegaly,
hormones are synthesized within the same mass are different increased IGF-1 levels are unable to counteract the insulin-resistance
from so-called double adenoma. Meij, etal. (2004) reported the induced by the excessive GH concentrations (Resmini etal, 2009). In
concurrent existence of a somatotroph and a corticotroph adenoma normal individuals, insulin resistance is compensated by an increased
in a cat with diabetes mellitus. Immunohistochemistry confirmed insulin production from the -cells and normoglycemia is maintained.
that the GH-cell adenoma and the ACTH-cell adenoma were Diabetes mellitus only develops in individuals in which -cells with
separated by unaffected adenohypophyseal tissue. The clinical time fail to maintain high insulin synthesis to meet the increased
picture was dominated by insulin-resistant diabetes mellitus demand. Various mechanisms have been proposed to explain -cell
and hyperadrenocorticism; physical changes of acromegaly were failure. See Chapter 7 for details. So far, the cause for -cell failure
not obvious. Very recently, another case of double adenoma was in acromegaly is unknown. The vast majority of acromegalic cats
reported (Sharman etal, 2013). The cat was referred for insulin- suffer from diabetes mellitus. In many but not all diabetic cats,
resistant diabetes mellitus and physical changes consistent with insulin-resistance is pronounced at the time of diagnosis. Acromegaly
acromegaly; 16 months later, the cat developed additional signs in cats is almost always due to a GH-producing pituitary tumor.
consistent with hyperadrenocorticism. The presence of double Neurological signs may develop as a result of a large tumor involving
adenoma was confirmed by necropsy: one acidophilic adenoma the hypothalamus and further areas of the brain.
stained strongly positive for GH, with some positivity for
-endorphin, FSH, and TSH and was considered consistent with a Signalment
somatotroph adenoma; the other chromophobe adenoma stained
positive for ACTH, melanocyte-stimulating hormone (MSH), Acromegaly is typically diagnosed in elderly cats. Most cats are
FSH, and -endorphin consistent with a plurihormonal pituitary 8 years and older. The average age is 10 to 11 years with a range
tumor. In summary, most cats with acromegaly have acidophil between 4 and 17 years (Feldman and Nelson, 2004). Pedigree
pituitary tumors, which predominantly secrete GH. Some of them cats are rarely affected; the vast majority of acromegalic cats are
also secrete other pituitary hormones albeit in small amounts. In Domestic Short-Haired and some are Domestic Long-Haired.
the latter cases, the clinical picture is usually dominated by the There appears to be a clear male predisposition, because approxi-
excessive secretion of GH. On rare occasions, cats may have mately 88% of the cats described during the last decades were
double adenomas. The clinical manifestations depend on their male or male-castrated. It should be noted that there is also a male
secretory products. Interestingly, in a few cats with acromegaly predisposition for diabetes in general (i.e., 70% to 80% of diabetic
the histological diagnosis was pituitary acidophilic hyperplasia cats are male). Interestingly, however, in one study, only 50% of
instead of acidophilic adenoma (Norman and Mooney, 2000; acromegalic cats were male (Fischetti et al, 2012). Body weight
Niessen et al, 2007a). Because hyperplasia of the somatotropic ranges between 4 kg and 9 kg; most affected cats weigh between
cells is difficult to distinguish from GH-cell adenoma (Melmed 5 kg and 7 kg.
and Kleinberg, 2011), it may be that the lesions in fact were
adenomas. However, the possibility of true hyperplasia has to Clinical Manifestations
be taken into account, which points to a different etiology. In
acromegalic humans, hyperplasia usually results from excessive Clinical signs mainly result from the diabetogenic effect of GH
GHRH, either caused by hypothalamic or peripheral tumors (see and the effects of GH and IGF-1 with regard to acral enlargement
Box 2-6). It is important to be aware of somatotroph hyperplasia, and on growth of soft tissues and organs. In some cats, expan-
as in those cats, pituitary imaging by CT/MRI may be negative sion of the pituitary tumor causes additional neurological signs
(Niessen etal, 2007a). (Table 2-2; Fig. 2-14 and Fig. 2-15).
The earliest and most common clinical signs usually are
polyuria, polydipsia, and polyphagia associated with GH-induced
Pathophysiology
diabetes mellitus. Polyphagia may also develop as a direct effect
In acromegaly, circulating GH concentrations are chronically of the GH excess and can become extreme. Weight loss may or
increased, although secretion remains episodic. GH has direct may not be present during the initial phases. Often, initial weight
and indirect metabolic effects; the latter are mediated through the loss is followed by a period of stabilization and thereafter slow
stimulation of IGF-1 synthesis in the liver and in other tissues. See and progressive weight gain develops. Weakness, ataxia, and a
TABLE 2-2 C
LINICAL SIGNS AND PHYSICAL plantigrade stance caused by diabetic neuropathy may be seen in
EXAMINATION FINDINGS IN CATS some cats. A poor unkempt hair coat is another albeit unspecific
WITH ACROMEGALY possible finding (Feldman and Nelson, 2004). During the first
few weeks or months after initiating therapy, insulin requirement
CLINICAL FINDINGS PERCENT OF OCCURRENCE may be relatively low (i.e., 1 to 3 units per cat b.i.d. [bis in die;
twice a day]) and then starts to increase as the insulin resistance
Diabetes mellitus (usually poorly controlled) 96% 100%
worsens. Insulin requirement may easily exceed 1.5 to 2.0 U/
Polyuria/polydipsia 83% 100% kg body weight b.i.d., and the use of 30 units b.i.d. and more
Polyphagia 78% 100% has been reported (Peterson et al, 1990; Norman and Mooney
Enlargement of head, abdomen, paws 50% 83% 2000; Niessen et al, 2007a). The possibility of an underlying
Prognathia inferior 35% 71%
endocrinopathy (e.g., acromegaly) is often considered only
after the diabetes becomes difficult to control or high insulin
Weight gain 35% 59% doses are needed to decrease blood glucose concentrations into
Hepatomegaly and/or renomegaly 26% 100% an acceptable range. A cat with difficult to regulate diabetes
Heart murmur and/or gallop rhythm 17% 64% and weight gain at the same time should alert the clinician to
Weight loss 9% 57% consider the possibility of acromegaly. Poor glycemic control is
CNS signs 9% 14% usually associated with weight loss, whereas weight gain is seen
in cases with insulin overdose (because insulin is an anabolic
Diabetic neuropathy (plantigrade stance) 6% 26%
hormone) and with acromegaly. It is important to note that
Enlargement of tongue 6% 21% not all acromegalic cats are (severely) insulin resistant. In some
Lameness or degenerative arthropathy 5% 43% cats normal insulin doses (1 to 3 units per cat b.i.d.) are
Respiratory stridor 4% 53% sufficient for long-term adequate glycemic control. It has been
the impression of the author and other investigators that in some
Data are compiled from Feldman EC, Nelson RW: Disorders of growth hormone. In Feldman EC, cases, even diabetic remission may occur in acromegalic cats
Nelson RW, editors: Canine and feline endocrinology and reproduction, St. Louis, 2004, Saunders; without the treatment of the GH excess. This, however, would
Niessen SJM, et al: Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med
be an extremely rare event, and further studies are needed to
21:899, 2007a; and Peterson ME, et al: Acromegaly in 14 cats, J Vet Intern Med 4:192, 1990.
CNS, Central nervous system.
confirm the observation. Interestingly, in human medicine, only
C
FIGURE 2-14 Three cats with diabetes mellitus and acromegaly revealing different degrees of physical changes. A,
Domestic Short-Haired (mc, 8 y) with nearly normal facial features. The chin may be slightly prominent. B, Domestic
Short-Haired (mc, 11 y) with more obvious prognathia inferior than in cat A. C, Domestic Short-Haired (mc, 12 y)
with the typical broad head and prognathia inferior in more advanced acromegaly.
|
involves the heart but also liver, kidney, spleen, and pancreas as
well as other endocrine organs, such as adrenal glands, thyroid,
and parathyroid glands. Hepatomegaly, renomegaly, and thyroid/
parathyroid enlargement may be evident during physical
examination. Central nervous system (CNS) signs as a result
of pituitary tumor growth are seen in approximately 10% to
15% of cats and include lethargy, behavioral changes, impaired
vision, adipsia, anorexia, temperature dysregulation, circling,
somnolence, stupor, and seizures.
Clinical Pathology
The (often poorly) controlled diabetes mellitus is responsible
for most of the abnormalities identified on the complete
blood count (CBC), biochemistry profile, and urinalysis.
Hyperglycemia, glucosuria, and increased serum fructosamine
is almost always present. In a recent study, a trend toward blood
FIGURE 2-15 Prognathia inferior in a cat with acromegaly. glucose and fructosamine being more elevated in diabetic cats
with than without acromegaly has been found; however, there
was considerable overlap (Niessen, 2010). Hyponatremia,
approximately one-third of patients with acromegaly develop overt hypercholesterolemia, and a mild increase in alanine
diabetes mellitus (Wass etal, 2011). So far, all acromegalic cats aminotransferase (ALT) and alkaline phosphatase (ALP) activities
described in case reports and case series had concurrent diabetes are seen in some cats. Ketonuria is usually absent. A substantial
mellitus, and the majority of them were difficult to regulate due percentage of acromegalic cats reveal hyperproteinemia or total
to GH-induced insulin resistance. It may be possible that in the protein concentrations in the upper range of normal, reflecting
beginning of the acromegalic disease or in cats with very mild either increased protein synthesis induced by the GH excess
GH excess, glucose tolerance is maintained. It is also possible that and/or dehydration associated with poorly regulated diabetes.
cats suffer from acromegaly without ever developing diabetes; Hyperproteinemia was the only parameter being more frequently
however, this is extremely uncommon. The physical changes of present in acromegalic compared to non-acromegalic diabetic
acromegaly are induced by the anabolic effects of GH and IGF-1; cats (Niessen, 2010). Hyperphosphatemia (without azotemia)
they have an insidious onset and progress very slowly. Clinical has occasionally been seen and is due to the GH/IGF-1 mediated
signs may be obvious at the time diabetes is diagnosed or may increased renal tubular resorption (Peterson etal, 1990; Javorsky
become apparent during the following weeks to months. Because etal, 2011). There is some controversy as to which chronic renal
of the slow progression, the owners often do not notice the subtle failure develops more frequently in acromegalic cats. Peterson,
changes in the appearance of their cat until they are specifically etal. (1990) reported the development of chronic renal failure
questioned. It is important to note that a cat with acromegaly in 50% of acromegalic cats within 8 to 36 months after initial
may initially be unremarkable during physical examination and examination, whereas the prevalence of azotemia was low (12%)
may be indistinguishable from other diabetic cats (Niessen etal in the study by Niessen, et al. (2007a). Chronic renal failure
2007a; Niessen, 2010). The soft tissue overgrowth and the osseous is very common in the elderly cat population, and further
changes cause weight gain, enlargement (broadening) of the head, studies are needed to investigate the potential role of GH excess.
enlargement of the mandible (prognathia inferior), widening of Other occasional findings include erythrocytosis, leukocytosis,
the interdental spaces, and sometimes a large tongue. Diffuse and proteinuria; the latter is often associated with azotemia.
thickening of oropharyngeal tissue can lead to respiratory stridor In summary, acromegalic cats show various abnormalities.
and respiratory distress. Enlargement of the abdomen and the However, the findings are not helpful to distinguish acromegalic
paws (clubbed paws) are also identified regularly. The general from non-acromegalic diabetic cats.
impression is that of a large cat. Degenerative arthropathy due to
proliferation of chondrocytes and disruption of joint geometry is
Diagnostic Imaging
common and involves shoulder, elbow, carpus, digits, stifle, and
spine. Those lesions may result in lameness; however, they may also Conventional Radiography
be clinically silent and just be detected radiographically (Peterson Abdominal radiographs most often reveal hepatomegaly, which is
et al, 1990; Feldman and Nelson, 2004; Niessen et al, 2007a; also seen in non-acromegalic diabetic cats. Further findings may
Niessen et al, 2013a). Systolic heart murmur is common, and include renomegaly and rarely splenomegaly. Thoracic radiographs
further work-up may reveal cardiomegaly and echocardiographic may show mild to moderate cardiomegaly and pulmonary edema
abnormalities. Cardiomegaly has been reported to worsen over or pleural effusion if congestive heart failure is present. Findings
time, and congestive heart failure may develop during later of radiographs of skull, joints, and spine include diffuse increase
stages of the acromegalic disease. Electrocardiography is usually of soft tissue in the oropharyngeal region, enlargement of the
unremarkable (Peterson et al, 1990; Niessen et al, 2007a). mandible, hyperostosis of the bony calvarium and nasal bones,
Cardiomyopathy may be the result of the GH excess. In some degenerative arthropathy of shoulder, elbow, stifle, carpus, digits,
cases, however, there may have been pre-existing cardiomyopathy and spondylosis deformans of the spine. Radiography may also
that worsens during the course of acromegaly. In humans, cardiac be completely normal or reveal only very mild abnormalities. The
involvement and a specific cardiomyopathy is a consistent feature presence and severity of the changes depend on the severity and
of acromegaly (Chanson and Salenave, 2008). Blood pressure is duration of the GH excess (Peterson et al, 1990; Feldman and
usually normal or only slightly increased. Organomegaly not only Nelson, 2004; Fig. 2-16).
Adrenal gland left
Dist 1.34 cm 4.0

L A Dist 0.670 cm
Adrenal gland right
FIGURE 2-16 Abdominal radiographs of a 7-year-old male-castrated Domestic

Short-Haired cat with diabetes mellitus and acromegaly. Note the enlargements
of liver and kidneys. (Courtesy Dr. Matthias Dennler and Prof. Patrick Kircher,
Division of Diagnostic Imaging, Vetsuisse Faculty, Zurich, Switzerland.)
Dist 0.628 cm
B Dist 1.23 cm
4.0
Abdominal Ultrasonography
Hepatomegaly is the most consistent finding, as mentioned earlier, FIGURE 2-17 Ultrasonographic images of the left and right adrenal gland of
and it is also the most frequent finding in non-acromegalic diabetic a 13-year-old male-castrated Domestic Short-Haired cat with diabetes mellitus
cats. Further abnormalities include renal enlargement with or without and acromegaly. Note the slight to moderate bilateral symmetrical enlargement
reduced corticomedullary definition and/or mild pelvic dilation, of the glands with maintained shape. A, The width of the left adrenal gland
enlarged pancreas, splenomegaly, and bilateral adrenomegaly (Posch measured 0.67 cm. B, The width of the right adrenal gland 0.63 cm. Adrenal
etal, 2011). The width (or thickness) of the adrenal glands is the most gland width in healthy cats ranges between 0.3 to 0.53 cm. (Courtesy Dr. Mat-
important parameter to determine their size by ultrasonography. thias Dennler and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse
In healthy cats, width of the left and right adrenal gland ranged Faculty, Zurich, Switzerland.)
between 0.3 to 0.53 cm and 0.29 to 0.45 cm, respectively (Zimmer
etal, 2000). In cats with diabetes mellitus (without acromegaly), left
and right adrenal gland width ranged between 0.24 to 0.46 cm and of the somatotrophic cells, which is usually visible by the time
0.26 to 0.48 cm, respectively, and it was not different to the width in of presentation. In fact, the masses can become quite large, and
healthy cats (Kley etal, 2007). Both studies were performed in the suprasellar extension with involvement of the diencephalon
institution of the author and are therefore comparable, because the is a frequent finding (Posch et al, 2011). However, if pituitary
same measuring approach was used. A typical finding in our diabetic imaging is performed in early stages of the disease, the mass
cats with acromegaly is a slight bilateral symmetrical enlargement may still be small and difficult to visualize. MRI with adequate
of the adrenal glands; the width often is between 0.5 and 0.65 resolution is superior to conventional CT to detect small masses.
cm. Adrenomegaly is not pathognomonic for acromegaly, because If dynamic CT is available, the evaluation and displacement of
it is also found in cats with pituitary-dependent hypercortisolism. the so-called pituitary flush is helpful for the documentation of
Adrenomegaly in conjunction with enlargement of other abdominal small pituitary tumors (Meij et al, 2010b; Hecht and Schwarz,
organs, in particular the kidney, however, should raise suspicion for 2011). On rare occasions, CT/MRI imaging of the pituitary gland
the presence of acromegaly (Fig. 2-17). is unremarkable. Potential causes are a very small size of the tumor
or a different etiology of the acromegalic disease. In approximately
Echocardiography 2% of human patients with acromegaly, the disease is due to
Echocardiography findings include generalized or focal (septal, somatotrophic hyperplasia caused by hypersecretion of GHRH,
basal, free wall) left ventricular hypertrophy with or without left which either derives from a hypothalamic or a peripheral tumor
atrial dilation. In some cats, right heart disease with right-sided (Melmed and Kleinberg, 2011). Such an etiology has not yet been
heart failure may predominate. Echocardiography, however, can demonstrated in cats; however, in one cat with normal CT and
also be unremarkable. MRI studies, histopathology revealed acidophilic proliferation,
not adenoma in the pituitary gland (Niessen et al, 2007a; Fig.
Computed Tomography and Magnetic Resonance Imaging 2-18, Fig. 2-19, and Fig. 2-20).
Pituitary imaging plays a major role in the work-up of cats with
suspected acromegaly. The demonstration of a pituitary mass Hormonal Evaluation
is important to establish the final diagnosis of acromegaly in
concert with the clinical findings and the results of the hormonal Acromegaly should be considered in cats with difficult to
evaluations. Determination of the exact size of the mass is also regulate diabetes in which problems associated with the insulin
required for the discussion on treatment options with the owner. and the insulin administration, short duration of insulin effect,
CT/MRI studies should always include post-contrast images, and other common concurrent problems (e.g., glucocorticoid
because the mass may not be visualized on native studies. In administration, severe stomatitis/gingivitis, urinary tract infection)
the vast majority of cats, the disease is caused by an adenoma have been excluded. See Chapter 7 for more details.
|
from the pituitary gland below a certain threshold. In contrast,

L R in patients with acromegaly, GH levels remain either unchanged,
show a paradoxical increase, or decrease slightly. The threshold
(also called the GH nadir) has been lowered over time with the
development of more sensitive GH assays. Nevertheless, some
patients (in particular those with mild disease) may suppress GH
below the threshold and diagnosis may be missed. The GHRH
test has no diagnostic value (Dimaraki etal, 2002; Freda, 2003;
Ribeiro-Oliveira and Barkan, 2012).
IGF-1 directly reflects GH activity as it is synthesized in the
liver (and other tissues) under the control of GH. Blood levels
are relatively stable throughout the day, and measurement requires
only a single randomly-obtained blood sample. Measurement of
IGF-1 is routinely used to screen for acromegaly in humans, and
high IGF-1 levels are sensitive markers for GH excess. IGF-1 lev-
els correlate with the mean 24-hour GH output; if mean GH lev-
els are very high, IGF-1 levels, however, reach a plateau due to the
FIGURE 2-18 Computed tomography (CT) image of the pituitary region in a limited capacity of the liver to synthesize the polypeptide (Freda,
7-year-old male castrated Domestic Short-Haired cat with diabetes mellitus and 2003; Ribeiro-Oliveira and Barkan, 2012). The drawbacks of the
acromegaly. A large mass was identified (arrows). (Courtesy Dr. Matthias Dennler test are the requirement for age- and sex-adjusted reference ranges
and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty, and the possibility of biological and technical problems. Various
Zurich, Switzerland.) conditions, including malnutrition, liver and renal failure, hypo-
thyroidism, poorly controlled diabetes, and oral estrogen intake
may lower IGF-1 levels and therefore mask acromegaly. Technical
problems are mainly due to the interference of the IGF-1 bind-
L R ing proteins (IGFBPs) with the IGF-1 measurement. For correct
IGF-1 measurement, the binding proteins need to be removed by
a separate step; however, assays differ in the quality of this removal
(Freda, 2003; Ribeiro-Oliveira and Barkan, 2012).
Cats
As in humans, diagnosis of acromegaly in cats requires the
demonstration of GH excess and/or high IGF-1 concentrations.
Feline GH can be measured in heterologous canine and ovine
radioimmunoassays (Eigenmann et al, 1984b; Niessen et al,
2007b). However, availability of the assays may be a problem.
Eigenmann, etal. (1984b) described extremely elevated GH levels
in an acromegalic cat that did not decrease during an intravenous
glucose tolerance test (IVGTT). This test can, in principle, be
regarded as the pendent to the aforementioned oral glucose tolerance
FIGURE 2-19 Selected image of the transverse dynamic computed tomography test, which is routinely used in humans. However, suitability of
(CT) study of the pituitary region in a 6-year-old cat with diabetes mellitus and the IVGTT is limited because glucose infusions in healthy cats
acromegaly. The pituitary gland is not enlarged; however, the pituitary flush also do not result in a GH decrease (Kokka etal, 1971). Random
(corresponding to the neurohypophysis) is displaced to the right indicating a small GH concentrations were measured in several studies. So far, all
space occupying lesion of the adenohypophysis on the left side (arrow). (Courtesy acromegalic cats had increased GH concentrations. In some cats,
Dr. Matthias Dennler and Prof. Patrick Kircher, Division of Diagnostic Imaging, GH was highly elevated; in others, the increase above normal was
Vetsuisse Faculty, Zurich, Switzerland.) only small (Table 2-3). The cats of those studies most likely were in
an advanced stage of the disease. With increased awareness, however,
milder cases of acromegaly of cats at an earlier stage of the disease
Human Medicine will be worked-up, and due to the episodic nature of GH secretion,
The diagnosis is traditionally based on the demonstration of GH random GH levels may at times be in the normal range. It is also
hypersecretion and increased IGF-1 levels (Ribeiro-Oliveira and important to note, that a single elevated GH level is not diagnostic
Barkan, 2012). The episodic nature of GH secretion renders for acromegaly, because it may be the result of a secretory pulse in a
the measurement of basal GH levels unreliable, because ranges non-acromegalic cat. Mildly increased GH levels have been seen in
of acromegalic and healthy humans overlap. Even if multiple diabetic cats without acromegaly (Reusch etal, 2006; Niessen etal,
samples for GH measurement are taken throughout the day, a 2007a). It is currently recommended to collect three to five samples
reliable differentiation between individuals with and without for GH measurement at 10-minute intervals (Meij et al, 2010a).
acromegaly is not possible. The standard procedure is to evaluate The more of those samples that reveal an increased GH level and the
GH concentrations during an oral glucose tolerance test. After an higher those levels are, the more likely the cat has acromegaly.
overnight fast, blood samples are usually taken at baseline and at Blood samples should be handled carefully to avoid degradation
several times after ingestion of a glucose drink. The protocols may of the hormone. We routinely collect the samples into EDTA-coated
vary slightly between different institutions. In healthy humans, ice-chilled tubes. After immediate centrifugation, they are stored at
the sudden increase in blood glucose suppresses GH secretion 20o C until shipping to the laboratory on dry ice with express
R L R L
A B C
R L R L R L
D E F
FIGURE 2-20 Magnetic resonance imaging (MRI) images of the pituitary region of a 12-year-old Domestic Short-
Haired cat with acromegaly. Transverse (A), sagittal (B), and dorsal (C) T2 weighted images show a space-occupying
lesion (white arrows), hypointense in comparison to white matter, which originates from the right aspect of the
pituitary gland. D, Transverse T2: The sequence reveals susceptibility artifact (black arrowhead) in the center of the
space-occupying lesion, which is highly suspicious for pituitary apoplexy. This is a hemorrhagic insult and occurs often
in pituitary tumors and may be responsible for an acute deterioration of the clinical signs. E, T1 3D turbo field echo
(TFE): The described space occupying lesion is isointense to white matter. The pituitary lesion causes distortion and
displacement of the normally rounded and centrally located T1W-hyperintensity of the neurohypophysis (black arrow).
F, T1 3D TFE in the equilibrium phase after intravenous-administration of gadodiamide (Omniscan; 0.3 mmol/kg): The
space occupying lesion exhibits moderate contrast medium uptake with a hypointense center. (Courtesy Dr. Matthias
Dennler and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty, Zurich, Switzerland.)
service. In a recent study, GH was stable with less strict sampling 3. It is stable, and a serum sample can be sent by regular mail.

and storage conditions (Niessen et al, 2007b). It is important to IGF-1 concentrations have been measured in several of the
contact the laboratory prior to sampling for the specific details. studies published during the past years and found to be increased
Measurement of IGF-1 has become a popular test for feline in the vast majority of acromegalic cats. Normal IGF-1 levels
acromegaly during the last years. IGF-1 reflects the 24-hour have been seen in a few cases, which may reflect an early stage
GH secretion (see the section Hormonal Evaluation, Human of the disease. Some of those cats were retested after some time,
Medicine) and its measurement has several advantages over the and IGF-1 was then found to be increased (Norman and Mooney,
measurement of GH (IGF-1 flyer, Dechra Specialist Laboratories 2000; Berg etal, 2007). Several other potential causes should be
UK, www.thehormonelab.com; IGF-1 Collection Protocol, considered if a normal IGF-1 level is found in a cat with suspected
Diagnostic Center for Population and Animal Health, Michigan acromegaly. First, in humans, various concurrent problems are
State University, www.dcpah.msu.edu):
known to decrease IGF-1 concentrations (see earlier). Not all of
1. IGF-1 is not secreted in pulses, and its concentration is con- them have been evaluated in cats yet; however, serious disease
stant throughout the day, requiring just a single random blood (e.g., lymphoma) was shown to drastically decrease IGF-1
sample (Fig. 2-21). concentrations (Tschuor etal, 2012; Fig. 2-22).
2. Its structure is conserved across species, and it can be measured Second, IGF-1 level may be normal in acromegalic cats if the
in assays designed for humans. measurement is performed prior to the start of insulin therapy.
|
TABLE 2-3 GH CONCENTRATIONS IN PUBLISHED CASES OF CATS WITH ACROMEGALY
NUMBER OF CATS WITH ACROMEGALY GH CONCENTRATION (G/L) REFERENCE RANGE REFERENCE

1 335 3.2 0.7 Eigenmann etal, 1983
1 100 1.2 0.14 Morrison etal, 1989
14 22 131 < 1 8.5 Peterson etal, 1990
3 14, 41, 42 1.5 7.9 Goosens etal, 1998
4 > 29.7 1.5 7.9 Elliott etal, 2000
4 9.5, > 17, > 18, 158 25 Norman and Mooney, 2000
1 24 <6 Meij etal, 2004
7 8, 10.4, 11, 16, 21.9, 32, 40 1.5 7.9 Reusch etal, 2006
2 8, 23 1.5 7.9 Berg etal, 2007
9 9 33.7 1.9 6.3 Niessen etal, 2007a
5 16/16, 18/16, 20/22, 35/25, 415/230* 0.8 7.2 Slingerland etal, 2008
1 51 0.8 7.2 Meij etal, 2010b
*In each cat, GH was measured in 2 separate samples taken within a 15 min interval.
400 A third reason why the diagnosis of acromegaly may be missed is

the currently used cut-off values, which may be too high to detect
milder or early stages of the disease. For instance, for many of the
300 currently available assays, IGF-1 concentrations greater than 1000
IGF-1 ng/mL
ng/mL are considered to be suspicious of acromegaly. However,

200 IGF-1 levels in healthy cats and non-acromegalic cats usually are
less than 800 ng/mL. The range between 800 and 1000 ng/mL
should be considered as grey zone. If the suspicion of acromegaly
100 is strong, pituitary imaging would be a logical next step. In other
cases, IGF-1 measurement should be repeated after a few weeks.
0 An increasing level would then strengthen the suspicion of acro-
9:00 AM 12:00 PM 4:00 PM 8:00 PM megaly. Reference ranges may differ depending on the methodol-
Time ogy; therefore, interpretation of IGF-1 results should be based on
the reference range established in cats by the laboratory.
FIGURE 2-21 Insulin-like growth factor-1 (IGF-1) concentrations in five cats
As with any other test, IGF-1 measurement may also be false
with diabetes mellitus measured at four different times, demonstrating that the
positive. Lewitt, etal. reported in 2000 that IGF-1 concentrations
blood levels are stable throughout the day. (Modified from Reusch CE, etal.:
in eight non-acromegalic diabetic cats were significantly higher
Measurement of growth hormone and insulin-like growth factor 1 in cats with
than those of healthy cats. Those results were surprising because
diabetes mellitus, Vet Rec 158:195, 2006.)
it was already known from humans, dogs, and rats that insulin
deficiency reduces IGF-1 levels. As mentioned earlier, the same
IGF-1 has been shown to be significantly lower in untreated mechanism was then also shown to exist in cats (Reusch etal, 2001;
diabetic cats (without acromegaly) compared to healthy controls; Reusch et al, 2006; see Fig. 2-23). Insulin treatment increases
after the start of insulin treatment, IGF-1 increased and was not IGF-1 levels, and it was hypothesized that the high IGF-1 levels
different from levels in controls after a few weeks (Fig. 2-23). found by Lewitt, etal. (2000) had been due to long-term insulin
The same observation was made in a small number of diabetic therapy (Starkey et al, 2004). However, it is important to note,
cats with acromegaly in which the initially low IGF-1 levels that technical issues may also contribute to false increase in IGF-1
increased markedly after insulin therapy was started (Reusch levels. Circulating IGF-1 is nearly completely bound to binding
etal, 2006). Insulin deficiency is also known to decrease IGF-1 proteins, which are known to interfere with the measurement;
levels in humans, dogs, and rats. This phenomenon is explained depending on the assay, they lead to spuriously high or low IGF-1
by the fact that high insulin concentrations are needed in the values. Most immunoassays are therefore preceded by methods that
portal vein for the expression and function of GH receptors on remove those binding proteins. Unfortunately, they are not equally
hepatocytes and that this mechanism is disturbed in insulin- effective and constitute a notorious source of error (Chestnut
deficient states (Eigenmann et al, 1977; Yang et al, 1990; and Quarmby, 2002; Frystyk etal, 2010). Recently, three assays
Bereket et al, 1999; Ekmann et al, 2000; Reusch et al, 2001; preceded by different sample preparation methods were compared
Reusch etal, 2006; Lim etal, 2007). In our institution, diabetic against an assay using acid chromatography for removal of binding
cats that are suspected to suffer from acromegaly are therefore proteins (which is considered to be the gold standard) in groups
treated with insulin for approximately 6 to 8 weeks before of healthy and non-acromegalic diabetic cats as well as cats with
IGF-1 is measured (Reusch, 2010). Cats in advanced stages of various medical problems. The most remarkable finding was, that
the acromegalic disease may have high IGF-1 levels already at with one of the assays, 8 of the 60 cats (amongst them two healthy
initial presentation. However, if we find a normal or borderline and one non-acromegalic diabetic cat) had IGF-1 concentrations
IGF-1 result, we repeat the testing after several weeks of insulin more than 1000 ng/mL, whereas their concentrations were clearly
therapy. below 1000 ng/mL with all the other assays (see Fig. 2-22). It
1200
1100
1000
900
800
IGF-1 [ng/mL]
700
600
500
400
300
200
100
0
Healthy Diabetes mellitus Hyperthyroidism Lymphoma Chronic renal failure
middle aged/old
A AC - RIA A - ICMA AEE - IRMA IE - RIA
1200
1100
1000
900
800
IGF-1 [ng/mL]
700
600
500
400
300
200
100
0
Healthy Anorexia Obesity
middle aged/old
B AC - RIA A - ICMA AEE - IRMA IE - RIA
FIGURE 2-22 Scatterplots of plasma insulin-like growth factor-1 (IGF-1) concentrations in healthy middle-aged
to older cats and cats with diabetes mellitus, hyperthyroidism, lymphoma, and with chronic renal failure (A),
as well as in cats with anorexia of 3-days duration and obesity (B). IGF-1 concentrations were measured with
four different assays with different methods of removal of IGF-1 binding proteins. AC-RIA, Acid chromatography
radioimmunoassay; A-ICMA, acidification immunochemiluminescence assay, AEE-IRMA, acid-ethanol extraction
immunoradiometric assay, IE-RIA, insulin-like growth factor-2 excess radioimmunoassay. (Modified from Tschuor
F, etal.: Evaluation of four methods used to measure plasma insulin-like growth factor 1 concentrations in healthy
cats and cats with diabetes mellitus or other diseases, Am J Vet Res 73[12]:1925-1931, 2012.)
is likely, that the high levels were due to incomplete removal of IGF-1 and the cats bodyweight (Reusch et al, 2006). In the
binding proteins by the acid/ethanol extraction (Tschuor et al, study by Tschuor, etal. (2012), IGF-1 levels of younger cats (2 to
2012). It is certainly worthwhile to use one of the other assays. 4 years) were higher than those of elderly cats (6 to 14 years).
We have seen IGF-1 more than 1000 ng/mL in several diabetic However, the difference was significant only for one of the four
cats in which further work-up and follow-up examinations did assays. Ideally, laboratories offering IGF-1 measurements should
not reveal any signs of acromegaly. When aliquots of the serum establish assay-specific reference ranges for different age-groups.
samples were measured with different assays, including the gold
standard assay, IGF-1 levels continued to stay high, rendering Establishing the Diagnosis
interference with binding proteins as cause highly unlikely. So far,
the reason is unknown; it may be that vigorous and/or long-term Most cats with acromegaly are presented to the veterinarian
insulin treatment plays a role (Box 2-7). because of poorly controlled diabetes mellitus. Physical changes
In human patients, IGF-1 levels are compared to age- and typical of acromegaly may be obvious. However, a substantial
sex-dependent normative data. In cats, no difference was found number of acromegalic cats reveal only very minor alterations or
between males and females, and there was no correlation between may even look like any other diabetic cat. If typical changes are
|
800
* BOX 2-7 P
otential Causes for False Negative and False
Positive Insulin-Like Growth Factor-1 Results
*
600 Potential Causes for Normal Potential Causes for Increases
* Insulin-like Growth Factor-1 Insulin-like Growth Factor-1
* Concentrations in Cats with Levels in Cats without
IGF-1 ng/mL
Acromegaly Acromegaly
400 Early stage of the acromegalic Incomplete removal of IGF-1
disease binding proteins prior to mea-
Currently used cut-off values surement and interference with
too high to detect milder or early assay
200 stages of the acromegalic disease Vigorous and/or long-term
Serious concurrent disease insulin treatment
Starvation

Lack of insulin (i.e., measure-
0 ment performed prior to insulin
t0 t1 t2 t3 t4 therapy)
Poorly controlled diabetes
Time
FIGURE 2-23 Insulin-like growth factor-1 (IGF-1) in 11 diabetic cats (without IGF-1, Insulin-like growth factor-1.
acromegaly) before they were treated with insulin (t0) and 1 to 3 weeks (t1), 4 to
8 weeks (t2), 9 to 12 weeks (t3), and 13 to 16 weeks (t4) after the treatment with
insulin was started. * Significantly different (P > 0.05) from t0. Box and whisker moderate adrenomegaly, and a pituitary mass. Ultimately, differ-
plots are used to show the distribution of data. In the same study, IGF-1 levels in entiation of the two diseases is based on the results of GH and/or
healthy cats ranged between 196.0 and 791.0 ng/mL. (Modified from Reusch CE, IGF-1 measurements and tests of the pituitary-adrenocortical axis
etal.: Measurement of growth hormone and insulin-like growth factor 1 in cats (see Chapter 11).
with diabetes mellitus, Vet Rec 158:195, 2006). Not all acromegalic cats are (severely) insulin-resistant. In some
cats, a more or less adequate glycemic control can be achieved
with insulin doses less than 1 U/kg body weight b.i.d. (e.g., with
present, the next step would be to measure GH (3 to 5 samples doses of 1 to 3 U per cat b.i.d.). In some of those cases, the disease
at 10-minute intervals) or IGF-1 concentrations (one random progresses and work-up usually becomes necessary at a later stage.
sample). Different to the very limited availability of the GH assay,
most laboratories offer IGF-1 measurements. A high IGF-1 level,
Treatment
however, does not by itself confirm the diagnosis, because false
positive test results may occur. The finding of a high IGF-1 level Humans
would, however, support the suspicion of acromegaly and provide The aims of treatment are to relieve symptoms, to reduce the size
justification for imaging of the pituitary gland by CT or MRI of the pituitary tumor, to avoid tumor relapse, and to improve
(Berg etal, 2007). A pituitary mass is visible in the vast majority long-term morbidity and mortality. Several consensus documents
of cases at the time of presentation. The finding of a normal IGF-1 have been published on disease management and on the criteria to
concentration, on the other hand, does not rule out acromegaly. define good control of acromegaly. Both, GH and IGF-1 have to be
IGF-1 measurement should be repeated after a few more weeks measured as biochemical markers of response. GH concentrations
of insulin therapy (or 6 to 8 weeks after insulin therapy has been must return to less than 1.0 g/L if measured in a random sample,
initiated). Alternatively, GH concentrations may be measured (if or to a GH nadir of less than 0.4 g/L during an oral glucose
available) or an immediate search for a pituitary mass by CT/MRI tolerance test; IGF-1 levels also must return into the normal range
may be considered. (Chanson and Salenave, 2008; Melmed et al, 2009; Giustina
In cats without typical physical changes of acromegaly, other et al, 2010). The three approaches to therapy are neurosurgery,
more common causes of poor glycemic control should be con- medical management, and radiation therapy. Transsphenoidal
sidered, and a systematic work-up should be pursued. See Chap- surgery is generally the first line treatment for small pituitary
ter 7 for more details. Hyperadrenocorticism is among the many tumors, non-invasive macroadenomas, and when the tumor is
differential diagnosis for poor glycemic control. It is often also causing compression symptoms. Success rates range between 75%
associated with insulin resistance and is also caused by a pituitary to 95% in patients with microadenomas and decrease to 40% to
tumor in many cases. Clinical signs, however, differ between the 68% in patients with non-invasive macroadenomas. Expertise of
two diseases. Hyperadrenocorticism is a debilitating disease that the neurosurgeon is known to be of utmost importance (Melmed
results in weight loss, potentially leading to cachexia, and it is et al, 2009). When surgery fails to achieve adequate control of
often associated with obvious hair coat and skin abnormalities the disease or when surgery is impossible or contraindicated,
(hair loss, change in coat color, thin skin, and fragile skin). In con- medical therapy and/or radiation therapy are offered. Medical
trast, cats with acromegaly usually do not show relevant hair coat therapy is usually considered the second line approach. Currently,
and skin abnormalities. They often have physical changes (e.g., three classes of drugs are available: somatostatin receptor ligands,
broad head and prognathia inferior), and they may gain weight dopamine agonists, and GH receptor antagonists.
despite poorly regulated diabetes (Feldman and Nelson, 2004). It Somatostatin inhibits GH secretion as well as secretion of
is important to note, however, that typical changes may be lacking many other hormones in the body. It also reduces proliferation
in early stages or mild forms of both diseases. Diagnostic imag- of various normal and tumoral cells. Those actions are mediated
ing findings in both diseases may include hepatomegaly, mild to through interaction with five different somatostatin receptors
(SSTR 1-5), GH release is mediated through SSTR 2 and 5. more localized irradiation, possibly minimizing the long-term
Somatotroph adenomas are characterized by a higher density of adverse consequences. It may produce beneficial effects on GH
SSTR 2 and SSTR 5; however, they can express multiple SSTR, and IGF-1 sooner than conventional radiation therapy, but this
explaining the variable response to somatostatin therapy. The assumption needs confirmation by further studies (Melmed etal,
very short half-life of somatostatin leads to the development of 2009; Minniti etal, 2011).
somatostatin receptor ligands, also called somatostatin analogs.
They are the first-line medical treatment option for human Cats
patients with acromegaly. Octreotide (Sandostatin) was the first The aims of therapy in cats are twofold: treatment of the acro-
analog to be marketed and has to be injected 2 to 3 times daily. megalic condition itself and treatment of the concurrent diabetes
During the recent years, a sustained release version of octreotide mellitus. In some of the cats, treatment is limited to the latter
(Sandostatin LAR) for once a month injection became available. because the owner denies treatment of the acromegalic condition.
Lanreotide is another somatostatin analog, coming as two See Chapter 7 for management guidelines. Insulin resistance varies
long-acting formulations (Somatuline LA every 10 to 14 days, widely between acromegalic cats. In some cats, glycemic control
Somatuline Depot or Autogel once a month). The main limitation may be achieved with normal insulin doses (1 to 3 U/cat b.i.d.);
of octreotide and lanreotide is their selective binding to the SSTR in others, much higher doses are required. We usually increase the
subtypes, because their binding affinity is high for SSRT 2 but insulin dose in steps of 0.5 to 1.0 U/cat b.i.d. approximately every
only moderate for SSTR 5 and SSTR 3 and very low for the other 5 to 7 days until glycemic control is acceptable (e.g., most blood
two. Reported efficacy with regard to normalization of GH and glucose levels throughout the day are between approximately 100
IGF-1 differs largely between studies and ranges between 20% to 300 mg/dL [5.6 to 17.0 mmol/L]). Close monitoring of the
and 80%. Tumor shrinkage, defined as 20% to 25% decrease in cats is mandatory, and we highly recommend home-monitoring
tumor volume, has been seen in up to 82% of human patients of glucose by the owners in those patients. Unfortunately, insu-
(Jallad and Bronstein, 2013). Common adverse effects consist lin resistance also varies within a given patient, and severe hypo-
of gastrointestinal signs. They usually decrease over the first few glycemia is possible in particular in conjunction with anorexia.
months of treatment (Melmed etal, 2009). Pasireotide (Signifor) Whenever possible, we do not increase the insulin dose above 12
is a new somatostatin analog with high affinity for SSTR 2 and to 15 U/cat b.i.d.
SSTR 5, as well as for SSTR 1 and SSTR 3. Due to the improved As in humans, specific treatment modalities for acromegaly
binding profile, it has the potential to be more effective in in cats include pituitary surgery, medical therapy, and radiation
patients with acromegaly than octreotide and lanreotide (Jallad therapy. See the section Treatment, Humans for some principal
and Bronstein, 2013; Petersenn etal, 2013). explanations. Pituitary surgery has the potential to become the
The use of pegvisomant (Somavert), which is the only currently treatment of choice also in cats. The procedure, however, is tech-
available GH receptor antagonist, is another treatment modality. It nically highly demanding and currently only offered in very few
reduces the synthesis of IGF-1; however, it does not suppress GH specialized centers. So far, only a few case reports have been pub-
secretion and does not have any inhibitory effect on the pituitary lished (Abrams-Ogg etal, 1993; Blois and Holmberg, 2008; Meij
tumor growth (Jallad and Bronstein, 2013). The drug usually et al, 2010b). Transsphenoidal cryohypophysectomy resulted in
has to be injected daily. Adverse effects include gastrointestinal a decrease in insulin requirement, well-controlled diabetes mel-
signs and increase in liver enzymes. Pegvisomant is currently litus, and no signs of acromegaly during an observation period
mainly reserved for patients who have failed therapy with surgery of 18 months in one cat (Blois and Holmberg, 2008). In another
and somatostatin receptor ligands (Javorsky et al, 2011). The cat, transsphenoidal hypophysectomy led to a decrease in insulin
dopamine agonist cabergoline is effective in less than 10% of requirement by 95% during the first days after surgery and to
patients with acromegaly, and its use is limited to a few particular diabetic remission after 3 weeks. The cat was followed up for 18
clinical situations (patient prefers oral medication, or drug is used months after surgery, GH and IGF-1 levels normalized, and the
as part of a combination therapy) (Melmed etal, 2009). Medical cat was doing well without the need of exogenous insulin (Meij
treatment options are an area of intensive research and novel etal, 2010b). Recently, the same group reported three more cases
treatment modalities are currently in development (Jallad and with favorable outcome after transsphenoidal hypophysectomy. In
Bronstein, 2013). all three cats, diabetic remission occurred within the first 4 weeks
Radiation therapy is generally considered for third-line treat- after surgery, and GH as well as IGF-1 levels normalized (Meij
ment and occasionally as second line treatment. It is currently et al, 2012b). The latter cases demonstrate that -cells have the
proposed to a subset of patients with persistent active disease after potential for recovery in acromegalic cats with appropriate treat-
surgery and/or during medical therapy (Minniti etal, 2011). With ment. Very close monitoring of blood glucose is essential to avoid
conventional radiation therapy, normalization of GH and IGF-1 life-threatening hypoglycemia.
levels is seen in 5% to 60% of human patients after a median So far, medical treatment has shown very little to no effect.
follow-up of 7 years. Longer follow-up studies revealed hormone The number of treated cats, however, is small, and no systematic
normalization in more than 70% of patients after 10 to 15 years. evaluations of dose-responses have been performed. One cat was
The long latency period to hormonal normalization of up to sev- treated with the dopamine agonist L-deprenyl (initial dose 5 mg
eral years is one of the major disadvantages of radiotherapy, usu- s.i.d. [semel in die; once a day], increased to 10 mg s.i.d. after
ally requiring additional medical treatment. Further limitations 1 month) for 9 months without any improvement in clinical
are the possible side effects of conventional radiation therapy, signs and insulin requirement (Abraham et al, 2002). The use
including impairment in neurocognitive function, visual dysfunc- of somatostatin receptor ligand octreotide has been reported
tion caused by optic neuropathy, and radiation induced secondary in five acromegalic cats (Morrison et al, 1989; Peterson et al,
malignancy (Jagannathan etal, 2009). A major additional concern 1990). Doses ranged between 5 and 100 g given two or three
is hypopituitarism, which occurs in up to 60% of patients within times daily for up to 4 weeks without improvement of glycemic
10 years after treatment. Stereotactic radiotherapy is a refinement control and GH hypersecretion. We have used the sustained
of conventional radiotherapy with the principle aim to deliver release octreotide in a few cats during the last years. The effect on
|
insulin requirement, however, was small. As mentioned earlier, IGF-1 is often not followed long-term after radiation therapy. It is
the main limitations of the somatostatin analogs octreotide and therefore unknown if resolution of the GH excess is ever achieved.
lanreotide in humans is their selective binding to the SSTR Persistently high IGF-1 levels have been reported in some cats after
subtypes because their density and distribution pattern varies in radiation. Interestingly, in several of those cases, diabetes was well
acromegalic patients. The same may hold true for acromegalic controlled or even in remission (Littler etal, 2006; Dunning etal,
cats. A recent study investigated if a single application of 2009). In a few other studies, a decrease of GH concentrations was
octreotide to acromegalic cats would be useful as a pre-entry test demonstrated in some of the cats (Goosens etal, 1998; Peterson
for treatment with somatostatin analogs. GH concentrations etal, 1990). It is likely that radiation therapy results in a substantial
were measured prior to and 15, 30, 60, 90, and 120 minutes decrease in GH production, which is sufficient to restore -cell
after the intravenous administration of octreotide (5 g/kg function. However, GH levels (or pulses) may not be completely
bodyweight). Two of the five acromegalic cats showed a clear-cut normal and still high enough to stimulate excessive IGF-1
decrease in GH concentrations, whereas the decrease in the other production. So far, measurement of IGF-1 levels after radiation
three cats was small (Slingerland et al, 2008). Further studies does not appear to be helpful to predict the course of diabetes.
are needed to evaluate if the responders of the octreotide test Radiation therapy is well tolerated in the vast majority of cats. Late
will also show favorable treatment response. A recently presented radiation side effects (e.g., hearing impairment or ischemic brain
study showed promising results by using the new somatostatin necrosis) are rare and can be avoided with the use of appropriate
analog pasireotide in eight cats with acromegaly. All cats showed fractionation protocol; hypopituitarism, a common adverse effect
a significant decrease in blood glucose and IGF-1 concentrations in humans, has not yet been reported in cats. The disadvantages of
(Niessen etal, 2013b). No information on the use of pegvisomant, radiation therapy are limited availability, expense, need for frequent
a GH receptor antagonist, is available at this time. anesthesia, as well as the unpredictable outcomes in terms of
Radiation therapy is currently the most frequently used hormonal control. Some of those disadvantages may potentially be
treatment modality in acromegalic cats. In the studies described in overcome with the use of more sophisticated radiation techniques
the past, types and techniques of radiation (Cobalt-60, betatron, and radiation protocols (e.g., hypofractionated stereotactic [image-
linear accelerator), treatment planning (manual or computerized), guided] radiation therapy, and stereotactic radiosurgery), allowing
as well treatment protocols (number of fractions, total radiation more precise radiation fields and less exposure of normal tissue. In
dose) varied considerably (Goossens et al, 1998; Peterson et al, cats with favorable response to radiation therapy, survival times for
1990; Kaser-Hotz et al, 2002; Brearley et al, 2006; Littler et al, up to 5 years have been reported (Dunning etal, 2009; Fig. 2-24).
2006; Mayer etal, 2006; Dunning etal, 2009; Sellon etal, 2009).
Additionally, follow-up periods and parameters to evaluate treatment
Histopathology
outcome also differed, rendering direct comparison between the
studies impossible. Many of the treatments are not state-of-the- In most cases, histopathology reveals an acidophil adenoma of
art anymore and, therefore, results have to be interpreted with the pituitary gland with or without involvement (compression
care. The most consistent effect of radiotherapy is improvement or invasion) of the pars intermedia, pars distalis, hypothalamus,
or resolution of neurological signs. In cats with large pituitary and thalamus. On rare occasions, no tumor but proliferation of
tumors, improvement is often seen during or soon after radiation
therapy. If tumor size is reevaluated by CT or MRI a few months
after completion of radiation therapy, considerable size reduction Dose
105.0 %
(e.g., partial or complete remission) may be seen. Improvement of 105.0
100.0%
clinical signs of diabetes is more variable and difficult to predict. 95.0%
90.0%
Insulin requirement may start to decrease already during radiation 85.0%
therapy or soon thereafter. In a recent study, the mean time to 80.0%
75.0%
improved glycemic control was 5 weeks after the completion of 70.0%
65.0%
radiotherapy, with a range of 0 to 20 weeks. In 6 of 14 cats, diabetic 60.0%
remission was achieved after a mean time of 3.6 months with a 55.0%
50.0
range of 0 to 6 months (Dunning et al, 2009). It is important 50.0 % 104.2%
111_ICRU
to note that diabetic remission may occur as late as 1 year after L
radiation. The unpredictable course of the diabetes is one of the
challenging problems because it requires close monitoring of the
cats blood glucose concentrations. Failure to identify improvement
or resolution of insulin resistance may result in hypoglycemia and
death. As already mentioned earlier, we highly recommend home-
monitoring of blood glucose in cats with acromegalyin particular
Standard
after they have undergone surgical or radiation therapy. In some
cats, diabetic remission is transient, and insulin therapy has to be
re-introduced. Based on the currently available data, improvement Head first-prone
of the clinical signs of diabetes is possible in approximately 70% to Z: 14.35 cm
80% of cases; in approximately 50% of cases, diabetic remission may FIGURE 2-24 Transversal view of a treatment plan (arc) for pituitary adenoma.
be achieved. However, the physical changes of acromegaly usually The colors represent the dose distribution within the planning target volume
persist or improve only slightly. In human medicine, the goal of (red line surrounding the tumor) with red and orange colors representing the
any therapy in acromegalic patients is a normalization of GH and high-dose area (90% to 105% of the prescribed dose) and blue and green colors
IGF-1 concentrations. After radiation therapy, hormone levels in displaying the rapid fall-off of dose outside the target structure. (Courtesy of Dr.
humans decrease only slowly, and it may take many years until they Carla Rohrer Bley, Division of Radiation Oncology, Vetsuisse Faculty, University
are within the normal range. In cats GH is rarely measured, and of Zurich.)
the acidophilic cells is found (Niessen etal, 2007a). Microscopic test; however, he was not overtly diabetic as basal blood glucose
findings of other organs include adenomatous hyperplasia of the concentrations were measured repetitively and found to be normal.
thyroid and the parathyroid glands, multinodular hyperplasia of GH and IGF-1 levels were increased, and CT imaging revealed a
the adrenal cortices, multifocal or disseminated nodular hyper- pituitary mass. The dog was left untreated and was euthanized
plasia of the pancreas with ductal fibrosis, interstitial lympho- after a few months because of progressive worsening of the clinical
cytic or lymphocytic-plasmacytic infiltration, hyalinization of the signs. Histology and immunohistochemistry confirmed the
islets, and amyloid deposition. Kidneys usually reveal findings presence of an acidophilic adenoma that stained positive for GH.
consistent with glomerulopathy/glomerulonephritis and intersti- It is interesting to note, that in one of the two dogs the insulin-
tial nephritis, including thickening of the glomerular basement antagonistic actions occurred; in the other dog, however, the
membrane, thickening of the Bowman capsule, expansion of the anabolic effects of GH excess dominated the clinical picture. In
mesangial matrix, periglomerular fibrosis, interstitial fibrosis with our institution, we recently diagnosed another case in a 7-year-old
lymphocytic-plasmacytic infiltration, and renal tubular degener- male castrated Labrador Retriever with both difficult to regulate
ation. Steatosis and lymphocytic-plasmacytic cholangiohepatitis diabetes mellitus and typical physical features of acromegaly.
are typical liver abnormalities. Myocardial lesions are character-
ized by myofiber hypertrophy, myocytolysis, interstitial fibrosis, Endogenous and Exogenous Progestagens
and arteriosclerosis. Microscopic joint alterations include erosion In dogs, circulating GH does not only derive from the anterior
and ulceration of cartilage with chondroid hyperplasia and fissure pituitary but also originates from the mammary gland. Mammary
formation (Middleton etal, 1985; Peterson etal, 1990; Abrams- GH is stimulated by progesterone, which is a physiological
Ogg et al, 1993; Abraham et al, 2002; Niessen et al 2007a; event and occurs in all intact bitches. See Mammary Growth
Greco, 2012). Hormone at the beginning of the chapter for more details.
Administration of synthetic progestagens for estrus prevention
may result in excessive GH secretion and increased IGF-1
Prognosis
synthesis and potentially acromegaly and diabetes mellitus.
If the cat is not treated for acromegaly, the prognosis is guarded to Treatment in male dogs (e.g., for benign prostatic hyperplasia)
poor. In most cats, clinical signs and insulin resistance are progres- may have the same effect. GH excess may also occur in some
sive, rendering insulin treatment increasingly difficult. Most cats middle-aged to elderly bitches during the luteal phase of the
are euthanized within a few months after diagnosis, because the estrus cycle (Kooistra, 2013).
owner becomes frustrated by the poor control of the diabetes and The phenomenon of progestagen-induced GH excess was dis-
the increasing or fluctuating insulin requirement. Other cats are covered in the 1970s and 1980s. Rijnberk, etal. (1980) described
euthanized or die because of the development of congestive heart acromegalic features and increased GH concentrations in a dog
failure, renal failure, respiratory distress, or neurological signs that had received twelve injections of MPA for estrus preven-
associated with expansion of the pituitary tumor. Cats in which tion over the course of 4 years. The dog was not overtly diabetic
the GH excess is treated with either pituitary surgery or radiation but revealed glucose intolerance during an oral glucose tolerance
therapy may have a favorable outcome. Glycemic control often test. After cessation of MPA application, physical changes gradu-
improves, and diabetic remission is possible; survival for several ally improved; GH and insulin concentrations as well as glucose
years has been seen. intolerance normalized with time. Soon thereafter, Eigenmann
and Venker-van Haagen (1981) reported on another fifteen dogs
that had received MPA injections twice yearly for estrus preven-
HYPERSOMATOTROPISM (ACROMEGALY) IN DOGS
tion. All dogs had typical physical features of acromegaly, and
The etiopathogenesis of acromegaly is quite different in dogs and thirteen of the fifteen dogs showed hyperglycemia. The latter was
cats. In dogs, acromegaly is almost always induced by endogenous mild (blood glucose 180 mg/dL, 10 mmol/L) in eight dogs
or exogenous progestagens giving rise to GH hypersecretion from and severe (blood glucose more than 180 mg/dL, 10 mmol/L)
the mammary gland. Acromegaly, due to a GH-producing tumor in five dogs. GH concentrations were increased in all fifteen
in the pituitary gland, which is the cause of feline acromegaly, is dogs with marked variation from dog to dog (11 to 178 g/L,
an extremely rare event in the dog (Kooistra, 2010). median 34.2; normal dogs less than 5 g/L). Clinical signs and
hyperglycemia improved after cessation of MPA administration.
Experimental studies confirmed the causal relationship between
Etiology
the application of progestagens and the development of acro-
Pituitary Neoplasia megaly, glucose intolerance, and diabetes mellitus (Concannon
So far, the occurrence of a somatotrophic adenoma has only been et al, 1980; Eigenmann and Rijnberk, 1981; Eigenmann and
described in two dogs. Van Keulen, etal. (1996) reported a 9-year- Eigenmann 1981a, Scott and Concannon, 1983; Selman et al
old male Doberman Pinscher with difficult to regulate diabetes 1994b; Selman etal, 1997).
mellitus but without obvious physical changes of acromegaly. Selman et al (1994b) administered 10 mg/kg MPA and 50
Necropsy revealed an acidophilic adenoma with strong positive mg/kg PROL to castrated Beagle bitches at intervals of 3 weeks
immunohistochemical staining for GH. More recently, Fracassi, for a total of eight injections. The doses were twice as high as
et al. (2007) described a 10-year-old Dalmatian dog with recommended for estrus prevention, and application frequency
typical acromegalic features, including polyphagia, weight gain, was much higher (for estrus prevention only once every 6 months).
inspiratory stridor, enlargement of head and tongue, widening GH levels were significantly higher compared to the initial levels
of interdental spaces, thickening of the skin particularly of already after the second injection and increased steadily, with
head and neck with redundant skin folds, panting, and chronic considerable inter-individual variation. IGF-1 concentrations
progressive stiffness and neck rigidity. The dog also suffered from increased simultaneously, and large increases in GH were associated
polyuria and polydipsia. His insulin levels were increased and with large increases in IGF-1 levels. Both progestagen preparations
glucose intolerance was demonstrated during a glucose tolerance resulted in similar increases. Insulin levels also increased and were
|
significantly higher compared with pre-treatment levels after the Pathophysiology

third injection but did not increase further. After six injections,
glucose intolerance became apparent, and one dog in each group See the section Metabolic Actions on Growth Hormone and
developed severe diabetes mellitus. During the recovery period of Insulin-like Growth Factor-1 and the section Hypersomatotro-
30 weeks after the last injection, neither GH nor IGF-1 returned to pism (Acromegaly) in Cats, Pathophysiology.
normal, and glucose tolerance remained impaired.
In summary, application of progestagens to dogs results in Signalment
increase in GH and IGF-1 concentrations, albeit with large
inter-individual differences. The increases appear to be dose- GH-secreting pituitary tumors have so far only been seen in male
related: higher doses, and more frequent applications lead to dogs of large breeds (Doberman Pinscher, Dalmatian, Labrador
more pronounced increase. The effects are similar with different Retriever), with age ranges between 7 and 10 years (Van Keulen
progestagen preparations. The hormone excess is associated with etal, 1996; Fracassi etal, 2007).
the development of acromegalic features; their severity also varies GH-excess due to exogenous progestagen application has
between individuals. Initially, glucose tolerance is maintained by been seen by us and others in numerous breeds of different sizes,
increased insulin production. With time, however, further insulin including Dachshund, French Bulldog, Scottish Terrier, English
increase is not possible, resulting in glucose intolerance. Some Cocker Spaniel, American Cocker Spaniel, Springer Spaniel,
dogs may develop overt diabetes mellitus. The abnormalities are Standard Poodle, English Setter, Dalmatian, Belgian Shepherd, and
potentially reversible after weeks to months; however, bone lesions mixed breed dogs. The dogs were intact females and developed the
usually persist. Progesterone-induced GH excess may also occur disorder after receiving progestagens for estrus prevention, with
in some middle-aged to elderly intact bitches associated with the age ranges between 4 and 11 years. Similarly, GH excess associated
luteal phase of their estrus cycle. The increase in GH and IGF-1 is with the luteal phase of the estrus cycle has been seen in various
a physiological event (e.g., it occurs also in healthy intact bitches). breeds; the bitches were usually middle-aged to elderly (6 to 13
Basal GH levels are highest during the first part of the luteal phase years). The breeds included Dachshund, Beagle, English Cocker
(luteal phase 1), when progesterone levels are also highest, both Spaniel, Dalmatian, Golden Retriever, German Shepherd, Bouvier,
hormones decrease in parallel and are lowest in anestrus. GH and mixed breed dogs (Rijnberk etal, 1980; Eigenmann, 1981b;
concentrations were shown to be 2.2 0.3 in luteal phase 1 and 1.4 Eigenmann and Venker-van Haagen, 1981). A study undertaken in
0.2 g/L in anestrus; progesterone concentrations were 123 15 Sweden showed that in some breeds (e.g., Swedish and Norwegian
and 0.9 0.2 nmol/L, respectively (Kooistra et al, 2000b). In Elkhounds, Border Collies, and Beagles), diabetes mellitus occurs
bitches developing spontaneous acromegaly, progesterone levels almost exclusively in intact females, and it was assumed that in
are within the range of normal dogs, whereas GH concentrations many of the dogs the disease is diestrus-associated (Fall etal, 2007).
are increased (Eigenmann, 1986). As seen after exogenous Gestational diabetes was reported in Elkhounds, Alaskan Malamute,
progesterone application, GH levels vary markedly between Siberian Husky, Drever, Border Collie, Labrador Retriever, and
individual dogs, ranging between 11.8 to 1476 g/L (median 31.7; Yorkshire Terrier, with age ranges between 6 to 8 years (Norman
normal dogs less than 5 g/L) in seven bitches with spontaneous etal, 2006; Fall etal, 2007; Fall etal, 2008; Fall etal, 2010; Armenise
GH excess (Eigenmann and Venker-van Haagen, 1981). Dogs etal, 2011).
with spontaneous GH excess may be overtly diabetic or reveal The two dogs with assumed mammary-tumor derived
glucose intolerance during a glucose tolerance test, and insulin GH-excess were a 10-year-old Miniature Dachshund and a
levels are usually high (Eigenmann, 1981b; Eigenmann et al, 13-year-old Papillon, both were female-intact (Murai etal, 2012).
1983). Recovery is potentially possible after ovariohysterectomy.
The reason why some intact bitches develop diestrus-associated Clinical Manifestations
acromegaly and diabetes has not yet been clarified. Gestational
diabetes mellitus has been reported several times (Norman etal, The clinical signs of GH excess tend to develop slowly. In cases,
2006; Fall et al, 2008; Fall et al, 2010; Armenise et al, 2011). in which the disorder is induced by exogenous progestagens, the
Usually, the signs associated with diabetes mellitus dominate the onset is variable and depends in part on dosage and frequency
clinical picture; obvious acromegalic features have only been seen of application of the compound (Feldman and Nelson, 2004).
in one dog (Norman etal, 2006). In case of diestrus-associated hypersecretion of GH, dogs are
Of note, circulating GH may not only originate from nor- often presented 3 to 5 weeks after estrus. The owner may report,
mal mammary tissue but also from mammary tumors. There however, that similar signs (e.g., inspiratory dyspnea, polyuria/
is an association with tumor characteristics, because GH and polydipsia) had already been apparent after the previous estrus,
IGF-1 levels in plasma and tumor tissue were shown to be albeit milder and improved during anestrus. Although the increase
significantly higher in dogs with malignant tumors than in of GH during the luteal phase is a physiological event, it should be
dogs with benign tumors (Queiroga et al, 2008; Queiroga remembered that only very few intact bitches develop pathological
etal, 2010). Very recently, acromegalic features were described GH hypersecretion (Fig. 2-25).
in two dogs with mammary tumors staining positive for GH Clinical signs mainly result from the anabolic, growth-
(Murai et al, 2012). Mammary tumor-induced acromegaly, promoting effect of GH and IGF-1 and the diabetogenic effects
however, is generally rare. of GH. Cats with acromegaly are almost always presented because
of diabetes mellitus, which is difficult to regulate in many cases.
Hypothyroidism Acromegalic features often only become obvious with time. In
Dogs with primary hypothyroidism were shown to have elevated dogs, manifestations, however, are more variable. Some dogs
basal GH concentrations and increased IGF-1. It is suggested that only reveal the typical physical changes of acromegaly, some
some of the physical changes seen in hypothyroidism (thick skin, predominantly show clinical signs of diabetes mellitus, and others
skin folds) are, at least in part, due to increased GH and IGF-1 have both categories of symptoms. Part of the variability may be
levels (Lee etal, 2001). breed-related. As for instance in Elkhound dogs, diestrus-associated
20
15
GH (mcg/L)
10
0
15 0 15 30 45 60 75 90
Minutes after load
FIGURE 2-25 Female 9-year-old intact Golden Retriever with diestrus-associated GH

acromegaly. The dog was presented with inspiratory stridor, dyspnea, lethargy,
thickening of the skin, excessive skin folds in the head and neck area, and coarse FIGURE 2-26 Serum growth hormone (GH) concentrations at 15, 0, 15, 30, 45,
facial features. Blood glucose concentration was normal. The circulating proges- 60, and 90 minutes after the intravenous administration of 10 g/kg somatosta-
terone concentration was 13.5 ng/mL and consistent with diestrus, the insulin- tin per kg body weight in a 10-year-old male Dalmatian dog with acromegaly
like growth factor-1 (IGF-1) concentration was 1600 ng/mL and severely increased due to a somatotroph adenoma. Basal GH concentration was markedly elevated
(normal < 800). Two weeks after ovariohysterectomy, the progesterone concentra- (reference range: 2 to 5 g/L) and did not decrease after somatostatin. (Repro-
tion was 1.9 ng/mL, and IGF-1 had decreased to 383 ng/mL. The acromegalic duced with permission from Fracassi F, etal.: Acromegaly due to a somatotroph
features resolved with time. adenoma in a dog, Domest Anim Endocrinol 32[1]:43-54, 2007.)
the very rare event of GH hypersecretion due to a tumor of the

diabetes, but no physical changes of acromegaly have been reported somatotrophic cells, CT/MRI will reveal a pituitary mass.
(Fall etal, 2010). In dogs, typical and early signs are inspiratory
stridor and possibly dyspnea, panting, and exercise intolerance Hormonal Evaluation
due to an increase in soft tissue mass in the oropharyngeal
region. Further physical changes include enlargement of the Circulating GH and IGF-1 levels are usually increased in dogs with
tongue, prognathia inferior, widening of interdental spaces, acromegaly. As GH is secreted in pulses, a single measurement is
broadening of the head, increased skin thickness and excessive often not sufficient for the diagnosis. A high GH level may just be the
skin folds mainly in the head and neck area and distal extremities, result of a secretory pulse. The exception would be a dog with several-
enlargement of abdomen due to visceromegaly, enlargement of fold increase from normal. On the other hand, in dogs with mild or
paws, weight gain, thickened hair coat with long and curly hair, beginning acromegaly, basal GH levels may still be within the normal
difficulties to rise or walk due to degenerative arthropathy, and range. There are several options to increase the diagnostic accuracy:

mammary tumors (Rijnberk etal, 1980; Eigenmann and Venker- 1. Measurement of GH in three to five samples taken at 10
van Haagen, 1981; Scott and Concannon, 1983; Feldman and minute intervals. The more of those samples that reveal an
Nelson, 2004; Norman etal, 2006; Fracassi etal, 2007; Meij etal, increased GH level and the higher those levels are, the more
2010a; Murai etal, 2012). Overt diabetes mellitus develops in a likely the dog has acromegaly.
substantial percentage of dogs and is associated with polyuria and 2. Measurement of GH during a somatostatin suppression test. The
polydipsia. However, mild to moderate polyuria and polydipsia latter is performed by collecting blood samples for GH determi-
may also be present without diabetes and is probably related to nation before and 15, 30, 45, 60, and 90 minutes after the intra-
either exogenous progestagens and/or the GH excess. In the very venous application of 10 g/kg body weight somatostatin. GH
rare event of GH excess caused by a pituitary tumor, additional should show minimal or no decrease in dogs with acromegaly.
neurological signs may be present. 3. Measurement of GH during an IVGTT. The additional mea-
surement of the insulin concentrations allows evaluation of the
Clinical Pathology degree of glucose intolerance. The test is, therefore, suitable
for dogs with normal or only mildly increased blood glucose
Blood glucose concentrations may be normal, or range from mildly concentrations. Blood samples for determination of GH, in-
to severely increased. Depending on the degree of hyperglycemia, sulin, and glucose are taken before and 15, 30, 60, and 90
glucosuria may or may not be present. Similarly, serum fructosamine minutes after the IV administration of 1 g/kg body weight of a
concentrations may be normal or increased. Ketonuria and diabetic 50% glucose solution. GH concentrations should show no or
ketoacidosis have been seen in diestrus-associated diabetes, but they minimal decrease in the case of acromegaly. Basal insulin con-
are rare. In case of overt diabetes mellitus, additional abnormalities centrations are often very high without further increase after
(e.g., increased cholesterol, increased ALT and ALP) may be found. the glucose load, more moderately increased basal insulin levels
may show some increase; despite high insulin levels, glucose
tolerance is impaired (i.e., delayed return to normal).
Diagnostic Imaging
GH should be determined in a canine-specific radioimmunoas-
Potential radiological and/or ultrasonographic abnormalities say. Unfortunately availability is often limited (Eigenmann etal,
include increase in soft tissue in the oropharyngeal region, 1983; Feldman and Nelson, 2004; Fracassi etal, 2007; Kooistra
degenerative arthropathy, spondylosis, and organomegaly. In 2010, 2013; Fig. 2-26 and Fig. 2-27). Sample handling for GH
|
350 used. IGF-1 measurement may be associated with some biological

Insulin (mU/L)
300 and technical problems; see the discussion on IGF-1 in the section
250 Hypersomatotropism in Cats, Hormonal Evaluation.
200 Baseline T4 and TSH concentrations are usually normal in dogs
150 with acromegaly. Conversely, in dogs with primary hypothyroid-
100 ism, basal GH and IGF-1 levels are increased.
50
The intrinsic glucocorticoid-activity of exogenous progesta-
0
gens may suppress endogenous ACTH secretion, causing low
0 15 30 45 60 75 90 basal cortisol concentration and impaired cortisol response
after ACTH administration (Concannon et al, 1980; Court
Minutes after load
etal, 1998).
Insulin
Establishing the Diagnosis
40
A tentative diagnosis of acromegaly is based on the presence
35
30
of typical physical changes of acromegaly and/or diabetes
GH (mcg/L)
25 mellitus in association with the history of chronic progestagen

20 administration or diestrus. In case of diestrus-associated GH
15 hypersecretion, dogs are often presented 3 to 5 weeks after
10 estrus. Careful questioning of the owner often reveals that milder
5 signs had already been apparent after the previous estrus and
0 improved during anestrus. The definitive diagnosis requires the
0 15 30 45 60 75 90 documentation of increased GH (and impaired suppression after
Minutes after load somatostatin or glucose) or increased IGF-1 concentrations. The
most important differential diagnosis for a dog with physical
GH changes of acromegaly is hypothyroidism. The latter disease
may also be associated with clinical signs (e.g., thickening of the
400 skin, abundant skin folds particular in the head area, lethargy
350 and weight gain) and therefore, dogs with acromegaly and
Glucose (mg/dL)
300 hypothyroidism may look alike. It is very important to realize

250 that dogs with primary hypothyroidism have elevated GH and
200 IGF-1 concentrations (Lee etal, 2001). Dogs with acromegaly
150 typically have normal T4 and TSH levels. In male dogs with
100
no history of progestagen administration, the possibility of a
50
pituitary tumor should be explored by CT or MRI imaging. In
0
0 15 30 45 60 75 90 dogs with polyuria and polydipsia (without diabetes mellitus
and without acromegalic features) various diagnoses have to be
Minutes after load
considered (see Chapters 1 and 3).
Glucose
Treatment
FIGURE 2-27 Serum concentrations of growth hormone (GH), insulin, and glucose
at 0, 15, 30, 60, and 90 minutes after the intravenous administration of 1g/kg In bitches with diestrus-associated acromegaly, ovariohysterectomy
body weight of a 50% glucose solution in a 10-year-old male Dalmatian dog should be performed as soon as possible. GH and IGF-1
with acromegaly due to a somatotroph adenoma. Basal insulin concentration concentrations return to normal very soon thereafter. In case of
was high and increased considerably after the glucose load. Glucose concentra- diabetes mellitus, immediate measures are highly recommended
tions, however, did not return to normal, indicating glucose intolerance. Basal to limit the deleterious effects of glucose toxicity on -cell
GH concentration was markedly elevated (reference range; 2 to 5 g/L) and did function, thereby improving the chance of diabetic remission. We
not decrease after the glucose load. (Reproduced with permission from Fracassi usually do not wait until we receive the results of the GH/IGF-1
F, etal.: Acromegaly due to a somatotroph adenoma in a dog, Domest Anim En- measurements. Insulin therapy is initiated immediately in all
docrinol 32[1]:43-54, 2007.) dogs with moderate to highly increased blood glucose concentrations
(>140 mg/dL, 8 mmol/L); the insulin dose depends on
the severity of hyperglycemia and ranges between approximately
determination is critical, and the laboratory should be contacted 0.05 to 0.25 U/kg b.i.d. If ovariohysterectomy has to be delayed
prior to performing the test. for more than one day, we routinely administer the progesterone
Measurement of IGF-1 is a suitable alternative test. Because receptor aglpristone (Alizin, Virbac) in a dose of 10 mg/
IGF-1 is not secreted in pulses, one single random blood sample kg subcutaneously and repeat the same dose after 24 hours.
is required. It can be measured with assays designed for humans, During surgery and during the following days to weeks, blood
and the sample can be sent by regular mail. In acromegalic dogs, glucose concentrations should be monitored closely. Insulin
IGF-1 levels are often highly increased (e.g., two to three times requirements may decrease rapidly due to the cessation of
the upper limit of normal is no exception). As with any other insulin resistance, and hypoglycemia may occur if insulin doses
disease, however, in mild or beginning disease, there may be over- are not amended. In dogs with acromegaly due to exogenous
lap between healthy and affected dogs. IGF-1 levels correlate with progestagens, their administration should be discontinued
body size; therefore, size-dependent reference ranges should be immediately. Insulin treatment is initiated as described earlier
if diabetes is present. Usually, those dogs were treated with to the rarity of cases, experience with regard to outcome, however,
depot progestagen preparations with long lasting effects. In is lacking.
dogs with severe signs of acromegaly and in all dogs which are
diabetic, we administer aglpristone (Alizin, Virbac) in a dose Prognosis
of 10 mg/kg subcutaneously twice at 24-hour intervals. Because
the progestagen effect is usually much longer lasting than the The prognosis of progestagen-induced acromegaly is usually
effect of aglpristone, the administration of the latter is repeated good. The soft-tissue changes usually resolve over weeks to
approximately once a week. This approach is empirical and based months, and the dog may regain a more or less normal appear-
on the study of Bhatti, etal. (2006d) and our own experience. ance. If the bony changes persist, usually they do not cause
The optimal protocol has not yet been established. Mammary clinical problems (Kooistra, 2013). The course of the diabetes
tumors should be removed surgically, because they may be a mellitus is more variable and depends on the degree of -cell
source of GH/IGF-1 production. damage. Diabetic remission may occur within a few weeks (1 to
In dogs with acromegaly due to a pituitary tumor, either 8 weeks after ovariohysterectomy) if treatment is instituted early;
radiation therapy or hypophysectomy should be considered; due however, persistence of diabetes is also possible.
REFERENCES
Abraham LA, etal.: Treatment of an acro- Beijerink NJ, etal.: Evaluation of pulsatile Brent GA, Davies TF: Hypothyroidism and thy-
megalic cat with the dopamine agonist plasma concentrations of growth hormone roiditis. In Melmed S, Polonsky KS, Larsen
L-deprenyl, Aus Vet J 80:479, 2002. in healthy dogs and dogs with dilated PR, Kronenberg HM, editors: Williams
Abrams-Ogg ACG, etal.: Acromegaly in a cat: cardiomyopathy, Am J Vet Res 72:59, textbook of endocrinology, ed 12, Philadel-
diagnosis by magnetic resonance imaging 2011. phia, 2011, Saunders Elsevier.
and treatment by cryohypophysectomy, Can Bereket A, etal.: Alterations in the growth Brki CD: Wachstumshormon (GH) und
Vet J 34:682, 1993. hormone-insulin-like growth factor axis in Insulin-hnliche Wachstumsfaktoren
Abribat T, etal.: Growth hormone response insulin dependent diabetes mellitus, Horm (IGF) beim wachsenden Hund in Relation
induced by synthetic human growth Metab Res 31:172, 1999. zur Krpergrsse am Modell des Pudels,
hormone-releasing factor (1-44) in healthy Berg RIM, etal.: Serum insulin-like growth Inaugural-Dissertation, Departement fr
dogs, J Vet Med 36:367, 1989. factor-I concentrations in cats with diabetes Veterinrphysiologie und Tierernhrung der
Allgoewer I, etal.: Somatotropes Hypophy- mellitus and acromegaly, J Vet Intern Med Universitt Zrich, Zrich, 2000.
senadenom mit Lsion des n. oculomoto- 21:892, 2007. Capen CC: Endocrine glands. In ed 5, Maxie
rius bei einer Katze, Tierrztl Prax 26:267, Bhatti SF, etal.: Effects of growth hormone- MG, editor: Jubb, Kennedy, and Palmers
1998. releasing peptides in healthy dogs and in pathology of domestic animals, Vol 3. St
Andresen E: Herkunft und Verbreitung von dogs with pituitary-dependent hyperadre- Louis, 2007, Saunders Elsevier.
hypophysrem Zwergwuchs beim Hund nocorticism, Mol Cell Endocrinol 197:97, Castro-Peralta F, Barrera-Saldaa HA: Cloning
und Grundlage zur Ermittlung von Anlage 2002. and sequencing of cDNA encoding the cat
trgern verschiedener genetisch bedingter Bhatti SF, etal.: Ghrelin, an endogenous growth hormone, Gene 160:311, 1995.
Krankheiten unter Anwendung biochemischer growth hormone secretagogue with diverse Cerundolo R, etal.: Alopecia in pomeranians
Methoden, Kleintierpraxis 23:65, 1978. endocrine and nonendocrine effects, Am and miniature poodles in association with
Andresen E, Willeberg P: Pituitary dwarfism J Vet Res 67:180, 2006a. high urinary corticoid:creatinine ratios and
in German shepherd dogs: additional Bhatti SF, etal.: Effects of growth hormone resistance to glucocorticoid feedback, Vet
evidence of simple, autosomal recessive secretagogues on the release of adeno- Rec 160:393, 2007.
inheritance, Nord Vet Med 28:481, 1976. hypophyseal hormones in young and old Chanson P, Salenave S: Acromegaly, Orphanet
Andresen E, Willeberg P: Pituitary dwarfism healthy dogs, Vet J 172:515, 2006b. J Rare Dis 3:17, 2008.
in Carelian bear-dogs: evidence of simple, Bhatti SF, etal.: Ghrelin-stimulation test in the Chanson P, etal.: Acromegaly, Best Pract Res
autosomal recessive inheritance, Hereditas diagnosis of canine pituitary dwarfism, Res Clin Endocrinol Metab 23:555, 2009.
84:232, 1977. Vet Sci 81:24, 2006c. Chestnut RE, Quarmby V: Evaluation of total
Aragon-Alonso A, etal.: Adult growth hormone Bhatti SF, etal.: Treatment of growth hormone IGF-I assay methods using samples from
deficiency. In Wass JAH, Stewart PM, Amiel excess in dogs with the progesterone type I and type II diabetic patients, J Im-
SA, Davies MJ, editors: Oxford textbook of receptor antagonist aglpristone, Therio- munol Methods 259:11, 2002.
endocrinology and diabetes, ed 2, Oxford, genology 66:797, 2006d. Childs GV: Growth hormone cells as co-
2011, Oxford University Press. Blois SL, Holmberg DL: Cryohypophysectomy gonadotropes: partners in the regulation of
Armenise A, etal.: Gestational diabetes used in the treatment of a case of feline the reproductive system, Trends Endocrinol
mellitus with diabetes ketoacidosis in a acromegaly, J Small Anim Pract 49:596, Metab 11:168, 2000.
Yorkshire Terrier bitch, J Am Anim Hosp 2008. Childs GV: Pituitary gland (cell types, mediators,
Assoc 47:285, 2011. Boisclair YR, etal.: The acid-labile subunit development). In Larry R, Squire LR, editors:
Ascacio-Martinez JA, Barrera-Saldaa HA: (ALS) of the 150 kDa IGF-binding protein Encyclopedia of neuroscience, University of Ar-
A dog growth hormone cDNA codes for complex: an important but forgotten kansas for Medical Sciences, 2009. Elsevier
a mature protein identical to pig growth component of the circulating IGF system, J Clemmons DR: Metabolic actions of insulin-
hormone, Gene 143:277, 1994. Endocrinol 170:63, 2001. like growth factor-I in normal physiology
Bach LA, etal.: Insulin-like growth factor- Boyko AR: The domestic dog: mans best friend and diabetes, Endocrinol Metab Clin N Am
binding protein-6 and cancer, Clin Sci in the genomic era, Genome Biol 12:216, 41:425, 2012.
124:215, 2013. 2011. Concannon P, etal.: Growth hormone, prolactin,
Barrett KE, etal.: The pituitary gland. In Barrett Brearley MJ, etal.: Coarse fractionated radiation and cortisol in dogs developing mammary
KE, Barman SM, Boitano S, Brooks HL, therapy for pituitary tumours in cats: a ret- nodules and an acromegaly-like appearance
editors: Ganongs review of medical physiol- rospective study of 12 cases, Vet Comparat during treatment with medroxyprogesterone
ogy, ed 24, McGraw-Hill Companies, 2012. Oncol 4:209, 2006. acetate, Endocrinol 106:1173, 1980.
|
Cooke DW, etal.: Normal and aberrant growth. Eigenmann JE, Eigenmann RY: Radioimmu- Fischetti AJ, etal.: CT and MRI evaluation of
In Melmed S, Polonsky KS, Larsen PR, noassay of canine growth hormone, Acta skull bones and soft tissues in six cats with
Kronenberger HM, editors: Williams text- Endocrinol 98:514, 1981b. presumed acromegaly versus 12 unaffected
book of endocrinology, ed 12, Philadel- Eigenmann JE, Patterson DF: Growth hormone cats, Vet Radiol Ultrasound 53:535, 2012.
phia, 2011, Saunders Elsevier. deficiency in the mature dog, J Am Anim Fracassi F, etal.: Acromegaly due to a soma-
Court EA, etal.: Effects of delmadinone ac- Hosp Assoc 20:741, 1984. troph adenoma in a dog, Domest Anim
etate on pituitary-adrenal function, glucose Eigenmann JE, Rijnberk A: Influence of Endocrinol 32:43, 2007.
tolerance and growth hormone in male medroxyprogesterone acetate (Provera) Frank LA: Growth hormone-responsive alopecia in
dogs, Aust Vet J 76:555, 1998. on plasma growth hormone levels and on dogs, J Am Vet Med Assoc 226:1494, 2005.
Cowan JS, etal.: Secretory bursts of growth carbohydrate metabolism, Acta Endocrinol Freda PU: Current concepts in the biochemical
hormone secretion in the dog may be 98:599, 1981. assessment of the patient with acromegaly,
initiated by somatostatin withdrawal, Can Eigenmann JE, Venker-van Haagen AJ: Growth Horm IGF Res 13:171, 2003.
J Physiol Pharmacol 62:199, 1984. Progestagen-induced and spontaneous Freda PU, etal.: Analysis of GNAS mutations
Daughaday WH, etal.: Somatomedin: proposed canine acromegaly due to reversible growth in 60 growth hormone secreting pituitary
designation for sulphation factor, Nature hormone overproduction: clinical picture tumors: correlation with clinical and
14:107, 1972. and pathogenesis, J Am Anim Hosp Assoc pathological characteristics and surgical
Delafontaine P, etal.: Sequence of a cDNA 17:813, 1981. outcome based on highly sensitive GH
encoding dog insulin-like growth factor I, Eigenmann JE, etal.: Decrease of non- and IGF-I criteria for remission, Pituitary
Gene 130:305, 1993. suppressible insulin-like activity after pan- 10:275, 2007.
Diaz-Espieira MM, etal.: Functional and mor- createctomy and normalization by insulin French MB, etal.: Secretory pattern of canine
phological changes in the adenohypophysis therapy, Acta Endocrinol 85:818, 1977. growth hormone, Am J Physiol 252:E268,
of dogs with induced primary hypothyroid- Eigenmann JE, etal.: Progesterone-controlled 1987.
ism: loss of TSH hypersecretion, hyperso- growth hormone overproduction and Frystyk J: Quantification of the GH/IGF-axis
matotropism, hypoprolactinemia, and pitu- naturally occurring canine diabetes and ac- components: lessons from human studies,
itary enlargement with transdifferentiation, romegaly, Acta Endocrinol 104:167, 1983. Domestic Animal Endocrinol 43:186, 2012.
Domest Anim Endocrinol 35:98, 2008. Eigenmann JE, etal.: Insulin-like growth fac- Frystyk J, etal.: The current status of IGF-I
Dimaraki EV, etal.: Acromegaly with appar- tor I in the dog: a study in different dog assaysa 2009 update, Growth Horm IGF
ently normal GH secretion: implications for breeds and in dogs with growth hormone Res 20:8, 2010.
diagnosis and follow-up, J Clin Endocrinol elevation, Acta Endocrinol (Copenh) Gembardt C, Loppnow H: Pathogenesis of spon-
Metab 87:3537, 2002. 105:294, 1984a. taneous diabetes mellitus in the cat. II. Aci-
Doga M, etal.: Growth hormone deficiency in Eigenmann JE, etal.: Elevated growth hormone dophilic adenoma of the pituitary gland and
the adult, Pituitary 9:305, 2006. levels and diabetes mellitus in a cat with diabetes mellitus in 2 cases, Berl Munch
Dominici FP, etal.: Influence of the crosstalk acromegalic features, J Am Anim Hosp Tierarztl Wochenschr 89:336, 1976.
between growth hormone and insulin signal- Assoc 20:747, 1984b. Gevers EF, etal.: Localization and regula-
ling on the modulation of insulin sensitivity, Eigenmann JE, etal.: Body size parallels tion of the growth hormone receptor and
Growth Horm IGF Res 15:324, 2005. insulin-like growth factor I levels but not growth hormone-binding protein in the rat
Donaldson D, etal.: Congenital hyposomatotro- growth hormone secretory capacity, Acta growth plate, J Bone Miner Res 17:1408,
pism in a domestic shorthair cat present- endocrinol (Copenh) 106:448, 1984c. 2002.
ing with congenital corneal oedema, J Eigenmann JE, etal.: Growth hormone and Ghigo E, etal.: Diagnosis of adult GH
Small Anim Pract 49:306, 2008. insulin-like growth factor I in German deficiency, Growth Horm IGF Res 18:1,
Dunning MD, etal.: Exogenous insulin treat- Shepherd dwarf dogs, Acta Endocrinol 2008.
ment after hypofractionated radiotherapy 105:289, 1984d. Giustina A, Veldhuis JD: Pathophysiology of
in cats with diabetes mellitus and acro- Ekman B, etal.: Circulating IGF-I concentra- the neuroregulation of growth hormone
megaly, J Vet Intern Med 23:243, 2009. tions are low and not correlated to glycae- secretion in experimental animals and the
Eigenmann JE: Diagnosis and treatment of mic control in adults with type 1 diabetes, human, Endocrine Reviews 19:717, 1998.
dwarfism in a german shepherd dog, J Am Europ J Endocrinol 143:505, 2000. Giustina A, etal.: A consensus on criteria
Anim Hosp Assoc 17:798, 1981a. Elliott DA, etal.: Prevalence of pituitary tumors for cure of acromegaly, J Clin Endocrinol
Eigenmann JE: Diabetes mellitus in elderly fe- among diabetic cats with insulin resistance, Metab 95:3141, 2010.
male dogs: recent findings on pathogenesis J Am Vet Med Assoc 216:1765, 2000. Gobello C, etal.: Secretory patterns of growth
and clinical implications, J Am Anim Hosp Fall T, etal.: Diabetes mellitus in a population hormone in dogs: circannual, circadian,
Assoc 17:805, 1981b. of 180,000 insured dogs: incidence, sur- and ultradian rhythms, Canad J Vet Res
Eigenmann JE: Diagnosis and treatment of pitu- vival, and breed distribution, J Vet Intern 66:108, 2002.
itary dwarfism in dogs, Proceedings of the Med 21:1209, 2007. Goossens MM, etal.: Cobalt 60 irradiation of
6th Kal Kan Symposium 107110, 1982a. Fall T, etal.: Gestational diabetes mellitus in pituitary gland tumors in three cats with
Eigenmann JE: Diabetes mellitus in dogs and 13 dogs, J Vet Intern Med 22:1296, 2008. acromegaly, J Am Vet Med Assoc 213:374,
cats, Proceedings of the 6th Kal Kan Sym- Fall T, etal.: Diabetes mellitus in elkhounds is 1998.
posium, 5158, 1982b. associated with diestrus and pregnancy, Grf KJ, El Etreby MF: Endocrinology of repro-
Eigenmann JE: Acromegaly in the dog, Vet Clin J Vet Intern Med 24:1322, 2010. duction in the female beagle dog and its
North Am Small Anim Pract 14:827, 1984. Favier RP, etal.: Large body size in the dog significance in mammary gland tumori-
Eigenmann JE: Disorders associated with growth is associated with transient GH excess genesis, Acta Endocrinol Suppl (Copenh)
hormone oversecretion: diabetes mellitus at a young age, J Endocrinol 170:479, 222:1, 1979.
and acromegaly. In Kirk RW, editor: Current 2001. Gray MM, etal.: The IGF1 small dog haplo-
veterinary therapy IX, small animal practice, Feldman EC, Nelson RW: Disorders of growth type is derived from Middle Eastern grey
Philadelphia, 1986, Saunders Elsevier. hormone. In Feldman EC, Nelson RW, edi- wolves, BMC Biology 8:16, 2010.
Eigenmann JE, Eigenmann RY: Influence of tors: Canine and feline endocrinology and Greco DS: Feline acromegaly, Topics in Com-
medroxyprogesterone acetate (Provera) reproduction, St Louis, 2004, Saunders. pan An Med 27:31, 2012.
on plasma growth hormone levels and on Firth SM, Baxter RC: Cellular actions of the Greer KA, etal.: Connecting serum IGF-1, body
carbohydrate metabolism, Acta Endocrinol insulin-like growth factor binding proteins, size, and age in the domestic dog, AGE
98:603, 1981a. Endocr Rev 23:824, 2002. 33:475, 2011.
Gross TL, etal.: Atrophic diseases of the adnexa. Kley S, etal.: Evaluation of the low-dose dexa- Lewitt MS, etal.: Regulation of insulin-like
In Gross TL, Ihrke PJ, Walder EJ, Affolter methasone suppression test and ultraso- growth factor-binding protein-3 ternary
VK, editors: Skin diseases of the dog and nographic measurements of the adrenal complex in feline diabetes mellitus,
cat, clinical and histopathologic diagnosis, glands in cats with diabetes mellitus, J Endocrinol 166:21, 2000.
Oxford, 2005, Blackwell Science Ltd. Schweiz Arch Tierheilk 149:493, 2007. Lim DJ, etal.: Acromegaly associated with type
Guler HP, etal.: Insulin-like growth factors I Knottenbelt CM, Herrtage ME: Use of prolige- 2 diabetes showing normal IGF-1 levels
and II in healthy man. Estimations of half- stone in the management of three German under poorly controlled glycemia, Endo-
lives and production rates, Acta Endocrinol shepherd dogs with pituitary dwarfism, J crine J 54:537, 2007.
(Copenh) 121:753, 1989a. Small Anim Pract 43:164, 2002. Littler RM, etal.: Resolution of diabetes
Guler HP, etal.: Small stature and insulin- Kojima M, etal.: Ghrelin is a growth-hormone- mellitus but not acromegaly in a cat with
like growth factors: prolonged treatment releasing acylated peptide from stomach, pituitary macroadenoma treated with hypo-
of mini-poodles with recombinant human Nature 402:656, 1999. fractionated radiation, J Small Anim Pract
insulin-like growth factor I, Acta Endocri- Kokka N, etal.: Immunoassay of plasma 47:392, 2006.
nol (Copenh) 121:456, 1989b. growth hormone in cats following fasting Liu JC, etal.: Episodic evolution of growth hor-
Hamann F, etal.: Pituitary function and morphol- and administration of insulin, arginine, mone in primates and emergence of the spe-
ogy in two German shepherd dogs with con- 2-deoxyglucose and hypothalamic extract, cies specificity of human growth hormone
genital dwarfism, Vet Rec 144:644, 1999. Endocrinol 88:359, 1971. receptor, Mol Biol Evol 18:945, 2001.
Hampshire J, Altszuler N: Clonidine or xylazine Kooistra HS: Adenohypophyseal function in Lopes MBS: Growth hormone-secreting adeno-
as provocative tests for growth hormone se- healthy dogs and in dogs with pituitary mas: pathology and cell biology, Neurosurg
cretion in the dog, Am J Vet Res 42:1073, disease, Thesis Universiteit Utrecht, 2000. Focus 29:1, 2010.
1981. Kooistra HS: Growth hormone disorders: acro- Low MJ: Neuroendocrinology. In Melmed S,
Hansen I, etal.: Insulin resistance in acromegaly: megaly and pituitary dwarfism. In Ettinger Polonsky KS, Larsen PR, Kronenberger HM,
defects in both hepatic and extrahepatic SJ, Feldman EC, editors: Textbook of editors: Williams textbook of endocrinol-
insulin action, Am J Physiol 250:269, 1986. veterinary internal medicine, ed 7, ogy, ed 12, Philadelphia, 2011, Saunders
Hanson JM, etal.: The leukemia inhibitory St Louis, 2010, Elsevier Saunders. Elsevier.
factor receptor gene is not involved in the Kooistra HS: Acromegaly in dogs. In Rand J, Mauras N, Haymond MW: Are the metabolic
etiology of pituitary dwarfism in German editor: Clinical endocrinology of companion effects of GH and IGF-I separable? Growth
shepherd dogs, Res Vet Sci 81:316, 2006. animals, Ames, IA, 2013, Wiley-Blackwell. Horm IGF Res 15:19, 2005.
Hecht S, Schwarz T: Pituitary gland. In Schwarz Kooistra HS, etal.: Progestin-induced growth- Mausberg EM, etal.: Inherited alopecia X in
T, Saunders J, editors: Veterinary computed hormone (GH) production in the treatment Pomeranians, Dtsch Tierarztl Wochenschr
tomography, Wiley-Blackwell, 2011. of dogs with congenital GH deficiency, 114:129, 2007a.
Heinrichs M, etal.: Immunocytochemical Domest Anim Endocrinol 15:93, 1998. Mausberg EM, etal.: Evaluation of the CTSL2
demonstration of growth hormone in an Kooistra HS, etal.: Combined pituitary hor- gene as a candidate gene for alopecia X
acidophilic adenoma of the adenohypophy- mone deficiency in German shepherd dogs in pomeranians and keeshonden, Anim
sis in a cat, Vet Pathol 26:179, 1989. with dwarfism, Domest Anim Endocrinol Biotechnol 18:291, 2007b.
Ho KK: Consensus guidelines for the diagnosis 19:177, 2000a. Mausberg EM, etal.: Exclusion of patched ho-
and treatment of adults with GH deficiency Kooistra HS, etal.: Pulsatile secretion pattern molog 2 (PTCH2) as a candidate gene for
II: a statement of the GH research society of growth hormone during the luteal phase alopecia X in pomeranians and keeshon-
in association with the European Soci- and mid-anoestrus in beagle bitches, den, Vet Rec 163:121, 2008.
ety for Pediatric Endocrinology, Lawson J Reprod Fertil 119:217, 2000b. Maxwell A, etal.: Nutritional modulation of canine
Wilkins Society, European Society of Lantinga-van Leeuwen IS, etal.: Canine mam- insulin-like growth factors and their binding
Endocrinology, Japan Endocrine Society, mary growth hormone gene transcription proteins, J Endocrinol 158:77, 1998.
and Endocrine Society of Australia, Eur J initiates at the pituitary-specific start site Mayer MN, etal.: Outcomes of pituitary tumor
Endocrinol 157:695, 2007. Kooistra H.S., in the absence of Pit-1, Mol Cell Endocri- irradiation in cats, J Vet Intern Med
personal communication, 2013. nol 150:121, 1999. 20:1151, 2006.
Ida T: Variety of acyl modifications in mammalian Lantinga-van Leeuwen IS, etal.: Cloning of the Mayo KE, etal.: Regulation of the pituitary so-
ghrelins, Methods Enzymol 514:63, 2012. canine gene encoding transcription factor matotroph cell by GHRH and its receptor,
Jagannathan J, etal.: Gamma knife radio- Pit-1 and its exclusion as candidate gene Recent Prog Horm Res 55:237, 2000.
surgery to the surgical cavity following in a canine model of pituitary dwarfism, McCann JP, etal.: Growth hormone, insulin,
resection of brain metastasis, J Neurosurg Mamm Genome 11:31, 2000a. glucose, cortisol, luteinizing hormone, and
111:431, 2009. Lantinga-van Leeuwen IS, etal.: Cloning, diabetes in beagle bitches treated with me-
Jallad RS, Bronstein MD: The place of medical characterization, and physical mapping droxyprogesterone acetate, Acta Endocrinol
treatment of acromegaly: current status of the canine Prop-1 gene (PROP1): (Copenh) 116:73, 1987.
and perspectives, Expert Opin Pharmaco- exclusion as a candidate for combined Meij BP: Transsphenoidal hypophysectomy for
ther 14:1001, 2013. pituitary hormone deficiency in German treatment of pituitary-dependent hyperad-
Javorsky BR, etal.: Hypothalamus and pituitary Shepherd dogs, Cytogenet Cell Genet renocorticism in dogs, Thesis Universiteit
gland. In Gardner DG, Shoback D, editors: 88:140, 2000b. Utrecht, 1997.
Greenspans basic & clinical endocrinology, Lee WM: Growth hormone secretion in healthy Meij BP, etal.: Assessment of a combined
ed 9, San Francisco, 2011, McGrawHill. and diseased dogs, Thesis Universiteit anterior pituitary function test in beagle
Kaser-Hotz B, etal.: Radiotherapy of pituitary Utrecht, 2004. dogs: rapid sequential intravenous admin-
tumours in five cats, J Small Anim Pract Lee WM, etal.: Primary hypothyroidism in dogs istration of four hypothalamic releasing
43:303, 2002. is associated with elevated GH release, hormones, Domest Anim Endocrinol
Kelberman D, etal.: Genetic regulation of J Endocrinol 168:59, 2001. 13:161, 1996a.
pituitary gland development in human and Lee WM, etal.: Pulsatile secretion pattern of Meij BP, etal.: Thyroid-stimulating hormone
mouse, Endocr Rev 30:790, 2009. growth hormone in dogs with pituitary- responses after single administration of
Kineman RD, etal.: Steroids can modulate dependent hyperadrenocorticism, Domest thyrotropin-releasing hormone and com-
transdifferentiation of prolactin and growth Anim Endocrinol 24:59, 2003. bined administration of four hypothalamic
hormone cells in bovine pituitary cultures, Le Roith D, etal.: The somatomedin hypothesis: releasing hormones in beagle dogs, Domest
Endocrinol 130:3289, 1992. 2001, Endocrine Rev 22:53, 2001. Anim Endocrinol 13:465, 1996b.
|
Meij BP, etal.: Alterations in anterior pituitary Mol JA, Meij BP: Pituitary function. In Posch B, etal.: Magnetic resonance imaging
function of dogs with pituitary-dependent Kaneko JJ, Harvey JW, Bruss ML, edi- findings in 15 acromegalic cats, Vet Radiol
hyperadrenocorticism, J Endocrinol tors: Clinical biochemistry of domestic Ultrasound 52:422, 2011.
154:505, 1997. animals, ed 6, San Diego, 2008, Elsevier Queiroga FL, etal.: Crosstalk between GH/IGF-I
Meij BP, etal.: Somatotroph and corticotroph Saunders. axis and steroid hormones (progesterone,
pituitary adenoma (double adenoma) in a Morrison SA, etal.: Hypersomatotropism and 17beta-estradiol) in canine mammary
cat with diabetes mellitus and hyperadre- insulin-resistant diabetes mellitus in a cat, tumours, J Steroid Biochem Mol Biol
nocorticism, J Comp Path 130:209, 2004. J Am Vet Med Assoc 194:91, 1989. 110:76, 2008.
Meij BP, etal.: Hypothalamus-pituitary system. Mller-Peddinghaus R, etal.: Hypophysrer Queiroga FL, etal.: Serum and intratumoural
In Rijnberk A, Kooistra HS, editors: Clini- Zwergwuchs beim Deutschen Schferhund, GH and IGF-I concentrations: prognostic
cal endocrinology of dogs and cats, ed 2, Vet Pathol 17:406, 1980. factors in the outcome of canine mammary
Hannover, 2010a, Schltersche. Murai A, etal.: GH-producing mammary cancer, Res Vet Sci 89:396, 2010.
Meij BP, etal.: Successful treatment of acro- tumors in two dogs with acromegaly, J Vet Randolph JF, etal.: Delayed growth in two Ger-
megaly in a diabetic cat with transsphe- Med Sci 74:771, 2012. man Shepherd dog littermates with normal
noidal hypophysectomy, J Feline Med Surg Nass R, etal.: The role of ghrelin in GH secre- serum concentrations of growth hormone,
12:406, 2010b. tion and GH disorders, Mol Cell Endocrinol thyroxine, and cortisol, J Am Vet Med As-
Meij BP, etal.: Lymphocytic hypophysitis in a 340:10, 2011. soc 196:77, 1990.
dog with diabetes insipidus, J Comp Path Nicholas F: Pituitary dwarfism in German Rao NAS, etal.: Gene expression profiles of
147:503, 2012a. Shepherd dogs: a genetic analysis of progestin-induced canine mammary hyper-
Meij BP, etal.: Surgical treatment of acromeg- some Australian data, J Small Anim Pract plasia and spontaneous mammary tumors,
aly in cats, Abstracts European Veterinary 19:167, 1978. J Physiol Pharmacol (Suppl 1)73, 2009.
Conference Voorjaarsdagen, Amsterdam, Niessen S: Feline acromegaly, an essential Rathke M: ber die Entstehung der Glandula
The Netherlands, p. 232-233, 2012b. differential diagnosis for the difficult dia- pituitaria, Archiv fr Anatomie, Physiologie
Melmed S: Update: idiopathic adult growth betic, J Feline Med Surg 12:15, 2010. und wissenschaftliche, Medicin, Berlin,
hormone deficiency, J Clin Endocrin Metab Niessen SJM, etal.: Feline acromegaly: an un- S482485, 1838.
98:2187, 2013. derdiagnosed endocrinopathy? J Vet Intern Regnier A, Garnier F: Growth hormone
Melmed S, etal.: Guidelines for acromegaly Med 21:899, 2007a. responses to growth hormone, Vet Sci
management: an update, J Clin Endocrinol Niessen SJM, etal.: Validation and application 58:169, 1995.
Metab 94:1509, 2009. of a radioimmunoassay for ovine growth Reichlin S: Medical progresssomatostatin,
Melmed S, etal.: Pituitary physiology and diag- hormone in the diagnosis of acromegaly in N Engl J Med 309:1495, 1983.
nostic evaluation. In Melmed S, Polonsky cats, Vet Rec 160:902, 2007b. Resmini E, etal.: Secondary diabetes associ-
KS, Larsen PR, Kronenberg HM, editors: Niessen SJM, etal.: Hypersomatotropism, ated with principal endocrinopathies: the
Williams textbook of endocrinology, ed 12, acromegaly, and hyperadrenocorticism and impact of new treatment modalities, Acta
Philadelphia, 2011, Saunders Elsevier. feline diabetes mellitus, Vet Clin Small Diabetol 46:85, 2009.
Melmed S, Kleinberg D: Pituitary masses and Anim 43:319, 2013a. Reusch CE: Feline diabetes mellitus. In Et-
tumors. In Melmed S, Polonsky KS, Larsen Niessen SJM, etal.: Pasireotide (som230) tinger SJ, Feldman EC, editors: Textbook
PR, Kronenberger HM, editors: Williams opens doors to medical management of of veterinary internal medicine, ed 7, St
textbook of endocrinology, ed 12, Philadel- feline hypersomatotropism, J Vet Intern Louis, 2010, Saunders Elsevier.
phia, 2011, Saunders Elsevier. Med 27:685, 2013b. abstract. Reusch CE, etal.: Alteration in the growth
Metherell LA, etal.: Genetic defects of the hu- Norman EJ, Mooney CT: Diagnosis and man- hormone-insulin-like growth factor axis in
man somatotropic axis. In Wass JAH, Stew- agement of diabetes mellitus in five cats cats with diabetes mellitus, J Vet Intern
art PM, Amiel SA, Davies MJ, editors: Oxford with somatotrophic abnormalities, J Feline Med 15:297, 2001.
textbook of endocrinology and diabetes, ed Med Surg 1:183, 2000. Reusch CE, etal.: Measurements of growth
2, Oxford, 2011, Oxford University Press. Norman EJ, etal.: Pregnancy-related diabetes hormone and insulin-like growth factor
Middleton DJ, etal.: Growth hormone-producing mellitus in two dogs, New Zealand Vet J 1 in cats with diabetes mellitus, Vet Rec
pituitary adenoma, elevated serum somato- 54:360, 2006. 158:195, 2006.
medin C concentration and diabetes mel- Owen LN, Briggs MH: Contraceptive steroid Ribeiro-Oliveira A, Barkan A: The changing
litus in a cat, Can Vet J 26:169, 1985. toxicology in the Beagle dog and its rel- face of acromegalyadvances in diagnosis
Miller WH, etal.: Endocrine and metabolic dis- evance to human carcinogenicity, Curr Med and treatment, Nat Rev Endocrinol 8:605,
eases. In Miller WH, Griffin CE, Campbell Res Opin 4:309, 1976. 2012.
KL, editors: Muller and Kirks small animal Petersenn S, etal.: Long-term efficacy and Rijnberk A: Growth hormone: its clinical rel-
dermatology, ed 7, Saunders, 2013. safety of subcutaneous pasireotide in evance, Vet Q 17:17, 1995.
Minniti G, etal.: Radiation techniques for acro- acromegaly: results from an open-ended- Rijnberk A, Kooistra HS: Protocols for function
megaly, Radiat Oncol 6:167, 2011. multicenter, Phase II extension study, tests. In Rijnberk A, Kooistra HS, editors:
Mller N, Jrgensen OL: Effects of growth Pituitary 17:132, 2014. Clinical endocrinology of dogs and cats:
hormone on glucose, lipid, and protein Peterson ME, Altszuler N: Suppression of an illustrated text, ed 2, Hannover, 2010,
metabolism in human subjects, Encocr growth hormone secretion in spontane- Schltersche.
Rev 30:152, 2009. ous canine hyperadrenocorticism and its Rijnberk A, Mol JA: Progestin-induced
Mol JA, etal.: Growth hormone mRNA in mam- reversal after treatment, Am J Vet Res hypersecretion of growth hormone: an
mary gland tumors of dogs and cats, J Clin 42:1881, 1981. introductory review, J Reprod Fertil Suppl
Invest 95:2028, 1995. Peterson ME: Effects of megestrol acetate on 51:335, 1997.
Mol JA, etal.: The role of progestins, insulin- glucose tolerance and growth hormone Rijnberk A, etal.: Acromegaly associated
like growth factor (IGF) and IGF-binding secretion in the cat, Res Vet Sci 42:354, with transient overproduction of growth
proteins in the normal and neoplastic 1987. hormone in a dog, J Am Vet Med Assoc
mammary gland of the bitch: a review, J Peterson ME: Acromegaly in cats: are we only 177:534, 1980.
Reprod Fertil Suppl 51:339, 1997. diagnosing the tip of the iceberg? J Vet Rijnberk A, etal.: Disturbed release of growth
Mol JA, etal.: Mammary growth hormone and Intern Med (editorial) 21:889, 2007. hormone in mature dogs: a comparison
tumorigenesislessons from the dog, Vet Peterson ME, etal.: Acromegaly in 14 cats, with congenital growth hormone deficiency,
Q 21:111, 1999. J Vet Intern Med 4:192, 1990. Vet Rec 133:542, 1993.
Rijnberk A, etal.: Endocrine diseases in dogs Selman PJ, etal.: Effects of progestin adminis- Voorbij MWY, Kooistra HS: Pituitary dwarfism in
and cats: similarities and differences with tration on the hypothalamic-pituitary-adrenal German Shepherd dogs, JVCS 2:4, 2009.
endocrine diseases in humans, Growth axis and glucose homeostasis in dogs, Voorbij AM, etal.: A contracted DNA repeat in
Horm IGF Res 13:S158, 2003. J Reprod Fertil Suppl 51:345, 1997. LHX3 intron 5 is associated with aberrant
Rinderknecht E, Humbel RE: The amino acid Sharman M, etal.: Concurrent somatotroph splicing and pituitary dwarfism in German
sequence of human insulin-like growth fac- and plurihormonal pituitary adenomas in a Shepherd dogs, PLoS One 6(11):1, 2011.
tor I and its structural homology with pro- cat, J Feline Med Surg 15:945, 2013. Wallis M: Mammalian genome projects reveal
insulin, J Biol Chem 253:2769, 1978a. Sjaastad OV, etal.: The endocrine system. In new growth hormone (GH) sequences.
Rinderknecht E, Humbel RE: Primary structure Sjaastad OV, Sand O, Hove K, editors: Characterization of the GH-encoding genes
of human insulin-like growth factor II, Physiology of domestic animals, Oslo, of armadillo (Dasypus novemcinctus),
FEBS Lett 89:283, 1978b. 2010, Scandinavian Veterinary Press. hedgehog (Erinaceus europaeus), bat
Roth JA, etal.: Thymic abnormalities and Slingerland LI, etal.: Growth hormone excess (Myotis lucifugus), hyrax (Procavia capen-
growth hormone deficiency in dogs, Am and the effect of octreotide in cats with sis), shrew (Sorex araneus), ground squirrel
J Vet Res 41:1256, 1980. diabetes mellitus, Domest Anim Endocri- (Spermophilus tridecemlineatus), elephant
Rutteman GR, etal.: Medroxy-progesterone nol 35:352, 2008. (Loxodonta africana), cat (Felis catus) and
acetate administration to ovariohyster- Sloan JM, Oliver IM: Progestogen-induced dia- opossum (Monodelphis domestica), Gen
ectomized, oestradiol-primed beagle betes in the dog, Diabetes 24:337, 1975. Comp Endocrinol 155:271, 2008.
bitches, Acta Endocrinol (Copenh) Starkey SR, etal.: Investigation of serum IGF-I Warren WC, etal.: Cloning of the cDNAs coding
114:275, 1987. levels amongst diabetic and non-diabetic for cat growth hormone and prolactin, Gene
Salmon WD, Daughaday WH: A hormonally cats, J Feline Med Surg 6:149, 2004. 168:247, 1996.
controlled serum factor which stimulates Stratikopoulos E, etal.: The hormonal action Wass JAH, etal.: Acromegaly. In Wass JAH,
sulfate incorporation by cartilage invitro, of IGF1 in postnatal mouse growth, PNAS Stewart PM, Amiel SA, Davies MC, editors:
J Lab Clin Med 49:825, 1957. 105:19378, 2008. Oxford textbook of endocrinology and
Sato T, etal.: Structure, regulation and func- Styne D: Growth. In Gardner DG and Shoback diabetes, ed 2, Oxford, 2011, Oxford
tion of ghrelin, J Biochem 151:119, D, editors: Greenspans basic & clinical University Press.
2012. endocrinology, ed 9, San Francisco, 2011. Watson ADJ, etal.: Effect of somatostatin
Savage JJ, etal.: Transcriptional control during Sutter NB, etal.: A single IGF1 allele is a analogue SMS 201-995 and antiproges-
mammalian anterior pituitary development, major determinant of small size in dogs, tin agent RU 486 in canine acromegaly.
Gene 319:1, 2003. Science 316:112, 2007. In Rijnberk A, van Wimersma Greidanus
Savage MO, etal.: Genetic defects in the Tschuor F, etal.: Evaluation of four methods TB, editors: Front horm res, comparative
growth hormone-IGF-I axis causing growth used to measure plasma insulin-like pathophysiology of regulatory peptides, ed
hormone insensitivity and impaired linear growth factor 1 concentrations in healthy 17, Basel, 1987, Karger.
growth, Front Endocrinol 2:95, 2011. cats and cats with diabetes mellitus and Wayne RK, vonHoldt BM: Evolutionary genom-
Schfer S, etal.: Evaluation of insulin-like other diseases, Am J Vet Res 73:1925, ics of dog domestication, Mamm Genome
growth factor (IGF-1), T4, feline pancreatic 2012. 23:3, 2012.
lipase immunoreactivity (FPLI) and urinary van Garderen E, etal.: Expression of growth Wolfesberger B, etal.: Sudden death in a dog
corticoid creatinine ratio (UCCR) in cats hormone in canine mammary tissue and with lymphoplasmacytic hypophysitis, J
with diabetes mellitus in Switzerland and mammary tumors, evidence for a potential Comp Path 145:231, 2011.
the Netherlands, Liverpool, UK, 2013, autocrine/paracrine stimulatory loop, Am Xu J, Messina JL: Crosstalk between growth
abstr ECVIM. 12.-14.09. J Pathol 150:1037, 1997. hormone and insulin signaling, Vitam
Schmeitzel LP, Lothrop CD: Hormonal abnor- van Garderen E, etal.: Expression and molecu- Horm 80:125, 2009.
malities in Pomeranians with normal coat lar characterization of the growth hormone Yang H, etal.: Effects of streptozotocin-induced
and in Pomeranians with growth hormone- receptor in canine mammary tissue and diabetes mellitus on growth and hepatic
responsive dermatosis, J Am Vet Med mammary tumors, Endocrinol 140:5907, insulin-like growth factor I gene expression
Assoc 197:1333, 1990. 1999. in the rat, Metabol 39:295, 1990.
Scott DW, Concannon PW: Gross and micro- Van Herpen H, etal.: Production of antibodies Yokoyama M, etal.: Relationship between
scopic changes in the skin of dogs with to biosynthetic human growth hormone in growth and plasma concentrations of
progestagen-induced acromegaly and el- the dog, Vet Rec 134:171, 1994. ghrelin and growth hormone in juvenile
evated growth hormone levels, J Am Anim Van Keulen LJM, etal.: Diabetes mellitus in a beagle dogs, J Vet Med Sci 67:1189,
Hosp Assoc 19:524, 1983. dog with a growth hormone-producing aci- 2005.
Scott DW, Walton DK: Hyposomatotropism in dophilic adenoma of the adenohypophysis, Zangger I, etal.: Insulin-like growth factor
the mature dog: a discussion of 22 cases, Vet Pathol 33:451, 1996. I and II in 14 animal species and man as
J Am Anim Hosp Assoc 22:467, 1986. Van Oost BA, etal.: Exclusion of the lim home- determined by three radioligand assays
Sellon RK, etal.: Linear-accelerat or-based odomain gene LHX4 as a candidate gene and two bioassays, Acta Endocrinol (Co-
modified radiosurgical treatment of for pituitary dwarfism in German shepherd penh) 114:107, 1987.
pituitary tumors in cats: 11 cases (1997- dogs, Mol Cell Endocrinol 197:57, 2002. Zapf J, etal.: Intravenously injected insulin-like
2008), J Vet Intern Med 23:1038, 2009. Vidal S, etal.: Transdifferentiation of somato- growth factor (IGF) I/IGF binding protein-3
Selman PJ, etal.: Progestins and growth hor- trophs to thyrotrophs in the pituitary of complex exerts insulin-like effects in hy-
mone excess in the dog, Acta Endocrinol patients with protracted primary hypothy- pophysectomized, but not in normal rats,
125:42, 1991. roidism, Virchows Arch 436:43, 2000. J Clin Invest 95:179, 1995.
Selman PJ, etal.: Progestin-induced growth Vijayakumar A, etal.: Biological effects of Zezulak KM, Green H: The generation of
hormone excess in the dog originates in growth hormone on carbohydrate and lipid insulin-like growth factor-Isensitive
the mammary gland, Endocrinol 134:287, metabolism, Growth Horm IGF Res 20:1, cells by growth hormone action, Science
1994a. 2010. 233:551, 1986.
Selman PJ, etal.: Progestin treatment in the Villalobos C, etal.: Anterior pituitary thyro- Zimmer C, etal.: Ultrasonographic examination
dog. I. Effects on growth hormone, insulin- tropes are multifunctional cells, Am J of the adrenal gland and evaluation of the
like growth factor I and glucose homeosta- Physiol Endocrinol Metab 287:E1166, hypophyseal-adrenal axis in 20 cats,
sis, Europ J Endocrinol 131:413, 1994b. 2004. J Small Anim Pract 41:156, 2000.
SECTION 2 THE THYROID GLAND
CHAPTER 3 Hypothyroidism
J. Catharine Scott-Moncrieff
CHAPTER CONTENTS Serum Thyroid Hormone Autoantibodies, 109

Anatomy and Physiology of the Thyroid Gland, 77 Factors Affecting Thyroid Gland Function Tests, 109
Thyroid Hormone Synthesis, 78 Age, 109
Regulation of Thyroid Function, 79 Body Size, 110
Thyroid Hormones in Plasma, 79 Breed, 111
Physiologic Functions of Thyroid Hormones, 79 Athletic Training, 111
Thyroid Hormone Metabolism, 80 Gender and Reproductive Stage of the Female, 111
CANINE HYPOTHYROIDISM, 80 Diurnal Rhythm, 112
Classification, 80 Random Fluctuations, 112
Etiology, 81 Concurrent Illness (Nonthyroidal Illness Syndrome), 112
Primary Hypothyroidism, 81 Environmental and Body Temperature, 115
Secondary Hypothyroidism, 85 Obesity, Fasting, and Cachexia, 115
Tertiary Hypothyroidism, 85 Drugs, 115
Congenital Hypothyroidism, 85 Thyroid Biopsy, 117
Clinical Features of Hypothyroidism in the Adult Dog, 86 Establishing the Diagnosis, 118
Signalment, 86 Treatment, 118
Clinical Signs, 86 Response to Levothyroxine Sodium Therapy, 120
Clinical Features of Congenital Hypothyroidism, 92 Therapeutic Monitoring, 120
Clinical Features of Secondary Hypothyroidism, 92 Treatment of Dogs with Concurrent Nonthyroidal Illness, 121
Clinicopathologic Abnormalities of Hypothyroidism, 92 Treatment with Liothyronine Sodium (Synthetic Triiodothyronine), 123
Dermatohistopathologic Findings in Hypothyroidism, 95 Combination Thyroxine/Triiodothyronine Products, 123
Radiography, Ultrasonography, and Nuclear Imaging, 95 Thyroid Extracts, 123
Blood Tests of Thyroid Gland Function, 96 Treatment of Myxedema Coma, 123
Baseline Serum Total Thyroxine Concentration, 98 Thyrotoxicosis, 124
Baseline Serum Total Triiodothyronine Concentration, 102 Prognosis, 124
Baseline Serum Free Thyroxine Concentration, 103 FELINE HYPOTHYROIDISM, 124
Baseline Serum Free Triiodothyronine Concentration, 104 Etiology, 124
Baseline Serum Reverse Triiodothyronine Concentration, 104 Clinical Signs, 125
Baseline Serum Thyrotropin Concentration, 104 Tests of Thyroid Gland Function, 126
Thyrotropin Stimulation Test, 105 Establishing the Diagnosis, 128
Thyrotropin-Releasing Hormone Stimulation Test, 105 Treatment and Prognosis, 128
Tests for Lymphocytic Thyroiditis, 107
Serum Thyroglobulin Autoantibodies, 107
gland from the Greek word thyreos, or shield, based on its physi-
ANATOMY AND PHYSIOLOGY OF THE THYROID
cal appearance. One of the rst described thyroid disorders was
GLAND
an association between iodine deciency and enlargement of the
The thyroid gland was rst described in detail by Vesalius in the thyroid (goiter), which was initially suspected in the 1500s to be
sixteenth century. Thomas Wharton (1614-1673) named the a possible cause of cretinism. This description also represents the
77
78 SECTION 2 THE THYROID GLAND
Sternothyroideus muscle Thyroid cartilage
Thyroid branch of Cricothyroideus muscle

cranial laryngeal nerve
Cranial thyroid artery Caudal laryngeal nerve
and vein
Parathyroid gland Parathyroid gland
Sternohyoideus Trachea
muscle
Esophagus
Right lobe of
thyroid gland
Middle thyroid Thyroidea ima
vein vein
Sternocephalicus Caudal thyroid
muscle vein
Caudal thyroid
Internal jugular
artery
vein
Internal jugular
Common carotid vein
artery
Retropharyngeal Thyrohyoid muscle

lymph node
Cricothyroideus muscle
Sternothyroideus muscle
Vagosympathetic trunk
Common carotid artery Isthmus of thyroid gland
FIGURE 3-1 A and B, Thyroid anatomy of the dog and

cat. (From Hullinger RL: The endocrine system. In Evans
HE, de Lahunta A, editors: Millers anatomy of the dog,
ed 4, St Louis, 2013, Elsevier.) B
rst mention of thyroid gland enlargement. Endemic cretinism in and is dependent upon ingestion of adequate iodide from the diet.
the region around Salzburg, Austria, was described by the Swiss- Iodide is actively transported from the extracellular fluid into the
German physician Paracelsus (1493-1541). thyroid follicular cell by the sodium-iodine symporter (NIS), where
The thyroid gland develops in the embryo in close association with it is rapidly oxidized by thyroid peroxidase (TPO) into a reactive
the gastrointestinal tract, which explains why both the gastric and intermediate (Fig. 3-3). At the apical membrane, iodine is incorpo-
salivary glands concentrate iodide in their secretions. In dogs and rated into the tyrosine residues of Tg (Salvatore etal, 2011). TPO
cats the thyroid gland is comprised of two lobes in the mid-cervical also catalyzes the coupling of the non-biologically active iodinated
region that lie to either side of the trachea. The lobes are elongated tyrosine residues (monoiodotyrosine [MIT], and diiodotyrosine
dark red structures adjacent to the right and left lateral surfaces of [DIT]) to form the biologically active iodothyroninesT4 and T3
the proximal trachea (Fig. 3-1) and are not normally palpable. The (Fig. 3-4). These iodination reactions are referred to as organification
thyroid gland has an extensive vascular supply primarily from the and occur within Tg rather than on the free amino acids.
cranial and caudal thyroid arteries. The functional unit of the thyroid Tg is stored extracellularly in the follicular lumen. As a prerequisite
gland is the follicle, a sphere of cells with a lumen containing a clear for thyroid hormone secretion into the blood, Tg must rst reenter
proteinaceous colloid (Fig. 3-2). The colloid contains primarily thy- the thyroid cell and undergo proteolysis. Pseudopods from the apical
roglobulin (Tg), a large glycoprotein dimer that serves as a reservoir cell surface extend into the colloid in the follicular lumen, and large
for thyroid hormone. Parafollicular cells (C cells) lie in the intersti- colloid droplets enter the cytoplasm by endocytosis (Salvatore etal,
tium between the follicles and synthesize and secrete calcitonin. 2011). Each colloid droplet is enclosed in a membrane derived from
the apical cell border. Electron-dense lysosomes then fuse with the
colloid droplets to produce phagolysosomes. These phagolysosomes
Thyroid Hormone Synthesis
migrate toward the basal aspect of the cell, while lysosomal proteases
Thyroxine (T4) and 3,5,3-triiodothyronine (T3) are iodine hydrolyze Tg. T4 and, to a much lesser degree, T3 liberated from
containing amino acids. Thyroid hormone synthesis requires iodine Tg by the proteolytic process pass from the phagolysosome into the
|
CHAPTER 3 Hypothyroidism 79
OH
OH
I
I I I0 HO
I I I
HO
I I
I I
HO O
I I
HO
I
A I O I
I
FIGURE 3-3 Thyroid hormone synthesis. Thyroglobulin (Tg) is synthesized within

thyroid follicular cells and secreted into the colloid. Iodide is oxidized and bound
to tyrosine residues on the Tg molecule by thyroid peroxidase (TPO). Iodinated
tyrosine residues (monoiodotyrosine [MIT] and diiodotyrosine [DIT]) within the
Tg molecule then undergo oxidative condensation to form the iodothyronines (T3
and T4), which remain bound to Tg until secreted. Tg is ingested by endocytosis
from the colloid; the peptide bonds between the iodinated residues and the Tg
are hydrolyzed; and MIT, DIT, T4, and T3 are released into the cytoplasm. MIT and
DIT are de-iodinated and the iodine is recycled, whereas T4 and T3 are released
into the bloodstream. (Modified from Mountcastle VB: Medical physiology, ed 14,
vol 2, St Louis, 1980, Mosby.)
B
FIGURE 3-2 A and B, Histologic section of a thyroid gland from a healthy dog,
illustrating variable-sized follicles, each lined by follicular epithelial cells with Thyroid Hormones in Plasma
a lumen containing colloid. The follicle is surrounded by a basement membrane T4 is the major secretory product of the normal thyroid gland.
which separates the follicular cells from a capillary bed. The wall of the follicle Thyroid hormones in plasma are highly protein bound with T4
is a single layer of follicular epithelial cells, which are cuboidal when quiescent more highly bound than T3. Less than 1% of T4 and T3 circulate in
and columnar when active. (A, H&E 40; B, H&E 160.) the unbound free state. In the dog, the thyroid binding proteins
are thyroxine-binding globulin (TBG), thyroxine-binding preal-
blood by diffusion. Most of the liberated iodotyrosines (MIT, DIT) bumin (TBPA), albumin, and certain plasma lipoproteins. TBG is
are de-iodinated, releasing iodide, which can be reused for Tg iodin- the major binding protein in the dog but is absent in the cat. The
ation or diffuse out into the circulation. A small quantity of intact lower concentration of TBG and differences in structure between
Tg also enters the circulation. This leakage is increased when the species may explain the low serum T4 levels and rapid T4 metabo-
thyroid cells are damaged, such as in lymphocytic thyroiditis. lism seen in dogs compared to humans. Only free or unbound thy-
roid hormones enter cells to produce a biologic effect or regulate
pituitary TSH secretion. Protein-bound thyroid hormones serve
Regulation of Thyroid Function
as a large reservoir that is slowly drawn upon as the free hormone
Thyroid hormone synthesis and secretion are regulated by extra- dissociates from the binding proteins and enters the cells.
thyroidal (thyrotropin) and intrathyroidal (autoregulatory) Thyroid hormone entry into cells is mediated by transporter
mechanisms. Thyroid-stimulating hormone (also known as thy- proteins. T3 enters cells more rapidly, has a more rapid onset of
rotropin; TSH) increases both synthesis and secretion of T4 and action, and is three to five times more potent than T4. Thyroid
T3 and is the major modulator of thyroid hormone concentration hormones bind to receptors in the nuclei; the hormone recep-
(Fig. 3-5). TSH secretion by the pituitary is modulated by thyroid tor complex then binds to DNA and influences the expression
hormone in a negative feedback regulatory mechanism. At the of many genes coding for regulatory enzymes. Thyroid hormone
pituitary, it is primarily T3, produced locally by the monodeio- is also believed to have some non-genomic effects mediated by
dination of T4 that inhibits TSH secretion (Salvatore etal, 2011). receptors in the plasma membrane and the cytoplasm (Yen and
TSH secretion from the pituitary gland is modulated by thyrotro- Brent, 2013).
pin-releasing hormone (TRH) from the hypothalamus (see Fig.
3-4). Hypothalamic production and release of TRH are controlled Physiologic Functions of Thyroid Hormones
by poorly understood neural pathways from higher brain centers.
Autoregulatory intrathyroidal mechanisms also regulate iodide Thyroid hormones regulate many metabolic processes, influencing
uptake and thyroid hormone synthesis. Examples of autoregula- the concentration and activity of numerous enzymes; the metabo-
tory mechanisms include the Wolff-Chaikoff block (decrease in lism of substrates, vitamins, and minerals; the secretion and deg-
Tg iodination and thyroid hormone synthesis with increasing radation rates of virtually all other hormones; and the response of
iodide intake), intrathyroidal alterations in thyroid sensitivity to their target tissues to those hormones. Thyroid hormones are criti-
TSH stimulation, and increased ratio of T3 to T4 secretion by the cally important in fetal development, particularly of the neural
thyroid gland during periods of iodide insufciency. and skeletal systems. Thyroid hormones stimulate calorigenesis,
I
NH2 NH2
HO CH2 CH COOH HO CH2 CH COOH
I I
3-monoiodotyrosine 3,5-diodotyrosine
I I
NH2
5' 5
HO O CH2 CH COOH
3' 3
I I
3,5,3',5'-tetraiodo L-thyronine (thyroxine, T4)
I- I-
I I NH2
NH2
HO O CH2 CH COOH HO O CH2 CH COOH
I I I I
3,5,3'-triiodo L-thyronine (T3) 3,3',5-triiodo L-thyronine (reverse T3)

FIGURE 3-4 Structure of the thyroid hormones and their precursors.
Central Nervous System both formation and resorption of bone (Greenspan, 2001). In
essence, no tissue or organ system escapes the adverse effects of
+ thyroid hormone excess or insufciency.
?
Hypothalamus
Thyroid Hormone Metabolism
?
TRH + The major pathway of T4 metabolism is the progressive deiodin-
ation of the molecule. The initial deiodination of T4 may occur
Pituitary Thyrotropes ? in the outer ring, producing T3, or in the inner ring, producing
reverse T3 (rT3; see Fig. 3-4). Because conversion of T4 to T3
+
TSH increases biologic activity, whereas conversion of T4 to rT3 has
the opposite effect, the conversion of T4 to T3 or rT3 by outer or
Thyroid Follicular Cells inner ring iodothyronine deiodinase is a pivotal regulatory step
in determining thyroid hormone biologic activity. Three unique
deiodinases (D1, D2, and D3) with different tissue distribu-
tions, and different affinity for inner or outer ring deiodination,
T4, rT3, T3 play a major regulatory role in thyroid hormone homeostasis by
Circulation influencing the concentration of intracellular T3. The integra-
tion of plasma T3 and local deiodinase produced T3 together
FIGURE 3-5 Regulation of thyroid hormone concentration by the hypothalam- with local inactivation of thyroid hormone, ultimately deter-
ic-pituitary-thyroid axis. Thyroid hormone concentrations are controlled by the mines nuclear T3 concentration and the thyroid status of the cell
hypothalamic-pituitary-thyroid axis, which operates as a negative feedback (Bianco and Kim, 2013). In dogs approximately 40% to 60% of
loop. Thyrotropin (TSH) causes synthesis and release of thyroxine (T4) and lesser T3 is believed to be derived from outer ring monodeiodination
amounts of 3,5,3-triiodothyronine (T3) from the thyroid gland. Intracellular T3, of T4 in peripheral tissues. Conjugation of thyroid hormone to
derived from de-iodination of T4 within the pituitary gland, causes decreased soluble glucuronides and sulfates with subsequent excretion in
TSH synthesis and secretion and is the main determinant of TSH concentration. the bile and urine represents another major metabolic pathway
Thyrotropin-releasing hormone (TRH), secreted by the hypothalamus, modulates for thyroid hormone.
TSH release from the pituitary gland. Increased thyroid hormone concentrations
are also believed to decrease TRH synthesis and secretion. Hormones that inhibit
TSH secretion include dopamine, somatostatin, serotonin, and glucocorticoids. CANINE HYPOTHYROIDISM
TRH, prostaglandins, and alpha-adrenergic agonists increase TSH secretion. rT3,
Reverse 3,3,5-triiodothyronine; +, stimulation; , inhibition. CLASSIFICATION
protein and enzyme synthesis, and virtually all aspects of carbo- Canine hypothyroidism may occur due to thyroid gland destruc-
hydrate and lipid metabolism, including synthesis, mobilization, tion, decreased stimulation by TSH from the pituitary gland, or
and degradation (Yen and Brent, 2013). Furthermore, thyroid failure in any of the steps of thyroid hormone synthesis. Hypothy-
hormones have marked chronotropic and inotropic effects on the roidism is the most common thyroid disorder in dogs and may be
heart; increase the number and affinity of beta-adrenergic recep- acquired or congenital. Hypothyroidism is classified as primary
tors; enhance the response to catecholamines; are necessary for if it is due to an abnormality at the level of the thyroid gland,
normal hypoxic and hypercapnic drive to the respiratory centers; secondary if it is due to decreased TSH secretion, and tertiary if
stimulate erythropoiesis; and stimulate bone turnover, increasing it is due to TRH deficiency. Primary hypothyroidism is the most
|
BOX 3-1 Potential Causes of Hypothyroidism in the Dog
Primary Hypothyroidism
Lymphocytic thyroiditis*
Idiopathic atrophy*
Neoplastic destruction*
Iodine deficiency*
Goitrogen ingestion
Iatrogenic*
Surgical removal*
Anti-thyroid medications/potentiated sulfonamides*
Radioactive iodine treatment*
Congenital*
Thyroid gland dysgenesis* A
Dyshormonogenesis*
Defective thyroid hormone transporters/receptors
Iodine deficiency
Maternal antibodies
Maternal medications
Secondary Hypothyroidism
Pituitary malformation*
Pituitary cyst
Pituitary hypoplasia
Pituitary destruction*
Neoplasia
Defective TSH molecule
Defective TSH-follicular cell receptor interaction
Iatrogenic*
Drug therapy, most notably glucocorticoids B
Radiation therapy FIGURE 3-6 A and B, Histologic section of a thyroid gland from a dog with lym-
Hypophysectomy phocytic thyroiditis and hypothyroidism. Note the mononuclear cell infiltration,
Tertiary Hypothyroidism disruption of the normal architecture, and loss of colloid-containing follicles.
Congenital hypothalamic malformation (A, H&E 63; B, H&E 250.)
Acquired destruction of hypothalamus
Neoplasia* include iodine deficiency, goitrogen ingestion, congenital hypo-
Hemorrhage thyroidism, thyroid gland destruction by neoplasia, drug therapy,
Abscess surgical thyroidectomy, and treatment with radioactive iodine.
Granuloma
Inflammation Lymphocytic Thyroiditis
Deficient/defective TRH molecule Lymphocytic thyroiditis is characterized histologically by diffuse
Defective TRH-thyrotroph receptor interaction inltration of lymphocytes, plasma cells, and macrophages into
the thyroid gland, resulting in progressive destruction of follicles
TRH, Thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone (also known
and secondary brosis (Gosselin etal, 1981b; Fig. 3-6). Destruc-
as thyrotropin).
*Established etiology in the dog
tion of the thyroid gland is progressive, and clinical signs do not
become evident until at least 80% of the gland has been destroyed.
Studies suggest that the onset of clinical signs and development of
common cause of hypothyroidism in dogs. Secondary hypothy- decreased serum thyroid hormone and increased serum TSH con-
roidism due to impaired secretion of TSH is rare in dogs, and centrations occurs over a prolonged time period of 1 to 3 years,
tertiary hypothyroidism is presumed to be extremely rare. suggesting a slowly progressive destructive process (Nachreiner
etal, 2002; Graham etal, 2007). Graham, etal. (2007) have pro-
ETIOLOGY posed four stages in the development of lymphocytic thyroiditis
in dogs. The first stage (subclinical thyroiditis) is characterized
Primary Hypothyroidism by focal lymphocytic thyroid gland infiltration and positive Tg
and thyroid hormone autoantibody tests. In stage 2 (antibody
Acquired primary hypothyroidism is the most common cause positive subclinical hypothyroidism) loss of greater than 60% to
of naturally occurring thyroid failure in the adult dog, account- 70% of thyroid mass results in a compensatory increase in TSH,
ing for more than 95% of cases. Two histologic forms of primary which stimulates the thyroid gland to maintain normal T4 con-
hypothyroidism are recognized in dogs; lymphocytic thyroiditis centrations. In stage 3 (antibody positive overt hypothyroidism)
and idiopathic atrophy (Box 3-1). It is likely that some cases of most functional thyroid tissue is destroyed, and decreased serum
idiopathic atrophy are the end result of severe lymphocytic thy- thyroid hormone concentrations and increased TSH concentra-
roiditis. Other much more rare causes of primary hypothyroidism tion are present (Table 3-1). Stage 4 (noninflammatory atrophic
TABLE 3-1 PROPOSED FUNCTIONAL STAGES OF LYMPHOCYTIC THYROIDITIS IN DOGS
CLINICAL SIGNS OF SERUM THYROXINE SERUM ANTI-THYROGLOBULIN

STAGE OF THYROIDITIS HYPOTHYROIDISM AND FREE THYROXINE THYROTROPIN ANTIBODY
I: Subclinical thyroiditis Not present Normal Normal Positive
II: Subclinical hypothyroidism Not present Normal Increased Positive
III: Overt hypothyroidism Present Decreased Increased Positive
IV: Noninflammatory atrophic Present Decreased Increased Negative
hypothyroidism
Adapted from Graham PA, etal.: Lymphocytic thyroiditis, Vet Clin North Am Small Anim Pract 37(4):617, 2007.
hypothyroidism) is characterized by replacement of thyroid tis- was identied as an autosomal-recessive trait in a family of Borzoi
sue by fibrous and adipose tissue and disappearance of inflam- dogs (Conaway etal, 1985a). An increased prevalence of circulat-
matory cells and circulating antibodies. What proportion of cases ing thyroid hormone autoantibodies has also been found in certain
of antibody negative idiopathic thyroid atrophy is actually due breeds, and the progression rate is different for different breeds
to stage 4 thyroiditis has not been determined. Analysis of age (Nachreiner et al, 2002; Graham et al, 2007; Ferm et al, 2009;
distributions of dogs with laboratory test results (i.e., Tg antibody, Table 3-2). A strong association between thyroiditis and certain
T4, and TSH) consistent with the different stages or classications major histocompatibility complex DLA class II haplotypes has been
of lymphocytic thyroiditis suggests that the age of peak preva- demonstrated in Doberman Pinchers, English Setters, Rhodesian
lence progresses by 1 to 2 years through each of the classications Ridgebacks, and Giant Schnauzers (Kennedy etal, 2006a; 2006b;
(Graham etal, 2001; Fig. 3-8). Studies also suggest that there are Wilbe etal, 2010). Environmental risk factors for canine thyroid-
breed-specific differences in the progression rate and likelihood of itis have not been well dened. Infection-induced damage to the
progression of thyroiditis. thyroid gland, causing release of antigens into the circulation and
Lymphocytic thyroiditis is an immune-mediated disorder, and their subsequent exposure to the hosts immune system, or antigenic
both humoral and cell mediated immunity play a role in pathogen- mimicry of thyroid antigens by viral or bacterial agents could initi-
esis. The major thyroid antigens that initiate an immune response ate the immune-mediated inflammatory process. The proportion of
in the thyroid gland are Tg and TPO. Tg is the main antigen in euthyroid dogs with evidence of thyroiditis is highest in the summer
colloid, and anti-thyroglobulin antibodies (ATAs) are a sensitive and lowest in the winter months (Graham etal, 2007). The signifi-
indicator of canine thyroiditis (Gosselin etal, 1980; Nachreiner cance of this finding is unclear, but it could indicate a relationship
etal, 1998). TPO is a membrane bound glycosylated hemopro- between infection and thyroiditis. Vaccine administration has also
tein that catalyzes the biosynthesis of thyroid hormones. Despite been hypothesized to be a contributing factor for development of
being the most prevalent anti-thyroid antibody in humans with lymphocytic thyroiditis. A signicant increase in ATAs was docu-
Hashimoto thyroiditis, anti-TPO antibodies are found in only mented in Beagles after repeated vaccination beginning at 8 weeks
17% of dogs with thyroiditis (Skopek etal, 2006). Evidence for of age (Scott-Moncrieff etal, 2002; 2006); however further research
humoral mechanisms in the pathogenesis of canine thyroiditis is did not document an increased prevalence of thyroiditis in the vac-
the presence of circulating autoantibodies to thyroid antigens; cinated beagles at necropsy after 5 years of follow-up.
identication by electron microscopy of thickened basement
membranes containing electron-dense deposits that are believed to Lymphocytic Thyroiditis and Polyglandular Autoimmune Syndromes
be antigen-antibody complexes in thyroid follicles; and the induc- Because autoimmune mechanisms play an important role in the
tion of lesions similar to lymphocytic thyroiditis in dogs following pathogenesis of lymphocytic thyroiditis, it is not surprising that
the intrathyroidal injection of Tg antibodies (Gosselin etal, 1980; lymphocytic thyroiditis may sometimes occur together with other
1981a; 1981b; 1981c; Gaschen et al, 1993). Antibody binding immune-mediated endocrine deciency syndromes. Combina-
to the follicular cell, colloid, or Tg antigens is believed to activate tions of immune-mediated endocrine deciency disorders such
the complement cascade, antibody-dependent cell-mediated cyto- as hypothyroidism and diabetes mellitus, and hypothyroidism
toxicity, or both, causing follicular cell destruction. In humans and hypoadrenocorticism have been documented in dogs (Hargis
anti-TPO antibodies but not ATAs have been demonstrated to etal, 1981; Haines and Penhale, 1985; Bowen etal, 1986; Ford
fix complement. The cell-mediated immune system may also play etal, 1993; Kooistra etal, 1995; Greco, 2000; Blois etal, 2011).
an important, and possibly primary, role in the development and These combined disorders are rare, occurring in less than 2% of
perpetuation of lymphocytic thyroiditis. Canine peripheral blood dogs with immune-mediated endocrinopathies (Blois etal, 2011).
mononuclear cells in hypothyroid dogs that are positive for ATAs In a retrospective study of 225 dogs with hypoadrenocorticism,
show proliferation in response to canine Tg. There was a positive 4% of the dogs also had hypothyroidism, 0.5% had concurrent
correlation between the number of CD4+ cells and the concentra- diabetes mellitus, and one dog had concurrent hypothyroid-
tion of Tg in the cultures, suggesting that a loss of self-tolerance of ism, diabetes mellitus, and hyperparathyroidism (Peterson et al,
CD4 + cells is important in the pathogenesis of canine thyroiditis 1996). In a retrospective study of multiple endocrine disease in
(Tani etal, 2005). 35 dogs, the most common combination of immune-mediated
The initiating factors involved in the development of lympho- endocrine disorders were hypothyroidism and diabetes mellitus in
cytic thyroiditis are poorly understood. Genetics undoubtedly plays 10 dogs and hypothyroidism and hypoadrenocorticism in 8 dogs
a major role, especially given the increased incidence of this disorder (Blois etal, 2011). Concurrent thyroiditis and orchitis have been
in certain breeds. Lymphocytic thyroiditis is an inherited disorder documented in a colony of related Beagles and both disorders are
in colony-raised Beagles, with a polygenic mode of inheritance, and highly heritable (Fritz etal, 1976). In humans, two polyglandular
|
TABLE 3-2 N
INETEEN BREEDS WITH THE autoimmune syndromes, type I and type II, have been described.
HIGHEST AND TWENTY BREEDS In polyglandular autoimmune syndrome type II (Schmidt syn-
WITH THE LOWEST PREVALENCE drome), which is the most common of the immunoendocrinopa-
OF THYROGLOBULIN ANTIBODY thy syndromes in humans, there is primary adrenal insufciency
IN 140,821 SERUM SAMPLES in combination with autoimmune thyroiditis, insulin-dependent
SUBMITTED FOR INVESTIGATION diabetes mellitus, or both; whereas in type I the components are
OF THYROID DISEASE* more variable (Eisenbarth etal, 2004).
Polyglandular autoimmune syndromes should be suspected
THYROGLOBULIN
when multiple endocrine gland failure is identied in a dog.
TOTAL AUTOANTIBODY
Hypoadrenocorticism, hypothyroidism, and diabetes mellitus are
NAME SERA POSITIVE PREVALENCE
the most common disorders involved, and the time between diag-
nosis of the first and second disorder ranges from 0 to 53 months
English Setter 585 184 31% (median 4 months). Diagnosis and treatment are directed at each
Old English Sheepdog 368 86 23% disorder as it becomes recognized, because it is not possible to
Boxer 2642 496 19% reliably predict or prevent any of these disorders. It is important
Giant Schnauzer 263 49 19% to recognize that the clinician must consider the effects that one
endocrine disorder may have on the tests used to diagnose another
American Pit Bull Terrier 345 64 19% disorder (e.g., untreated diabetes mellitus suppresses circulating
Beagle 2452 449 18% thyroid hormone concentrations) and the effects that treating
Dalmatian 1372 246 18% one endocrine disorder may have on the treatment of concurrent
German Wirehaired Pointer 112 20 18% endocrine disorders (e.g., initiation of thyroid supplementation
may dramatically improve insulin sensitivity in a diabetic animal;
Maltese Dog 594 105 18%
thyroid supplementation may precipitate an Addisonian crisis in
Rhodesian Ridgeback 626 107 17% hypoadrenocorticism). Immunosuppressive drug therapy is not
Siberian Husky 1129 164 15% indicated in these syndromes and may actually create problems
American Staffordshire Terrier 151 24 16% (e.g., insulin resistance or thyroid suppression with high-dose glu-
cocorticoid therapy).
Cocker Spaniel 8576 1305 15%
Chesapeake Bay Retriever 509 74 15% Idiopathic Atrophy
Tibetan Terrier 106 15 14% Idiopathic atrophy of the thyroid gland is characterized micro-
Shetland Sheepdog 5765 813 14% scopically by progressive reduction in the size of the thyroid fol-
Golden Retriever 17782 2397 13% licles, and replacement of the degenerating follicles with adipose
tissue (Fig. 3-7). An inflammatory inltrate is absent, even in areas
Borzoi 266 35 13% in which small follicles or follicular remnants are present (Gosselin
Brittany Spaniel 556 71 13% et al, 1981b) and tests for lymphocytic thyroiditis are negative.
Dachshund 3612 115 3% The parathyroid glands are not affected, and variable numbers of
Basset Hound 699 22 3% parafollicular cells remain.
Idiopathic thyroid atrophy may be either a primary degener-
Cairn Terrier 590 18 3%
ative disorder (Gosselin et al, 1981b), or an end stage of lym-
Schnauzer (unspecified) 1257 38 3% phocytic thyroiditis. Evaluation of the morphologic changes
Wirehaired Fox Terrier 170 5 3% involved in lymphocytic thyroiditis in a colony of related Borzoi
Cavalier King Charles Spaniel 274 8 3% dogs revealed initial degenerative thyroidal parenchymal changes,
which progressed to progressively worsening inflammation, sub-
Welsh Corgi (undetermined) 457 13 3%
sequent brosis, and thyroid gland destruction, that was histo-
Yorkshire Terrier 1178 33 3% logically similar to idiopathic follicular atrophy (Conaway etal,
Norwegian Elkhound 263 7 3% 1985b). However, residual inflammation was still evident. Idio-
Belgian Tervuren 235 6 3% pathic atrophy can be distinguished from the atrophy associated
Chihuahua 611 15 2%
with decreased TSH secretion (i.e., secondary hypothyroidism),
because in secondary degeneration, the follicles are lined by low
Greyhound 1409 32 2% cuboidal epithelial cells with no indication of degeneration.
Pekingese 407 9 2% In one study, the mean age at the time of diagnosis of hypothy-
Boston Terrier 500 11 2% roidism was older in dogs with suspected idiopathic atrophy when
Pomeranian 1301 26 2% compared with dogs diagnosed with lymphocytic thyroiditis; a
nding that supports the theory that idiopathic atrophy may be an
Irish Wolfhound 210 4 2%
end stage of lymphocytic thyroiditis (Graham etal, 2001). Results
Whippet 114 2 2% for serum Tg and thyroid hormone autoantibody tests also prog-
Soft-coated Wheaten Terrier 214 3 1% ress from positive to negative with time in dogs with lymphocytic
Bichon Frise 657 8 1% thyroiditis, suggesting that the inciting antigens for lymphocytic
thyroiditis disappear with time. Although idiopathic atrophy may
Miniature Schnauzer 828 10 1%
represent an end-stage form of autoimmune lymphocytic thyroid-
From Graham PA, etal.: Etiopathologic findings of canine hypothyroidism, Vet Clin North itis, the inability to demonstrate an inflammatory cell inltrate,
Am Small Anim Pract 37(4):617-631, 2007; with permission. even when follicles are still present, suggests that there may be
*Overall thyroglobulin autoantibody prevalence in this study was 10%. more than one etiology for thyroid atrophy in the dog. Unlike for
may metastasize to or invade the thyroid gland from adjacent

tissues. Because most thyroid tumors are unilateral and do not
destroy more than 80% of thyroid tissue, hypothyroidism due to
thyroid gland destruction is only identified in approximately 10%
of thyroid tumors. Interpretation of thyroid hormone concentra-
tions in dogs with thyroid tumors is complicated by the effects of
concurrent illness on serum thyroid hormone concentrations and
because hypothyroidism may be a pre-existing condition in dogs
with thyroid neoplasia (Benjamin etal, 1996). For more informa-
tion on canine thyroid tumors, see Chapter 5.
Iodine Deficiency/Excess
The iodine requirement in the adult Beagle is estimated to be
140 g/day. In one study, decreased concentrations of serum T4
A and serum T3 did not occur until iodine intake was restricted
to 20 to 50 g/day, and even when thyroid hormone concentra-
tions decreased, clinical signs of hypothyroidism did not develop
(Belshaw etal, 1975). Free T4 (fT4) concentrations, determined
by equilibrium dialysis, remained in the reference range regard-
less of the amount of dietary iodine restriction. Two histologic
changes were observed in the thyroids of dogs with iodine
deciency. In one group, thyroid follicles were small and con-
tained minimal amounts of colloid. Follicular cell hyperplasia
was present, and increased uptake and rapid release of radioio-
dine occurred. In the second group, thyroid follicles were larger
and contained more colloid. Increased uptake but slower release
of radioiodine occurred. TSH-secreting cells of the pituitary were
enlarged and sparsely granulated, suggesting increased activity
and secretion of TSH. Iodine deciency is a rare cause of hypo-
B thyroidism in dogs because commercial pet foods usually contain
adequate amounts of iodine; however interest in bone and raw
food diets has increased in recent years, and such diets may be
deficient in iodine (Dillitzer etal, 2011). Clinical hypothyroid-
ism due to iodine deficiency has been reported in working dogs
fed all meat diets (Nuttall, 1986).
Excessive iodine intake inhibits iodide uptake and organication
and thyroid hormone secretion by thyroid follicular cells, result-
ing in a small but significant compensatory increase in circulating
TSH concentrations (Wolff-Chaikoff effect) (Roti and Vagenakis,
2013). Ingestion of diets containing an excessive amount of iodine
caused impairment of thyroid function and hypothyroidism in
puppies fed a high iodine diet for 45 days (Castillo etal, 2001).
In humans, high iodine diets can result in transient or subclinical
hypothyroidism (Roti and Vagenakis, 2013).
C
Miscellaneous Causes
FIGURE 3-7 A and B, Histologic section of a thyroid gland from a dog with id-
Acquired primary hypothyroidism may rarely result from ingestion
iopathic atrophy of the thyroid gland and hypothyroidism. Note the small size of
of goitrogens, administration of anti-thyroid medications (e.g.,
the gland (compare with C), decrease in follicular size and colloid content, and
propylthiouracil and methimazole), and chronic use of high
lack of a cellular infiltration. (A, H&E 40; B, H&E 250.) C, Histologic section of
doses of potentiated sulfonamides. A palpable goiter may develop
a normal thyroid gland at the same magnification as A. Note the increased size
in dogs treated chronically with potentiated sulfonamides (Seelig
of the gland, the follicles, and the colloid content compared with the gland in A.
et al, 2008; Taeymans and OMarra, 2009). Surgical removal of
(C, H&E 40.)
the thyroid gland for treatment of thyroid neoplasia may also result
in hypothyroidism, but because accessory thyroid tissue may be
lymphocytic thyroiditis, there are no blood tests currently avail- found from the base of the tongue to the base of the heart in dogs,
able that establish the diagnosis of idiopathic atrophy. Hence the hypothyroidism does not always occur after surgery. In a report of
diagnosis is one of exclusion; that is, if the tests for lymphocytic 15 dogs undergoing bilateral thyroidectomy for treatment of thy-
thyroiditis are negative, a diagnosis of idiopathic atrophy is made. roid tumors, approximately 50% of dogs required long-term thy-
roid hormone supplementation (Tuohy etal, 2012). Use of high
Neoplastic Destruction dose radioactive iodine (iodine-131 [131I]) for treatment of thyroid
Clinical signs of hypothyroidism may develop following destruc- neoplasia also results in hypothyroidism (Turrel etal, 2006). Other
tion of more than 80% of the normal thyroid gland by an rare causes of primary hypothyroidism include leishmaniasis and
inltrative tumor. Tumors may arise from the thyroid gland or congenital hypothyroidism (see Congenital Hypothyroidism).
|
Summary case, secondary hypothyroidism may result from suppression of

Although there are several potential causes of canine hypothyroid- thyrotroph function and suppressed TSH secretion, rather than
ism (see Box 3-1), lymphocytic thyroiditis and idiopathic atrophy from destruction of thyrotrophs by the tumor.
account for most of the clinical cases of primary hypothyroidism
diagnosed in dogs. Both cause progressive loss of thyroid function Pituitary Thyrotroph Suppression
as a result of either immune-mediated destruction (lymphocytic The most common cause of secondary hypothyroidism is believed
thyroiditis) or degeneration (idiopathic atrophy) of the thyroid. to be suppression of TSH secretion due to concurrent illness,
The result is a deciency in thyroid hormone synthesis and secre- drugs, hormones, or malnutrition (see Factors Affecting Thyroid
tion and development of clinical signs of hypothyroidism. Gland Function Tests). Although endogenous and exogenous glu-
cocorticoids are believed to suppress pituitary TSH secretion, in a
Secondary Hypothyroidism study of 47 dogs with pituitary dependent hyperadrenocorticism,
basal and TRH stimulated TSH concentrations did not differ
Secondary hypothyroidism results from failure of pituitary thyro- from those of control dogs (Meij etal, 1997).
trophs to develop due to pituitary malformation or acquired dys-
function of the pituitary thyrotrophs causing impaired secretion of Miscellaneous Causes
TSH. Deciency of TSH leads to decreased thyroid hormone syn- In humans, secondary hypothyroidism may also develop follow-
thesis and secretion and thyroid gland hypoplasia. Histologically, ing production of a defective TSH molecule or impaired interac-
the thyroid gland has small hypoplastic follicles that lack or contain tion between TSH and the TSH receptor on follicular epithelial
only scant colloid and apical resorption follicles (Gal etal, 2012). cells. These causes have not yet been reported in the dog. Sec-
Potential causes of secondary hypothyroidism include congeni- ondary hypothyroidism can also result from radiation therapy or
tal malformations of the pituitary gland, pituitary destruction, and hypophysectomy for ACTH-secreting pituitary tumors (Lantz
pituitary suppression. In the dog, secondary hypothyroidism caused etal, 1988; Meij etal, 1998).
by naturally acquired defects in pituitary thyrotroph function or
destruction of pituitary thyrotrophs (e.g., pituitary neoplasia) is
Tertiary Hypothyroidism
uncommon. In contrast, suppression of pituitary thyrotroph func-
tion by hormones or drugs (e.g., glucocorticoids, spontaneous hyper- Tertiary hypothyroidism is dened as a deciency in the secre-
adrenocorticism) is quite common. Serum TSH concentrations tion of TRH by peptidergic neurons in the supraoptic and para-
should be decreased or undetectable with secondary hypothyroid- ventricular nuclei of the hypothalamus. Lack of TRH secretion
ism. Unfortunately, current assays used to measure endogenous TSH causes deciency of TSH secretion and follicular atrophy of the
in dogs are insensitive and unable to differentiate between decreased thyroid gland. In humans, impaired secretion of TRH by the
and normal concentrations (see Baseline Serum Thyrotropin Con- hypothalamus may result from a congenital defect, acquired
centration), making conrmation of secondary hypothyroidism destruction secondary to a mass lesion or hemorrhage, a defec-
difcult; although one would expect the serum TSH concentration tive TRH molecule, or defective TRH-thyrotroph receptor
to be undetectable in a dog with secondary hypothyroidism, such a interaction (Sunthornthepvarakul, 1994; Persani, 2013). Neuro-
nding does not conrm the diagnosis. logic signs and additional pituitary dysfunction may be present,
depending on the cause. Diagnosis of tertiary hypothyroidism is
Pituitary Malformation based on measurement of a low TSH concentration that increases
Congenital abnormalities involving the pituitary gland have been after administration of TRH. Tertiary hypothyroidism is assumed
recognized in many breeds but are reported most commonly in to be rare in dogs. Unfortunately the poor sensitivity of the cur-
German Shepherd dogs. In German Shepherd dogs, pituitary rent canine TSH assay would make confirmation of this diagnosis
dwarfism is caused by a simple autosomal recessive mutation of difficult. Tertiary hypothyroidism was suspected in a 9-year-old
the LHX3 gene, which leads to combined pituitary hormone defi- Labrador Retriever with a highly infiltrative pituitary adenoma
ciency. Combined pituitary hormone deficiency is characterized by that invaded the hypothalamus (Shiel etal, 2007b).
deficiency of growth hormone (GH), TSH, prolactin, and gonado-
trophins. Because the various cell types of the adenohypophysis
Congenital Hypothyroidism
arise from the progenitor cells in a distinct order with corticotrophs
differentiating first, secretion of adrenocorticotrophic hormone Congenital hypothyroidism is rare in dogs. Unfortunately, congeni-
(ACTH) is unaffected. Pituitary cysts may be detected at a young tal hypothyroidism frequently results in early puppy death, and the
age and gradually increase in size with time (Eigenmann, 1981; cause of death is rarely documented. A defect anywhere in the hypo-
Hamann etal, 1999; Kooistra etal, 2000a). Because of the involve- thalamic-pituitary-thyroid axis or of the thyroid hormone receptor
ment of other anterior pituitary hormonesmost notably GH, can result in congenital hypothyroidism (see Box 3-1). Congenital
congenital defects affecting the anterior pituitary usually result in hypothyroidism with goiter (CHG) develops if the hypothalamic-
the development of proportionate dwarsm (see Chapter 2). pituitary-thyroid gland axis is intact; TSH binds appropriately with
its receptor, but there is an intra-thyroidal defect in thyroid hormone
Pituitary Destruction synthesis (dyshormonogenesis). Increased serum TSH concentrations
Although uncommon, pituitary tumors may cause secondary hypo- result in development of thyroid hyperplasia and a goiter. If the hypo-
thyroidism, following destruction of thyrotrophs by an expanding, thalamic-pituitary-thyroid gland axis is not intact (e.g., as occurs with
space-occupying mass. Other endocrinopathies, such as hypocor- pituitary TSH deciency), a goiter will not develop.
tisolism (secondary adrenal insufciency), diabetes insipidus, and Documented causes of congenital primary hypothyroidism in the
reproductive dysfunction, may occur when pituitary dysfunction dog include dietary iodine deficiency, dyshormonogenesis (i.e., iodine
is due to neoplasia. The most common pituitary tumor affecting organication defect), and thyroid dysgenesis (Chastain etal, 1983;
thyroid gland function in the dog is a functional corticotrophic Greco et al, 1985). CHG caused by a nonsense mutation in the
tumor causing pituitary-dependent hyperadrenocorticism. In this TPO gene has been recognized in Toy Fox Terriers and Rat Terriers
(Fyfe etal, 2003; Pettigrew etal, 2007). In a study of Rat Terrier pup- breed popularity and geographic variation in breed distribution
pies with congenital goiter and a mutation in the TPO gene, central may influence the perception of which breeds are predisposed to
nervous system (CNS) hypomyelination was demonstrated in affected the disease. Hypothyroidism is typically a disease of middle-aged
puppies (Pettigrew etal, 2007). The hypomyelination was regionally to older dogs. Golden Retrievers and Doberman Pinschers are the
distributed and most severe in the corpus callosum. Myelin reduction breeds most commonly reported to be at increased risk for hypo-
was paralleled by axon reduction, suggesting that hypomyelination was thyroidism, although many breeds are represented in published
due to reduced axonal formation. Different mutations of the TPO gene studies (Table 3-3). Based upon measurement of serum Tg and
cause CHG in Tenterfield Terriers and Spanish Water dogs. (Dodgson thyroid hormone autoantibodies, many breeds have been reported
etal, 2012; Fyfe 2013). Both defects are autosomal-recessive traits. to have an increased incidence of lymphocytic thyroiditis (see Table
Secondary hypothyroidism resulting from an apparent 3-2), and this is likely due to a genetic predisposition to thyroiditis
deciency of TSH was reported in a family of Giant Schnauzers (Nachreiner etal, 2002; Kennedy etal, 2006a; 2006b). Thyroiditis
(Greco et al, 1991) and a Boxer dog (Mooney and Anderson, is usually documented at an earlier age (2 to 4 years) than develop-
1993). Pedigree analysis suggested an autosomal recessive mode ment of clinical signs (4 to 6 years), which fits with the hypothesis
of inheritance in the family of Giant Schnauzers. Pituitary dwarfs that thyroiditis may progress to complete thyroid failure over time.
with combined anterior pituitary hormone deciencies usually Of 143,800 serum samples from dogs with thyroid disease, the
lack TSH in addition to GH and prolactin (Hamann etal, 1999; age distribution profile peaked at 2 years for dogs with subclinical
Kooistra etal, 2000a; see Chapter 2). Lack of TSH may contrib- thyroiditis, 4 years for dogs with anti-Tg positive hypothyroidism,
ute to abnormal body maturation and growth in pituitary dwarfs. and 5 to 8 years for dogs with anti-Tg negative hypothyroidism
(Graham etal, 2007; Fig. 3-8). Age of onset of symptomatic hypo-
thyroidism may vary between breeds, presumably as a result of the
CLINICAL FEATURES OF HYPOTHYROIDISM
underlying etiology and rate of progression of thyroid pathology.
IN THE ADULT DOG
The majority of studies do not suggest a consistent association of
hypothyroidism with sex or neuter status.
Signalment
Reports regarding breed incidence and genetics of canine hypo- Clinical Signs
thyroidism should always be examined critically, because confirm-
ing a definitive diagnosis of hypothyroidism is challenging, and A deciency in circulating thyroid hormone affects the metabolic
function of almost all organ systems. Destruction of the thyroid
gland is typically slowly progressive, and the onset of clinical signs
TABLE 3-3 B
REED DISTRIBUTION OF may be gradual and initially subtle. Clinical signs are quite variable
154 DOGS WITH PRIMARY and may differ among breeds. For example, different breeds have
HYPOTHYROIDISM* markedly different hair cycles and follicular morphology, which
may influence the clinical and histologic features of the disease
BREED NUMBER (%) OF DOGS (Credille etal, 2001). Because of the slow progression of the disease,
Golden Retriever 26 (17%) owners may fail to recognize the clinical signs until they become
severe. Only after the dog returns to normal following initiation of
Doberman Pinscher 21 (14%)
thyroid hormone supplementation does the owner recognize that
Labrador Retriever 7 (5%) the problem existed for much longer than initially believed.
Mixed breed 24 (16%) In the adult dog, the most consistent clinical signs of hypo-
Other breeds 76 (49%)
thyroidism are those due to decreased cellular metabolism and
dermatologic manifestations (Box 3-2 and Table 3-4). Additional
*Based on four published and one unpublished study (Peterson etal, 1997; clinical signs may affect the cardiovascular system, neuromuscular
Scott-Moncrieff etal, 1998; Ramsey etal, 1997; Panciera, 1994). system, gastrointestinal system, and reproductive system.
18
16 SCThyroiditis (n = 4059)
LTHypoT4 (n = 5640)
14 IdioHypoT4 (n = 5453)
% of disease category
12
10
8
FIGURE 3-8 Age distribution profiles for different categories of thy-
roid disease and dysfunction based on findings in 143,800 samples 6
submitted for the investigation of thyroid disease in which an age 4
was provided. IdioHypoT4, thyroglobulin autoantibodynegative
hypothyroidism; LTHypoT4, thyroglobulin autoantibodypositive 2
hypothyroidism; SC Thyroiditis, subclinical thyroglobulin autoanti- 0
bodypositive thyroiditis. (From Graham PA, etal.: Etiopathologic 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
findings of canine hypothyroidism, Vet Clin North Am Small Anim Age
Pract 37[4]: 620, 2007.)
|
General Metabolic Signs dullness, lethargy, exercise intolerance or unwillingness to exercise,

Most adult dogs with acquired hypothyroidism have clinical signs cold intolerance, and a propensity to gain weight without a cor-
that result from a generalized decrease in metabolic rate. Energy responding increase in appetite or food intake. Obesity occurs in
expenditure, as measured by indirect calorimetry, is approximately approximately 40% of hypothyroid dogs, but it is important to
15% lower in hypothyroid dogs, compared with healthy dogs, and remember that the most common cause of obesity is overnutrition
energy expenditure returns to normal after initiating levothyrox- rather than hypothyroidism.
ine (L-thyroxine; L-T4) sodium treatment (Greco et al, 1998). Metabolic signs are usually gradual in onset and initially very
Clinical signs due to the decreased metabolic rate include mental subtle but become more obvious with longer duration of hypothy-
roidism. Sometimes these clinical signs are missed on the history
and physical examination and not recognized until the dog shows
BOX 3-2 C
linical Manifestations of Hypothyroidism improvement in activity within 7 to 10 days of initiating thyroid
in the Adult Dog hormone supplementation.
Metabolic Neuromuscular Dermatologic Signs

Lethargy* Polyneuropathy/myopathy Alterations in the skin and hair coat occur in 60% to 80% of
Mental dullness Vestibular signs (central or hypothyroid dogs and are the most commonly observed abnor-
Inactivity* peripheral) malities in dogs with hypothyroidism. Dermatologic changes can
Weight gain* Facial/trigeminal nerve paralysis be quite varied and dependent on the breed of dog and severity
Cold intolerance Seizures and chronicity of the disease. The classic cutaneous sign of hypo-
Disorientation/circling thyroidism is bilaterally symmetric, nonpruritic truncal alopecia.
Dermatologic Thyroid hormone is necessary to initiate and maintain the ana-
Myxedema coma
Endocrine alopecia* gen, or growing, phase of the hair cycle (Credille et al, 2001).
Laryngeal paralysis (?)
Symmetric or asymmetrical With thyroid hormone deciency, hair follicles prematurely enter
Areas of friction and pressure Ocular the telogen phase of the hair cycle. Excessive shedding with lack
Rat tail Corneal lipid deposits of hair regrowth leads to alopecia. Decreased concentrations of
Dry, brittle hair coat cutaneous fatty acids and prostaglandin E2 in canine hypothy-
Cardiovascular
Hyperpigmentation roidism may lead to sebaceous gland atrophy, hyperkeratosis,
Bradycardia
Seborrhea scale formation, seborrhea sicca, and a dry and lusterless hair coat
Cardiac arrhythmias
Pyoderma (Campbell and Davis, 1990). The hair coat may appear faded
Otitis externa Gastrointestinal
in color, and subtle changes in hair coat quality may initially be
Myxedema Esophageal hypomotility (?)
appreciated by the owner but not the veterinarian. In the early
Diarrhea
Reproductive stages of hypothyroidism, hair loss is often asymmetric and devel-
Constipation
Prolonged parturition ops over areas of excessive wear or pressure, such as the caudal
Periparturient mortality Hematologic thighs, ventral thorax, tail base, and tail (i.e., development of a
Low birth weight puppies Anemia* rat tail; Fig. 3-9). As hypothyroidism becomes more severe or
Female infertility Hyperlipidemia* chronic, alopecia becomes more symmetric and truncal, eventu-
Inappropriate galactorrhea or ally developing into the classic cutaneous nding of bilaterally
gynecomastia symmetric, nonpruritic truncal alopecia that tends to spare the
head and distal extremities (Fig. 3-10). Although nonpruritic
*Common. endocrine alopecia is not pathognomonic for hypothyroidism,
?indicates that a causal relationship is not proven. when it is present in a dog with other signs of decreased meta-
bolic rate and no polyuria or polydipsia, hypothyroidism is the
most likely diagnosis.
TABLE 3-4 INCIDENCE OF CLINICAL SIGNS There are breed variations in the dermatologic effects of hypo-
IN 162 ADULT DOGS WITH thyroidism presumably because of differences in the hair cycle
HYPOTHYROIDISM and follicular morphology. In some breeds, failure to shed leads
to hypertrichosis, and in other breeds primary hairs are lost giving
CLINICAL SIGN PERCENT OF DOGS the hair coat a wooly appearance. In some dogs there is a loss
Dermatologic 88 of the undercoat, and the remaining primary hairs give the coat
Obesity 49 a coarse appearance. In some breeds the hair shafts within telo-
gen follicles may be retained for long periods (months to years)
Lethargy 48
without falling out. In a study evaluating the effect of induced
Weakness 12 hypothyroidism on the skin of Beagle dogs, none of the untreated
Neurologic hypothyroid dogs had a discernible alopecia after 10 months of
Facial nerve paralysis 4 observation despite the hypothyroid dogs having one-third fewer
hair shafts than healthy Beagles (Credille etal, 2001). The most
Peripheral vestibular 3
common nding was a failure of the hypothyroid dogs to regrow
Polyneuropathy 2 their hair after clipping. Retaining telogen hairs maintains the pel-
Reproductive <2 age, which explains why truncal alopecia does not usually develop
Cardiovascular (bradycardia) 10
in hypothyroid Beagle dogs.
Hyperpigmentation is common in hypothyroidism, especially
Adapted from Panciera DL: Conditions associated with canine hypothyroidism, Vet Clin in regions of alopecia and areas of wear, such as the axilla and
North Am 31:935, 2001. inguinal regions (Fig. 3-11). In severe cases of hypothyroidism, the
hygroscopic glycosaminoglycan, hyaluronic acid may accumulate

in the dermis, bind water, and result in increased thickness and
non-pitting edema of the skin, referred to as myxedema, or cuta-
neous mucinosis (Doliger etal, 1995). Myxedema predominantly
affects the forehead, eyelids, and lips, and it contributes to the
development of the classic tragic facial expression described in
hypothyroid dogs (see Fig. 3-9). A rare complication of myxedema
is cutaneous mucinous vesiculation (Miller and Buerger, 1990).
Thyroid hormone is believed to play a role in the normal
immune response. Depletion of thyroid hormone suppresses
humoral immune reactions, impairs T cell function, and reduces
the number of circulating lymphocytes. Dogs with hypothy-
roidism may develop supercial bacterial infections (folliculitis,
supercial spreading pyoderma, impetigo) characterized by pap-
ules, pustules, epidermal collarettes, and/or focal areas of alopecia.
A
Bacterial infections are usually caused by Staphylococcus spp. and
are variably pruritic. Hypothyroidism may also predispose to adult
onset demodicosis and chronic otitis externa (Duclos etal, 1994).
The skin changes associated with hypothyroidism are generally
nonpruritic; however secondary infection, seborrhea, or concur-
rent pruritic diseases (e.g., atopy or flea bite hypersensitivity) may
cause pruritus. The presence of pruritic skin disease therefore does
not rule out underlying hypothyroidism.
Neurologic Signs
Both the peripheral nervous system and CNS may be affected by
hypothyroidism (Indrieri etal, 1987; Bichsel etal, 1988; Jaggy etal,
1994). Diffuse peripheral neuropathy characterized by exercise
intolerance, weakness, ataxia, quadriparesis or paralysis, deficits of
conscious proprioception, and decreased spinal reflexes has been
reported to occur in dogs with hypothyroidism. Single or multifo-
B cal cranial nerve dysfunction with predisposition for the facial,
vestibulocochlear, and trigeminal nerves has also been reported.
Neurologic dysfunction may be multifocal, acute or chronic, and
static or progressive. Other physical examination findings con-
sistent with hypothyroidism may be absent. Hypothyroid dogs
with vestibular deficits may have abnormal brainstem auditory
evoked responses and electromyographic abnormalities identified
in the appendicular muscles. Proposed mechanisms include nerve
entrapment from accumulation of mucinous deposits, demyelin-
ation due to disrupted Schwann cell metabolism, vascular nerve
damage due to alterations in the blood-nerve barrier, and dis-
turbances in axonal cell transport. Although there are numerous
reports of the association between hypothyroidism and periph-
eral nerve dysfunction, the cause and effect relationship has been
questioned, because in an experimental model of canine hypothy-
roidism, it was not possible to reproduce a peripheral neuropathy
(Rossmeisl, 2010). It has been proposed that other factors such as
immune dysregulation may play a role in the pathogenesis of the
peripheral neurologic abnormalities. Because immune-mediated
thyroiditis is present in as many as 50% of hypothyroid dogs, it
is conceivable that immune-mediated mechanisms contribute to
the pathogenesis of the neuromuscular changes observed in hypo-
thyroid dogs. Clinical signs of peripheral neuropathy resolve with
L-T4 sodium supplementation; however this finding must be
interpreted carefully because peripheral vestibular disease, facial
C
nerve paralysis, and polyradiculoneuritis of unknown etiology
FIGURE 3-9 An 8-year-old male Chesapeake Bay Retriever with hypothyroidism. may also improve or resolve over time.
Note the poor hair coat, lethargic appearance, myxedema of the face with droop- A subclinical myopathy has been well-documented in hypothy-
ing of the eyelids (A and B), and rat tail (C). roid dogs and also occurs in experimental models of canine hypo-
thyroidism (Delauche, 1998; Rossmeisl etal, 2009). Hypothyroid
myopathy is accompanied by increased plasma creatine kinase,
aspartate aminotransferase, and lactate dehydrogenase activities.
|
A B
FIGURE 3-10 A 5-year-old male Miniature Poodle (A) and a 6-year-old spayed Miniature Poodle (B) with hypothy-
roidism and endocrine alopecia. Note the truncal alopecia and hyperpigmentation, which have spared the head
and extremities, in both dogs.
A B
FIGURE 3-11 A, Truncal hyperpigmentation in a 4-year-old female spayed Boxer with hypothyroidism. B, Severe
hyperpigmentation involving the inguinal region in a 6-year-old spayed mixed-breed dog with hypothyroidism.
Histopathologic abnormalities include nemaline rod inclusions, Central vestibular dysfunction has also been reported in associa-
predominance of type I myofibers, decrease in mean type II fiber tion with hypothyroidism. In 10 dogs with central vestibular dys-
area, subsarcolemmal accumulations of abnormal mitochondria, function associated with hypothyroidism, lesions consistent with
and myofiber degeneration (Delauche, 1998; Rossmeisl et al, an infarct were identified in three dogs, but cranial imaging stud-
2009). Substantial depletion of skeletal muscle free carnitine has ies were normal in the other five dogs that were imaged (Higgins
also been documented in affected dogs. Although an obvious clin- etal, 2006). Albuminocytologic dissociation was identified in five
ical myopathy is not recognized associated with these changes, the of six cerebrospinal fluid (CSF) analyses and most dogs had hyper-
abnormalities may contribute to nonspecific clinical signs, such as cholesterolemia or hypertriglyceridemia. Clinical signs completely
lethargy and exercise intolerance in canine hypothyroidism. resolved after 4 weeks of supplementation with L-thyroxine, apart
from residual head tilt in one dog. Cerebral dysfunction manifested weakness; hypothermia; non-pitting edema of the skin, face, and
by seizures, disorientation, and circling may also rarely occur in jowls (myxedema); bradycardia; hypotension; and hypoventila-
canine hypothyroidism, although there is little evidence to sug- tion. Myxedema results from the accumulation of acid and neutral
gest that hypothyroidism is a common cause of seizure disorders mucopolysaccharides and hyaluronic acid in the dermis, which
in dogs. In a series of 113 dogs with seizure disorders, 38% of dogs bind water and result in increased thickness of the skin. Labora-
with idiopathic epilepsy had thyroid hormone profiles consistent tory ndings may include hypoxemia, hypercarbia, hyponatremia,
with nonthyroidal illness, but fewer than 3% of dogs were defini- and hypoglycemia in addition to the typical ndings of hyper-
tively diagnosed with hypothyroidism (von Klopmann etal, 2006). lipidemia, hypercholesterolemia, and nonregenerative anemia.
In a retrospective study of 96 dogs with metabolic and toxic causes Serum thyroid hormone concentrations are usually extremely low
of seizures, hypothyroidism was the suspected cause in only three or undetectable; serum TSH concentration is variable but typi-
dogs (Brauer etal, 2011). An incorrect diagnosis of hypothyroidism cally increased. There is commonly a precipitating event, such as
may be made in dogs already being treated for idiopathic epilepsy hypothermia or infection. Mortality is high, likely because of late
because anticonvulsant therapy may influence thyroid hormone recognition and concurrent illness.
testing (see Anticonvulsants). The reason for CNS dysfunction in
canine hypothyroidism is poorly understood and is likely multi- Alterations in Behavior
factorial. Atherosclerosis, hyperlipidemia, vascular encephalopa- A relationship between thyroid function and behavioral changes is
thy, and functional metabolic derangements of neuronal or glial well established in humans. Neurologic and psychiatric symptoms
cell populations due to hypothyroidism may all play a role. Dogs (e.g., slowing of thought and speech, memory loss, poor concentra-
with atherosclerosis, which is likely due to hypercholesterolemia, tion, anxiety, depression, and psychosis) may occur in hypothyroid
are over 50 times more likely to have hypothyroidism than dogs adults (Schuff etal, 2013). These changes are proposed to result
without atherosclerosis (Hess etal, 2003). Severe hyperlipidemia from alterations in expression of neurotransmitters, neuromodu-
has been reported to cause neurologic dysfunction in hypothyroid lators, and growth factors associated with thyroid dysfunction.
dogs, and it has been proposed that Labrador Retrievers may be The influence of thyroid dysfunction on serotonergic receptors
predisposed to this manifestation of hypothyroidism (Vitale etal, has received particular attention because of the role of serotonin
2007). Dogs with experimentally induced hypothyroidism have in depressive illness. It has been postulated that canine hypothy-
disruption of the blood brain barrier as evidenced by albumino- roidism may lead to aberrant behavior, including aggression, sub-
cytologic dissociation and increased CSF concentrations of plasma missiveness, shyness, fearfulness, excitability, passivity, irritability,
vascular endothelial growth factor (VEGF) (Pancotto etal, 2010). moodiness, and unstable temperament (Dodds, 1995). To date,
Two of nine dogs with induced hypothyroidism in this study devel- most reports on alterations in behavior and hypothyroidism have
oped CNS signs and evidence of cerebrovascular disease during the been anecdotal and based on apparent improvement in behav-
18-month study. Myxedema coma or a pituitary tumor causing ior following initiation of thyroid hormone treatment. Proposed
secondary hypothyroidism may also rarely cause CNS signs. mechanisms for hypothyroidism associated aggression include a
lowered threshold for aggression due to lethargy and irritability
Other Neurologic Disorders and disturbances in serotonergic or noradrenergic pathways. Two
Laryngeal paralysis and megaesophagus may both occur in associ- small prospective studies in dogs failed to demonstrate an asso-
ation with hypothyroidism; however, a causal relationship has not ciation between hypothyroidism and behavioral problems, such
been established, and treatment of hypothyroidism does not con- as aggression (Carter et al, 2009; Radosta et al, 2012); however
sistently result in improvement of clinical signs of either disorder further larger prospective studies would be required to prove the
(MacPhail and Monnet, 2001; Gaynor etal, 1997). Myasthenia absence of such a relationship. The benets, if any, of using thyroid
gravis has been identied in dogs with hypothyroidism (Dewey hormone to treat behavioral disorders remain to be claried.
etal, 1995) and is a well-recognized cause of acquired megaesoph-
agus in the dog. Concurrent hypothyroidism may exacerbate Reproductive Signs
clinical signs of myasthenia gravis, such as muscle weakness and Historically, hypothyroidism was believed to cause lack of libido,
megaesophagus. In human beings, there is a link between autoim- testicular atrophy, and oligospermia or azoospermia in male dogs.
mune thyroiditis and acquired myasthenia gravis, and myasthenia However, work by C. Johnson, etal. (1999) in Beagles failed to
gravis is a recognized component of polyglandular autoimmune document any deleterious effect of experimentally induced hypo-
syndrome type II. Presumably a common abnormality in immune thyroidism on any aspect of male reproductive function. Although
function allows development of autoimmune attack on both the other classic clinical signs and clinicopathologic abnormalities of
thyroid gland and acetylcholine receptors. Myasthenia gravis was hypothyroidism developed in the hypothyroid dogs studied, libido,
documented in only 1 of 162 dogs with hypothyroidism reviewed testicular size, and the total sperm count per ejaculate remained
by Panciera (2001), implying that hypothyroidism is rarely associ- normal. These ndings suggest that hypothyroidism is an uncom-
ated with myasthenia gravis. A causal relation between hypothy- mon cause of reproductive dysfunction in male dogs; however, the
roidism and myasthenia gravis remains to be established. duration of the study (2 years) may have been too short to allow
reproductive abnormalities to develop, or the induced model used
Myxedema Coma in the study may not have been representative of naturally occur-
Myxedema coma is an extremely rare syndrome of severe hypothy- ring hypothyroidism, which commonly is due to lymphocytic
roidism characterized by profound weakness, hypothermia, brady- thyroiditis. It is possible that lymphocytic thyroiditis and lym-
cardia, and a diminished level of consciousness, which can rapidly phocytic orchitis are comorbid conditions, which could account
progress to stupor and then coma (Chastain et al, 1982; Kelly for the clinical observation of reproductive dysfunction in male
and Hill, 1984; Henik and Dixon, 2000; Atkinson and Aubert, hypothyroid dogs. Hypothyroidism appears to be an uncommon
2004). Clinical signs in addition to the more typical clinical signs cause of infertility in male dogs. However, it should be considered
of hypothyroidism, include mental dullness, depression, unre- when other causes for infertility cannot be identied, especially if
sponsiveness, and weakness. Physical ndings include profound decreased libido is part of the clinical picture.
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Although thyroid hormone is believed to be necessary for normal increased systemic vascular resistance, decreased vascular volume,
follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and atherosclerosis (Klein, 1990; Hess etal, 2003). It is not known
secretion, an association between hypothyroidism and infertility which of these alterations contribute to the myocardial abnormali-
in the female dog has been poorly documented in the veterinary ties identied in dogs with hypothyroidism. Fortunately, the decrease
literature. Two prospective studies failed to identify an association in cardiac contractility in dogs with hypothyroidism is usually mild
between poor reproductive performance and hypothyroidism in and asymptomatic, but it may become relevant during a surgical pro-
pure bred dogs (Beale etal, 1992b; Segalini etal, 2009). In a procedure requiring prolonged anesthesia and aggressive fluid therapy.
spective study of female dogs with experimentally induced hypo- Cardiac abnormalities are usually reversible with thyroid hormone
thyroidism, short-term hypothyroidism (median 19 weeks) was supplementation although it may take months of supplementation to
associated with prolonged parturition and reduced periparturient restore normal cardiovascular function (Panciera, 1994).
puppy survival (Panciera etal, 2007). In the same study, dogs with It is important to emphasize that although hypothyroidism can
more chronic hypothyroidism (56 weeks) had higher periparturient induce echocardiographic changes, thyroid hormone deciency alone
mortality and lower puppy birth weights than control dogs. Fertility rarely causes heart failure. In most cases heart failure associated with
was decreased in the hypothyroid dogs compared to control dogs, primary hypothyroidism is considered to represent an exacerbation of
but the difference was not statistically significant, likely due to the intrinsic cardiac disease by the superimposed hemodynamic effects of
small numbers of dogs in each group (Panciera etal, 2012). Hypo- thyroid hormone deciency. Both cardiomyopathy and hypothyroid-
thyroidism has also been implicated in causing prolonged inter- ism are common problems in Doberman Pinschers, and Calvert, etal.
estrus intervals and failure to cycle in the female dog. However this speculated on a possible cause-and-effect relationship between these
was not documented in the studies by Panciera, etal (2007, 2012). two disorders in 1982. However, subsequent studies failed to iden-
Additional reproductive abnormalities that have been reported in tify any relationship between hypothyroidism and cardiomyopathy
the veterinary literature include weak or silent estrus cycles, pro- in Doberman Pinschers (Lumsden etal, 1993; Calvert etal, 1998).
longed estrual bleeding, and inappropriate galactorrhea and gyne- Although low baseline serum thyroid hormone concentrations occur
comastia. The latter is believed to develop following a thyroid in dogs with idiopathic dilated cardiomyopathy and heart failure, the
hormone deciencyinduced increase in TRH secretion, which in thyroid gland in most of these dogs is responsive to TSH, suggesting
turn stimulates prolactin secretion (Chastain and Schmidt, 1980; that the low thyroid hormone concentrations are due to nonthyroi-
Cortese etal, 1997). Increased prolactin concentrations were docu- dal illness rather than hypothyroidism. One case report documented
mented in dogs with experimentally induced hypothyroidism 39 dramatic long-term improvement in cardiac function after treatment
weeks after induction of hypothyroidism, but this was not associ- with T4 in two Great Danes with concurrent dilated cardiomyopathy
ated with abnormalities in progesterone concentrations or ovula- and hypothyroidism (Phillips, 2003). Pericardial disease has also been
tion (Kolster etal, 2010). Evaluation of thyroid gland function is associated with canine hypothyroidism. Aortic thromboembolism
recommended as part of the evaluation of female dogs for infertility, and a cholesterol-based pericardial effusion that resolved after L-T4
fetal resorption, or periparturient mortality, although it appears that sodium supplementation were reported in a 9-year-old mixed-breed
hypothyroidism is an uncommon cause of reproductive failure. dog with hypothyroidism (MacGregor, 2004).
Cardiovascular Signs Ocular Signs

Clinical signs related to dysfunction of the cardiovascular system Ocular signs are rare in hypothyroid dogs and most commonly
are uncommon in canine hypothyroidism. Abnormalities identied are secondary to hyperlipidemia. Corneal lipid deposits (i.e., arcus
on physical examination may include bradycardia and a weak apex lipoides corneae) have been described in a group of hypothyroid
beat. Atrial brillation has been suggested to be associated with Alsatians with concomitant hyperlipidemia (Crispin, 1978). Cor-
hypothyroidism in dogs (Gerritsen etal, 1996), but this appears to neal ulceration, uveitis, lipid effusion into the aqueous humor,
be rare based on ndings in other studies (Panciera, 2001). More secondary glaucoma, lipemia retinalis, retinal detachment, kera-
commonly, functional abnormalities are identied on electrocardi- toconjunctivitis sicca (KCS), and Horners syndrome have been
ography or echocardiography in dogs exhibiting the more common reported in hypothyroid dogs, but the evidence for a causal asso-
clinical signs of hypothyroidism. Electrocardiographic abnormali- ciation is weak (Kern and Riis, 1980; Gosselin etal, 1981b; Peruc-
ties include sinus bradycardia, decreased amplitude of the P and R cio, 1982; Kern etal, 1989). Dogs with experimentally induced
waves, inversion of the T waves, and rst-degree and second-degree hypothyroidism did not develop ocular signs over a 6-month
atrioventricular block (Panciera, 1994; 2001). Echocardiographic period (Miller, 1994). In another study decreased tear production
abnormalities include increased left ventricular end systolic diam- was documented in hypothyroid dogs compared to control dogs,
eter, prolonged preejection period, and decreases in left ventricular but only 2 of 12 dogs evaluated had clinical signs of keratocon-
posterior wall thickness during systole, percentage change in left junctivitis sicca (Williams etal, 2007).
ventricular posterior wall from diastole to systole, interventricular
wall thickness during systole and diastole, aortic diameter, veloc- Gastrointestinal Signs
ity of circumferential ber shortening, and fractional shortening Clinical signs related to the gastrointestinal system have been
(Panciera, 1994; 2001). Many of the hemodynamic effects of hypo- described but are not common in hypothyroid dogs. Constipa-
thyroidism appear to be attributable to direct effects of hypothyroid- tion may occur, presumably as a result of alterations in electrical
ism on the myocardium, which include decreased cardiac muscle control activity and smooth muscle contractile responses in the
myosin adenosine triphosphatase (ATPase) activity, decreased sarco- gastrointestinal tract. Diarrhea has also been reported with hypo-
plasmic reticulum calcium-ATPase activity, decreased calcium chan- thyroidism, although a cause-and-effect relationship has not been
nel activity, decreased sodium-potassium ATPase activity, and reduced established, and some of these dogs may have had nonthyroidal
-adrenergic receptors in the myocardium (Bilezikian and Loeb, illness rather than hypothyroidism.
1983; Haber and Loeb, 1988; Hawthorn etal, 1988; Dowell etal, Generalized megaesophagus has been identied in some dogs
1994). Alterations in the circulatory system may also contribute to with hypothyroidism, and some investigators have theorized that
the decrease in cardiac output present in hypothyroidism, including megaesophagus is caused by hypothyroidism, presumably as a
result of hypothyroid-induced neuropathy or myopathy (Jaggy

et al, 1994). Unfortunately, no published reports document a BOX 3-3 C
linical Signs Associated with Congenital
cause-and-effect relationship between hypothyroidism and mega- Hypothyroidism
esophagus, and one recent retrospective study failed to identify an
association between hypothyroidism and acquired megaesopha- Dwarfism
gus in dogs (Gaynor etal, 1997). As with cardiomyopathy, a low Short, broad skull
baseline thyroid hormone concentration in a dog with generalized Shortened mandible
megaesophagus more often represents nonthyroidal illness rather Enlarged cranium
than hypothyroidism. The thyroid gland in most of these dogs is Shortened limbs
responsive to TSH, megaesophagus persists despite thyroid hor- Kyphosis
mone supplementation, and treatment has minimal to no effect Mental dullness
on clinical signs (Panciera, 1994; Jaggy etal, 1994). Constipation
Inappetence
Coagulopathy Gait abnormalities
In humans, hypothyroidism may cause several abnormalities in Delayed dental eruption
the coagulation system, including a reduction in concentration Alopecia
of factors VIII and IX, a reduction in factor VIIIrelated anti- Puppy hair coat
gen (von Willebrand factor), reduced platelet adhesiveness, and Dry hair
increased capillary fragility (Hymes etal, 1981; Rogers etal, 1982; Thick skin
Dalton et al, 1987). These abnormalities account for the easy Lethargy
bruising observed in some humans with hypothyroidism. Numer- Dyspnea
ous studies have evaluated the association between canine hypo- Goiter
thyroidism and the concentration of factor VIIIrelated antigen
both in euthyroid and hypothyroid dogs and found no evidence
of an association (Avgeris etal, 1990; Heseltine, 2005; Panciera Abnormalities detected on neuromuscular examination may
and Johnson, 1994; 1996). Evaluation of the coagulation cascade include mental dullness, weakness, hyporeflexia, joint laxity,
or factor VIIIrelated antigen is not recommended in dogs with spasticity, ataxia, hypermetria, and muscle tremors. Differential
untreated hypothyroidism unless concurrent bleeding problems diagnoses for failure to grow include endocrine (e.g., pituitary
are present. Thyroid hormone supplementation in euthyroid dogs dwarsm) and non-endocrine causes. See Chapter 2 for more
with von Willebrand disease is not recommended. information on pituitary dwarsm.
CLINICAL FEATURES OF CONGENITAL CLINICAL FEATURES OF SECONDARY

HYPOTHYROIDISM HYPOTHYROIDISM
Normal physical and mental development depends on the pres- The array of clinical signs is similar for primary and secondary
ence of normal plasma thyroid hormone concentrations. Thy- hypothyroidism in the adult dog; however, other clinical signs may
roid hormone is critical for normal neurologic development and dominate depending on the underlying cause. If acquired second-
bone growth. Thyroid hormone acts synergistically with GH and ary hypothyroidism is caused by a pituitary tumor, the clinical signs
insulin-like growth factor-1 (IGF-1) to promote chondrogenesis. will depend on the hormonal activity of the tumor and the degree of
Retardation of growth and impaired mental development are the compression/destruction of surrounding structures. Clinical signs
hallmarks of congenital hypothyroidism (cretinism) (Box 3-3). of hypoadrenocorticism or hyperadrenocorticism, diabetes insipi-
Clinical signs of hypothyroidism are not usually present at birth dus, or hypothalamic/thalamic dysfunction (i.e., lethargy, stupor,
but develop postnatally. Abnormalities usually become obvious to anorexia, adipsia, loss of temperature regulation) may predominate.
owners between 2 and 12 weeks of age. Puppies with congenital Subtle changes associated with hypothyroidism, GH deciency, or
hypothyroidism are typically of normal weight at birth, but fail reproductive dysfunction are less likely to be observed by an owner.
to thrive and gain weight in the weeks after birth. They develop
disproportionate dwarfism with a large, broad head, short thick
CLINICOPATHOLOGIC ABNORMALITIES
neck, enlarged or protruding tongue, wide/square trunk, and
OF HYPOTHYROIDISM
short limbs (Fig. 3-12). This is in contrast to the proportion-
ate dwarsm caused by GH deciency (see Chapter 2). Delayed There are a number of laboratory abnormalities associated with
epiphyseal development and retarded epiphyseal growth with hypothyroidism. Although most of the changes are nonspecic
reduced long bone growth cause the disproportionate dwarfism of and observed in many other disorders, their presence adds support
congenital hypothyroidism (Saunders and Jezyk, 1991). for a diagnosis of hypothyroidism in an animal with appropriate
Affected puppies are mentally dull and lethargic, may be unable clinical signs.
to eat without assistance, and lack the typical playfulness seen in
normal puppies. They often have stenotic ear canals and delayed Complete Blood Count
opening of the eyelids. The soft, fluffy puppy hair coat persists, A normocytic, normochromic, nonregenerative anemia (packed cell
and diffuse truncal thinning of the hair with lack of guard hairs volume [PCV], 28% to 36%) is identified in approximately 30%
develops, which may progress to complete alopecia often with of dogs (Panciera, 2001). The cause is unknown but is believed to
seborrhea. Additional clinical signs may include inappetence, con- be due to decreased erythrocyte production. Decreased erythropoi-
stipation, delayed dental eruption, and goiter (Fig. 3-13). The pres- etin, decreased erythroid progenitor response to erythropoietin, and
ence of goiter is variable and dependent on the underlying etiology lack of a direct effect of thyroid hormone on early hemopoietic plu-
(see Congenital Hypothyroidism). ripotent stem cells may all contribute to the anemia. Erythrocyte
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A B
C D
E
FIGURE 3-12 A and B, Eight-month-old female Giant Schnauzer littermates. The dog on the left is normal, whereas
the smaller dog on the right has congenital hypothyroidism (cretinism). Note the small stature, disproportionate
body size, large broad head, wide square trunk, and short limbs in the hypothyroid dog. C and D, A 3-year-old male
Doberman Pinscher with congenital hypothyroidism. Note the small stature, juvenile appearance, and retention of
a soft, fluffy puppy hair coat. E, Same dog as in C and D, shown next to his female littermate.
A B C
FIGURE 3-13 A, External appearance of a goiter in a 5-week-old Toy Fox Terrier puppy with congenital hypothyroidism.
(Reprinted with permission from Fyfe JC, et al.: Congenital hypothyroidism with goiter in toy fox terriers, J Vet Intern Med
17:50, 2003.) B, A 16-month-old Spanish Water dog with congenital hypothyroidism and goiter. The dog was started
onsupplementation at 4- week-old and avoided all growth and morphologic abnormalities except the huge goiter.
Histopathologic appearance of goiter from the Spanish Water dog shown above at 17-months-old. The gland measured
4.5 x 2.5 x 2 cm. There are typical dyshormonogenic features including diffuse follicular epithelial cell hyperplasia,
with colloid spaces largely filled with cuboidal to columnar epithelial cells piled up as blunt papillae (Courtesy of
Dr. John C. Fyfe, Associate Professor Microbiology and Molecular Genetics, Michigan State University.)
survival time is not affected by hypothyroidism. Evaluation of red

blood cell morphology may reveal increased concentrations of lepto- BOX 3-4 Causes of Hyperlipidemia in the Dog and Cat
cytes (target cells). These cells are believed to develop from increased
erythrocyte membrane cholesterol loading, a direct result of the con- Postprandial hyperlipidemia
comitant hypercholesterolemia associated with thyroid deciency. Secondary hyperlipidemia
Platelet counts are normal to increased, and platelet size is normal to Hypothyroidism
decreased in dogs with hypothyroidism (Sullivan etal, 1993). Hyperadrenocorticism
Diabetes mellitus
Serum Biochemistry Panel Pancreatitis
The classic abnormality seen on a screening biochemistry panel is Cholestasis
fasting hypercholesterolemia, which is present in approximately Hepatic insufficiency
75% of hypothyroid dogs. Fasting hypertriglyceridemia is also very Nephrotic syndrome
common. Thyroid hormones stimulate virtually all aspects of lipid Protein-losing enteropathy
metabolism, including synthesis, mobilization, and degradation. Primary hyperlipidemia
Both the synthesis and degradation of lipids are depressed in hypo- Idiopathic hyperlipoproteinemia (Miniature Schnauzer)
thyroidism, with degradation affected more than synthesis. The net Idiopathic hyperchylomicronemia (cat)
effect is an accumulation of plasma lipids in hypothyroidism and Lipoprotein lipase deficiency (cat)
the potential for development of atherosclerosis (Hess etal, 2003). Idiopathic hypercholesterolemia
Lipoprotein electrophoretic evaluation of plasma from 26 Drug-induced hyperlipidemia
hypothyroid dogs revealed three general groups of ndings: (1) Glucocorticoids
normal plasma lipid concentrations and lipoprotein electro- Megestrol acetate (cat)
phoresis; (2) hypercholesterolemia with increased intensity of
the alpha2-lipoprotein band; and (3) hypercholesterolemia and
hypertriglyceridemia with prominent pre-beta, beta, and alpha2- with healthy dogs. Thyroid hormone deciency-induced decrease
lipoprotein bands (Rogers et al, 1975). Hyperlipidemia and in hepatic LDL receptor activity and reduced activities of lipo-
altered lipoprotein electrophoretic patterns normalized follow- protein lipase and hepatic lipase were proposed as the underlying
ing supplementation with thyroid hormone. A more recent study mechanisms responsible for the lipoprotein cholesterol abnormali-
used a combined ultracentrifugation and precipitation technique ties identied in hypothyroid dogs (Valdermarsson et al, 1983).
to quantify plasma lipoprotein concentrations in 10 dogs with Fasting hypercholesterolemia and hypertriglyceridemia can be
hypothyroidism (Barrie et al, 1993). The plasma concentrations associated with several other disorders (Box 3-4) and thus are not
of cholesterol, verylow-density lipoprotein (VLDL) cholesterol, pathognomonic for hypothyroidism. However, their presence in a
low-density lipoprotein (LDL) cholesterol, and high-density lipo- dog with appropriate clinical signs is strong supportive evidence
protein (HDL) cholesterol were signicantly higher, compared for hypothyroidism.
|
Mild hypercalcemia has been reported in some dogs with con- hypothyroidism, radiographic abnormalities include delayed
genital hypothyroidism and has also been reported in an adult epiphyseal ossication (Fig. 3-14); epiphyseal dysgenesis (i.e.,
dog with hypothyroidism (Lobetti, 2011). Hypercalcemia has irregularly formed, fragmented, or stippled epiphyseal centers),
been documented in hypothyroid children secondary to increased most common in the humeral, femoral, and proximal tibial con-
intestinal absorption and decreased urinary excretion of calcium. dyles; short broad skulls; shortened vertebral bodies; and delayed
Hyponatremia occurs in dogs with myxedema coma (Atkinson maturation (Greco etal, 1991; Saunders and Jezyk, 1991; Mooney
and Aubert, 2004; Henik and Dixon, 2000). and Anderson, 1993). Ventral borders of vertebral bodies may be
Hypothyroid dogs may have a mild to moderate increase in scalloped, suggesting lack of normal longitudinal growth (see Fig.
serum lactate dehydrogenase (LDH), aspartate aminotransferase 3-14). Overall length of the diaphyses of long bones is reduced, and
(AST), alanine aminotransferase (ALT), and alkaline phosphatase carpal and tarsal bones appear to have retarded ossication. Valgus
(AP) activities. These increases are believed to be associated with deformities are common. Accelerated epiphyseal ossication occurs
hypothyroid myopathy. In a study of nine dogs with experimen- during thyroid hormone supplementation, but degenerative joint
tally induced hypothyroidism, a subclinical myopathy associated changes with consequent osteoarthritis may develop despite thy-
with increases in creatine kinase, AST, and lactate dehydrogenase roid hormone supplementation (Saunders and Jezyk, 1991).
was documented within 6 months of induction of hypothyroidism
(Rossmeisl etal, 2009). Ultrasonography
The thyroid gland can be identied and its size, shape, and echo-
Urinalysis genicity determined using real-time ultrasonography in dogs. Ultra-
Results of urinalysis are usually normal in dogs with hypo- sonography is commonly employed for evaluation of suspected
thyroidism. In dogs with lymphocytic thyroiditis, concurrent thyroid neoplasms, especially for guidance in performing needle
immune-complex glomerulonephritis may result in proteinuria biopsy (see Chapter 5). Ultrasound may also be helpful in differen-
(Mansfield and Mooney, 2006). Although an increased risk of tiating between hypothyroidism and the euthyroid sick syndrome.
glomerulonephritis would be expected in dogs with thyroiditis, The normal thyroid gland is homogenous and well delineated with
there are few reports of dogs with both conditions in the pub- a hyperechoic capsule. The parenchyma is hyperechoic to the sur-
lished literature. rounding muscles, and the size is correlated with the size (body sur-
face area) of the dog (Brmel, 2006). The thyroid lobe in healthy dogs
Other Hormone Concentrations is fusiform in shape with a triangular to oval shape on the transverse
Hypothyroidism can affect the secretion of nonthyroidal hor- view (Fig. 3-15). Differences in thyroid lobe size and echogenicity
mones from other endocrine glandsmost notably the pituitary between hypothyroid and euthyroid dogs have been documented
gland. In dogs, chronic hypothyroidism induces hypersecretion of and are helpful in assessment of thyroid function (Brmel et al,
GH possibly due to transdifferentiation of somatotrophic pituitary 2005; Reese etal, 2005; Taeymans etal, 2007a; 2007b). In dogs with
cells to thyrosomatotropes (Diaz-Espieira 2008a; 2008b; 2009). hypothyroidism, the thyroid lobes tend to be round or oval in shape
Thyroid hormone deciencyinduced increase in TRH secretion on the transverse plane, are hypoechoic compared to surrounding
can stimulate prolactin secretion, resulting in hyperprolactinemia musculature, and have a smaller volume and cross-sectional area rela-
and, in intact female dogs, inappropriate lactation (Chastain and tive to body size. One study reported a diagnostic specificity of 96%
Schmidt, 1980; Cortese etal, 1997, Diaz-Espieira, 2009). for diagnosis of hypothyroidism using relative thyroid volume and
relative cross sectional area (Reese etal, 2005). Sensitivity was 98%
for diagnosis of hypothyroidism when combining evaluation of rela-
DERMATOHISTOPATHOLOGIC FINDINGS IN
tive thyroid volume and echogenicity relative to the echogenicity of
HYPOTHYROIDISM
the sternothyroid muscle (Reese etal, 2005). Changes in the thyroid
Histopathology of skin biopsies is sometimes recommended as gland progress with time, and in early hypothyroidism the thyroid
part of the diagnostic evaluation for hypothyroidism. Unfortu- lobes may appear relatively normal on ultrasound examination. It is
nately histopathology findings in the various disorders associ- also important to recognize that there is relatively high interobserver
ated with noninflammatory alopecia are often nonspecific and variability for thyroid gland measurements, and sequential studies
do not discriminate between Alopecia X, hyperadrenocorticism, should ideally be performed by the same operator.
hyperestrogenism, recurrent flank alopecia, and hypothyroidism.
Histopathologic findings common to all these disorders include Nuclear Imaging
increased kenogen (hairless) follicles, decreased anagen and cata- Thyroid scintigraphy is useful for evaluating the size, shape, and loca-
gen follicles, excessive trichilemmal keratinization, follicular atro- tion of thyroid tissue (see Chapters 4 and 5). Either technetium-99m
phy, or follicular dystrophy. The only feature that distinguished pertechnetate (99mTcO4) or iodine-123 (123I) can be used for scin-
hypothyroid biopsies from those of other noninflammatory causes tigraphy in dogs. 99m-TcO4 is concentrated but not organified by
of alopecia was a significantly thicker epidermis and dermis and the thyroid gland and is the most commonly used isotope used for
fewer atrophic follicles (Mntener et al, 2012). thyroid scintigraphy in veterinary medicine because of its low cost,
short half-life, and safety (no beta emissions). On scintigraphy, nor-
mal canine thyroid lobes appear as two uniformly dense, symmetric
RADIOGRAPHY, ULTRASONOGRAPHY,
ovals in the mid-cervical area (Fig. 3-16), although asymmetrical
AND NUCLEAR IMAGING
uptake has been reported in some euthyroid dogs, particularly Grey-
hounds (Pinilla etal, 2009). The thyroid lobes are slightly smaller
Conventional Radiography than the parotid salivary glands, which also concentrate 99mTcO4.
Conventional radiography is not a routine procedure for evalua- A 1:1 thyroid-to-salivary ratio is considered normal in the dog,
tion of acquired canine hypothyroidism. Cervical radiography is although there is some variability depending upon the time of
ineffective in determining the status of the thyroid gland except the scan in relation to radioisotope administration (Adams 1997,
when thyroid neoplasia is suspected (see Chapter 5). In congenital Taeymans etal, 2007a). Percentage thyroidal uptake of radioisotope
C
FIGURE 3-14 A and B, Lateral and ventrodorsal radiographs of the spine of a dog with congenital hypothyroidism.
Note the shortened vertebral bodies with scalloped ventral borders and only partially calcified vertebral endplates.
C, Lateral and anteroposterior radiograph of the tibia and fibula of a dog with congenital hypothyroidism, illustrat-
ing epiphyseal dysplasia and poor calcification of the bones.
can also be calculated with euthyroid dogs having a percentage dogs with nonthyroidal illness uptake ranged from 0.39% to 1.86%
uptake of approximately 1% of the administered dose. Scintigraphy with no overlap between the groups (Diaz-Espieira et al, 2007;
is regarded as one of the gold standard methods for differentiating Fig. 3-17). In another study, however, some dogs had uptake in the
between hypothyroid and euthyroid dogs. Adult dogs with primary equivocal range of 0.3% to 0.33% (Shiel etal, 2012). Thyroiditis
hypothyroidism typically have low or non-detectable accumulation may cause false positive results on scintigraphy (normal or increased
of radioisotope by the thyroid gland, and the thyroid gland may uptake in a hypothyroid dog) and increased iodine intake may cause
also appear smaller than normal (see Fig. 3-16). Similar results are a false positive (low uptake in a euthyroid dog). Glucocorticoid
found in puppies with congenital hypothyroidism caused by thy- administration may also cause suppression of thyroidal radioisotope
roid dysgenesis and dogs with secondary hypothyroidism (Greco uptake into the equivocal range (Shiel etal, 2012). Isotope uptake is
etal, 1991; Kintzer and Peterson, 1991). In contrast, puppies with typically normal or increased in dogs with hypothyroidism induced
congenital hypothyroidism caused by iodination defects have nor- by potentiated sulfonamides (Hall etal, 1993; Gookin etal, 1999).
mal to enlarged thyroid lobes and normal to increased 99mTcO4
uptake. Dogs with nonthyroidal illness should also have normal BLOOD TESTS OF THYROID GLAND FUNCTION
isotope uptake. In a study of 14 dogs with histologically confirmed
hypothyroidism and 13 dogs with nonthyroidal illness, the percent- Function of the thyroid gland is typically initially assessed by mea-
age uptake of technetium at 60 minutes in the hypothyroid dogs suring baseline serum thyroid hormone concentrations. Evaluating
ranged from 0.03% to 0.26% of the injected dose, whereas in the the responsiveness of the thyroid gland to provocative stimulation
|
A B
C D
FIGURE 3-15 Longitudinal and transverse ultrasound images of the left thyroid lobe in a healthy Golden Retriever
dog (A and B) and a Golden Retriever dog with hypothyroidism (C and D). Note the smaller size of the thyroid lobe
in the dog with hypothyroidism compared with the healthy dog. The maximum length, width, and height of the
thyroid lobe measured 24.8 mm, 7.9 mm, and 4.6 mm in the healthy dog and 20.2 mm, 4.1 mm, and 2.8 mm in
the hypothyroid dog.
(e.g., TSH stimulation test) is considered to be the gold standard protein-bound and free levels circulating in the blood, whereas fT4
for definitive diagnosis of thyroid dysfunction, but this is rarely concentration is a measure of the free hormone only.
performed in clinical practice because of the expense of recombi- Within the cell, fT4 is de-iodinated to form either T3 or rT3,
nant TSH. Baseline tests to assess thyroid gland function include depending on the metabolic demands of the tissues at that par-
measurement of T4, fT4, 3,5,3-T3, free T3 (fT3), 3,3,5-triiodo- ticular time (see Fig. 3-18). T3 is preferentially produced during
thyronine (rT3), and endogenous TSH concentration. T4 accounts normal metabolic states, whereas rT3, which is biologically inac-
for the majority of the thyroid hormone secreted by the thyroid tive, is produced during periods of illness, starvation, or excessive
gland, with only small quantities of T3 and minor amounts of rT3 endogenous catabolism. Intracellular T3 binds to nuclear recep-
released. Once secreted into the circulation, more than 99% of T4 tors and exerts its physiologic effects by activation of target genes.
is bound to plasma proteins. The unbound, or free, T4 is biologi- T3 is believed to be the primary hormone that induces physiologic
cally active, exerts negative feedback inhibition on pituitary TSH effects, because of its greater biologic activity and volume of distri-
secretion (see Fig. 3-5), and is capable of entering cells through- bution compared with T4, the preferential de-iodination of T4 to
out the body (Fig. 3-18). Protein-bound T4 acts as a reservoir and T3 within the cell, and the presence of specic intracellular recep-
buffer to maintain a steady concentration of free hormone in the tors for T3 (Yen and Brent, 2013).
plasma, despite rapid alterations in the delivery of thyroid hor- All serum T4, both protein-bound and free, comes from the
mone to tissues. Serum T4 concentrations represent the sum of the thyroid gland. Therefore tests that measure the serum total and
A B
C
FIGURE 3-16 A and B, Lateral and ventrodorsal views of a sodium pertechnetate nuclear scan performed in a
normal dog. The normal thyroid lobes appear as two uniformly dense symmetric spots in the cervical region. The
parotid salivary glands are also visible. C, Ventrodorsal view of a sodium pertechnetate nuclear scan performed in
a dog with primary hypothyroidism. Uptake of sodium pertechnetate is normal by the parotid salivary glands, which
are readily visible, but is markedly reduced by the thyroid lobes, which are barely visible.
fT4 concentrations, in conjunction with the serum TSH concen- concentration is not routinely recommended for the assessment of
tration, are currently recommended for the assessment of thyroid thyroid gland function in dogs.
gland function in dogs suspected of having hypothyroidism. In
contrast, most T3 and rT3 is formed through the deiodination Baseline Serum Total Thyroxine Concentration
of T4 in extrathyroidal sitesmost notably the liver, kidney,
and muscle. Serum T3 concentration is a poor gauge of thyroid Assay Technique
gland function because of its predominant intracellular location Baseline serum total T4 concentration is the sum of both protein-
and the minimal amount of T3 secreted by the thyroid gland bound and free hormone circulating in the blood. In the last
compared with T4. Thus measurement of serum T3, fT3, or rT3 few years, new methods for measurement of total T4 have been
|
2.0 technique must be sensitive enough to detect T4 concentrations

Primary hypothyroidism
Nonthyroidal illness
less than 1.0 g/dL to accurately differentiate hypothyroidism
from euthyroidism in dogs. For most laboratories, the serum T4
concentration in healthy dogs ranges between 1.0 and 3.5 g/dL.
1.6 The lower limit of the normal range varies between laboratories,
depending on whether the laboratory wants greater specicity or
% Uptake 99mTc (median + range)
sensitivity for the test (see Interpretation of Results later).
Chemiluminescent Immunoassays
1.2
Many reference laboratories now use chemiluminescent immuno-
assays for measurement of total T4 in dogs, and studies suggest
that these assays provide similar and consistent results compared
to RIA (Kemppainen and Birchfield, 2006). In chemiluminescent
0.8 assay systems, unlabeled hormone in the patient sample competes
for antibody sites with a known amount of thyroid hormone
labeled with an enzyme, such as alkaline phosphatase. The amount
of the labelled hormone binding to the antibody in the tube is
0.4 detected by addition of a chemiluminescent substrate rather than
a radioactive label. Sample and reagents are automatically pipetted
into the test unit, which is then incubated. Unbound material is
removed by washing, and a chemiluminescent substrate is added
to the test unit. Light emission is read with a sensitive photon
0.0
counter. These assays have the advantage of speed, automation,
0 30 60 90 120 and are much safer for laboratory personnel because radioactive
Time (min) isotopes are not utilized. Appropriate reference ranges provided by
FIGURE 3-17 Median values and ranges for thyroidal uptake of 99mTcO4- mea- laboratories should be used to interpret the results.
sured as percent uptake of injected dose, in 14 dogs with primary hypothyroid- Point-of-care enzyme-linked immunosorbent assays (ELISAs)
ism and 13 dogs with nonthyroidal illness. (From Diaz-Espieira, Assessment of for measuring serum T4 in dogs and cats are also available for in
thyroid function in dogs with low plasma thyroxine concentration, J Vet Intern Med clinic use. The advantage of an in-house test is that it is economi-
21[1]:25-32, 2007.) cal, quick, easy to perform, and it allows the clinician to make rec-
ommendations the same day the animal is evaluated. Evaluations
of an in-house ELISA (Snap T4 test kit and VetTest Snap Reader;
Blood vessel
IDEXX Laboratories Inc., Westbrooke, ME) for quantitative mea-
Free T4 (<1%) T4 plasma protein (>99%) surement of serum T4 concentration in dogs and cats have been
conflicting. In one study, substantial discrepancies between the in-
house ELISA and RIA results for T4 concentrations were detected
5D (Lurye etal, 2002). In dogs, the in-house ELISA both overesti-
Free T4 T3 mated and underestimated the serum T4 concentration compared
5D with a RIA assay. Interpretation of the ELISA results from 62%
T3 CBP of 50 samples would have led to inappropriate clinical decisions.
In cats, the in-house ELISA consistently overestimated the serum
rT3
T4 concentration obtained with RIA, and interpretation of the
ELISA results from 50% of 50 samples would have led to inap-
FIGURE 3-18 Schematic of intracellular metabolism of free T4 (fT4) to either propriate clinical decisions. In contrast, another study found good
triiodothyronine (T3) or reverse T3 (rT3) by 5- or 5-monodeiodinase, respectively. correlation between the in-house ELISA and both RIA and che-
Intracellular T3 formed from monodeiodination of fT4 can interact with T3 recep- miluminescent assays for measurement of serum T4 in feline and
tors on the cell membrane, mitochondria, or nucleus of the cell and stimulate the canine blood samples; in general total T4 concentrations measured
physiologic actions of thyroid hormone or bind to cytoplasmic binding proteins by RIA were lower than for the other two methods, emphasiz-
(CBP). The latter forms an intracellular storage pool for T3. ing that laboratory-specific reference ranges should always be uti-
lized (Kemppainen, 2006). Because a quality control system is an
important part of maintaining assay consistency, accuracy of any
developed and are increasingly replacing the use of radioimmuno- point-of-care ELISA should always be documented in an ongo-
assays (RIAs), which have been considered the gold standard for ing quality control program by comparing ELISA and RIA results
measurement of serum T4 concentration. from the same blood samples.
The reference range for serum T4 concentration varies between
laboratories because of differences in laboratory technique and the Stability and Factors Interfering with Measurement
specific commercial kit utilized. There is excellent cross-reactivity T4 is a relatively stable hormone that is resistant to degradation
for thyroid hormone between species. Most assays for measure- by contact with cells in blood, long-term storage following cen-
ment of serum thyroid hormones are manufactured for use in trifugation, hemolysis, or repeated thawing and freezing (Reimers
humans, although there are now some canine-specific commer- etal, 1991). In addition, serum may be stored in plastic tubes for
cial assays. Baseline serum T4 concentrations are lower in healthy 8 days at room temperature and for 5 days at 37 C without affect-
dogs than in humans (1.0 to 3.5 versus 4.0 to 10.0 g/dL, respec- ing the concentration of T4 (Behrend et al, 1998). This is also
tively) because of weaker protein binding in dogs, hence the RIA true for heparinized plasma and ethylenediaminetetraacetic acid
125
TH Serum laboratory should be contacted for information about assay inter-
ference by hyperlipidemia and hemolysis.
Serum TH-binding AB
Interpretation of Results
Lower tube radiation Measurement of the serum T4 concentration can be used as the
AB-coated tube initial screening test for hypothyroidism or used in a thyroid panel,
Higher serum TH which typically includes T4, fT4, TSH, and an antibody test for
Incubate and decant lymphocytic thyroiditis (Fig. 3-20). Theoretically, the interpreta-
tion of baseline serum T4 concentration should be straightfor-
AB-bound 125 TH ward; that is, dogs with hypothyroidism should have low values
compared with healthy dogs. Unfortunately, the range of serum
Scintillation counter T4 concentration overlaps between hypothyroid dogs and healthy
Serum AB-bound
125
Non-bound 125 TH
dogs, and this overlap becomes more evident in euthyroid dogs
TH
with nonthyroidal illness (Fig. 3-21). In one study, the range of
FIGURE 3-19Schematic illustration of how anti-thyroid hormone antibodies serum T4 concentration in 62 healthy dogs was 1.0 to 3.3 g/dL,
may cause spuriously increased thyroid hormone values for a radioimmunoas- and in 51 hypothyroid dogs it was from undetectable to 1.5 g/
say (RIA) using a single-step, antibody-coated tube separation system. Patient dL (Nelson et al, 1991). The amount of residual thyroid gland
serum and radiolabeled thyroid hormone (which comes with the assay) are added function at the time the sample is obtained, the suppressive effects
to a test tube coated with anti-thyroid hormone antibody. Thyroid hormone in of extraneous factors especially concurrent nonthyroidal illness
serum competes with radiolabeled thyroid hormone for antibody-binding sites in on serum thyroid hormone concentrations, and the presence of
the tube. After incubation, the liquid in the tube is decanted, the radioactivity of circulating anti-thyroid hormone antibodies all affect the sen-
the tube is measured in a scintillation counter, and the serum thyroid hormone sitivity and specicity of serum T4 concentration in diagnosing
concentration is determined based on the tube radioactivity. An inverse relation- hypothyroidism.
ship exists between tube radioactivity and serum thyroid hormone concentration. These overlap between euthyroidism and hypothyroidism cre-
If anti-thyroid hormone binding antibodies are present in the patients serum, ates a dilemma when a laboratory tries to establish its normal
these antibodies compete with the antibodies attached to the tube for serum range for serum T4 concentration. If the laboratory keeps the
thyroid hormone and radiolabeled thyroid hormone. Because serum thyroid hor- lower limit of the normal serum T4 range high (e.g., 1.5 g/dL),
mone antibodies are not attached to the tube, they are decanted along with any sensitivity of the test is sacriced for specicity. That is, the num-
radiolabeled thyroid hormone that has bound to them. This causes a falsely low ber of hypothyroid dogs misdiagnosed as euthyroid is minimized,
radioactivity of the tube and a corresponding spuriously high serum thyroid hor- but the number of euthyroid dogs misdiagnosed as hypothyroid
mone value. AB, Antibody; TH, thyroid hormone. is increased, leading to inappropriate thyroid replacement treat-
ment of euthyroid dogs. Alternatively, by decreasing the lower
limit of the normal serum T4 range (e.g., 0.8 g/dL), specicity is
sacriced for sensitivity. The number of euthyroid dogs misdiag-
(EDTA) plasma samples; however, storage of serum or plasma at nosed as hypothyroid is minimized, but the number of hypothy-
37 C in glass can cause a signicant increase in serum T4 concen- roid dogs misdiagnosed as euthyroid increases.
tration, compared with storage at 20 C (Behrend etal, 1998). The reference range for serum T4 concentration also varies
Because of potential for environmental extremes during shipping, between breeds. The reference range is usually established based
whenever possible, blood samples should be centrifuged, serum on the mean two standard deviations calculated from results of
should be decanted into plastic tubes, frozen, and sent to the labo- serum T4 measured in a large population of dogs without regard
ratory on cold packs. for breed. The reference range for serum T4 and fT4 measured
Many physiologic and pharmacologic factors influence the by modied equilibrium dialysis (MED) is now recognized to be
pituitary-thyroid axis and interfere with the accuracy of base- lower in some breedsmost notably Sighthounds (Gaughan and
line serum T4 concentration for differentiating hypothyroidism Bruyette, 2001; Shiel etal, 2007a; Table 3-5). These ndings sug-
from euthyroidism (see Factors Affecting Thyroid Gland Func- gest that breed-specic reference range values for thyroid hormone
tion Tests). However, the only factor that directly interferes with tests should be established and used when evaluating thyroid
the ability of an assay to measure T4 is the presence of anti-T4 gland function. Until such information is established, interpreta-
antibodies in the serum sample. Anti-thyroid hormone antibod- tion of thyroid hormone test results in such breeds will continue
ies occur in dogs with lymphocytic thyroiditis and are present in to be challenging.
approximately 2% of dogs with clinical signs of hypothyroidism The use of an arbitrary serum T4 value to separate euthyroidism
and 15% of hypothyroid dogs (Nachreiner etal, 2002; Graham from hypothyroidism is not recommended. Rather, the serum T4
et al, 2007). Anti-T4 antibodies may cause spuriously increased result should be evaluated in the context of the history, physical
or decreased serum T4 values (Thacker etal, 1992). The effect of examination ndings, and other clinicopathologic data (Tables
anti-thyroid hormone antibodies on the serum T4 value depends 3-6 and 3-7; see Fig. 3-20). All of this information yields an index
on the type of assay being used by the laboratory, but in most of suspicion for euthyroidism or hypothyroidism. For the clini-
currently utilized commercial assays, anti-T4 antibodies cause a cian, it is difcult to judge the influence of extraneous factors,
spurious increase in the measured T4 concentration (Fig. 3-19). especially concurrent illness, on the serum T4 concentration.
Although antibody interference can potentially lead to a falsely Although nonthyroidal illness can suppress the baseline serum T4
increased T4 concentration, the probability of antibody interfer- concentration to less than 0.5 g/dL in a euthyroid dog, hypo-
ence resulting in a falsely normal T4 concentration appears to be thyroid dogs rarely have serum T4 concentrations greater than 1.5
quite low (Piechotta etal, 2010). Hyperlipidemia and hemolysis g/dL, so the baseline serum T4 concentration is best used to rule
do not affect measurement of T4 in serum by RIA (Lee etal, 1991; out hypothyroidism. The higher the T4 concentration, the more
Reimers et al, 1991); for other assay methods, the individual likely the dog is euthyroid. The one exception is the hypothyroid
|
Diagnostic protocol for

cases of suspected
hypothyroidism
Measure:
Total thyroxine (T4)
Complete blood count
Chemistry profile
Low T4 Low T4 Borderline T4 Normal T4

No evidence of Evidence of Elevated cholesterol
nonthyroidal illness nonthyroidal illness Mild anemia
Not hypothyroid
Treat underlying disease
Repeat T4 in 4 weeks
Repeat T4 after
nonthyroidal symptoms
subside
Low or borderline T4 Normal
Low or borderline T4 Normal

Choose one of the following: Not hypothyroid
Canine thyroid-stimulating
hormone (cTSH) and free
T4 by equilibrium dialysis Choose one of the following: Not hypothyroid
Thyroid-stimulating hormone cTSH and free T4 by
(TSH) stimulation test equilibrium dialysis
Clinical trial TSH stimulation test
Clinical trial
High cTSH and low free T4 Normal cTSH and free

Inadequate response to TSH T4 levels
Response to T4 replacement Normal TSH response test
therapy and relapse with No response to T4
discontinuation replacement therapy
Hypothyroid Not hypothyroid

(all tests can be affected by
nonthyroidal illness)
High cTSH and low free T4 Normal cTSH and free

Inadequate response to TSH T4 levels
Response to T4 replacement Normal TSH response test
therapy and relapse with No response to T4
discontinuation replacement therapy
Hypothyroid Not hypothyroid

(all tests can be affected by
nonthyroidal illness)
FIGURE 3-20 Algorithm for diagnosis of canine hypothyroidism. (From EttingerSJ, Feldman EC, editors: Textbook of
veterinary internal medicine, ed 7, St Louis, 2010, Elsevier, p. 1756.)
dog with circulating anti-thyroid hormone antibodies (see Fig. T4 concentration is low, other factors such as nonthyroidal illness
3-19). Conversely, the lower the T4 value, the more likely the dog should be strongly considered.
has hypothyroidism, assuming the history, physical examination
ndings, and clinicopathologic data are also consistent with the Interpretation: Concurrent Thyroid Hormone Supplementation
disease and severe systemic illness is not present. If the clinicians Occasionally, a clinician wants to determine whether a dog
index of suspicion is not high for hypothyroidism but the serum receiving thyroid supplementation is, in fact, hypothyroid. The
exogenous administration of thyroid hormone, either T4 or T3, general rule, thyroid hormone supplements should be discontin-
will suppress pituitary TSH secretion and cause pituitary thy- ued a minimum of 4 weeks and preferably 6 to 8 weeks before
rotroph atrophy, and subsequently thyroid gland atrophy in a critically assessing thyroid gland function.
healthy euthyroid dog (Panciera et al, 1990). Immediately after
withdrawal of exogenous supplementation, serum T4, and fT4, Baseline Serum Total Triiodothyronine Concentration
may be decreased or undetectable; the severity of the decrease is
dependent on the severity of thyroid gland atrophy induced by Assay Technique
the thyroid hormone supplement. Basal serum T4 and response Serum total T3 concentrations are the sum of the protein-bound
to TRH and TSH results may be suggestive of hypothyroidism, and free levels circulating in the blood. Almost all commercial lab-
in a previously euthyroid dog, if the testing is performed within a oratories currently use either RIA or chemiluminescent techniques
month of discontinuing treatment (Panciera, 2002). Thyroid hor- for measuring T3 concentrations in the blood. Most human RIAs
mone supplementation must be discontinued, and the pituitaryfor T3 are suitable for use in the dog, because blood concentra-
thyroid axis must be allowed to recover function before meaningful tions are similar for both species. Using the RIA technique, an
results of baseline serum T4, fT4, and TSH concentrations can be approximate normal range for blood T3 concentrations is 0.8 to
obtained. The time interval between the discontinuation of thy- 2.1 nmol/Lalthough the exact range varies from laboratory to
roid hormone supplementation and the acquisition of meaningful laboratory because of differences in assays used and laboratory
results regarding thyroid gland function depends on the duration technique.
of treatment, the dosage and frequency of administration of the
thyroid hormone supplement, and individual variability. As a Stability and Factors Interfering with Measurement
Stability of serum T3 and factors interfering with its measurement
are as described for serum T4. In dogs with suspected hypothy-
roidism, the incidence of anti-T3 antibodies is greater than that of
8
anti-T4 antibodies (6% of dogs with suspected hypothyroidism)
7
(Nachreiner etal, 2002).
Interpretation of Results
6
Total thyroxine (g/dL)
Measurement of baseline serum T3 concentration is of minimal

5 value in differentiating euthyroidism from hypothyroidism in the
dog (Fig. 3-22). Essentially no difference exists in the mean or
4 range of serum T3 concentration between groups of healthy dogs,
dogs with hypothyroidism, and euthyroid dogs with concurrent
3 illness (Nelson etal, 1991; Miller etal, 1992). The majority of cir-
culating T3 is produced from deiodination of T4 at extra thyroidal
2
sites, and thyroidal secretion of T3 and peripheral tissue 5-deiodin-
1
ation of T4 to T3 may increase with mild thyroid gland dysfunction
(Utiger, 1980; Lum etal, 1984). In addition, the high proportion
0 of anti-T3 antibodies in hypothyroid dogs contributes to the poor
Healthy Euthyroid with Hypothyroid diagnostic performance of T3. When anti-T3 positive dogs were
concurrent disease excluded, the diagnostic performance of T3 was similar to that of
FIGURE 3-21 Serum total T4 concentrations in healthy dogs, hypothyroid dogs, T4 (Graham etal, 2007). Although serum T3 is included as part of
and euthyroid dogs with concurrent disease before and after administration of the canine thyroid panel run by some commercial diagnostic labo-
thyroid-stimulating hormone (TSH). (From Scott-Moncrieff J, Nelson RW: Change ratories, it has limited diagnostic value. Measurement of T3 may be
in serum thyroid-stimulating hormone concentration in response to administration justified in Greyhounds who tend to have low concentrations of
of thyrotropin-releasing hormone to healthy dogs, hypothyroid dogs, and euthyroid T4 and fT4 but T3 concentrations within the laboratory reference
dogs with concurrent disease, J Am Vet Med Assoc 213[10]:1435-1438, 1998.) range (Shiel etal, 2007a; Pinilla etal, 2009; see Table 3-5).
TABLE 3-5 CANINE BREEDS WITH UNIQUE THYROID HORMONE REFERENCE RANGES
TOTAL THYROXINE FREE THYROXINE THYROXINE RESPONSE

BREED ( OR N) ( OR N) TOTAL TRIIODOTHYRONINE ( OR N) THYROTROPIN ( OR N) TO TSH
Greyhound Usually N N Decreased
Whippet N N
Saluki N or
Sloughi or (ED) Normal to slightly
decreased
Basenji N
Irish Wolfhound
Conditioned Alaskan Variable
sled dogs
|
1.6
Baseline Serum Free Thyroxine Concentration
Although the gold standard technique for measurement of fT4 is
equilibrium dialysis, this technique is expensive and time consum-
ing and is only performed in research laboratories. In commercial
laboratories, canine serum fT4 is measured by one of three meth-
ods: modified equilibrium dialysis (MED), analog RIA, or analog 1.2
Serum T3 concentration (ng/mL)

chemiluminescent assay. In MED assays, a short dialysis step is
used to separate free from protein-bound T4 followed by radioim-
munoassay for fT4. Analog methods measure fT4 directly by RIA
or chemiluminescence, but the reagents are optimized for human
serum and depend upon the dominance of hormone binding by
0.8
TBG (Ferguson, 2007). MED techniques are regarded as the most
accurate commercially-available technique for determining serum
fT4 concentrations in dogs. In one study, the accuracy of one MED
technique for fT4 was 95% (Fig. 3-23) (Peterson etal, 1997). In
0.4
TABLE 3-6 INTERPRETATION OF BASAL
THYROID HORMONE AND
THYROTROPIN CONCENTRATIONS*
DECREASED OR BORDER-
NORMAL THYROXINE/FREE LINE NORMAL THYROXINE/ 0
THYROXINE FREE THYROXINE
Healthy Hypothyroid Euthyroid dogs
Normal Normal dog Hypothyroid, normal varia- dogs dogs with dermatopathy
TSH tion, or concurrent illness
FIGURE 3-22 Baseline serum T3 concentrations in 35 healthy dogs, 35 dogs with
Consider further thyroid testing Consider further diagnostic hypothyroidism, and 30 euthyroid dogs with concurrent dermatopathy. Note the
only if strong clinical suspi- evaluation of thyroid overlap in serum T3 results between the three groups of dogs.
cion of hypothyroidism function (e.g., thyroid au-
toantibodies, provocative
testing) or therapeutic trial
Increased Early subclinical hypothy- Hypothyroid 50
TSH roidism or recovery from
concurrent illness
Consider reevaluation of thyroid Lifelong therapy with L-T4 40
function in 1 to 3 months; if sodium is indicated; use
strong clinical suspicion for therapeutic monitoring to
Serum free T4 (pmol/L)
hypothyroidism, evaluate for adjust dose

thyroiditis by measuring ATAs 30
ATA, Anti-thyroglobulin antibody; L-T4, levothyroxine, or L-thyroxine; T4, thyroxine;

TSH, thyroid-stimulating hormone, or thyrotropin.
*T4, free T4, TSH. 20
TABLE 3-7 INTERPRETATION OF BASELINE

10
SERUM THYROXINE AND FREE
THYROXINE CONCENTRATION
IN DOGS WITH SUSPECTED
HYPOTHYROIDISM 0
Clinically normal Hypothyroid Euthyroid
SERUM THYROXINE SERUM FREE THYROXINE PROBABILITY OF FIGURE 3-23 Box plots of serum free T4 (fT4) concentrations in 150 clinically
CONCENTRATION (g/dL) CONCENTRATION (ng/dL) HYPOTHYROIDISM normal dogs, 54 hypothyroid dogs, and 54 euthyroid dogs with nonthyroidal dis-
> 2.0 g/dL > 2.0 ng/dL Very unlikely ease. The box represents the interquartile range (i.e., 25th to 75th percentile
range, or the middle half of the data). The horizontal bar in the box represents
1.5 to 2.0 g/dL 1.5 to 2.0 ng/dL Unlikely
the median value. For each box plot, the T bars represent the main body of data.
1.0 to 1.5 g/dL 0.8 to 1.5 ng/dL Unknown Outlying data points are represented by open circles. The shaded area indicates
0.5 to 1.0 g/dL 0.5 to 0.8 ng/dL Possible the reference range for the serum free T4 concentration. (From Peterson etal.:
< 0.5 g/dL < 0.5 ng/dL Very likely* Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thy-
rotropin concentrations for diagnosis of hypothyroidism in dogs, J Am Vet Med
*Assuming that a severe systemic illness is not present. Assoc 211[11]:1398, 1997.)
40 7
TABLE 3-8 S
ENSITIVITY, SPECIFICITY AND
ACCURACY OF FOUR FREE
6
THYROXINE ASSAYS IN DOGS*
30
Serum cTSH (ng/mL)

5
Serum T4 (ng/mL)
ASSAY SENSITIVITY (%) SPECIFICITY (%) ACCURACY (%)
Analog free T4 80 97 89 4
20
MED IVD 92 90 91 3
MED AN 71 100 86
2
Two-step 96 90 93 10
1
T4, Thyroxine.
*The dog population included 56 dogs with clinical signs of hypothyroidism (31 euthyroid,
0 0
25 hypothyroid). Assays included the IMMULITE 2000 Veterinary Free T4 (Analog free T4) 0 7 14 21 28 35 42 49 56 63 70 77
(Siemens Health Care Diagnostics), Direct Free T4 by Equilibrium Dialysis (MED IVD) (IVD Time (days)
technologies), free T4 by equilibrium dialysis (MED AN) (Antech Diagnostics), and Gam-
maCoat Free T4 (Two-step) radioimmunoassay (RIA) (Diasorin Inc). FIGURE 3-24 Mean serum thyroxine (T4; ) and canine thyroid-stimulating hor-
mone (cTSH; ) concentrations after experimental induction of hypothyroidism (day
0) and treatment with levothyroxine (L-T4 sodium; beginning on day 42). Bars rep-
resent SD. *Significantly (P < 0.05) different from day 0 values. (From Williams DA,
more recent studies, reported accuracy of different MED assays has etal.: Validation of an immunoassay for canine thyroid-stimulating hormone and
ranged from 86% to 93%, compared with an accuracy of 75% to changes in serum concentration following induction of hypothyroidism in dogs,
85% for serum T4 (Nelson etal, 1991; Scott-Moncrieff etal, 1994; J Am Vet Med Assoc 209[10]:1730, 1996.)
2011; Peterson etal, 1997). It is important to use a fT4 assay that
has been demonstrated to have adequate diagnostic performance in
dogs, because some human analog assays for fT4 have accuracy that can be measured by specic RIAs that do not cross-react with T4
is no better than measurement of total T4 in dogs (Schachter, 2004), or T3. The clinical benet of measuring rT3 has not yet been dem-
whereas others compare favorably to the MED methods (Table 3-8) onstrated in dogs, and the assay has limited availability.
(Scott-Moncrieff etal, 2011). Serum for measurement of fT4 can be
stored in plastic tubes and shipped without cooling if assayed within Baseline Serum Thyrotropin Concentration
5 days (Behrend etal, 1998); however, because of the potential for
extremes of temperature during transportation, it is recommended TSH is a highly glycosylated molecule with an alpha and beta
that serum samples are frozen and shipped to the laboratory on ice subunit. The alpha subunit is identical to that of the alpha sub-
packs. In general, serum fT4 concentrations greater than 1.5 ng/ unit of the related glycoprotein hormones LH, FSH, and chori-
dL are consistent with euthyroidism, and values less than 0.8 ng/ onic gonadotrophin, whereas the beta subunit is unique to TSH
dL (especially those less than 0.5 ng/dL) are suggestive of hypo- and confers the biologic properties of TSH. Assays for measure-
thyroidism, assuming that the history, physical examination, and ment of human TSH cannot be used to measure canine TSH.
clinicopathologic abnormalities are also consistent with the disorder The first assay for canine TSH was validated in 1996 (Williams
and severe systemic illness is not present (see Table 3-7). Circulating etal, 1996), and since that time there have been other commercial
anti-thyroid hormone antibodies do not affect the fT4 results deter- assays developed. Studies in dogs with 131I-induced hypothyroid-
mined by the MED technique but may still influence fT4 measured ism have shown good assay performance with a 35-fold increase
by analog methods. Serum fT4 is less affected by the suppressive in the mean serum TSH concentration after induction of hypo-
effects of nonthyroidal illness than is the serum T4, although severe thyroidism and return of the mean serum TSH concentration
illness can cause fT4 concentrations to decrease below 0.5 ng/dL; see to baseline after treatment with L-T4 sodium (Fig. 3-24) (Wil-
Concurrent Illness (Nonthyroidal Illness Syndrome). The reference liams etal, 1996). The assay used most commonly is the chemi-
range for serum fT4 concentration is also lower in some breeds, such luminescent TSH assay (Immulite Canine TSH), which has been
as the Greyhound (see Table 3-5) (Shiel etal, 2007a). demonstrated to have the highest precision compared to immu-
noradiometric and enzyme immunometric methods (Marca etal,
2001). Unfortunately all current commercial assays for canine
Baseline Serum Free Triiodothyronine Concentration
TSH have poor sensitivity for diagnosis of spontaneous hypothy-
Serum fT3 is derived from intracellular 5-deiodination of fT4 in roidism. Twenty percent to 40% of dogs with hypothyroidism
peripheral tissues and, to a lesser extent, in the thyroid gland. The have TSH concentrations within the reference range, giving a test
theoretical principle behind measuring serum fT3 is similar to that sensitivity of only 63% to 82% (Fig. 3-25). Although TSH as
for fT4. RIAs designed for measurement of serum fT3 in humans a stand-alone test also has poor specificity because of overlap in
have been used in the dog. A critical assessment of the sensitivity results between hypothyroid dogs and euthyroid dogs with con-
and specicity of these RIAs has not been reported in dogs, nor current illness (see Fig. 3-25), clinical studies have shown that
has the diagnostic usefulness of measuring serum fT3 for evaluat- a high serum TSH concentration has high specicity (90% or
ing thyroid gland function been demonstrated. higher) for diagnosis of hypothyroidism in dogs when the baseline
serum T4 or fT4 concentration is concurrently low (Dixon etal,
1996; Ramsey etal, 1997; Peterson etal, 1997; Scott-Moncrieff
Baseline Serum Reverse Triiodothyronine Concentration
etal, 1998).
rT3 is a relatively inactive product of T4 5-deiodination (see Fig. The reason for the low sensitivity of TSH concentration for diag-
3-4). The vast majority of rT3 is produced intracellularly from T4; nosis of canine hypothyroidism has been the subject of investiga-
very little is secreted by the thyroid gland. Serum rT3 concentration tion, because TSH is a highly sensitive diagnostic test in humans.
|
2.5 the diagnosis of primary hypothyroidism, whereas a nding of

normal serum T4, fT4, and TSH concentrations rules out hypo-
Canine thyrotropin concentration (ng/mL)
thyroidism. Any other combination of serum T4, fT4, and TSH

2.0 results is difcult to interpret (see Table 3-6).
1.5 Thyrotropin Stimulation Test

The TSH stimulation test evaluates the thyroid glands responsiveness
to exogenous TSH administration and is a test of thyroid gland
1.0
reserve. The TSH stimulation test is indicated in dogs with low
basal thyroid hormone concentrations to differentiate hypothy-
0.5 roidism from nonthyroidal illness syndrome (NTIS). The biologic
activity of the TSH molecule is not species-specic so human
recombinant TSH can be used for the test; however, this product
0.0 is extremely expensive and is only available in a vial containing 1.1
Healthy Euthyroid with Hypothyroid mg of lyophilized recombinant TSH synthesized in a genetically
concurrent disease modified Chinese hamster ovary cell line. TSH (Thyrogen; Gen-
FIGURE 3-25 Canine thyroid-stimulating hormone (thyrotropin [TSH]) concen- zyme Corporation, Cambridge, ME) is reconstituted in 1.2 mL of
trations in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent sterile water for injection (final solution 0.9 mg/mL). This is suf-
disease. (From Scott-Moncrieff JC, etal.: Comparison of serum concentrations ficient TSH for 7 to 15 stimulation tests depending upon the dose
of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid used. Recombinant TSH can be reconstituted and stored at 4 C
dogs with concurrent disease, J Am Vet Med Assoc 212[3]:389, 1998.) for 4 weeks or frozen at 20 C for up to 12 weeks (De Roover
etal, 2006; Daminet etal, 2007).
The protocol for the TSH stimulation test requires collection
Studies in dogs with 131I-induced hypothyroidism demonstrated of a serum sample for measurement of T4, followed by adminis-
that over several months time there was a loss of the TSH response tration of 75 to 150 g of TSH intravenous (IV). An additional
to the low T4 concentration, hypersecretion of GH, hyposecretion blood sample for measurement of total T4 is collected 6 hours later
of prolactin, and pituitary enlargement (Fig. 3-26). The enlarged (Boretti etal, 2006a; 2006b; De Roover etal, 2006). The higher
pituitary glands were characterized by thyrotroph hyperplasia, dose of TSH is recommended in dogs with concurrent disease and
presence of large pale staining vacuolated thyroid deficiency cells those receiving medication (e.g., glucocorticoids) that might sup-
similar to those observed in hypothyroid rats and humans, and press thyroid function (Boretti et al, 2009). Hypothyroidism is
double staining cells indicative of transdifferentiation of somato- confirmed by a pre and post total T4 concentration below the ref-
trophs into thyrotrophs. The presence of mitoses in the thyrotrophs erence range for basal total T4 concentration (< 1.5 g/dL). Euthy-
suggested that the division of pre-existing thyrotrophs or less dif- roidism is confirmed by a post total T4 concentration > 2.5 g/dL
ferentiated stem cells contributed to the thyroid deficiency cells. and at least 1.5 times the basal T4 concentration (see Fig. 3-21).
It was hypothesized by the study authors that persistent stimu- Serum fT4 concentrations increase in a manner similar to serum
lation of thyrotrophs via negative feedback led to TRH-receptor total T4, do not provide additional diagnostic information, and
desensitization and gradual loss of TSH secretion (Diaz-Espieira, therefore are not routinely measured in the TSH stimulation test.
2008b). Similar changes were demonstrated in dogs with spon- Although the TSH stimulation is more accurate for assessment
taneous chronic hypothyroidism, and this is likely the reason for of thyroid function than measurement of basal thyroid hormone
the poor sensitivity of the TSH assay in naturally occurring hypo- concentrations, false positive results can occur. In a study of 30
thyroidism (Diaz-Espieira, 2009). Other possible reasons that dogs in which the diagnosis of thyroid status was confirmed his-
hypothyroid dogs might have serum TSH concentrations within topathologically, some euthyroid dogs failed to respond to bovine
the reference range include pulsatile TSH secretion, resulting in TSH administration, and nuclear imaging had higher discrimina-
ultradian fluctuations (Fig. 3-27), secondary hypothyroidism, sup- tory power for diagnosis of true thyroid status than TSH stimula-
pression of pituitary TSH secretion by concurrent disease or drug tion testing (Diaz-Espieira et al, 2007). Stimulation results that
administration, and inability of the current TSH assay to detect all fall in the intermediate range may also lead to interpretation dif-
isoforms of circulating TSH (Kooistra etal, 2000b). Sample col- ficulties especially in dogs with nonthyroidal illness. Interpreta-
lection time does not appear to predictably influence serum TSH tion of the results of the TSH stimulation test should take into
test results (Bruner etal, 1998; see Fig. 3-27). The lower limit of consideration the clinical signs and severity of concurrent systemic
the reference range in dogs is currently below the sensitivity of the disease, results of other thyroid testing (total T4, fT4, TSH, ATA
TSH assay, so it is not possible to differentiate low from normal concentration), and results of nuclear scintigraphy if available.
serum TSH concentrations, which impairs the ability to identify
secondary hypothyroidism, suppression of pituitary TSH secre- Thyrotropin-Releasing Hormone Stimulation Test
tion by concurrent drugs and diseases, and excess administration
of L-T4 sodium during treatment of hypothyroidism. Indications
Because of the limitations discussed earlier, the serum TSH con- The TRH stimulation test evaluates the pituitary glands respon-
centration should always be interpreted in conjunction with the siveness to TRH and the thyroid glands responsiveness to TSH
serum T4 or fT4 concentration measured in the same blood sam- secreted in response to TRH administration. In humans, the TRH
ple and should never be used as the sole test for assessing thyroid stimulation test is used to differentiate secondary and tertiary
gland function. A low serum T4 or fT4 concentration and a high hypothyroidism. TRH response tests are not routinely performed
TSH concentration in a blood sample obtained from a dog with for evaluation of humans with suspected primary hypothyroidism;
appropriate history and physical examination ndings supports however, there is a greater and more prolonged increase in TSH
6 8
* *
*
5 *
* *
6
4 *
* *
TSH g/L
GH g/L
* * * *
3 * 4 *
** *
2 * *
* * *
* 2
* **
1
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Time (years) Time (years)
6 30
5 25
*
4 20 *
*
PRL g/L
LH g/L
3 * 15
*
* ** * * *
2 * 10
* *
1 * * 5
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Time (years) Time (years)
140
120 *
100
ACTH ng/L
80
60
40
20
*
0
0 1 2 3 4 5
Time (years)
FIGURE 3-26 Mean basal plasma concentrations of thyrotropin (TSH), growth hormone (GH), prolactin (PRL), lutein-
izing hormone (LH), and adrenocorticotropic hormone (ACTH) measured at monthly intervals in seven Beagle dogs with
hypothyroidism induced at time 0. Three of these dogs were followed up for another 1 years while on levothyroxine
(L-thyroxine; L-T4) sodium supplementation (arrow). (From Diaz-Espieira MM, etal.: Functional and morphological
changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hyper-
somatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation, Domest Anim Endocrinol
35[1]:98-111, 2008.)
concentration after TRH administration in humans with primary differentiate between hypothyroidism and the NTIS in dogs with
hypothyroidism than in healthy humans. In contrast, dogs with low basal thyroid hormone concentrations; however the test can
primary hypothyroidism have a lower change in TSH concen- be difcult to interpret because of the relatively small increase in
tration after TRH administration than do healthy dogs (Scott- serum T4 concentration after TRH administration, and the test
Moncrieff etal, 1998). This finding has been attributed to TRH has little advantage for diagnosis of hypothyroidism over measure-
receptor desensitization due to persistent stimulation of the pitu- ment of baseline TSH and total or free T4 concentration. The pri-
itary thyrotrophs by the negative feedback loop (Diaz-Espieira, mary current use of the TRH stimulation test is to assess anterior
2008b). In dogs, the TRH stimulation test has been used to pituitary function as part of a combined pituitary function test.
|
1.2 5.0
1.1
Thyrotropin concentration (ng/mL)
4.5
1.0
4.0
0.9
Total thyroxine (g/dL)

0.8 3.5
0.7 3.0
0.6
2.5
0.5
2.0
0.4
0.3 1.5
0.2 1.0
0.1
0.5
0.0
0.0
8 AM 10 AM 12 PM 2 PM 4 PM 6 PM 8 PM Healthy Euthyroid with Hypothyroid
concurrent disease
Time
A Groups of dogs
FIGURE 3-27 Serum thyrotropin (TSH) concentrations measured at 2-hour inter-
vals from 8 am to 8 pm in six dogs with naturally developing hypothyroidism. Refer-
5
ence range is between the horizontal dotted lines. Each symbol represents values
obtained for one hypothyroid dog. (From Bruner JM, etal.: Effect of time of sample
collection on serum thyroid-stimulating hormone concentrations in euthyroid and
hypothyroid dogs, J Am Vet Med Assoc 212[10]:1572, 1998.) 4
Protocol cTSH concentration (ng/mL) 3

TRH is administered at a dose of 10 g/kg or 200 g/dog IV; blood
for serum total T4 determination is obtained before and 4 hours
after TRH administration, and blood for serum TSH determina- 2
tion is obtained before and 30 minutes after TRH administration
(Scott-Moncrieff and Nelson, 1998). Measurement of serum TSH
concentration after TRH administration is used to assess pituitary 1
responsiveness to TRH, whereas measurement of serum T4 con-
centration is used to assess the thyroid glands responsiveness to
the TRH-induced increase in pituitary TSH secretion. Serum fT4
0
concentrations increase in a manner similar to serum T4, do not Healthy Euthyroid with Hypothyroid
provide additional diagnostic information, and therefore are not concurrent disease
routinely measured. B Groups of dogs
FIGURE 3-28 Thyroxine (T4) concentration (A) and thyrotropin (TSH) concentration
Interpretation (B) before (solid symbol) and 30 minutes (for TSH) and 4 hours (for T4) after (open
The increase in serum total T4 concentration is less dramatic with symbols) administration of TRH to healthy dogs, hypothyroid dogs, and euthyroid
TRH than with TSH (Frank, 1996). Euthyroid dogs should have dogs with concurrent diseases. The horizontal line represents the upper limit of the
a post-TRH serum T4 concentration greater than 1.5 to 2.0 g/dL reference range for T4 (A) and TSH (B). (From Scott-Moncrieff JC, Nelson RW: Change
(Scott-Moncrieff et al, 1998). In contrast, dogs with primary hypo- in serum thyroid-stimulating hormone concentration in response to administration
thyroidism have a post-TRH serum T4 concentration below the nor- of thyrotropin-releasing hormone to healthy dogs, hypothyroid dogs, and euthyroid
mal baseline serum T4 range (i.e., < 1.5 g/dL) (Fig. 3-28), but there is dogs with concurrent disease, J Am Vet Med Assoc 213[10]:1435, 1998.)
substantial overlap between the groups, and some euthyroid dogs fail
to have any increase in T4 after TRH administration. Because of these
findings, there is currently little indication for the use of the TRH ATAs and therefore dogs with thyroid hormone autoantibodies
stimulation test in the evaluation of dogs with suspected hypothyroid- also have autoantibodies against Tg, whereas the converse is not
ism. TRH is not currently commercially available in the United States. true (Graham et al, 2007). Thus the Tg autoantibody test is a
more sensitive test for lymphocytic thyroiditis than is measure-
TESTS FOR LYMPHOCYTIC THYROIDITIS ment of anti-T3 and anti-T4 antibodies. Anti-TPO antibodies are
the most common antibodies detected in human thyroiditis, but
During the inflammatory phase of lymphocytic thyroiditis, anti- they are only detected in 17% of dogs with thyroiditis and are not
bodies are released into the circulation. In dogs, the predominant detected in dogs that lack ATAs (Skopek etal, 2006). Assays for
antibody that arises is directed against Tg. Tg is a large complex anti-TPO antibodies, therefore, have little clinical utility and are
protein molecule with several epitopes and antibodies formed not currently commercially available.
against it are heterogenous. The thyroid hormones T3 and T4 are
haptens and do not elicit an antibody response unless attached to
Serum Thyroglobulin Autoantibodies
a larger protein molecule (Gaschen etal, 1993). When an epit-
ope contains a hormonogenic site, antibodies that cross-react with Circulating Tg autoantibodies are detected in approximately 50%
either T3 or T4 may develop. These antibodies are a subset of total of hypothyroid dogs (Nachreiner etal, 1998; Graham etal, 2007).
A commercially available ELISA (Oxford Biomedical Research Inc., hypothyroidism in dogs with consistent clinical findings and equiv-
Oxford, MI) for detection of Tg autoantibodies has been shown ocal basal thyroid hormone concentrations. Dogs with conrmed
to be sensitive and specic for identication of Tg autoantibodies hypothyroidism can have negative Tg autoantibody concentrations,
(Nachreiner etal, 1998). This ELISA is currently the most common and euthyroid dogs can be positive for Tg autoantibodies. The value
Tg autoantibody assay used by commercial laboratories and results of serum Tg autoantibodies as a marker for eventual development
are expressed as a percentage of a standardized positive control. Non- of hypothyroidism remains to be claried. A 1 year longitudinal
specific binding ELISA plates that do not contain Tg are included study of 171 dogs with positive Tg autoantibody and normal serum
to reduce the effect of nonspecific immunoglobulin G (IgG). Some fT4 and TSH test results, found that approximately 20% of dogs
of the initial concern about borderline positive results after vaccina- developed decreased fT4 and/or increased TSH concentrations con-
tion may have been related to nonspecific antibody binding. sistent with hypothyroidism during the 1 year of follow-up. Fifteen
Presence of serum Tg autoantibodies implies the presence of thy- percent of dogs reverted to negative Tg autoantibody status with
roiditis within the thyroid gland but provides no information on no change in fT4 and TSH concentrations, and 65% remained Tg
the severity or progressive nature of the inflammatory response or autoantibody positive or had an inconclusive result with no change
the function of the thyroid gland. Detection of Tg autoantibod- in fT4 and TSH test results (Graham etal, 2001).
ies should not be used as the sole criteria to establish the diagno- The prevalence of Tg autoantibodies varies with the breed (Table
sis of hypothyroidism but can increase the index of suspicion for 3-2). Measurement of Tg autoantibodies has been advocated for
TABLE 3-9 O
DDS OF HAVING SERUM THYROID HORMONE AUTOANTIBODIES (THAA) AMONG BREEDS
WITH AN INCREASED RISK OF THAA COMPARED WITH DOGS OF ALL OTHER BREEDS
Percentage with Autoantibodies

TRIIODOTHYRONINE THYROXINE
BREED NUMBER OF DOGS AUTOANTIBODIES AUTOANTIBODIES BOTH TOTAL ODDS RATIO P VALUE
Pointer 118 11.86 0.85 6.78 19.49 3.61 0.001
English Setter 1,246 13.88 1.2 3.53 18.61 3.44 0.001
English Pointer 99 14.14 2.02 2.02 18.18 3.31 0.001
Skye Terrier 53 13.21 1.89 1.89 16.99 3.04 0.001
German Wirehaired Pointer 324 11.42 1.54 2.47 15.43 2.72 0.001
Old English Sheepdog 1,031 10.96 0.87 3.20 15.03 2.65 0.001
Boxer 5,239 9.14 0.88 3.47 13.49 2.37 0.001
Maltese 962 9.56 0.94 2.60 13.10 2.25 0.001
Kuvasz 180 10.56 2.22 0.00 12.78 2.18 0.001
Petit Basset Griffon Vendeen 63 6.35 3.17 3.17 12.69 2.16 0.036
American Staffordshire Terrier 246 8.54 1.22 1.22 10.98 1.84 0.003
Beagle 3,988 7.70 0.80 2.16 10.66 1.79 0.001
American Pit Bull Terrier 676 9.02 0.44 1.18 10.64 1.78 0.001
Dalmatian 2,332 6.82 1.07 2.53 10.42 1.74 0.001
Giant Schnauzer 406 8.37 0.74 1.23 10.34 1.72 0.001
Rhodesian Ridgeback 1,025 8.39 0.39 1.56 10.34 1.72 0.001
Golden Retriever 36,016 7.19 0.77 2.37 10.33 1.90 0.001
Shetland Sheepdog 11,423 7.84 0.61 1.51 9.96 1.69 0.001
Chesapeake Bay Retriever 1,005 7.26 0.70 1.49 9.45 1.56 0.001
Siberian Husky 1,153 6.94 0.69 1.21 8.84 1.45 0.001
Brittany 1,257 6.76 0.72 1.19 8.67 1.42 0.001
Borzoi 527 7.21 0.19 1.14 8.54 1.39 0.034
Australian Shepherd 1,328 5.72 0.60 1.58 7.90 1.28 0.016
Doberman Pinscher 11,084 6.21 0.64 0.77 7.62 1.24 0.001
Malamute 1.449 6.21 0.48 0.90 7.59 1.22 0.042
Cocker Spaniel 18,976 5.83 0.63 0.76 7.22 1.17 0.001
Mixed 42,647 4.92 0.66 0.99 6.57 1.05 0.012
Total all breeds 287,948 4.64 0.63 1.03 6.30 NA NA
From Nachreiner RF, etal.: Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism, J Am Vet Med Assoc 220:468, 2002.
NA, Not applicable.
|
screening breeding stock with the aim of ultimately eliminating hypothyroidism caused by lymphocytic thyroiditis if the dog has
heritable forms of thyroiditis. The Orthopedic Foundation for Ani- clinical signs, physical ndings, and thyroid hormone test results
mals (OFA) maintains a thyroid registry and issues a breed data- consistent with the disorder.
base number to all dogs found to have normal thyroid function
at 12 months of age (based on measurement of fT4, TSH, and FACTORS AFFECTING THYROID GLAND
Tg autoantibodies by an OFA-approved laboratory). Each dog also FUNCTION TESTS
must be examined by a veterinarian. Because hypothyroidism usu-
ally develops after 1 year of age, it is recommended that reexamina- Correct interpretation of tests of thyroid gland function is one of
tion and retesting occur at 2, 3, 4, 6, and 8 years of age. the primary diagnostic challenges in canine clinical endocrinol-
ogy. There are many factors that influence baseline thyroid hor-
mone and endogenous TSH concentrations, including age, breed,
Serum Thyroid Hormone Autoantibodies
body size, diurnal or random fluctuations, athletic training, gen-
Thyroid hormone autoantibodies are also considered an indicator der, reproductive status, concurrent illness, and drug therapy.
of lymphocytic thyroiditis and may be a better predictor of the Because many of these factors decrease baseline thyroid hormone
potential for development of hypothyroidism in dogs. In a recent concentrations and some can concomitantly increase endogenous
study, thyroid hormone autoantibodies were detected in 6.3% TSH in euthyroid dogs, misdiagnosis of hypothyroidism may
of 287,948 serum samples from dogs with clinical signs consis- occur if the clinician accepts the results out of context. In our
tent with hypothyroidism (Nachreiner etal, 2002; Table 3-9). T3 experience, the most common factors that result in lower baseline
autoantibodies alone were detected in 4.64%, T4 autoantibodies thyroid hormone concentrations in euthyroid dogs are concur-
alone were detected in 0.63%, and both T3 and T4 autoantibodies rent illness (i.e., NTIS), use of drugs (especially glucocorticoids),
were detected in 1.03% of the serum samples. An inverse correla- and random fluctuations in thyroid hormone concentrations. In
tion existed between prevalence of thyroid hormone autoantibod- any given dog, other factors may also influence baseline thyroid
ies and age of the dogs; females had a signicantly higher chance hormone concentrations. It is important to recognize the poten-
of being positive for thyroid hormone autoantibodies than did tial influence of these factors when interpreting thyroid hormone
males, and neutered males and females had a signicantly higher test results.
prevalence of thyroid hormone autoantibodies than did sexually
intact dogs. Breeds at increased risk for having thyroid hormone
Age
autoantibodies were also identied (Table 3-9).
Measurement of serum T4 and T3 autoantibodies is offered by In dogs there is a progressive decline in T4 concentration
some commercial endocrine laboratories as part of an extensive thy- with age; serum T4 concentration is highest in puppies, and
roid panel. Testing for serum T3 and T4 autoantibodies is indicated the T4 concentration progressively declines during adulthood.
in dogs with unexpected or unusual serum T3 or T4 test results. T3 In a study of 27 female Beagles of different ages, mean serum
and T4 autoantibodies may interfere with the RIAs used to mea- T4 concentrations in old dogs were 40% lower than those of
sure serum T3 or T4 concentrations, causing unexpected and often young adult dogs (Gonzalez and Quadri, 1988). In a larger
confusing test results (Graham et al, 2007; see Fig. 3-19). The study of serum collected from 1074 healthy dogs of differing
type of interference depends on the separation system employed ages, the mean total T4 concentration was 21% lower in in dogs
in the RIA. Falsely low results are obtained if nonspecic separa- older than 6 years of age compared to young adult dogs; similar
tion methods are used (e.g., ammonium sulfate, activated char- trends with age were not identified for serum T3 concentration
coal); falsely increased values are obtained if single-step separation (Reimers etal, 1990; Fig. 3-29). In a longitudinal study of 48
systems utilizing antibody-coated tubes are used. For most com- Labrador Retrievers studied for 12 years, the mean total T4
mercially available T4 assays, T4 autoantibodies will falsely increase decreased by 29% from the age of 6 to 12 years of age (Lawler
the measured T4 concentration. The false increase may be enough et al, 2007). Similar trends occur for fT4 and serum total T3
to raise a hypothyroid dogs result into the reference or hyperthy- concentrations, although this was not true in a study of healthy
roid range. The same false increase occurs with non-dialysis (direct) Salukis (Reimers et al, 1990; Lawler et al, 2007; Shiel et al,
RIAs used for measuring serum fT4 concentrations (Kemppainen 2010). Older dogs have a higher mean TSH concentration
et al, 1996). False elevations in serum fT4 concentration do not than younger dogs (Bhatti et al, 2006) and middle-aged and
occur if fT4 is measured using an assay that includes a dialysis step older dogs also have a blunted T4 response to TSH compared
(MED assays), because autoantibodies cannot pass through the to young animals (Gonzalez and Quadri, 1988). Changes in
dialysis membrane and interfere with the assay. Thus evaluation of other parameters of thyroid function have been less studied,
serum fT4 concentration measured by MED should be performed but increases in anti-T4 antibody in older dogs have been
in lieu of measurement of serum T4 in dogs suspected of having reported (Lawler etal, 2007). Although older dogs as a group
T4 autoantibodies. Fortunately spurious T4 values resulting from have lower total T4 concentrations than younger animals, the
clinically relevant concentrations of T4 autoantibody are uncom- mean and median total T4 concentration still falls within the
mon (Nachreiner etal, 2002; Piechotta etal, 2010). lower end of most reference ranges (Table 3-10). None of the
Positive serum thyroid hormone autoantibody test results imply studies cited earlier reported a range for total T4 in healthy
pathology in the thyroid gland but provide no information on geriatric dogs; it is likely that for many geriatric dogs a total T4
the severity or progressive nature of the inflammatory response below the reference range is a normal age related change. Rea-
or the extent of thyroid gland involvement, nor are these tests sons for the decline in thyroid hormone concentrations with
an indicator of thyroid gland function. T3 and T4 autoantibodies age in dogs are not fully understood; proposed reasons include
should not be used as the sole criteria for establishing the diagnosis effect of concurrent illness, change in responsiveness of the
of hypothyroidism. Dogs with conrmed hypothyroidism can be thyroid gland to TSH, subclinical thyroid pathology (fibrosis,
negative and euthyroid dogs can be positive for thyroid hormone atrophy, degenerative changes), and decreased biologic activity
autoantibodies. Identication of T3 or T4 autoantibodies support of TSH with age.
a
1.5 3.0
Serum T3 concentration (ng/mL SEM)
Serum T4 concentration (g/dL SEM)

1.2
c,d
b b b,d b
2.0 b b,c
0.9 a c,d
a d
0.6
1.0
0.3
0 0
1-6 6-12 3-6 6-12 1-6 6-11 1-6 6-12 3-6 6-12 1-6 6-11
weeks weeks months months years years weeks weeks months months years years
(n=237) (n=164) (n=222) (n=120) (n=196) (n=106) (n=237) (n=164) (n=222) (n=120) (n=199) (n=106)
A B
Age Age
FIGURE 3-29 Mean ( SEM) serum triiodothyronine (T3) (A) and thyroxine (T4) (B) concentrations in nursing pup-
pies (1 to 6 weeks), weanling puppies (6 to 12 weeks), juvenile dogs (3 to 6 months), young adults (6 to 12
months), middle-aged adults (1 to 6 years), and old dogs (6 to 11 years). Means having different superscripts
are significantly (P < 0.05) different. (Adapted from Reimers TJ, etal.: Effects of age, sex, and body size on serum
concentrations of thyroid and adrenocortical hormones in dogs, Am J Vet Res 51[3]:454, 1990.)
TABLE 3-10 M
EAN AND MEDIAN SERUM TOTAL 1.5 3.0
THYROXINE CONCENTRATION
Serum T3 concentration (ng/mL SEM)
Serum T4 concentration (g/dL SEM)

OF SAMPLES SUBMITTED TO A
REFERENCE LABORATORY FOR b
1.2
DOGS OF DIFFERENT AGES*
b a
2.0 a
MEAN THYROXINE, MEDIAN THYROXINE, NUMBER OF a a
AGE, y g/dL g/dL PATIENTS 0.9
0 to 2 1.94 1.9 1043

3 to 5 1.91 1.8 2773 0.6
6 to 8 1.83 1.6 6975 1.0
9 to 11 1.75 1.5 5064
12 to 14 1.67 1.4 4016 0.3
> 14 1.46 1.2 736

All ages 1.78 1.5 20,607 0 0
Total T4 refer- 1.0-4.0 Small Medium Large Small Medium Large
breeds breeds breeds breeds breeds breeds
ence range (n=246) (n=418) (n=407) (n=246) (n=420) (n=408)
Data was provided by IDEXX Laboratories, Inc., Westbrook, ME. Dog size Dog size
Modified from Scott-Moncrieff CJ: Thyroid disorders in the geriatric veterinary patient, Vet FIGURE 3-30 Mean ( SEM) serum triiodothyronine (T3) and thyroxine (T4) concen-
Clin North Am Small Anim Pract 42(4):709, 2012. tration in small breed dogs (mean body weight, 7.1 kg), medium breed dogs (mean
*Patients with an age listed as 0 were excluded. body weight, 23.3 kg), and large breed dogs (mean body weight, 30.6 kg). Means
having different superscripts are significantly (P < 0.05) different. (Adapted from
Reimers TJ, etal.: Effects of age, sex, and body size on serum concentrations of
thyroid and adrenocortical hormones in dogs, Am J Vet Res 51[3]:454, 1990.)
Body Size
a mean middle-aged body weight of 7.1 kg and included Poodles,
Comparison of normal thyroid hormone values between groups of Beagles, and Miniature Schnauzers; medium-sized dogs had a
dogs based on body size has identied differences in mean serum mean middle-aged body weight of 23.3 kg and included English
T4 and T3 concentrations (Reimers etal, 1990; Fig. 3-30). Dogs Pointers, English Setters, and Siberian Huskies; large dogs had a
were divided into three groups based on body size. Small dogs had mean middle-aged body weight of 30.6 kg and included Black
|
TABLE 3-11 T
HYROID FUNCTION TEST RESULTS IN HEALTHY AKITAS, GOLDEN RETRIEVERS, BEAGLES,
AND MINIATURE AND TOY POODLES*
BEAGLE TOY AND MINIATURE

VARIABLE AKITA (N = 12) GOLDEN RETRIEVER (36) (12) POODLES (12) REFERENCE RANGE
Serum T4 (g/dL) 2.4 0.9 2.0 0.5 1.9 0.6 1.9 0.5 1.0-3.6
Serum fT4 (ng/dL) 1.1 0.3 1.1 0.4 1.3 0.5 1.3 0.5 0.8-3.5
Serum cTSH (ng/mL) 0.1 0.1 0.1 0.1 0.2 0.1 0.2 0.1 0-0.6
Thyroglobulin autoantibody positive sera None None None None NA
From Brmel C, etal.: Comparn of ultrasonographic characteristics of the thyroid gland in healthy small-, medium-, and large-breed dogs, Am J Vet Res 67(1):72, 2006.
*Data for serum hormone concentrations are presented as mean SD.
and Tan Coonhounds, Labrador Retrievers, Doberman Pinschers, racing, total T4 but not fT4 concentration decreased after adjust-
and German Shepherd dogs. Mean serum T4 concentration was ment for hemoconcentration (Hill etal, 2001). Concentrations of
greater in small than in medium-sized and large dogs. However, T4, T3, and fT4 are below the non-breed specific reference range in
mean serum T3 concentration was greater in medium-sized than conditioned Alaskan sled dogs, and these concentrations decrease
in small and large dogs. In a smaller more recent study, there was further during prolonged endurance racing (Panciera etal, 2003;
no difference in total T4, fT4, or TSH concentrations between Lee etal, 2004; Evason etal, 2004). The reported effect of con-
groups of healthy Akitas, Golden Retrievers, Beagles, or Toy/Min- ditioning and racing on serum TSH is variable. Reasons for the
iature Poodles (Brmel etal, 2006; Table 3-11). change in thyroid hormone concentrations after endurance exer-
cise are poorly defined but likely include nutritional changes, effect
of ambient temperature, or an appropriate physiologic response to
Breed
increased metabolic rate associated with racing.
Most laboratories report reference ranges based on measurement of
thyroid hormone concentrations in large groups of dogs of various Gender and Reproductive Stage of the Female
breeds and ages; however there are significant differences between
breeds in regard to thyroid hormone concentration, particularly for When the specic stage of the female reproductive cycle is not
Sighthounds. In a study of 46 young healthy Greyhounds, 91% of considered and dogs are merely classied as male or female, gender
the dogs had total T4 concentration below the non-breed specific has no apparent effect on serum thyroid hormone concentrations
reference range, and 16% had total T4 concentrations that were (Reimers etal, 1990). The mean ( SE) serum T4 and T3 concen-
either at or below the limit of detection of the assay (Shiel etal, trations in approximately 550 female versus 515 male dogs were
2007a). Free T4 was lower than the non-breed specific reference 2.11 0.04 versus 2.08 0.04 g/dL and 0.94 0.01 versus 0.92
range in 21% of dogs and at or below the limit of detection in 13% 0.01 ng/mL, respectively.
of dogs. In the same study, T3 concentrations were all within the Testosterone decreases thyroid-binding protein and can decrease
non-breed specific reference range. Differences in reference ranges serum T4 while having little effect on serum fT4 concentrations
have also been reported for Whippets, Salukis, Sloughis, Basenjis, (Wenzel, 1981). The effect of testosterone on thyroid hormone
Borzois, Scottish Deerhounds, Irish Wolfhounds, and conditioned test results in dogs is unclear. In one study, serum T4 concentration
Alaskan sled dogs (van Geffen, 2006; Panacova, 2008; Seavers, increased signicantly after male Greyhound dogs were castrated and
2008; see Table 3-5). The reason for the difference in thyroid hor- when not in training (Hill etal, 2001). There was no effect of cas-
mone concentrations between Greyhounds and other breeds has tration on serum fT4 or TSH concentrations. However, in another
not yet been elucidated, but studies suggest that it is not due to study, serum T4, fT4, and TSH concentrations were not different
changes in concentration or function of thyroid binding globu- between testosterone-treated and untreated female Greyhound dogs,
lin (Shiel et al, 2011). These ndings suggest that breed-specic suggesting that exogenous testosterone administration may not
reference ranges for thyroid hormone tests need to be established affect thyroid hormone test results (Gaughan and Bruyette, 2001).
and used when evaluating thyroid gland function especially in In the female dog, progesterone (but not estrogen) affects serum
Sighthounds. For breeds in which total T4 and fT4 concentrations T4 and T3 concentrations. In one study, serum T4 and T3 con-
are close to the limit of detection in many healthy dogs, diagnosis centrations were greater in diestrus females, than in females in
of hypothyroidism should rely on history, physical examination, anestrus, proestrus, lactating females, or male dogs (Reimers etal,
results of the complete blood count (CBC) and serum biochem- 1984). Medroxyprogesterone treatment of five euthyroid bitches
istry panel and multiple tests of thyroid gland function. Measure- once a month for 11 months did not change basal plasma TSH
ment of total T3 may be more useful in Greyhounds than in other concentration or TRH stimulated TSH concentration (Beijer-
breeds, because it is the only measurement that typically falls within ink et al, 2007). In another study, dogs with hyperestrogenism
the non-breed specific reference range, and because there is a low did not have changes in baseline serum T4 or T3 concentrations,
prevalence of thyroiditis in this breed (Nachreiner etal, 2002). although the T4 response to TSH administration was mildly
depressed (Gosselin etal, 1980). It has been postulated that pro-
gesterone (elevated during diestrus with or without pregnancy)
Athletic Training
may enhance the binding afnity of plasma proteins for thyroid
Most studies on the effect of athletic training on thyroid function hormones, resulting in an increase in serum concentrations of
have focused on Alaskan sled dogs and Greyhounds. After sprint total T4 and T3 (Wenzel, 1981).
1.5 3.5
Dog 1
3.0 Dog 2
1.2 Dog 3
Serum T4 concentration (mcg/dL)

Serum T3 concentration (ng/mL)
Dog 4
2.5
0.9
2.0
1.5
0.6
1.0
0.3
0.5
00
8 AM 11 AM 2 PM 5 PM 8 PM 8 AM 11 AM 2 PM 5 PM 8 PM
FIGURE 3-31 Sequential baseline serum triiodothyronine (T3) and thyroxine (T4) concentrations from blood sam-
ples obtained at 8 am, 11 am, 2 pm, 5 pm, and 8 pm in four healthy dogs. Note the random fluctuation in serum T3
and T4 concentrations throughout the day and the occasional low value, which could result in a misdiagnosis of
hypothyroidism.
Diurnal Rhythm generally included within the definition of NTIS. Mechanisms

that are believed to contribute to NTIS include decreased TSH
In a study of 11 healthy mixed breed dogs in which blood samples secretion, decreased synthesis of T4, decreased concentration or
were collected every 3 hours between 8 am and 8 pm, total T4 binding afnity of circulating binding proteins, presence of serum
concentration was higher between 11 am and 8 pm compared to protein binding inhibitors, inhibition of the de-iodination of T4
8 am (Hoh etal, 2006). For fT4 the concentrations at 11 am and to T3, or any combination of these factors (Wiesinga and Van den
2 pm were higher than those at 8 am. This suggests the possibil- Berghe, 2013). Decreased serum thyroid hormone concentrations
ity of a diurnal rhythm with a peak in serum thyroid hormone are believed to be a physiologic adaptation that decreases cellular
concentration at mid-day in the dog. Further studies are needed metabolism during illness. Generally, the magnitude of the change
to confirm this finding. A diurnal rhythm in TSH secretion was in serum thyroid hormone concentrations is not related to the
not identified in healthy euthyroid dogs (Bruner etal, 1998; see specic disorder but rather reflects the severity of the illness, with
Fig. 3-27). more severe systemic illness resulting in more severe suppression
of serum thyroid hormone concentrations (Kaptein, 1988; Kan-
trowitz etal, 2001; Mooney etal, 2008; Fig. 3-32). In a study of
Random Fluctuations
dogs with idiopathic epilepsy, there was a significant correlation
Random or pulsatile fluctuations in baseline serum T4, and T3, between seizure frequency and thyroid hormone concentrations;
occur in healthy dogs, euthyroid dogs with concurrent illness, the longer the interval between seizures the higher the thyroid
and hypothyroid dogs (Fig. 3-31; Kemppainen and Sartin, 1984; hormone concentration (von Klopmann etal, 2006). There was
Miller etal, 1992). Although there was little fluctuation in TSH no correlation with the time span between the most recent sei-
concentration during the day in euthyroid dogs, sporadic and zure episode and blood collection, suggesting that it was the sever-
pulsatile fluctuations in TSH concentrations during the day were ity of illness rather than the seizure itself that suppresses thyroid
documented in hypothyroid dogs (Bruner et al, 1998; Kooistra hormone concentrations. Disorders that are frequently associated
etal, 2000a; see Fig. 3-27). with NTIS in dogs include neoplasia, renal disease, hepatic dis-
ease, cardiac failure, neurologic disease, inflammatory disorders,
and diabetic ketoacidosis. It may be difcult or impossible to
Concurrent Illness (Nonthyroidal Illness Syndrome)
establish a diagnosis of concurrent hypothyroidism in dogs with
The nonthyroidal illness syndrome (NTIS; euthyroid sick syn- NTIS, especially when relying on results of a single test of thyroid
drome) refers to suppression of serum thyroid hormone con- gland function. Normal test results are indicative of euthyroidism,
centrations that occur in euthyroid patients due to concurrent but abnormal test results do not conrm a diagnosis of hypothy-
illness. Causes of NTIS include almost any systemic illness, sur- roidism because dogs with NTIS often have serum T4 concentra-
gery, and trauma, as well as inadequate caloric intake. Disorders tions that are indistinguishable from true hypothyroidism.
such as dermatologic diseases and osteoarthritis are unlikely to In humans the pattern of thyroid hormone suppression is quite
cause NTIS (Paradis etal, 2003). Although drugs may also affect predictable, and T3 is more commonly suppressed than total T4
thyroid function, thyroid suppression induced by drugs is not or fT4 (low T3 syndrome). In dogs, however, most studies have
|
60
50
4.0
50
40
3.0
40
3.0
Serum free T4 (ng/dL)

Serum T4 (mcg/dL)
Serum T4 (nmol/L)
30
30 2.0
2.0
20
20
1.0
1.0 10
10
0 0 0 0
Mild Moderate Severe Mild Moderate Severe
A (66) (95) (62) B (66) (95) (62)
1.4
60
1.2
1.0
Serum TSH (ng/mL)
Serum TSH (mU/L)
0.8
40
0.6
0.4
20
0.2
0 0
Mild Moderate Severe
C (66) (95) (62)
FIGURE 3-32 Box plots of serum concentrations of total thyroxine (T4) (A), free T4 (fT4) (B), and thyrotropin (TSH)
(C) in 223 dogs with nonthyroidal disease stratified according to severity of disease. For each box plot, T-bars
represent the main body of data, which in most instances is equal to the range. Each box represents interquartile
range (25th to 75th percentile). The horizontal bar in each box is the median. Open circles represent outlying data
points. Numbers in parentheses indicate the numbers of dogs in each group. Reference range is indicated by the
shaded area. (From Kantrowitz LB, etal.: Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin
concentrations in dogs with nonthyroidal disease, J Am Vet Med Assoc 219[6]:765, 2001.)
reported that the most common finding in systemically ill dogs is without obvious deleterious consequences, it is not recommended
a decreased total T4. Alterations in serum concentrations of T3, especially if the concurrent illness is severe and there is nothing
fT4, and TSH are more variable and may depend in part on the in the history, physical examination, or blood work to support a
pathophysiologic mechanisms involved in the illness. Although diagnosis of concurrent hypothyroidism.
serum fT4 concentrations are decreased to a lesser extent than
total T4 concentrations (Peterson etal, 1997; Kantrowitz etal, Dermatologic Disorders
2001), in the presence of severe systemic illness, fT4 concentra- Hypothyroidism is frequently included in the differential diagno-
tions can also be markedly decreased. Results of TSH and TRH sis of many dermatologic disorders in the dog. Studies suggest that
stimulation testing can also be suppressed and suggestive of true common dermatologic disorders (e.g., pyoderma, flea hypersen-
hypothyroidism. Serum TSH concentrations are usually normal sitivity, allergic dermatitis) do not typically cause serum thyroid
but may be increased in a small percentage of patients especially hormone concentrations to decrease into the hypothyroid range
during recovery from NTIS. In one study of 223 dogs with NTIS, in euthyroid dogs (Slade et al, 1984; Nelson et al, 1991; Beale
approximately 31% of dogs had low total T4 concentrations and etal, 1992a; Daminet etal, 2000). Borderline serum T4 and fT4
22% had low fT4, whereas only 8% had high serum TSH con- concentrations however may occur in individual euthyroid dogs
centrations (Kantrowitz etal, 2001). In a more recent study of with skin disease.
196 dogs with NTIS, total T3, total T4, and fT4 were decreased
in 76%, 35%, and 5% of dogs respectively, whereas canine Diabetes Mellitus
TSH was increased in only 3% of dogs (Mooney et al, 2008). Thyroid hormones play an important role in glucose homeosta-
In this study, decreased total T3 concentrations were relatively sis. and hypothyroidism and diabetes mellitus can occur together
common, and total T3 was significantly lower in dogs that were (Hess etal, 2003; Dixon etal, 1999). Concurrent hypothyroidism
euthanized compared to those that survived. The high percent- in diabetic dogs may cause insulin resistance (Ford et al, 1993),
age of dogs in this study with a low total T3 is more similar to although in most hypothyroid dogs increased secretion of insulin
what is typically reported in humans with NTIS. Multiple stud- results in maintenance of normal blood glucose concentration.
ies in dogs, cats, and humans with NTIS have confirmed that the Increased concentrations of IGF-1 and GH have been documented
severity of suppression of serum thyroid hormone concentrations in hypothyroid dogs and likely contribute to insulin resistance
can be used as a prognostic indicator. Lower serum thyroid hor- (Diaz-Espieira, 2009; Hofer-Inteeworn, 2012). Hypothyroid
mone concentrations are associated with a higher mortality rate dogs have increased fructosamine concentrations due to decreased
(Peterson and Gamble, 1990; Elliott etal, 1995: Mooney etal, metabolic rate and resultant decreased protein turnover, which may
2008; Schoeman etal, 2007). In a study of 63 critically ill pup- complicate the assessment of glycemic control in hypothyroid dia-
pies with parvoviral enteritis, serum T4 and fT4 were significantly betic dogs (Reusch, 2002). Recognition of hypothyroidism may be
lower in non-survivors than survivors (Schoeman et al, 2007). difcult in dogs with poorly controlled diabetes mellitus, because
Similar findings have been documented in dogs with other severe clinical signs (e.g., lethargy and weakness) and abnormalities in
systemic illness. clinical pathologic values (e.g., lipemia and hypercholesterolemia)
The existence of NTIS makes it very difficult to confirm a may be present in both disorders. Reliance on baseline serum thy-
diagnosis of concurrent hypothyroidism in systemically ill dogs. roid hormone concentrations can be misleading because of NTIS.
If possible, evaluation of thyroid function should be postponed Evaluation of baseline thyroid hormone and TSH concentrations
until resolution of the underlying illness. In some circumstances, in the diabetic dog should not be undertaken until after treatment
however, treatment of concurrent hypothyroidism could improve for diabetes mellitus has improved the initial systemic signs of ill-
outcome if hypothyroidism is contributing to the pathogenesis of ness. Interpretation of test results should take into consideration
the disorder. Examples of clinical situations in which this might the degree of success achieved in controlling hyperglycemia and the
occur are dogs with laryngeal paralysis and megaesophagus in impact that poorly controlled diabetes mellitus may have on serum
which hypothyroidism may contribute to decreased neurologic T4, fT4, and TSH concentrations. If hypothyroidism is diagnosed
function. In this situation multiple thyroid parameters should be and treated in a diabetic patient, the blood glucose should be care-
evaluated in the context of history, physical examination findings, fully monitored when thyroid supplementation is initiated because
and other laboratory data. The simultaneous occurrence of low T4, establishment of euthyroidism results in increased insulin sensitiv-
fT4, and high TSH concentration is uncommon in NTIS, occur- ity and a decreased need for insulin.
ring in only 1.8% of 223 dogs with nonthyroidal illness in one
study and in none of 66 dogs in another study (Kantrowitz etal, Hyperadrenocorticism
2001; Torres, 2003). Therefore if this combination of findings is Endogenously produced and exogenously administered gluco-
identified in a dog with supportive clinical findings, a diagnosis corticoids frequently lower baseline serum T4, T3, and fT4 con-
of true hypothyroidism is more likely. A TSH stimulation test, centrations in the dog (Peterson etal, 1984; Nelson etal, 1991;
thyroid scintigraphy, or a therapeutic trial may all be appropriate Ferguson and Peterson, 1992). Most studies suggest that 40%
options in such a scenario. to 50% of dogs with spontaneous hyperadrenocorticism have
Treatment of NTIS should be directed at resolution of the con- decreased total T4 and T3 concentrations, whereas fT4 is usu-
current illness. Serum thyroid hormone concentrations return to ally maintained within the reference range (Peterson etal, 1984;
normal once the concurrent illness is corrected. Because NTIS is Ferguson and Peterson, 1992). There are several proposed mech-
believed to be a physiologic protective mechanism, it is not rec- anisms for the alterations in serum thyroid hormone concentra-
ommended to treat affected patients with thyroid supplementa- tions in dogs with hyperadrenocorticism (Box 3-5), including
tion, and there are no studies that document a benet of such inhibition of TSH secretion, reduced serum protein binding of
treatment. In a study of euthyroid dogs with congestive heart T4, reduced T3 production and degradation, and possibly inhi-
failure, supplementation with thyroid hormone did not improve bition of peripheral 5-deiodination of T4 (Kemppainen et al,
survival (Tidholm etal, 2003). Although many dogs with euthy- 1983; Ferguson and Peterson, 1992). Although glucocorticoids
roid sick syndrome are inadvertently treated with L-T4 sodium are believed to suppress pituitary TSH secretion, in a study of 47
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BOX 3-5 P
roposed Alterations in Thyroid Hormone TABLE 3-12 M
ECHANISMS BY WHICH DRUGS
Physiology Caused by Glucocorticoids INFLUENCE THYROID FUNCTION
IN HUMANS
Decreased 5-monodeiodination enzyme activity
MECHANISM EXAMPLE
Decreased binding affinity of plasma proteins for T4, T3
Decreased cellular binding of T4, T3 Decrease TSH secretion Glucocorticoids
Increased metabolic clearance rate of T4 Change thyroid hormone secretion Amiodarone
Decreased metabolic clearance rate of T3, rT3 Decrease gastrointestinal absorption Sucralfate
Inhibition of TSH secretion (secondary hypothyroidism)
Inhibition of TRH secretion Alter serum binding Phenylbutazone
Change hepatic metabolism Phenobarbital
T3, Triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone;
TSH, thyroid-stimulating hormone (also known as thyrotropin). Inhibit TPO Sulfonamides
TPO, Thyroid peroxidase; TSH, thyroid-stimulating hormone (also known as thyrotropin).

dogs with pituitary dependent hyperadrenocorticism, basal and
TRH stimulated TSH concentrations did not differ from those of In humans, fasting causes a signicant rapid decrease in serum
control dogs (Meij etal, 1997). concentrations of T3 and an increase in serum rT3 without affect-
In some cases it can be difficult to clinically differentiate hyper- ing serum T4 or TSH concentrations (Wartofsky and Burman,
adrenocorticism from hypothyroidism in dogs with endocrine 1982). Re-feeding with either a mixed-nutrient or carbohydrate-
alopecia, although usually the history (e.g., polydipsia, polyuria, rich diet causes the fasting-induced changes to reverse quickly.
polyphagia in hyperadrenocorticism but not hypothyroidism), the Impaired conversion of T4 to T3 from inhibition of peripheral
presence of additional physical abnormalities, and the presence 5-deiodinase has been proposed to account for these abnormali-
of abnormalities on a CBC, urinalysis, and serum biochemical ties (Borst etal, 1983), although studies in rats have also shown
panel (e.g., increased alkaline phosphatase activity) are helpful. decreased thyroidal secretion of T4. Fasting for up to 36 hours did
If hyperadrenocorticism is considered possible, a screening test, not affect baseline serum T4 or T3 concentrations in euthyroid
such as the urine cortisol/creatinine ratio or low dose dexametha- Beagles (Reimers et al, 1986). However, fasting in excess of 48
sone suppression test, should be considered in addition to tests of hours did decrease T3 concentrations in dogs (de Bruijne et al,
thyroid gland function to avoid a misdiagnosis of hypothyroid- 1981). In Labrador Retrievers subjected to life-time caloric restric-
ism in a dog with hyperadrenocorticism. If a dog with hyperad- tion, only T3 concentrations were consistently lower in dogs sub-
renocorticism is inadvertently treated with L-T4 sodium, a poor jected to dietary restriction (Lawler etal, 2007). Serum T4 and T3
response to treatment or development of additional clinical mani- but not fT4 concentrations were signicantly lower in dogs with
festations of hyperadrenocorticism (e.g., polyuria and polydipsia) chronic weight loss causing cachexia, compared with dogs that
will eventually lead the clinician back toward the diagnosis of had not undergone weight loss (Vail etal, 1994). The decrease in
hyperadrenocorticism. serum T4 and T3 concentration was proportional to the degree of
weight loss associated with their disease. The decline in serum T4
Environmental and Body Temperature and T3 was believed to be related to the severity of the illness or an
abnormal nutritional state.
Seasonal influence on thyroid hormone concentrations was evalu-
ated in healthy outdoor dogs in Hokkaido, Japan (Oohashi etal,
Drugs
2001). Serum T4 concentration decreased in January and increased
in August and September, fT4 concentration increased in January Our knowledge of the effect, if any, of various drugs and hor-
and November, and there was no signicant seasonal variation mones on serum thyroid hormone and TSH concentrations in
in serum TSH concentration. It is not known whether a simi- dogs is gradually expanding as investigators continue to exam-
lar seasonal variation occurs in dogs housed indoors or whether ine the interplay between medications and thyroid hormone test
temperature variation, photoperiod, or region of the world may results (Tables 3-12 and 3-13). Undoubtedly, many more as yet
impact the results. Acute cold exposure may increase serum con- unrecognized drugs also affect serum thyroid hormone and TSH
centrations of TSH and thyroid hormones in the rat and possibly concentrations in dogs. Until proved otherwise, any drug should
in humans, and acute exposure to heat may decrease serum TSH, be suspected of influencing thyroid hormone test results, espe-
T4, and T3 and increase serum rT3 concentrations (Wartofsky and cially if the drug has been shown to alter serum thyroid hormone
Burman, 1982). Hypothermia and hyperpyrexia may also alter concentrations in humans (see Table 3-13; Box 3-6).
serum T4, T3, rT3, and TSH. It is not known, however, whether
these alterations are a result of temperature fluctuations or other Glucocorticoids
factors associated with NTIS. Glucocorticoids are the most commonly used drugs that influ-
ence serum thyroid hormone concentrations. The effect of exog-
Obesity, Fasting, and Cachexia enously administered glucocorticoids on serum thyroid hormone
concentrations is similar to that seen with naturally occurring
An increase in serum T3 and T4 concentrations has been reported in hyperadrenocorticism (see Chapter 10). Serum T4, fT4, and T3
obese euthyroid dogs (Gosselin etal, 1980; Daminet etal, 2003a). concentrations are decreased, often into the hypothyroid range.
It is believed that increased serum thyroid hormone levels are the Proposed mechanisms for this decrease include decreased binding
result of increased caloric intake rather than obesity itself. The of T4 to carrier proteins, alterations in clearance and metabolism
changes reported are small and unlikely to influence clinical inter- of thyroid hormones, decreased conversion of T4 to T3 at periph-
pretation of thyroid hormone concentrations. eral sites, and suppressed pituitary TSH secretion (Woltz et al,
TABLE 3-13 DRUGS THAT HAVE BEEN DEMONSTRATED TO INFLUENCE THYROID FUNCTION IN DOGS
TOTAL THYROXINE FREE THYROXINE CLINICAL SIGNS OF

DRUG ( OR N) ( OR N) THYROTROPIN ( OR N) HYPOTHYROIDISM? (Y/N) NOTES
Glucocorticoids ( or N) N N Effect dose and dura-
tion dependent
Phenobarbital Slight N TSH not increased
outside reference
range
Trimethoprim/sulfon- Y Effect dose and dura-
amides tion dependent
Nonsteroidal anti- Effect varies depending
inflammatory drugs on specific drug used
Aspirin N or N N
Deracoxib N N N N
Ketoprofen N N N N
Meloxicam N N N N
Carprofen N N N N
Etodolac N or N N or N
Clomipramine N N
TSH, Thyroid-stimulating hormone (also known as thyrotropin).
1984; Kaptein et al, 1992; Moore et al, 1993). Because serum physical examination ndings are consistent with the disease. Any
TSH concentrations are not increased in dogs with hyperadreno- other combination of test results is difficult to interpret, and the
corticism, measurement of TSH can be helpful in distinguishing ideal approach is to discontinue glucocorticoid treatment and
hyperadrenocorticism and hypothyroidism. An increased TSH reassess serum thyroid hormone and TSH concentrations 4 to 8
concentration is consistent with hypothyroidism rather than weeks later. In hypothyroid dogs already being treated with thy-
hyperadrenocorticism, although it is important to recognize that roid hormone supplementation, prednisone at a dose of 1.0 mg/
the two disorders can occur together. The magnitude and duration kg for 7 days decreased total T4 but not fT4 or TSH. Every other
of suppression of serum thyroid hormone concentrations depend day treatment at the same dose did not alter any thyroid param-
on the type of glucocorticoid, dosage, route of administration, and eter over a 28-day period (ONeill and Reynolds, 2011).
duration of glucocorticoid administration. The higher the dosage,
the longer the administration, and the more potent the glucocor- Anticonvulsants
ticoid administered, the more severe the suppression of serum thy- In dogs, phenobarbital treatment at therapeutic dosages
roid hormone concentrations. Topical glucocorticoids can have a decreases serum T4 and fT4 concentrations into the range con-
similar effect as parenterally-administered glucocorticoids (Gott- sistent with hypothyroidism (Gaskill et al, 1999; Kantrowitz
schalk, 2011). Administration of exogenous glucocorticoids does etal, 1999; Gieger etal, 2000; Muller etal, 2000). Although the
not typically result in clinical signs of hypothyroidism, although mechanism remains unproven in dogs, increased metabolism
clinical signs of iatrogenic hyperadrenocorticism may mimic clini- and excretion of T4 secondary to hepatic microsomal enzyme
cal signs of hypothyroidism particularly in regard to dermatologic induction is believed to be the primary cause, although other
signs. Because of the overlap in clinical signs between iatrogenic mechanisms such as displacement of T4 from plasma protein
hyperadrenocorticism and hypothyroidism and the effects of glu- binding sites may also play a role. A delayed increase in serum
cocorticoids on laboratory evaluation of the thyroid axis, in some TSH concentration occurs as serum T4 and fT4 concentrations
situations it can be difficult or impossible to determine whether decline, although TSH concentrations do not usually exceed the
glucocorticoid induced hypothyroidism is contributing to a dogs upper limit of the reference range (Muller etal, 2000). Increased
clinical signs and on rare occasions a therapeutic trial may be serum TSH concentrations quickly return to the reference range
appropriate. following discontinuation of phenobarbital treatment, whereas
Because of the common use of glucocorticoid therapy in the serum T4 and fT4 concentrations may take up to 4 weeks to
management of various medical and dermatologic disorders, return to pretreatment values (Gieger etal, 2000). Although in
a thorough history regarding prior glucocorticoid therapy is most cases clinical signs of hypothyroidism do not develop in
extremely important before evaluating thyroid gland function, phenobarbital-treated dogs, rarely we have seen dogs with clini-
because failure to identify prior glucocorticoid administration cal signs suggestive of hypothyroidism in dogs treated chroni-
can result in a misdiagnosis of hypothyroidism. If glucocorticoids cally with phenobarbital.
have been administered in the recent past, measurement of base- Bromide, a halide similar to iodide, could potentially affect
line serum thyroid hormone concentrations should be delayed or the thyroid axis by interfering with iodide uptake or iodide
interpreted carefully. Normal serum T4, fT4, and TSH concen- organication by the thyroid gland. Potassium bromide treatment
trations in these dogs conrm normal thyroid function, whereas did not have a signicant effect on serum T4, fT4, T3, and TSH
low serum T4 and fT4 concentrations in conjunction with high concentrations in five healthy dogs or in eight dogs with a seizure
TSH concentrations suggest hypothyroidism if clinical signs and disorder (Kantrowitz etal, 1999; Paull etal, 2003).
|
to persistent TSH stimulation (Torres etal, 1996; Seelig etal,

BOX 3-6 S
ome Drugs and Diagnostic Agents that 2008). Thyroid gland function tests return to normal within 1
can Alter Basal Serum Thyroid Hormone to 12 weeks after cessation of the antibiotic depending upon the
Concentrations in Humans and Possibly Dogs dose and chronicity of treatment (Hall et al, 1993; Williamson
et al, 2002; Frank etal, 2005). Administration of sulfadiazine
Decrease T4 and/or T3 in combination with trimethoprim during the last 4 weeks of
Amiodarone (T3) pregnancy in female dogs did not affect the thyroid gland in the
Androgens neonates (Post etal, 1993).
Cholecystographic agents
Diazepam Nonsteroidal Anti-Inflammatory Drugs
Dopamine Nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease
Flunixin serum T4, fT4, T3, and TSH concentrations in humans and
Furosemide other species (Bishnoi etal, 1994). Proposed mechanisms include
Glucocorticoids displacement of thyroid hormone binding to plasma proteins,
Heparin decreased thyroid hormone de-iodination and inhibition of bind-
Imidazole ing of thyroid hormone to receptors in the plasma membrane,
Iodide cytoplasm, and nucleus. The effect of NSAIDs on thyroid func-
Methimazole tion tests varies depending on the drug. In dogs, administration of
Mitotane aspirin causes a decrease in total T4 and fT4 concentration but no
Nitroprusside change in TSH concentration. Etodolac, deracoxib, ketoprofen,
Penicillin meloxicam, and carprofen do not result in significant alterations
Phenobarbital in thyroid hormone concentrations in dogs (Ferguson, 1999; Pan-
Phenothiazines ciera and Johnston, 2002; Daminet, 2003b; Ness, 2003; Sauve,
Phenylbutazone 2003; Panciera, 2006; see Table 3-13).
Phenytoin
Primidone Tricyclic Antidepressants
Propranolol Clomipramine is a tricyclic antidepressant commonly used in
Propylthiouracil dogs with behavioral problems. Clomipramine inhibits thyroid
Radiopaque dyes (ipodate) (T3) hormone synthesis by altering thyroid follicular cell uptake of
Salicylates iodide and inhibition of TPO. Clomipramine at a dose of 3 mg/kg
Sulfonamides (sulfamethoxazole) every 12 hours decreased total T4 and fT4 in dogs after 28 days of
Sulfonylureas treatment but did not change TSH concentrations during the 112
days of the study (Gulickers and Panciera, 2003). Because hypo-
Increase T4 and/or T3 thyroidism has been implicated in causing behavioral changes in
Amiodarone (T4) dogs, it is important that thyroid function is not evaluated while
Estrogens dogs are being treated with clomipramine.
5-Fluorouracil
Halothane
Insulin THYROID BIOPSY
Narcotic analgesics The gold standard method for identifying pathology of the thyroid
Radiopaque dyes (e.g., ipodate) (T4) gland is histologic evaluation of a thyroid biopsy specimen. Severe
Thiazides lymphocytic thyroiditis or thyroid atrophy are readily identied
T3, triiodothyronine; T4, thyroxine. histologically (see Figs. 3-6 and 3-7), and in the dog with appropri-
ate clinical signs and diagnostic test results, these ndings conrm
the diagnosis of primary hypothyroidism (Diaz-Espieira et al,
Sulfonamide Antibiotics 2007). Unfortunately, histologic evaluation of a thyroid biopsy
Sulfonamides interfere with thyroid hormone synthesis by does not always clarify the status of thyroid gland function, espe-
means of dosage- and duration-dependent inhibition of TPO cially when clinical signs or diagnostic test results are vague and
activity (Doerge and Decker, 1994). TPO is responsible for changes in thyroid pathology are less severe. Thyroiditis can be
oxidation of iodide, iodination of tyrosine residues on Tg, and present in the thyroid gland without causing overt clinical thyroid
coupling of tyrosine residues prior to thyroid hormone secre- failure and does not always progress to cause clinical hypothyroid-
tion. Decreases in serum T4, fT4, and T3 and an increase in ism. Approximately 80% of both thyroid lobes must be destroyed
TSH concentrations have been documented in dogs treated before clinical thyroid gland failure is evident. Variants of normal
with potentiated sulfonamides (e.g., trimethoprim-sulfa- can be also difcult to differentiate from secondary hypothyroid-
methoxazole, trimethoprim-sulfadiazine; Hall etal, 1993; Tor- ism, primary atrophy, and follicular cell hyperplasia, especially
res etal, 1996; Gookin etal, 1999). Serum T4 concentrations when the last two conditions are in the early stages of development.
can decrease into the hypothyroid range within 1 to 2 weeks, The influence of concurrent illness on thyroid gland morphology
and serum TSH concentrations can increase above the reference may also affect biopsy results. Biopsies of the thyroid gland must
range within 2 to 3 weeks after initiating sulfonamide therapy be obtained surgically and are rarely performed because of the inva-
at doses of 15 mg/kg every 12 hours or higher (Hall etal, 1993; siveness of the procedure, cost to the client, and lack of guarantee
Williamson et al, 2002; Frank et al, 2005). Clinical signs of that diagnostically useful information will be obtained. The only
hypothyroidism may develop with sulfonamide administra- clinical indication for thyroid biopsy in dogs is identification of an
tion and chronic treatment may result in a palpable goiter due enlarged thyroid gland when thyroid neoplasia is suspected.
Credille et al, 2001). For this reason, a dog that has a positive
ESTABLISHING THE DIAGNOSIS
response to therapy either has hypothyroidism or has thyroid-
Recommendations regarding the approach to the diagnosis of responsive disease. Therefore, if a positive response to trial ther-
hypothyroidism are shown in Fig. 3-20. The presence of appropri- apy is observed, thyroid supplementation should be discontinued
ate clinical signs is imperative, especially when relying on baseline once clinical signs have resolved. If clinical signs recur, hypothy-
thyroid hormone concentrations for a diagnosis. Identication roidism is conrmed, and the supplement should be reinitiated.
of a mild nonregenerative anemia on the CBC and especially an If clinical signs do not recur, a thyroid-responsive disorder or
increased serum cholesterol concentration on a serum biochem- a benecial response to concurrent therapy (e.g., antibiotics, flea
istry panel adds further support for hypothyroidism. Baseline control) should be suspected.
serum T4 concentration is often used as the initial screening test
for thyroid gland function, in part because it is widely available at Diagnosis in a Previously Treated Dog
low cost and can be measured in-house. It is important to remem- Occasionally, a clinician wants to determine whether a dog receiv-
ber that serum T4 concentrations can be suppressed by a variety ing thyroid hormone supplementation is, in fact, hypothyroid.
of factors, most notably NTIS. Thus measurement of the serum The exogenous administration of thyroid hormone, either T4 or
T4 concentration should be used to conrm a euthyroid state. A T3, to a healthy euthyroid dog, suppresses pituitary TSH secre-
normal serum T4 concentration establishes euthyroidism in the tion and causes pituitary thyrotroph atrophy and, subsequently,
vast majority of dogs. The exceptions are a very small number thyroid gland atrophy. Once the supplement is withdrawn, serum
of hypothyroid dogs with lymphocytic thyroiditis and serum T4 T4, and T3 concentrations may be suggestive of hypothyroidism,
autoantibodies that interfere with the RIA used to measure T4 (see even in a previously euthyroid dog, if testing is performed within
Fig. 3-19). A low serum T4 concentration (i.e., less than 0.5 g/ a month of discontinuing treatment (Panciera etal, 1989). Thy-
dL) in conjunction with hypercholesterolemia and clinical signs roid hormone supplementation must be discontinued and the
strongly suggestive of the disease, supports the diagnosis of hypo- pituitary-thyroid axis allowed to regain function before meaning-
thyroidism, especially if systemic illness is not present. ful baseline serum T4 concentrations can be obtained. The time
Although measurement of serum T4 concentration can be used between the discontinuation of thyroid hormone supplementa-
as an initial screening test, measuring a combination of thyroid tion and the acquisition of meaningful results regarding thyroid
gland tests is preferred to confirm the diagnosis. Many diagnos- gland function depends on the duration of treatment, the dose
tic laboratories offer a variety of thyroid panels that incorporate and frequency of administration of the thyroid hormone supple-
two or more of the following: serum T4, fT4 by RIA or MED, ment, and individual variability. As a general rule, thyroid hor-
T3, fT3, rT3, TSH, and antibody tests for lymphocytic thyroid- mone supplements should be discontinued for a minimum of 4
itis. A normal serum T4, fT4, and TSH concentration rules out weeks, but preferably 6 to 8 weeks, before thyroid gland function
hypothyroidism. Low serum T4 and fT4 and increased serum is critically assessed.
TSH concentrations in a dog with appropriate clinical signs and
clinicopathologic abnormalities strongly support the diagnosis of Diagnosis in Puppies
hypothyroidism, especially if systemic illness is not present and An approach similar to the one described earlier is used to diag-
drugs known to affect thyroid test results have not been recently nose congenital hypothyroidism. In general, the clinical signs are
administered. Concurrent presence of Tg autoantibodies suggests more obvious in dogs with congenital hypothyroidism; and if the
lymphocytic thyroiditis as the underlying etiology. hypothalamic-pituitary-thyroid gland axis is intact, a goiter will be
Unfortunately, discordant test results are common. In this present (see Fig. 3-13). Serum TSH concentrations in dogs with
situation, reliance on presence of clinical signs, clinicopathologic congenital hypothyroidism are also dependent on the etiology of
abnormalities, and clinician index of suspicion become the most hypothyroidism. Serum TSH concentrations will be increased in
important parameters in deciding whether to treat the dog with dogs with primary dysfunction of the thyroid gland (e.g., iodine
L-T4 sodium (see Table 3-6). Serum fT4 concentration measured organication defect) and an intact hypothalamic-pituitary-thy-
by MED is the single most accurate test of thyroid gland function. roid gland axis. However, serum TSH concentrations will not be
The combination of a high TSH concentration and a low fT4 or increased in dogs with congenital hypothyroidism in which pituitary
total T4 has high specificity for a diagnosis of hypothyroidism. or hypothalamic dysfunction is the cause of the hypothyroidism.
Positive anti-thyroid antibodies alone do not equate with a diag-
nosis of hypothyroidism but increase the likelihood of the dis- TREATMENT
ease in the presence of borderline or discordant thyroid hormone
concentrations. Ultimately when discordant test results occur, the The initial treatment of choice, regardless of the underlying cause
clinician must decide whether to initiate trial therapy with L-T4 of hypothyroidism, is synthetic L-T4 sodium (Fig. 3-33; Box 3-7).
sodium or to repeat the testing in 3 to 6 months. In general the The same treatment protocol is used for both a therapeutic trial and
most important factor influencing this decision is the severity of definitive therapy. Treatment with L-T4 sodium preserves normal
clinical signs consistent with hypothyroidism. regulation of T4 to T3 de-iodination, which allows physiologic regu-
Trial therapy should be considered only when thyroid hormone lation of individual tissue T3 concentrations and decreases the risk
supplementation does not pose a risk to the patient. Response of iatrogenic hyperthyroidism. The plasma half-life of L-T4 sodium
to trial therapy with L-T4 sodium is nonspecic. Because of the in dogs ranges from 9 to 14 hours and depends, in part, on the dos-
general increase in the metabolic rate that can result from phar- age and frequency of administration, with higher dosages and more
macologic doses of thyroid hormone, thyroid hormone supple- frequent administration associated with a shorter half-life of L-T4
mentation can temporarily improve clinical signs in a dog without sodium (Nachreiner etal, 1993; Le Traon, 2007). In one study, the
thyroid dysfunction. The effect on the quality of the hair coat is mean ( SD) serum half-life of L-T4 sodium was 9.0 5.9 and 14.6
most notable. Thyroid hormone supplementation stimulates telo- 6.3 hours when L-T4 sodium was administered at 22 g/kg once
gen hair follicles to become anagen follicles and improves the hair a day or divided twice a day, respectively (Nachreiner etal, 1993).
coat, presumably even in euthyroid dogs (Gunaratnam, 1986; At this dosage, mean time to peak serum T4 concentration was 3.8
|
Treatment protocol for cases

of suspected hypothyroidism
Use brand name

Levothyroxine for animal use
(initial dose should be
0.02 mg/kg of body weight
twice daily with the maximum
initial dose of 0.8 mg/kg twice daily)
Evaluate clinical response

along with a 4- to 6-hour
postpill serum TT4 and
TSH concentration after 4 to
8 weeks of treatment*
Positive clinical response Negative clinical response
Postpill 4- to 6-hour Postpill 4- to 6-hour

concentration concentration
T4 low normal >6.0 (g/dL)

TSH high High normal to slightly
>6.0 (g/dL)
higher than normal
Decrease dose or
Increase dose consider once daily
therapy
Reevaluate diagnosis T4 low normal
TSH high
Recheck in
4 weeks Recheck in
4 weeks
Recheck in 8 weeks Increase dose
High normal to slightly

higher than normal
Positive clinical response Negative clinical response

No change
necessary
Repeat postpill 4- to 6-hour
concentration.
Recheck in Consider:
6 months 1. Increasing dose
2. Misdiagnosis
*Serum free T4 by equilibrium dialysis can also be measured.
Prepill serum T also recommended if daily therapy is administered.
4
FIGURE 3-33 Algorithm for treatment of canine hypothyroidism. TSH, thyroid-stimulating hormone, also known
as thyrotropin; TT4, total thyroxine. (Modified from Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal
medicine, ed 7, St Louis, 2010, Elsevier, p. 1760.)
2.0 hours after L-T4 sodium administration. Maximal and mini- to consistently normalize T3 concentration, but there is no evidence
mal serum T4 concentrations were higher and lower, respectively that normalization of T3 is necessary for a good clinical response.
with once daily L-T4 sodium administration, than with twice-daily The recommended initial dose for otherwise healthy hypothyroid
administration. As a result, serum T4 concentrations were above the dogs is 0.02 mg/kg by mouth every 12 hours (0.1 mg/10 lb; maxi-
physiologic range for a number of hours with single L-T4 sodium mum starting dose, 0.8 mg). This dosage is similar to the average
administration, whereas concentrations closer to physiologic ranges calculated oral replacement dosage (0.018 mg/kg) determined in a
were achieved by use of divided doses. The ideal dose and frequency study evaluating replacement T4 requirements in thyroidectomized
of L-T4 sodium supplementation varies among dogs because of vari- dogs (Ferguson and Hoenig, 1997). The dose for treatment of
ability in T4 absorption and serum half-life between individual dogs. hypothyroid dogs is 10 times higher than the dose used in hypo-
A dose of 0.02 mg/kg every 24 hours normalizes TSH concentration thyroid humans because of poorer gastrointestinal absorption and
in most dogs; higher doses (0.04 mg/kg every 12 hours) are required a shorter serum half-life of T4 in dogs compared to humans. Some
(FDA) allows variability in potency of 80% to 125%, which for

BOX 3-7 R
ecommendations for the Initial Treatment and a drug such as L-T4 sodium with a relatively narrow therapeu-
Monitoring of Hypothyroidism in Dogs tic window could have clinical consequences. In dogs the relative
bioavailability of a liquid L-T4 sodium solution was demonstrated
Initial Treatment to be 50% higher than that of a tablet formulation in euthyroid
Use a name brand synthetic L-T4 sodium product approved for animal use. dogs; however, the dose required for establishment of euthyroid-
The initial dosage per administration should be 0.02 mg/kg of body weight ism in hypothyroid dogs (0.02 mg/kg every 24 hours) was similar
(0.1 mg/10 pounds) with a maximum initial dose of 0.8 mg. to that required for an oral tablet formulation (Soloxine, Dan-
The initial frequency of administration is every 12 hours. iels Pharmaceuticals) (Le Traon et al, 2007; 2009; Dixon et al,
Initial Monitoring 2002). Because of the limitations of bioequivalence studies, it is
Response to treatment should be critically evaluated 6 to 8 weeks after recommended that clinicians use one formulation of L-T4 sodium
initiating treatment. consistently; and if a change in formulation needs to be made,
Serum T4 or fT4 (measured by equilibrium dialysis) and TSH concentra- therapeutic monitoring should be used to confirm that the dose
tion should be measured 4 to 6 hours after administration of thyroid of the new product is appropriate. Many other factors, including
hormone. concurrent drug administration, nutritional supplements, food
Serum T4 or fT4 concentration should be in the normal range or in- type, timing of meals, concurrent illness, and physiologic condi-
creased. tions such as age and obesity influence L-T4 sodium absorption
Serum TSH concentration should be in the normal range. from the gastrointestinal tract. For example in people, consump-
Measuring serum T4 or fT4 (measured by equilibrium dialysis) concentration tion of a meal at the time of L-T4 sodium administration decreases
immediately prior to thyroid hormone administration (i.e., trough level) is absorption. Administration of L-T4 sodium with food has been
optional but is recommended if thyroid hormone is being given once a day. shown to decrease bioavailability of liquid L-T4 sodium formula-
Serum T4 or fT4 concentration should be in the normal range at this time. tions in dogs (Le Traon etal, 2007). If possible, it is recommended
to avoid giving L-T4 sodium supplements at the time of a meal.
Adapted from consensus recommendations reached at an international symposium When therapeutic monitoring is performed, it is important not
on canine hypothyroidism held in August 1996 (Canine Practice, vol 77, 1997).
to change any of the aforementioned variables. For example, if
fT4, Free thyroxine; L-T4, levothyroxine (also known as L-thyroxine), T4, thyroxine;
TSH, thyroid-stimulating hormone (also known as thyrotropin).
the medication is given at the time of a meal, the same protocol
should be followed on the day of testing.
investigators believe that the dose of L-T4 sodium may correlate Response to Levothyroxine Sodium Therapy
better with body surface area than with body weight (Chastain,
1982). The recommended dosage of L-T4 sodium based on body Thyroid hormone supplementation should be continued for a
surface area is 0.5 mg/m2, however the authors prefer to dose L-T4 minimum of 6 to 8 weeks before critically evaluating the effec-
sodium based on body weight rather than body surface area. Most tiveness of treatment. With appropriate therapy, all of the clinical
studies have shown that the majority of dogs have a good clinical signs and clinicopathologic abnormalities associated with hypo-
response to treatment with once daily L-T4 sodium; however dose thyroidism should resolve (Fig. 3-34). An increase in mental alert-
adjustments are required in 20% to 50% of dogs started on once a ness and activity usually occurs within the rst week of treatment
day therapy (Le Traon etal, 2009; Dixon etal, 2002). Twice daily (Table 3-14); this is an important early indicator that the diagno-
administration of T4 is recommended initially to improve the likeli- sis of hypothyroidism was correct. Although some hair regrowth
hood of a positive response to treatment, which is especially impor- may be observed during the rst month in dogs with endocrine
tant when performing a therapeutic trial. If clinical signs resolve and alopecia, it may take several months for complete regrowth and
T4 concentrations are within the therapeutic range, the frequency a marked reduction in hyperpigmentation of the skin to occur.
of T4 administration can be decreased to once daily. The final L-T4 Initially, the hair coat may appear to worsen as hairs in the telogen
sodium dose should be adjusted based on the measured serum T4 stage of the hair cycle are shed (Credille etal, 2001). If obesity is
concentration and TSH concentration (see Fig. 3-33). In humans caused by hypothyroidism, it should also begin to improve within
the TSH concentration is used to titrate the dose, but this is prob- 2 months after initiating L-T4 sodium therapy along with adjust-
lematic in dogs because of the lower sensitivity of the TSH assay. ments in diet and exercise (Fig. 3-35). Improvement in myocar-
Most L-T4 sodium products are formulated as a tablet ranging in dial function is usually evident within 1 to 2 months, but it may
strength from 0.1 to 0.8 mg; chewable L-T4 sodium formulations be delayed for as long as 12 months. Neurologic deficits improve
and an L-T4 sodium solution (Leventa Merck Animal Health) rapidly after treatment, but complete resolution may take 2 to 3
solution are also available. There are differences in potency and months (Jaggy etal, 1994).
bioavailability between different brands and formulations of L-T4
sodium supplements. Unfortunately, even in human patients, Therapeutic Monitoring
not all available products have been directly compared for bio-
equivalence, and even when products have been documented to Therapeutic monitoring includes evaluation of the clinical response
be bioequivalent, the biologic response can vary between products to thyroid hormone supplementation and measurement of serum
in individual patients. The methods used to establish bioequiva- T4 and TSH concentrations before or after L-T4 sodium admin-
lence in humans also have some limitations. One concern is that istration, or both. Therapeutic monitoring allows treatment to be
the methods rely on administration of a supra-physiologic dose of individualized to the patient based on clinical response, thyroid hor-
L-T4 sodium to euthyroid volunteers. The outcome measures are mone concentrations, and presence or absence of concurrent illness.
area under the curve, maximum concentration, and time to maxi- Serum T4 and TSH should be measured 6 to 8 weeks after initiating
mum concentration, rather than measurement of TSH concentra- therapy, whenever signs of thyrotoxicosis develop, or when there is a
tion and adjustment for endogenous T4 secretion is not required poor response to therapy. T4 concentration and TSH should also be
(Di Girolamo etal, 2008). The Food and Drug Administration measured 2 to 4 weeks after any adjustment in L-T4 sodium therapy.
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A B
FIGURE 3-34 A, A 7-year-old male Maltese with hypothyroidism and diabetes mellitus. B, Same dog as in A after
3 months of levothyroxine (L-T4) sodium treatment. Note the marked improvement in appearance and hair coat.
TABLE 3-14 A
NTICIPATED TIME OF CLINICAL have resolved but the post-pill concentration is in lower half of
RESPONSE TO SODIUM the reference range, a serum TSH should be measured. If this is
LEVOTHYROXINE TREATMENT IN within the reference range indicating good biological response to
DOGS WITH HYPOTHYROIDISM supplementation, the dose does not need to be adjusted. Post dos-
ing serum T4 concentrations measured at times other than 4 to
AREA OF IMPROVEMENT TIME TO IMPROVEMENT 6 hours after L-T4 sodium administration should be interpreted
with the realization that serum T4 may not be at peak concen-
Mentation and activity 2 to 7 days trations. Ideally, all post-pill serum T4 concentrations should be
Lipemia and clinical pathology 2 to 4 weeks greater than 1.5 g/dL, regardless of the time interval between
Dermatologic abnormalities 2 to 4 months L-T4 sodium administration and post-pill blood sampling. The
post-dosing serum T4 concentration may also be affected by the
Neurologic abnormalities 1 to 3 months
pharmaceutical preparation administered, concurrent drugs such
Cardiac abnormalities 1 to 2 months as glucocorticoids, and possibly diet. Post-dosing serum T4 con-
Reproductive abnormalities 3 to 10 months centrations are frequently above the reference range. The nding
of an increased post-dosing serum T4 concentration is not an
absolute indication to reduce the dose of L-T4 sodium, especially
if there are no clinical signs of thyrotoxicosis. However, we recom-
Serum T4 and TSH concentrations are typically evaluated 4 to mend a reduction in the dose whenever serum T4 concentrations
6 hours after the administration of L-T4 sodium in dogs receiving exceed 6.0 g/dL. Dogs are relatively resistant to development of
the medication twice daily and just before and 4 to 6 hours after iatrogenic hyperthyroidism because of the short half-life of T4 in
administration in dogs receiving it once a day (Nachreiner and this species; however, the risk of long-term over-supplementation
Refsal, 1992). This information allows the clinician to evaluate of thyroid hormone in dogs has not been investigated. Current
the dose, frequency of administration, and adequacy of intestinal assays for TSH are not sensitive enough to distinguish a nor-
absorption of L-T4 sodium. Measurement of serum fT4 by the mal from a low TSH concentration and thus cannot distinguish
MED technique can be done in lieu of T4 but is more expensive between those dogs that are adequately supplemented and those
and usually does not have benefit except in dogs with serum T4 that are over-supplemented. If the clinical response is poor to thy-
autoantibodies. Although the presence of thyroid hormone auto- roid hormone supplementation, post dosing serum T4 concentra-
antibodies does not interfere with the physiologic actions of thy- tions are within or above the reference range, and serum TSH
roid hormone supplements, they will interfere with measurement concentrations are less than 0.6 ng/mL, other causes of the clinical
of total T4 concentration (see Fig. 3-19). Results of serum fT4 signs of concern should be investigated. Although trial therapy
measured by assays that use a dialysis step (e.g., MED technique) with liothyronine sodium may be attempted, it is usually ineffec-
are not affected by thyroid hormone autoantibodies. Measure- tive in producing a benecial response in a dog that has failed to
ment of serum TSH is only useful in dogs in which the TSH con- respond to L-T4 sodium and whose serum T4 concentrations are
centration was above the reference range at the time of diagnosis. in the normal range during treatment.
Post dosing serum T4 and TSH results and recommendations
for changes in therapy are given in Fig. 3-33. If the dose of the Treatment of Dogs with Concurrent Nonthyroidal Illness
thyroid hormone supplement and the dosing schedule are appro-
priate, the serum T4 concentration should be in the upper half of Cardiomyopathy
or a little above the reference baseline range (i.e., 3.0 to 6.0 g/dL) Because euthyroid dogs with cardiac disease may have decreased
when measured 4 to 6 hours after thyroid hormone administra- thyroid hormone concentrations, accurate diagnosis of hypothy-
tion, and the serum TSH concentration should be in the reference roidism may be challenging. It is important to be confident of the
range (i.e., less than 0.6 ng/mL) in all blood samples evaluated. diagnosis in such dogs to avoid inappropriate treatment. In hypo-
If the clinical signs do not resolve and the post-pill T4 is below thyroid dogs with cardiac disorders, thyroid hormone supplemen-
or within the lower half of the reference range (< 2.0 g/dL), tation increases myocardial oxygen demand, increases heart rate,
the dose of L-T4 sodium should be increased. If the clinical signs and may reduce ventricular lling time. Decompensation of the
A B
FIGURE 3-35 A, An 8-year-old male castrated Beagle with hypothyroidism. The primary owner complaints were
obesity, lethargy, and weakness. The dog weighed 31 kg. B, Same dog as in A after 6 months of levothyroxine (L-T4)
sodium treatment and adjustments in caloric intake and type of diet to promote weight loss. The owner reported
marked improvement in the dogs alertness and activity, and its body weight had decreased to 19 kg.
cardiac disease can therefore occur with initiation of thyroid hor-

mone supplementation. Because of these concerns the initial dose of BOX 3-8 P
otential Reasons for Poor Clinical Response
thyroid hormone replacement in dogs with cardiac diseases such as to Treatment with Levothyroxine Sodium
cardiomyopathy should be 25% to 50% of the usual starting dose. (Synthetic Thyroxine)
The dose may then be increased incrementally based on the results
of therapeutic monitoring and reevaluation of cardiac function. Owner compliance problems
Use of inactivated or outdated product
Hypoadrenocorticism Use of some generic levothyroxine (L-T4) sodium preparations
In dogs with concurrent hypoadrenocorticism and hypothyroid- Inappropriate L-T4 sodium dose
ism, replacement of mineralocorticoid and glucocorticoid defi- Inappropriate frequency of administration
ciency should be initiated before treatment with L-T4 sodium, Use of thyroid extracts or combination thyroxine/triiodothyronine products
because the increased basal metabolic rate resulting from thyroid Poor bioavailability (e.g., poor gastrointestinal absorption)
hormone supplementation may exacerbate electrolyte distur- Inadequate time for clinical response to occur
bances and cause decompensation of hypoadrenocorticism. Incorrect diagnosis of hypothyroidism
Concurrent disease causing clinical signs (e.g., allergic dermatitis)
Diabetes Mellitus
In dogs with concurrent hypothyroidism and diabetes melli-
tus, hypothyroidism can cause insulin resistance that resolves
with treatment of hypothyroidism (Ford et al, 1993). When Treatment Failure
hypothyroidism is diagnosed and treated in a diabetic patient, There are several possible reasons for a poor response to T4
the blood glucose should be carefully monitored for hypogly- supplementation (Box 3-8). An inappropriate diagnosis of
cemia during the 1 to 2 weeks after initiation of thyroid sup- hypothyroidism is the most common cause. Hyperadrenocor-
plementation. Once euthyroidism is reestablished, increased ticism can be mistaken for hypothyroidism especially if other
insulin sensitivity and a decreased need for insulin may lead to clinical signs, such as polyuria and polydipsia, characteristic of
hypoglycemia. hyperadrenocorticism are not present. This confusion results
because of the suppressive effects of cortisol on serum thyroid
Other Concurrent Illness hormone concentrations. Other causes of skin disorders (e.g.,
The appropriate therapeutic range for hypothyroid dogs with con- atopy and flea allergic dermatitis) may also be confused with
current nonthyroidal illness, for geriatric dogs, and for dogs being hypothyroidism. Failure to recognize the impact of concurrent
treated with drugs, such as phenobarbital and glucocorticoids, that illness on thyroid hormone test results is another common cause
influence serum total T4, is unknown. The target serum total T4 for misdiagnosing hypothyroidism. When a dog shows a poor
concentration should be lower in dogs with concurrent illness and response to L-T4 sodium therapy, the history, physical examina-
those being treated with drugs known to lower thyroid hormone tion ndings, and diagnostic test results that prompted the ini-
concentrations. In such cases, the decision whether to adjust the tiation of L-T4 sodium therapy should be critically reevaluated
dose of thyroid supplementation should be based primarily on and a thorough evaluation for concurrent disease undertaken.
response to therapy. If a positive response to therapy occurs but In addition, problems with the treatment regimen should be
the post-pill T4 concentration is low, no further dosage increase investigated, including poor owner compliance in administering
should be recommended. the hormone, the use of outdated preparations, an inappropriate
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dose or frequency of administration of L-T4 sodium, the use of should be within the normal range in a dog receiving an adequate
some generic L-T4 sodium products, the use of thyroid extracts dosage of a T3 supplement.
or combination thyroxine/triiodthyronine products, or poor
intestinal absorption of L-T4 sodium due to concurrent gastro- Combination Thyroxine/Triiodothyronine Products
intestinal disorders or administration of thyroid supplements
with food. If poor gastrointestinal absorption is suspected, T3 Synthetic preparations are available that contain both L-T4 sodium
may be substituted for T4. and liothyronine (Liotrix, Thyrolar). The T4-to-T3 ratio is gener-
ally 4 to 1 and the unphysiologic proportion of T3 can make it dif-
ficult to maintain euthyroidism (Siegmund etal, 2004). Whether
Treatment with Liothyronine Sodium (Synthetic
there are benefits to using such products for treatment of hypothy-
Triiodothyronine)
roid human patients is controversial. Although most controlled
Liothyronine sodium is not the initial thyroid hormone supplement studies have not provided evidence that treatment with combina-
of choice for the treatment of hypothyroidism. Liothyronine sodium tion products improves patient outcome (Siegmund etal, 2004),
supplementation results in normal serum T3 but low to non-detect- anecdotally some patients report improved quality of life when
able serum T4 concentrations. In contrast, L-T4 sodium therapy treated with combination products. Combination T4/T3 prod-
results in normal serum concentrations of both T3 and T4 because ucts are not recommended in dogs for the following reasons: (1)
L-T4 sodium is converted to T3. Treatment with L-T4 sodium pre- the rate of metabolism and thus the frequency of administration
serves normal regulation of T4 to T3 conversion, which allows physi- differ between L-T4 sodium and liothyronine; (2) L-T4 sodium
ologic regulation of tissue T3 concentrations and decreases the risk therapy provides adequate serum concentrations of both T4 and
of iatrogenic hyperthyroidism (Siegmund etal, 2004). T3; and (3) the use of synthetic combinations may result in serum
Liothyronine therapy is indicated when L-T4 sodium therapy has concentrations of T3 that could cause thyrotoxicosis. In addition,
failed to achieve a response in a dog with conrmed hypothyroid- synthetic combination products tend to be more expensive than
ism, when gastrointestinal malabsorption is the suspected cause for either synthetic L-T4 sodium or liothyronine alone.
failure to respond to the L-T4 supplement. Impaired absorption of
L-T4 sodium should be suspected when baseline serum T4 concen- Thyroid Extracts
trations are low, serum TSH is high, and no increase in serum T4
concentration occurs following oral L-T4 sodium administration. Animal-origin preparations are desiccated thyroid that is derived
Thyroid hormone autoantibodies that interfere with the RIA tech- from cleaned, dried, and powdered thyroid glands of slaughter-
nique should also be considered in this scenario. Gastrointestinal house origin. The porcine product is the most commonly avail-
absorption of ingested T3 approaches 100%, whereas absorption able (Armour Thyroid). The United States Pharmacopeia requires
of L-T4 sodium is only 10% to 50% of the administered dose. thyroid extracts to contain approximately 38 g of T4 and 9 g of
This more complete absorption of T3 reflects less binding afnity T3 for each 60 to 65 mg tablet giving a T4-to-T3 ratio of approxi-
of intestinal contents for T3, especially plasma proteins secreted in mately 4:1, which is similar to combination products. Potential
the bowel lumen. problems with such products include the potential for allergy or
Historically, liothyronine sodium has been used for treatment of sensitivity, batch to batch variability, variable shelf life, and the
hypothyroidism in dogs with normal serum T4 but low serum T3 difficulties outlined earlier in maintaining euthyroidism with the
concentration. These dogs were often suspected of having a defect unphysiologic ratio of T4 to T3. For these reasons crude animal-
in the conversion of T4 to T3. It is now recognized that most of origin thyroid preparations are not recommended for the treat-
these dogs are either normal, have NTIS, or have T3 autoantibod- ment of hypothyroidism in dogs.
ies that cause a false lowering of the serum T3 concentration. T4
to T3 conversion abnormalities have not been documented in any Treatment of Myxedema Coma
species, including dogs. Conceptually, conversion defects are most
likely to be congenital, and thus, affected puppies should either Early recognition and aggressive therapy are critical to survival of
die shortly after birth or develop cretinism. If the decision is made myxedema coma. Consequently, the diagnosis should be made
to treat the dog with normal serum T4 and low serum T3 concen- clinically, and therapy should be initiated without waiting for
tration, L-T4 sodium should be used initially. results of serum thyroid hormone concentrations if this disorder
The initial dosage of liothyronine is 4 to 6 g/kg body weight every is suspected. Treatment consists of thyroid hormone administra-
8 hours. As with L-T4 sodium, the plasma half-life and time of peak tion and correction of the associated physiologic disturbances,
plasma concentration after administration of liothyronine are vari- such as hypothermia, hypovolemia, electrolyte disturbances, and
able among dogs. In most dogs, the plasma half-life of liothyronine is hypoventilation. Because concurrent nonthyroidal disorders com-
approximately 5 to 6 hours, with peak plasma concentrations occur- monly precipitate myxedema coma, diagnosis and treatment of
ring 2 to 5 hours after administration. Once clinical improvement is these disorders is critical. Because of the sluggish circulation and
observed, the frequency of administration may be reduced to twice severe hypometabolism of profound hypothyroidism, absorption
a day. If clinical signs recur, three daily doses should be reinstituted. of therapeutic agents from the gut or from subcutaneous or intra-
Blood for therapeutic monitoring should be obtained just muscular sites is unpredictable, and if possible, thyroid hormone
before and 2 to 4 hours after administration of liothyronine should be administered intravenously. The recommended initial
sodium. Evaluation of serum T3 is mandatory with this supple- dosage for injectable L-T4 sodium is 4 to 5 g/kg every 12 hours
ment because the risk of thyrotoxicosis is much higher. Serum (Pullen and Hess, 2006). A 50% to 75% reduction in the dos-
T4 concentrations are low to non-detectable with adequate T3 age should be considered if there is pre-existing cardiac disease
supplementation because of the negative feedback suppression of or failure (Henik and Dixon, 2000). Oral administration of L-T4
TSH and the inability of T3 to be converted to T4. Guidelines for sodium can also be administered every 12 hours to provide sus-
adjustments in T3 therapy are similar to those for T4 supplements. tained delivery of T4. Appropriate supportive care should also be
Serum T3 concentrations before and following T3 administration initiated, including IV sodium-containing fluids with dextrose
supplementation; slow, passive rewarming with blankets; and are the biomechanical abnormalities caused by radial bowing
assisted ventilation, if needed. Clinical improvement is usually with subsequent humeroradial joint widening and humeroulnar
seen within 24 hours, although death due to concurrent illness joint subluxation, which is seen in some dogs with congenital
is common. Once the dog has stabilized, oral thyroid hormone hypothyroidism. In puppies with CHG due to TPO deficiency,
treatment can be started. the goiter persists and TSH concentrations remain high despite
normalization of total T4 concentrations with twice daily L-T4
sodium at appropriate doses (Fyfe, 2003; Pettigrew etal, 2007).
Thyrotoxicosis
Whether further adjustment of thyroid hormone supplementa-
It is unusual for thyrotoxicosis to develop as a result of excessive tion by therapeutic monitoring would result in resolution of the
administration of L-T4 sodium in the dog, because of the short goiter is unknown.
half-life of L-T4 sodium in the dog as well as physiologic adap- The prognosis for dogs with secondary hypothyroidism
tations that impair gastrointestinal tract absorption and enhance caused by malformation or destruction of the pituitary gland is
clearance of thyroid hormone by the liver and kidneys (Nach- guarded to poor. The life expectancy is shortened in dogs with
reiner and Refsal, 1992). Nevertheless, thyrotoxicosis may develop congenital malformation of the pituitary gland (i.e., pituitary
in dogs receiving excessive amounts of L-T4 sodium (especially dwarsm), primarily because of the multiple problems that
in dogs receiving L-T4 sodium twice daily) and in dogs with develop in early life (see Chapter 2). Acquired secondary hypo-
impaired metabolism of L-T4 sodium (e.g., concurrent renal or thyroidism is usually caused by destruction of the pituitary by
hepatic insufciency). a space-occupying mass, which has the potential to expand into
Clinical signs of thyrotoxicosis include panting, nervousness, the brainstem.
anxiety, tachycardia, aggressive behavior, polyuria, polydipsia,
polyphagia, and weight loss. Sinus tachycardia, atrial flutter, and FELINE HYPOTHYROIDISM
syncope have been reported in dogs with iatrogenic hyperthy-
roidism and concurrent cardiac disease (Fine etal, 2010). Docu- Naturally acquired hypothyroidism is a rare clinical entity in
mentation of mild to marked increased serum thyroid hormone the cat, and most clinical descriptions of feline hypothyroidism
concentrations supports the diagnosis; however, these concentra- in the veterinary literature have been case reports of either pri-
tions can occasionally be within the upper end of the reference mary congenital or adult onset hypothyroidism (Arnold et al,
normal range in a dog with signs of thyrotoxicosis, and conversely 1984; Sjollema etal, 1991; Jones etal, 1992, Rand etal, 1993;
some dogs with increased thyroid hormone concentrations have Mellanby etal, 2005; Traas etal, 2008; Blois etal, 2010; Quante
no clinical signs of thyrotoxicosis. A cardiac evaluation should be et al, 2010). In contrast, iatrogenic hypothyroidism following
performed in dogs with arrhythmias due to suspected thyrotoxi- any of the three common treatments for hyperthyroidism is well
cosis. Adjustments in the dose or frequency of administration of recognized (Nykamp etal, 2005; Williams etal, 2010).
thyroid hormone medication are indicated if clinical signs of thy- Low serum T4 concentrations in cats are frequently documented
rotoxicosis develop in a dog receiving thyroid hormone supple- by veterinarians because of inclusion of serum T4 concentration in
ments. Supplementation may have to be discontinued for a few the typical feline geriatric panel offered by many commercial
days in such animals if the clinical signs are severe. Signs of thy- laboratories. Unfortunately, the blood sample is usually submitted
rotoxicosis should resolve within 1 to 3 days if they are due to for evaluation of another problem (e.g., systemic illness) and the
the thyroid medication and the adjustment in treatment has been low T4 concentration is almost always the result of the suppres-
appropriate, although the presence of underlying heart disease sive effects of nonthyroidal illness on serum T4 concentration (i.e.,
may lead to persistence of cardiac arrhythmias. It is recommended NTIS) and not hypothyroidism.
that therapeutic monitoring should be repeated 2 to 4 weeks after
the dose of L-T4 sodium has been decreased. It is also important ETIOLOGY
to review the criteria used for diagnosis in order to determine
whether T4 supplementation was appropriate in the first place.
Iatrogenic Hypothyroidism
Iatrogenically induced hypothyroidism is usually the result of
PROGNOSIS
treatment of hyperthyroidism and is far more common than natu-
The prognosis for dogs with hypothyroidism depends on the rally acquired hypothyroidism in cats. Iatrogenic hypothyroidism
underlying cause. The life expectancy of an adult dog with can result from bilateral thyroidectomy, radioactive iodine treat-
primary hypothyroidism that is receiving appropriate therapy ment, or treatment with anti-thyroid drugs. Depending on the
should be normal. All the clinical manifestations should resolve treatment used for hyperthyroidism, plasma thyroid hormone
in response to thyroid hormone supplementation. Prognosis in concentrations can decline to subnormal concentrations within
myxedema coma is dependent on early recognition and treat- hours (surgery), days (anti-thyroid drugs), or weeks to months
ment. The prognosis for puppies with hypothyroidism (i.e., cre- (radioactive iodine) after treatment. In a study of 165 cats treated
tinism) is guarded and depends on the severity of skeletal and with radioactive iodine, 30% developed hypothyroidism defined
joint abnormalities at the time treatment is initiated. Although by a total T4 concentration less than the lower reference limit
many of the clinical signs resolve with therapy, musculoskeletal 3 months after treatment (Nykamp et al, 2005). Cats that had
problems, especially degenerative osteoarthritis, may develop as evidence of bilateral thyroid disease were more likely to become
a result of abnormal bone and joint development (Greco etal, hypothyroid than those with unilateral dysfunction. In another
1991; Saunders and Jezyk, 1991). Degenerative osteoarthritis study of 80 non-azotemic hyperthyroid cats treated with anti-
is more prevalent in joints with adjacent epiphyseal dysgenesis. thyroid drugs, 35% became hypothyroid (as defined by a total
Epiphyseal dysgenesis may result in increased susceptibility to T4 concentration below the reference range and a serum TSH
trauma, articular cartilage damage, osteochondrosis-type lesions, concentration above the reference range) 6 months after initiat-
and degenerative joint changes. Contributing to these changes ing treatment (Williams etal, 2010). Hypothyroid cats were more
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likely to become azotemic after treatment than euthyroid cats, and

cats that were both hypothyroid and azotemic had shorter sur- BOX 3-9 Clinical Manifestations of Feline Hypothyroidism
vival times than those that were azotemic but not hypothyroid.
Azotemia was presumed to be due to a decrease in glomerular Adult-Onset Hypothyroidism
filtration rate in cats with underlying chronic kidney disease and Lethargy
concurrent hypothyroidism. Prolonged iatrogenic hypothyroid- Inappetence
ism should therefore be avoided especially in cats with known Obesity
concurrent chronic kidney disease. In cats with iatrogenic hypo- Dermatologic
thyroidism, the clinical signs are usually mild with decreased Seborrhea sicca
activity and weight gain typically observed. These clinical signs are Dry, lusterless hair coat
usually not worrying to the owner of a previously hyperthyroid Easily epilated hair
cat; however, because of the risk of progressive azotemia, thyroid Poor regrowth of hair
hormone supplementation should be instituted in hypothyroid Endocrine alopecia
azotemic cats, in cats with clinical signs of hypothyroidism, and Alopecia of pinnae
in cats with hypothyroidism that persists 3 to 6 months beyond Thickened skin
definitive treatment with radioactive iodine or thyroidectomy. In Myxedema of the face
cats treated with oral anti-thyroid drugs that become hypothyroid, Bradycardia
a decreased drug dose should be implemented. Mild hypothermia
Adult-Onset Hypothyroidism Disproportionate dwarfism
Naturally acquired adult-onset primary hypothyroidism is rarely Failure to grow
documented in the cat. Two well documented cases have been Large head
published. One cat had lymphocytic thyroiditis, whereas in Short, broad neck
another cat the thyroid gland could not be identified at necropsy Short limbs
(Rand etal, 1993; Blois etal, 2010). Secondary hypothyroidism Lethargy
due to head trauma was reported in an 18-month-old cat with Mental dullness
stunted growth and a history of head trauma at 8 weeks of age Constipation
(Mellanby etal, 2005). The diagnosis was made by documenta- Hypothermia
tion of low total T4 and TSH and no increase in T4 or TSH after Bradycardia
administration of TRH. A magnetic resonance imaging (MRI) Retention of kitten hair coat
scan of the brain revealed an almost empty sella turcica and a very Retention of deciduous teeth
small pituitary gland.
Congenital primary hypothyroidism causing disproportionate are lethargy, inappetence, dermatologic abnormalities, and obesity
dwarsm is recognized more frequently than adult-onset hypothy- (Fig. 3-36). Lethargy and inappetence may become severe. Der-
roidism in the cat. Reported causes of congenital hypothyroidism matologic signs are quite variable and often develop secondary to
include thyroid dyshormonogenesis (Sjollema et al, 1991; Jones a decrease in grooming behavior by the cat. Affected cats develop
etal, 1992), thyroid dysmorphogenesis (Traas etal, 2008), and TSH a dull, dry, unkempt hair coat with matting and seborrhea. Easily
resistance. Goiter is expected in congenital hypothyroidism due to epilated and poor regrowth of hair may lead to alopecia affect-
dyshormonogenesis. An inherited defect in iodine organication ing the pinnae, pressure points, and the dorsal and lateral tail
was documented in a family of Abyssinian cats with congenital base region (Peterson, 1989; Rand etal, 1993; Blois etal, 2010).
hypothyroidism and goiter (Jones etal, 1992); an autosomal reces- Asymmetric or bilaterally symmetric alopecia involving the lateral
sive mode of inheritance was suspected. CHG due to TPO defi- neck, thorax, and abdomen may also develop. Myxedema of the
ciency was reported in a family of Domestic Short-Hair cats and was face, causing a puffy appearance, was reported in one cat with
also thought to be inherited as an autosomal recessive trait (Mazrier naturally acquired adult-onset hypothyroidism (Rand etal, 1993).
etal, 2003). A colony of cats with hypothyroidism and thyroiditis Bradycardia and mild hypothermia may be additional ndings on
with severe signs of hypothyroidism developing 40 to 60 days after physical examination.
birth has also been reported (Schumm-Draeger et al, 1996). The
severity of thyroiditis was decreased by early treatment with thyroid Congenital Hypothyroidism
hormone. TSH resistance was proposed to be the cause of inherited The clinical signs of congenital hypothyroidism are similar to
primary hypothyroidism in a colony of Japanese cats (Tanase etal, those in dogs. Affected kittens typically appear normal at birth,
1991). The cats in this colony of hypothyroid cats did not develop but a decrease in growth rate usually becomes evident by 6 to 8
a goiter, and the defect was inherited as an autosomal recessive trait. weeks of age. Disproportionate dwarsm develops over the ensu-
Although rare, iodine deciency has been reported to cause hypo- ing months with affected kittens developing large heads, short
thyroidism in kittens fed a strict all-meat diet. broad necks, and short limbs. Additional ndings include leth-
argy, mental dullness, constipation, hypothermia, bradycardia,
CLINICAL SIGNS and prolonged retention of deciduous teeth (Arnold etal, 1984;
Peterson, 1989; Sjollema etal, 1991; Jones etal, 1992; Traas etal,
2008; Fig. 3-37). The hair coat consists mainly of the undercoat
Adult-Onset Hypothyroidism with primary guard hair scattered thinly throughout. Radio-
The clinical signs that have been associated with feline hypothy- graphic abnormalities are similar to those described for the dog.
roidism are listed in Box 3-9. Of these, the most commonly seen Two littermate kittens with hypothyroidism had a concurrent
C
FIGURE 3-36 A, A 12-year-old spayed female cat with spontaneous adult onset hypothyroidism. The cat presented
for evaluation of obesity, lethargy, and a dull dry hair coat. B, Close up of the hair coat showing dry dull coat with
dry flaky skin. C, Same cat after 3 months of thyroid supplementation. Clinical signs had all resolved.
Baseline Serum Thyroxine Concentration

Measurement of baseline serum T4 concentration is the best ini-
tial screening test for hypothyroidism in a cat with appropriate
clinical signs. Cats with hypothyroidism typically have baseline
serum T4 concentrations below the lower limit of the reference
range, and sometimes T4 is undetectable. A total T4 within the
reference range is useful to exclude a diagnosis of hypothyroid-
ism, but because nonthyroidal illness and administration of drugs
(e.g., glucocorticoids) can lower serum T4 concentration into the
hypothyroid range (Fig. 3-38), a low serum T4 concentration does
not, by itself, conrm hypothyroidism. As in the dog, the total T4
should be interpreted in the context of the clinical signs and pres-
ence or absence of other concurrent illness and concurrent drug
therapy. If the history and physical ndings are consistent with
FIGURE 3-37 Lateral abdominal radiograph of a young cat with constipation the disease, the lower the T4 value, the more likely it is that the
due to hypothyroidism. cat truly has hypothyroidism. If the clinicians index of suspicion
is not high for hypothyroidism but the serum T4 concentration
is low, then other factors such as nonthyroidal illness are much
more likely.
seizure disorder but whether the seizures were related to hypothy- Baseline Serum Triiodothyronine Concentration
roidism was unclear (Traas etal, 2008). Measurement of baseline serum T3 concentration is not rou-
tinely performed in cats, and reported total T3 concentrations
TESTS OF THYROID GLAND FUNCTION have been variable in those cases of feline hypothyroidism in
which it has been measured. Presumably, the problems encoun-
Hormone measurements that have been used for documenta- tered with serum T3 measurements in differentiating euthy-
tion of feline hypothyroidism include total T4, fT4, total T3, and roidism from hypothyroidism in the dog also exist in the cat.
TSH concentration. For a detailed discussion of thyroid hormone Ideally, baseline serum T3 concentration should be less than the
assays in cats see Chapter 4. lower limit of normal for the laboratory used in the cat with
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50 100 8
40 80
6
3

Serum T4 (g/dL)
60
Serum T4 (nmol/L)
30
4
2
20 40
1 2
10 20
0 0 0 0
A Mild Moderate Severe B Mild Moderate Severe
FIGURE 3-38 Box plots of serum total thyroxine (T4) (A) and free T4 (fT4) (B) concentrations in 221 cats with
nonthyroidal disease stratified according to severity of disease. Of the 221 cats, 65 had mild disease, 83 had
moderate disease, and 73 had severe disease. For each box plot, T-bars represent the main body of data, which
in most instances is equal to the range. Each box represents the interquartile range (25th to 75th percentile). The
horizontal bar in each box is the median. Open circles represent outlying data points. The shaded area indicates the
reference range. (From Peterson ME, etal.: Measurement of serum concentrations of free thyroxine, total thyroxine,
and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease, J Am Vet Med Assoc
218[4]:529, 2001.)
hypothyroidism. However, a normal serum T3 concentration in Baseline Serum Thyroid-Stimulating Hormone Concentration
a cat with appropriate history, physical examination ndings, A canine TSH assay (Immulite canine TSH assay, Diagnostic
and low serum T4 concentration does not rule out hypothy- Products Corporation). has been validated for use in cats (Wakel-
roidism. Similarly, a low serum T3 concentration in a cat with ing et al, 2008; 2011). Although the sensitivity of the assay is
normal serum T4 concentration is not consistent with hypothy- suboptimal, a high TSH concentration in a cat with a concurrent
roidism, especially if the remainder of the clinical picture does decrease in total T4 is highly specific for a diagnosis of hypothy-
not support the diagnosis. roidism. Increased TSH has been documented in cats with con-
genital hypothyroidism, spontaneous adult unset hypothyroidism,
Baseline Serum Free Thyroxine Concentration and iatrogenic hypothyroidism.
Cats with hypothyroidism should have baseline serum fT4 con-
centrations below the lower limit of normal for the laboratory Tests for Lymphocytic Thyroiditis
used. As with serum T4, a low serum fT4 concentration does Tests for the presence of circulating Tg and microsomal antibodies
not, by itself, conrm hypothyroidism. Nonthyroidal factors, were reported to be positive in a colony of cats with early onset
most notably concurrent illness and administration of drugs thyroiditis; however commercial assays for these antibodies are not
(e.g., glucocorticoids), can falsely lower the serum fT4 concurrently available in the cat (Schumm-Draeger etal, 1996).
centration into the hypothyroid range (see Fig. 3-38). Serum
fT4 is believed to be less influenced by factors such as nonthy- Factors Affecting Baseline Thyroid Hormone Concentrations
roidal illness and administration of drugs than serum T4, but Many of the nonthyroidal factors known to influence serum thy-
serum fT4 concentrations have been reported to increase rather roid hormone concentrations in dogs have yet to be evaluated in
than decrease in some euthyroid cats with nonthyroidal illness cats. The effects of age, gender, and breed on serum T4 and T3 con-
(Mooney et al, 1996a; Peterson et al, 2001). The comparative centrations in cats are controversial. In one study, serum T4 and,
sensitivity and specicity of serum fT4 versus serum T4 for eval- to a lesser extent, serum T3 concentrations in both genders tended
uation of thyroid gland function in cats with suspected hypo- to decrease until approximately 5 years of age and then increase
thyroidism is unknown. again; females (intact and neutered) had signicantly higher
serum T4 but not T3 concentrations than males (intact or neu- ranged from 111% to 300%, and in cats with nonthyroidal illness
tered); and serum T3 but not T4 concentration was signicantly total T4 increased by 146% to 414% (van Hoek etal, 2010). Cats
higher in pedigree cats than in Domestic Short- and Long-Haired with iatrogenic hypothyroidism after radioactive iodine treatment
cats (Thoday etal, 1984). Serum thyroid hormone concentrations had a percent increase in total T4 of 11% or less. These results sug-
remained within the reference range in these cats regardless of gest that the TSH stimulation test is useful for diagnosis of hypo-
any influence of age, gender, or breed on blood thyroid hormone thyroidism in cats; however, the TSH stimulation test is rarely
levels. In another study, Zerbe, etal. (1998) identied values for used clinically because of the expense of rhTSH.
serum T4 and fT4 concentrations within reference range for adult
cats in kittens from birth to 12 weeks of age, whereas serum T3 Thyrotropin-Releasing Hormone Stimulation Test
concentrations were low until kittens were 5 weeks of age. Other The TRH stimulation test has been recommended for diagnosis
investigators have not identied an effect of age, gender, and/or of hyperthyroidism in cats (see Chapter 4) but is currently rarely
breed on serum thyroid hormone concentrations. A diurnal varia- used for this purpose and it has not been evaluated for diagnosis of
tion in blood thyroid hormone concentrations apparently does hypothyroidism in cats. Theoretically in a cat with a functionally
not occur in the cat (Hoenig and Ferguson, 1983), so the time of intact pituitary-thyroid axis, the serum T4 concentration should
day that the blood is sampled should not affect the results. increase 1 to 2 g/dL or greater than 50% above baseline serum T4
Nonthyroidal illness causing NTIS has been documented in the concentration, after administration of TRH. Failure of serum T4
cat (Peterson and Gamble, 1990; Mooney etal, 1996a; Peterson concentration to increase after TRH administration suggests dys-
et al, 2001; see Fig. 3-38). As with the dog, serum T4 and T3 function of either the pituitary or the thyroid gland or suppression
concentrations are more likely to be decreased with nonthyroi- of the pituitary-thyroid axis by nonthyroidal factors. If results of
dal illness than serum fT4 concentrations, and there is a direct a previous TSH stimulation test were normal, an abnormal TRH
correlation between the severity of illness and the magnitude of stimulation test implies pituitary dysfunction.
the decrease in serum thyroid hormone concentrations (see Fig.
3-38). The more severe the nonthyroidal illness, the more likely ESTABLISHING THE DIAGNOSIS
serum thyroid hormone concentrations will decrease into the
hypothyroid range. Serum T4 values less than 0.5 g/dL and The diagnosis of hypothyroidism in the cat should be based on
fT4 values less than 0.5 ng/dL may occur with severe systemic a combination of history, clinical signs, physical examination
illness in a euthyroid cat. It is interesting to note that some euthy- ndings, low serum thyroid hormone concentrations and increased
roid cats with nonthyroidal disease will have decreased serum T4 serum TSH concentration. A minimum data base of CBC, serum
concentrations but increased serum fT4 concentrations when an chemistry profile, and urinalysis should be performed to identify
equilibrium dialysis technique is used to measure fT4. Increased changes supportive of hypothyroidism and assess for the presence
serum fT4 concentrations were found in 12% of 98 euthyroid cats of nonthyroidal illness. The most consistent findings in hypothy-
with nonthyroidal illness in one study (Mooney etal, 1996a) and roid cats include hypercholesterolemia; normocytic, normochro-
6.3% of 221 euthyroid cats with nonthyroidal illness in another mic non-regenerative anemia; and an increase in creatine kinase. A
study (Peterson etal, 2001). Nonthyroidal illnesses in these cats low serum T4 concentration in conjunction with an increased TSH
included diabetes mellitus, gastrointestinal tract disease, hepatic concentration supports the diagnosis of primary hypothyroidism.
disease, renal insufciency, and neoplasia. The reason for increased Hypothyroidism is much more likely in a cat that has undergone
serum fT4 concentrations in some cats with nonthyroidal illness is thyroidectomy or radioactive iodine treatment or a kitten with dis-
not known but may be related to decreased protein binding of cir- proportionate dwarsm; spontaneous adult onset hypothyroidism
culating T4 and/or impaired clearance of T4 from the circulation. is so rare that nonthyroidal illness should be carefully considered
The effects of drugs on serum thyroid hormone concentrations prior to making a diagnosis of hypothyroidism. Further diagnos-
have not been extensively evaluated in the cat. Two classes of drugs tic testing that should be considered to confirm the diagnosis and
that can decrease serum thyroid hormone concentrations into the localize the location of the defect includes scintigraphy and a TSH
hypothyroid range are glucocorticoids and anti-thyroid hormone stimulation test. Response to trial therapy with L-T4 sodium also
drugs (i.e., methimazole, propylthiouracil). Undoubtedly, many supports the diagnosis.
more drugs also affect serum thyroid hormone concentrations Because naturally acquired primary hypothyroidism is rare and
in cats. Until proven otherwise, any drug should be suspected a low serum T4 concentration in an adult cat is almost always
of affecting thyroid hormone test results, especially if the drug caused by nonthyroidal illness, it is important to avoid making
has been shown to alter serum thyroid hormone concentrations a diagnosis of hypothyroidism based solely on serum T4 con-
in humans and dogs (see Table 3-13 and Box 3-6) and the his- centration in an adult cat that has not been previously treated
tory and clinical signs of the patient do not support a diagnosis of for hyperthyroidism (see Chapter 4). A serum fT4 concentration
hypothyroidism. and TSH concentration should be measured prior to confirming
the diagnosis. It is important to remember that response to trial
Thyroid-Stimulating Hormone Stimulation Test therapy with L-T4 sodium is nonspecic and does not, by itself,
The indications, protocol, and interpretation of the TSH stimula- prove the diagnosis.
tion test are similar for the cat and dog except that a lower dose of
recombinant human thyrotropin (rhTSH) (25 micrograms IV) is TREATMENT AND PROGNOSIS
used in the cat (Stegeman etal, 2003; van Hoek etal, 2010). In
euthyroid cats, there is a two- to threefold increase in total T4 6 to For cats with iatrogenic hypothyroidism due to thyroidectomy
8 hours after TSH administration. Although responses of healthy or radioactive iodine treatment, transient hypothyroidism is
euthyroid cats to TSH have been studied, there are few studies expected after treatment, but cats should become euthyroid after
reporting changes in total T4 after TSH administration in cats 2 to 3 months. Treatment with L-T4 sodium is indicated if clinical
with nonthyroidal illness or hypothyroidism. In one small study, signs of hypothyroidism are present, if the cat is azotemic, or if
the percent increase after TSH administration in healthy cats hypothyroidism does not resolve by 3 to 6 months after treatment.
|
Treatment of hypothyroidism is similar for the cat and dog. hormone concentrations are normal after 6 to 8 weeks of treat-
L-T4 sodium is the recommended thyroid hormone supplement but there is no clinical response, the clinician should reas-
ment. The initial dosage for cats is 0.05 to 0.1 mg once daily. sess the diagnosis.
A minimum of 6 to 8 weeks should elapse before critically The prognosis for feline hypothyroidism depends on the under-
assessing the cats clinical response to treatment. Subsequent lying cause and the age of the cat at the time clinical signs develop.
reevaluations should include history, physical examination, and With appropriate therapy, the clinical manifestations should
measurement of serum thyroid hormone concentrations and resolve following thyroid hormone supplementation and the life
serum TSH (see Therapeutic Monitoring). The goal of therapy expectancy of an adult cat with primary hypothyroidism should
is to resolve the clinical signs of hypothyroidism while avoiding be normal. The prognosis for kittens with congenital hypothy-
signs of hyperthyroidism. This can usually be accomplished by roidism is guarded and depends on the severity of skeletal changes
maintaining serum T4 concentration between 1.0 and 3.0 g/ at the time treatment is initiated and neurologic status. Although
dL. The dosage and frequency of L-T4 sodium administration many of the clinical signs resolve with therapy, musculoskeletal
may need modication to achieve these goals. If serum thyroid and neurologic problems may persist.
REFERENCES
Canine Hypothyroidism Bianco AC, Kim BW: Intracellular pathways of Brauer C, etal.: Metabolic and toxic causes
Adams WH, etal.: Quantitative 99 m Tc- iodothyronine metabolism: implications of of canine seizure disorders: a retrospec-
pertechnetate thyroid scintigraphy in deiodination for thyroid hormone action. tive study of 96 cases, Vet J 187:272,
normal beagles, Vet Radiol Ultrasound In Braverman LE, Cooper DS, editors: The 2011.
38(4):323, 1997. thyroid: a fundamental and clinical text, Braund KG, etal.: Hypothyroid myopathy in
Atkinson K, Aubert I: Myxedema coma leading ed 10, Philadelphia, 2013, WB Saunders, two dogs, Vet Pathol 18:589, 1981.
to respiratory depression in a dog, Can Vet p 103. Brmel C, etal.: Ultrasonographic evaluation
J 45(4):318, 2004. Bichsel P, etal.: Neurologic manifestations of the thyroid gland in healthy, hypothy-
Avgeris S, etal.: Plasma von Willebrand fac- associated with hypothyroidism in four roid, and euthyorid Golden Retrievers with
tor concentration and thyroid function dogs, J Am Vet Med Assoc 192:1745, nonthyroidal illness, J Vet Intern Med
in dogs, J Am Vet Med Assoc 196:921, 1988. 19(4):499, 2005.
1990. Bilezikian JP, Loeb JN: Increased myocardial Brmel C, etal.: Comparison of ultrasono-
Barrie J, etal.: Plasma cholesterol and beta-receptor and adrenergic responsive- graphic characteristics of the thyroid
lipoprotein concentrations in the dog: ness, Endocr Rev 4:3378, 1983. gland in healthy small-, medium-, and
the effects of age, breed, gender and Bishnoi A, etal.: Effects of commonly pre- large-breed dogs, Am J Vet Res 67(1):70,
endocrine disease, J Small Anim Pract scribed nonsteroidal anti-inflammatory 2006.
34:507, 1993. drugs on thyroid hormone measurements, Bruner JM, etal.: Effect of time of sample
Beale KM, etal.: Serum thyroid hormone Am J Med 96:235, 1994. collection on serum thyroid-stimulating
concentrations and thyrotropin responsive- Blois SL, etal.: Multiple endocrine diseases hormone concentrations in euthyroid and
ness in dogs with generalized dermatologic in dogs: 35 cases (1996-2009), J Am Vet hypothyroid dogs, J Am Vet Med Assoc
disease, J Am Vet Med Assoc 201:1715, Med Assoc 238:1616, 2011. 212:1572, 1998.
1992a. Boretti FS, etal.: Evaluation of recombinant Calvert CA, etal.: Congestive cardiomyopathy
Beale K, etal.: Correlation of racing and repro- human thyroid-stimulating hormone to in Doberman Pinscher dogs, J Am Vet Med
ductive performance in Greyhounds with test thyroid function in dogs suspected Assoc 181:598, 1982.
response to thyroid function testing, J Am of having hypothyroidism, Am J Vet Res Calvert CA, etal.: Thyroid-stimulating hormone
Anim Hosp Assoc 28:263, 1992b. 67(12):2012, 2006a. stimulation tests in cardiomyopathic Do-
Behrend EN, etal.: Effect of storage condi- Boretti FS, etal.: Comparison of the biological berman Pinschers: a retrospective study,
tions on cortisol, total thyroxine, and activity of recombinant human thyroid- J Vet Intern Med 12:343, 1998.
free thyroxine concentrations in serum stimulating hormone with bovine thyroid- Campbell KL, Davis CA: Effects of thyroid
and plasma of dogs, J Am Vet Med Assoc stimulating hormone and evaluation of hormones on serum and cutaneous fatty
212:1564, 1998. recombinant human thyroid-stimulating acid concentrations in dogs, Am J Vet Res
Beijerink NJ, etal.: Adenohypophyseal func- hormone in healthy dogs of differ- 51:752, 1990.
tion in bitches treated with medroxyproges- ent breeds, Am J Vet Res 67(7):1169, Carter GR, etal.: Serum total thyroxine and
terone acetate, Domest Anim Endocrinol 2006b. thyroid stimulating hormone concentra-
32:63, 2007. Boretti FS, etal.: Comparison of 2 doses of tions in dogs with behavior problems, J Vet
Belshaw BE, etal.: The iodine requirement recombinant human thyrotropin for thyroid Behavior 4:230, 2009.
and influence of iodine intake on iodine function testing in healthy and sus- Castillo VA, etal.: Nutrition: commercial
metabolism and thyroid function in the pected hypothyroid dogs, J Vet Intern Med diet induced hypothyroidism due to high
adult beagle, Endocrinology 96:1280, 23(4):856, 2009. iodine. A histological and radiological
1975. Borst GC, etal.: Fasting decreases thyrotropin analysis, Vet Quarterly 23:218, 2001.
Benjamin SA, etal.: Associations between responsiveness to thyrotropin-releasing Chastain CB: Canine hypothyroidism, J Am Vet
lymphocytic thyroiditis, hypothyroidism, hormone: a potential cause of misinterpre- Med Assoc 181:349, 1982.
and thyroid neoplasia in beagles, tation of thyroid function tests in the criti- Chastain CB, Schmidt B: Galactorrhea associated
Vet Pathol 33:486, 1996. cally ill, J Clin Endocrinol Metab 57:380, with hypothyroidism in intact bitches, J Am
Bhatti SFM, etal.: Effects of growth hormone 1983. Anim Hosp Assoc 16:851, 1980.
secretagogues on the release of adeno- Bowen D, etal.: Autoimmune polyglandular Chastain CB, etal.: Myxedema coma in two
hypophyseal hormones in young and old syndrome in a dog: a case report, J Am dogs, Canine Pract 9:20, 1982.
healthy dogs, Vet J 172:515, 2006. Anim Hosp Assoc 22:649, 1986.
Chastain CB, etal.: Congenital hypothyroidism Diaz-Espieira MM, etal.: Functional and mor- Ferguson DC: Testing for hypothyroidism in
in a dog due to an iodide organication phological changes in the adenohypophysis dogs, Vet Clin Small Anim 37:647, 2007.
defect, Am J Vet Res 44:1257, 1983. of dogs with induced primary hypothyroid- Ferguson DC, Hoenig M: Re-examination of
Conaway DH, etal.: The familial occurrence of ism: loss of TSH hypersecretion, hyper- dosage regimens for l-thyroxine (T4) in the
lymphocytic thyroiditis in Borzoi dogs, Am somatotropism, hypoprolactinemia, and dog: bioavailability and persistence of TSH
J Med Genet 22:409, 1985a. pituitary enlargement with transdifferentia- suppression (abstract), J Vet Intern Med
Conaway DH, etal.: Clinical and histological tion, Domestic Anim Endocrinol 35(1):98, 11:120, 1997.
features of primary progressive, familial 2008b. Ferguson DC, Peterson ME: Serum free and
thyroiditis in a colony of Borzoi dogs, Vet Diaz-Espieira MM, etal.: Adenohypophyseal total iodothyroinine concentrations in dogs
Pathol 22:439, 1985b. function in dogs with primary hypothyroid- with hyperadrenocorticism, Am J Vet Res
Cortese L, etal.: Hyperprolactinaemia and ism and nonthyroidal illness, J Vet Intern 53:1636, 1992.
galactorrhoea associated with primary Med 23:100, 2009. Ferguson DC, etal.: Carprofen lowers total T4
hypothyroidism in a bitch, J Small Anim Di Girolamo G, etal.: Bioequivalence of two and TSH, but not free T4 concentrations in
Pract 38:572, 1997. levothyroxine tablet formulations without dogs (abstract), J Vet Intern Med 13:243,
Credille KM, etal.: The effects of thyroid and with mathematical adjustment for 1999.
hormones on the skin of Beagle dogs, J Vet basal thyroxine levels in healthy Argentin- Ferm K, etal.: Prevalence of diagnostic char-
Intern Med 15:539, 2001. ian volunteers: a single dose, randomized, acteristics indicating canine autoimmune
Crispin SM, Barnett KC: Arcus lipoides open-label, crossover study, Clin Ther lymphocytic thyroiditis in giant schnauzer
corneae secondary to hypothyroidism in 30(11):2015, 2008. and hovawart dogs, J Small Anim Pract
the Alsatian, J Small Anim Pract 19:127, Dillitzer N, etal.: Intake of minerals, trace ele- 50:176, 2009.
1978. ments and vitamins in bone and raw food Fine DM, etal.: Cardiovascular manifestations
Dalton RG, etal.: Hypothyroidism as a cause of rations in adult dogs, Br J Nutr 106:S53, of iatrogenic hyperthyroidism in two dogs,
acquired von Willebrands disease, Lancet 2011. J Vet Cardiology 12:141, 2010.
1:1007, 1987. Dixon RM, etal.: Serum thyrotropin concen- Ford SL, etal.: Insulin resistance in three dogs
Daminet S, Paradis M: Evaluation of thyroid trations: a new diagnostic test for canine with hypothyroidism and diabetes mellitus,
function in dogs suffering from recurrent hypothyroidism, Vet Rec 138:594, 1996. J Am Vet Med Assoc 202:1478, 1993.
flank alopecia, Can Vet J 41:699, 2000. Dixon RM, etal.: Epideiological, clinical, Frank LA: Comparison of thyrotropin-releasing
Daminet S, etal.: Evaluation of thyroid func- haematological and biochemical charac- hormone (TRH) to thyrotropin (TSH) stimula-
tion in obese dogs and in dogs undergo- teristics of canine hypothyroidism, Vet Rec tion for evaluating thyroid function in dogs,
ing a weight loss protocol, J Vet Med 145:481, 1999. J Am Anim Hosp Assoc 32:481, 1996.
A Physiol Pathol Clin Med 50(4):213, Dixon RM, etal.: Treatment and therapeutic Frank LA, etal.: Effects of sulfamethoxazole-
2003a. monitoring of canine hypothyroidism, trimethoprim on thyroid function in dogs,
Daminet S, etal.: Influence of acetylsalicylic J Small Anim Pract 43:334, 2002. Am J Vet Res 66(2):256, 2005.
acid and ketoprofen on canine thyroid Dodds WJ: Estimating disease prevalence with Fritz TE, etal.: Pathology and familial
function tests, Vet J 166(3):224, 2003b. health surveys and genetic screening, Adv incidence of orchitis and its relation to
Daminet S, etal.: Use of recombinant human Vet Sci Comp Med 39:29, 1995. thyroiditis in a closed beagle colony, Exp
thyroid-stimulating hormone for thyrotropin Dodgson SE, etal.: Congenital hypothyroidism Mol Pathol 24:142, 1976.
stimulation test in healthy hypothyroid and with goiter in Tenterfield Terriers, J Vet Fyfe JC, etal.: Congenital hypothyroidism with
euthyroid sick dogs, Can Vet J 48:1273, Intern Med 26:1350, 2012. goiter in toy fox terriers, J Vet Intern Med
2007. Doerge DR, Decker CJ: Inhibition of peroxidase- 17:50, 2003.
de Bruijne J, etal.: Fat mobilization and catalyzed reactions by arylamines: mechanism Fyfe JC, etal.: A thyroid peroxidase (TPO)
plasma hormone levels in fasted dogs, for the anti-thyroid action of sulfamethazine, mutation in dogs reveals a canid-specific
Metabolism 30:190, 1981. Chem Res Toxicol 7:164, 1994. gene structure, Mamm Genome 24:127,
Delauche AJ, etal.: Nemaline rods in canine Doliger S, etal.: Histochemical study of 2013.
myopathies: 4 case reports and literature cutaneous mucins in hypothyroid dogs, Vet Gal A, etal.: Congenital adenohypophyseal
review, J Vet Intern Med 12:424, Pathol 32:628, 1995. hypoplasia associated with secondary
1998. Dowell RT, etal.: Beta-adrenergic receptors, hypothyroidism in a 2 week old Portuguese
Dewey CW, etal.: Neuromuscular dysfunction adenylate cyclase activation, and myobril water dog, Can Vet J 53:659, 2012.
in ve dogs with acquired myasthenia gra- enzyme activity in hypothyroid rats, Am J Gaschen F, etal.: Recognition of triiodothyro-
vis and presumptive hypothyroidism, Prog Physiol 266:H2527, 1994. nine-containing epitopes in canine thyro-
Vet Neurol 6:117, 1995. Duclos DD, etal.: Prognosis for treatment of globulin by circulating thyroglobulin autoan-
De Roover K, etal.: Effect of storage of adult onset demodicosis in dogs: 34 cases, tibodies, Am J Vet Res 54:244, 1993.
reconstituted recombinant human thyroid- J Am Vet Med Assoc 204:616, 1994. Gaskill CL, etal.: Effects of phenobarbital
stimulating hormone (rhTSH) on thyroid- Eigenmann JE: Diagnosis and treatment of treatment on serum thyroxine and thyroid-
stimulating hormone (TSH) response dwarsm in a German Shepherd dog, J Am stimulating hormone concentrations
testing in euthyroid dogs, J Vet Intern Med Anim Hosp Assoc 17:798, 1981. in epileptic dogs, J Am Vet Med Assoc
20:812, 2006. Eisenbarth GS, etal.: Autoimmune polyendo- 215:489, 1999.
Diaz-Espieira MM, etal.: Assessment of crine syndromes, N Engl J Med 350:20, Gaughan KR, Bruyette DS: Thyroid function
thyroid function in dogs with low plasma 2004. testing in Greyhounds, Am J Vet Res
thyroxine concentrations, J Vet Intern Med Elliott DA, etal.: Thyroid hormone concentra- 62:1130, 2001.
21:25, 2007. tions in critically ill canine intensive care Gaynor AR, etal.: Risk factors for acquired
Diaz-Espieira MM, etal.: Thyrotropin releas- patients, J Vet Emerg Crit Care 5:17, 1995. megaesophagus in dogs, J Am Vet Med
ing hormone-induced growth hormone Evason MD, etal.: Alterations in thyroid hor- Assoc 211:1406, 1997.
secretion in dogs with primary hypo- mone concentrations in healthy sled dogs Gerritsen RJ, etal.: Relationship between atrial
thyroidism, Domestic Anim Endocrinol before and after athletic conditioning, Am brillation and primary hypothyroidism in
34(2):176, 2008a. J Vet Res 65(3):333, 2004. the dog, Vet Quart 18:49, 1996.
|
Gieger TL, etal.: Thyroid function and serum Hall IA, etal.: Effect of trimethoprim/sulfa- Kantrowitz LB, etal.: Serum total thyroxine,
hepatic enzyme activity in dogs after phe- methoxazole on thyroid function in dogs total triiodothyronine, free thyroxine, and
nobarbital administration, J Vet Intern Med with pyoderma, J Am Vet Med Assoc thyrotropin concentrations in epileptic
14:277, 2000. 202:1959, 1993. dogs treated with anticonvulsants, J Am
Gonzalez E, Quadri SK: Effects of aging on Hamann F, etal.: Pituitary function and mor- Vet Med Assoc 214:1804, 1999.
the pituitary-thyroid axis in the dog, Exp phology in two German Shepherd dogs with Kantrowitz LB, etal.: Serum total thyroxine,
Gerontology 23:151, 1988. congenital dwarsm, Vet Rec 144:644, total triiodothyronine, free thyroxine, and
Gookin JL, etal.: Clinical hypothyroidism as- 1999. thyrotropin concentrations in dogs with
sociated with trimethoprim-sulfadiazine Hargis AM, etal.: Relationship of hypothyroid- nonthyroidal illness, J Am Vet Med Assoc
administration in a dog, J Am Vet Med ism to diabetes mellitus, renal amyloido- 219:765, 2001.
Assoc 214:1028, 1999. sis, and thrombosis in pure-bred Beagles, Kaptein EM, etal.: Effects of prednisone
Gosselin SJ, etal.: Biochemical and immuno- Am J Vet Res 42:1077, 1981. on thyroxine and 3,5,3-triiodothyronine
logical investigation on hypothyroidism in Hawthorn MH, etal.: Effect of thyroid status metabolism in normal dogs, Endocrinology
dogs, Can J Comp Med 44:158, 1980. on beta-adrenoreceptors and calcium 130:1669, 1992.
Gosselin SJ, etal.: Lymphocytic thyroiditis in channels in rat cardiac and vascular tis- Kelly MJ, Hill JR: Canine myxedema stu-
dogs: induction with a local graft-versus- sue, Naunyn Schmiedebergs Arch Pharma- por and coma, Comp Cont Ed Pract Vet
host reaction, Am J Vet Res 42:1856, col 337:539, 1988. 6:1049, 1984.
1981a. Henik RA, Dixon RM: Intravenous adminis- Kemppainen RJ, Birchfield JR: Measurement
Gosselin SJ, etal.: Histopathologic and ul- tration of levothyroxine for treatment of of total thyroxine concentration in serum
trastructural evaluation of thyroid lesions suspected myxedema coma complicated by from dogs and cats by use of various meth-
associated with hypothyroidism in dogs, severe hypothermia in a dog, J Am Vet Med ods, Am J Vet Res 67:259, 2006.
Vet Pathol 18:299, 1981b. Assoc 216:713, 2000. Kemppainen RJ, Sartin JL: Evidence for epi-
Gosselin SJ, etal.: Induced lymphocytic Heseltine JC, etal.: Effect of levothyroxine sodic but not circadian activity in plasma
thyroiditis in dogs: effect of intrathyroidal administration on hemostatic analytes concentrations of adrenocorticotrophin,
injection of thyroid autoantibodies, Am J in Doberman Pinschers with von Wil- cortisol, and thyroxine in dogs, J Endocri-
Vet Res 42:1565, 1981c. lebrand disease, J Vet Intern Med 19:523, nol 103:219, 1984.
Gottschalk J, etal.: Influence of topical dexa- 2005. Kemppainen RJ, etal.: Effects of predni-
methasone applications on insulin, glu- Hess RS, etal.: Association between diabetes sone on thyroid and gonadal endocrine
cose, thyroid hormone and cortisol levels mellitus, hypothyroidism or hyperadreno- function in dogs, J Endocrinol 96:293,
in dogs, Res Vet Sci 90:491, 2011. corticism and atherosclerosis in dogs, J Vet 1983.
Graham PA, etal.: Lymphocytic thyroiditis, Vet Intern Med 17:489, 2003. Kemppainen RJ, etal.: Autoantibodies to
Clin North Am 31:915, 2001. Higgins MA, etal.: Hypothyroid associated triiodothyronine and thyroxine in a Golden
Graham PA, etal.: Etiopathologic findings of central vestibular disease in 10 dogs: Retriever, J Am Anim Hosp Assoc 32:195,
canine hypothyroidism, Vet Clin Small 1999-2005, J Vet Intern Med 20:1363, 1996.
Anim 37:617, 2007. 2006. Kennedy LJ, etal.: Association of hypothyroid
Greco DS: Polyendocrine gland failure in dogs, Hill RC, etal.: Effects of racing and training disease in Doberman Pinscher with a rare
Vet Med 95:477, 2000. on serum thyroid hormone concentra- major histocompatibility complex DLA
Greco DS, etal.: Juvenile-onset hypothyroidism tions in racing Greyhounds, Am J Vet Res class II haplotype, Tissue Antigens 67:53,
in a dog, J Am Vet Med Assoc 187:948, 62:1969, 2001. 2006a.
1985. Hofer-Inteeworn N, etal.: Effect of hypothy- Kennedy LJ, etal.: Association of canine hypo-
Greco DS, etal.: Congenital hypothyroid dwarsm roidism on insulin sensitivity and glucose thyroidism with a common major histo-
in a family of Giant Schnauzers, J Vet Intern tolerance in dogs, Am J Vet Res 73:529, compatibility complex DLA class II allele,
Med 5:57, 1991. 2012. Tissue Antigens 68:82, 2006b.
Greco DS, etal.: The effect of levothyroxine Hoh WP, etal.: Circadian variations of serum Kern TJ, Riis RC: Ocular manifestations of
treatment on resting energy expenditure of thyroxine, free thyroxine, and 3,5,3triiodo- secondary hyperlipidemia associated with
hypothyroid dogs, J Vet Intern Med 12:7, thyronine concentrations in healthy dogs, hypothyroidism and uveitis in a dog, J Am
1998. J Vet Sci 7:25, 2006. Anim Hosp Assoc 16:907, 1980.
Greenspan FS: The thyroid gland. In Greenspan Hymes K, etal.: Easy bruising, thrombo- Kern TJ, etal.: Horners syndrome in dogs and
FS, Gardner, editors: Basic and clinical en- cytopenia, and elevated platelet im- cats: 100 cases (1975-1985), J Am Vet
docrinology, ed 6, New York, 2001, Lange munoglobulin G in Graves disease and Med Assoc 195:369, 1989.
Medical Books/ McGraw Hill, p 201. Hashimotos thyroiditis, Ann Intern Med Kintzer PP, Peterson ME: Thyroid scintigraphy
Gulickers KP, Panciera DL: Evaluation of the 94:27, 1981. in small animals, Semin Vet Med Surg
effects of clomipramine on canine thyroid Indrieri RJ, etal.: Neuromuscular abnormali- Small Anim 6:131, 1991.
function tests, J Vet Intern Med 17:44, ties associated with hypothyroidism and Klein I: Thyroid hormone and the cardiovascu-
2003. lymphocytic thyroiditis in three dogs, J Am lar system, Am J Med 88:631, 1990.
Gunaratnam P: The effects of thyroxine on hair Vet Med Assoc 190:544, 1987. Kolster KA, etal.: Control of prolactin secretion
growth in the dog, J Small Anim Pract Jaggy A, etal.: Neurological manifestations in canine hypothyroidism, Clin Theriogenol
27:17, 1986. of hypothyroidism: a retrospective study 2:185, 2010.
Haber RS, Loeb JN: Selective induction of of 29 dogs, J Vet Intern Med 8:328, Kooistra HS, etal.: Polyglandular deciency
high-ouabain-afnity isoform of Na+-K+- 1994. syndrome in a Boxer dog: thyroid hormone
ATPase by thyroid hormone, Am J Physiol Johnson C, etal.: Effect of 131I-induced and glucocorticoid deciency, Vet Quart
255:E912, 1988. hypothyroidism on indices of reproductive 17:59, 1995.
Haines DM, Penhale WJ: Antibodies to function in adult male dogs, J Vet Intern Kooistra HS, etal.: Combined pituitary hor-
pancreatic islet cells in canine diabetes Med 13:104, 1999. mone deciency in German Shepherd dogs
mellitus, Vet Immunol Immunopathol with dwarsm, Domest Anim Endocrinol
8:149, 1985. 19:177, 2000a.
Kooistra HS, etal.: Secretion pattern of Meij BP, etal.: Alterations in anterior pituitary ONeill SH, Reynolds LM: Effect of an anti-
thyroid-stimulating hormone in dogs during function of dogs with pituitary depen- inflammatory dose of prednisone on thyroid
euthyroidism and hypothyroidism, Domest dent hyperadrenocorticism, J Endocrinol hormone monitoring in hypothyroid dogs,
Anim Endocrinol 18:19, 2000b. 154:505, 1997. Vet Dermatol 22:202, 2011.
Lantz GC, etal.: Transsphenoidal hypophysec- Meij BP, etal.: Results of transsphenoidal Oohashi E, etal.: Seasonal changes in serum
tomy in the clinically normal dog, Am J Vet hypophysectomy in 52 dogs with pituitary- total thyroxine, free thyroxine, and canine
Res 49:1134, 1988. dependent hyperadrenocorticism, Vet Surg thyroid-stimulating hormone in clinically
Lawler DF, etal.: Influence of lifetime food 27:246, 1998. healthy Beagles in Hokkaido, J Vet Med
restriction on physiologic variables in Miller AB, etal.: Serial thyroid hormone concen- Sci 63:1241, 2001.
Labrador retriever dogs, Exp Gerontology trations in healthy euthyroid dogs, dogs with Panacova L, etal.: Thyroid testing in Slough-
42:204, 2007. hypothyroidism, and euthyroid dogs with is, J Vet Intern Med 22:1144, 2008.
Lee DE, etal.: Effects of hyperlipemia on atopic dermatitis, Br Vet J 148:451, 1992. Panciera DL: An echocardiographic and elec-
radioimmunoassays for progesterone, tes- Miller PE, Panciera DL: Effects of experimen- trocardiographic study of cardiovascular
tosterone, thyroxine, and cortisol in serum tally induced hypothyroidism on the eye function in hypothyroid dogs, J Am Vet
and plasma samples from dogs, Am J Vet and ocular adnexa in dogs. AJVR 55:692, Med Assoc 205:996, 1994.
Res 52:1489, 1991. 1994. Panciera DL: Conditions associated with
Lee JA, etal.: Effects of racing and nontraining Miller WH, Buerger RG: Cutaneous mucinous canine hypothyroidism, Vet Clin North Am
on plasma thyroid hormone concentra- vesiculation in a dog with hypothyroidism, 31:935, 2001.
tions in sled dogs, J Am Vet Med Assoc J Am Vet Med Assoc 196:757, 1990. Panciera DL, Johnson GS: Plasma von Wil-
224:226, 2004. Mooney CT, etal.: Thyroid hormone abnormali- lebrand factor antigen concentration in
Le Traon G, etal.: Pharmacokinetics of total ties and outcome in dogs with non-thyroidal dogs with hypothyroidism, J Am Vet Med
thyroxine in dogs after administration of an illness, J Small Anim Pract 49:11, 2008. Assoc 205:1550, 1994.
oral solution of levothyroxine sodium, Vet Mooney CT, Anderson TJ: Congenital hypothy- Panciera DL, Johnson GS: Plasma von Wil-
Pharmacol Therap 31:95, 2007. roidism in a Boxer dog, J Small Anim Pract lebrand factor antigen concentration and
Le Traon G, etal.: Clinical evaluation of a 34:31, 1993. buccal mucosal bleeding time in dogs with
novel liquid formulation of L-thyroxine for Moore GE, etal.: Effects of oral administration experimental hypothyroidism, J Vet Intern
once daily treatment of dogs with hypo- of anti-inflammatory doses of prednisone Med 10:60, 1996.
thyroidism, J Vet Intern Med 23(1):43, on thyroid hormone response to thyrotro- Panciera DL, Johnston SA: Results of thyroid
2009. pin-releasing hormone and thyrotropin function tests and concentrations of plasma
Lobetti RG: Hypercalcemia in a dog with in clinically normal dogs, Am J Vet Res proteins in dogs administered etodolac, Am
primary hypothyroidism, J S Afr Vet Assoc 54:130, 1993. J Vet Res 63:1492, 2002.
82:242, 2011. Muller PB, etal.: Effects of long-term phe- Panciera DL, etal.: Thyroid function tests in
Lum SMC, etal.: Peripheral tissue mecha- nobarbital treatment on the thyroid and euthyroid dogs treated with l-thyroxine, Am
nism for maintenance of serum triiodothy- adrenal axis and adrenal function tests in J Vet Res 51:22, 1989.
ronine values in a thyroxine-decient state dogs, J Vet Intern Med 14:157, 2000. Panciera DL, etal.: Quantitative morphologic
in man, J Clin Invest 73:570, 1984. Mntener T, etal.: Canine noninflammatory study of the pituitary and thyroid glands
Lumsden JH, etal.: Prevalence of hypothyroid- alopecia: a comprehensive evaluation of of dogs administered l-thyroxine, Am J Vet
ism and von Willebrands disease in Dober- common and distinguishing histological Res 51:27, 1990.
man Pinschers and the observed relation- characteristics, Vet Derm 23:206, 2012. Panciera DL, etal.: Plasma thyroid hormone
ship between thyroid, von Willebrand, and Nachreiner RF, Refsal KR: Radioimmunoassay concentrations in dogs competing in a
cardiac status, J Vet Intern Med 7:115, monitoring of thyroid hormone concen- long-distance sled dog race, J Vet Intern
1993 (abstract). trations in dogs on thyroid replacement Med 17:593, 2003.
Lurye JC, etal.: Evaluation of an in-house therapy: 2,674 cases (1985-1987), J Am Panciera DL, etal.: Effects of deracoxib
enzyme-linked immunosorbent assay for Vet Med Assoc 201:623, 1992. and aspirin on serum concentrations
quantitative measurement of serum total Nachreiner RF, etal.: Pharmacokinetics of of thyroxine, 3,5,3-triiodothyronine,
thyroxine concentration in dogs and l-thyroxine after its oral administration in free thyroxine, and thyroid stimulating
cats, J Am Vet Med Assoc 221:243, dogs, Am J Vet Res 54:2091, 1993. hormone in dogs, Am J Vet Res 67:599,
2002. Nachreiner RF, etal.: Prevalence of auto- 2006.
MacGregor JM, etal.: Cholesterol based peri- antibodies to thyroglobulin in dogs with Panciera DL, etal.: Effect of short-term hypo-
cardial effusion and aortic thromboembo- nonthyroidal illness, Am J Vet Res 59:951, thyroidism on reproduction in the bitch,
lism in a 9-year-old mixed-breed dog with 1998. Theriogenology 68:316, 2007.
hypothyroidism, J Vet Intern Med 18:354, Nachreiner RF, etal.: Prevalence of serum thy- Panciera DL, etal.: Reproductive effects of
2004. roid hormone autoantibodies in dogs with prolonged experimentally induced hypo-
MacPhail CM, Monnet E: Outcome of and post- clinical signs of hypothyroidism, thyroidism in bitches, J Vet Intern Med
operative complications in dogs undergoing J Am Vet Med Assoc 220:466, 2002. 26:326, 2012.
surgical treatment of laryngeal paralysis: Nelson RW, etal.: Serum free thyroxine Pancotto T, etal.: Blood-brain-barrier disrup-
140 cases (1985-1998), J Am Vet Med concentration in healthy dogs, dogs with tion in chronic canine hypothyroidism, Vet
Assoc 218:1949, 2001. hypothyroidism, and euthyroid dogs with Clin Path 39:485, 2010.
Mansfield CS, Mooney CT: Lymphocytic- concurrent illness, J Am Vet Med Assoc Paradis M, etal.: Effects of moderate to
plasmacytic thyroiditis and glomerulo- 198:1401, 1991. severe osteoarthyritis in canine thyroid
nephritis in a boxer, J Small Anim Pract Ness TA, etal.: Effect of dosing and sampling function, Can Vet J 44:407, 2003.
47(7):396, 2006. time on serum thyroxine, free thyroxine, Paull LC, etal.: Effect of anticonvulsant
Marca MC, etal.: Evaluation of canine serum and thyrotropin concetrations in dogs fol- dosages of potassium bromide on
thyrotropin (TSH) concentration: compari- lowing multidose etodolac administration, thyroid function and morphology in
son of three analytical procedures, J Vet Vet Ther 4:340, 2003. dogs, J Am Anim Hosp Assoc 39:193,
Diag Invest 13:106, 2001. Nuttall WO: Iodine deficiency in working dogs, 2003.
N Z Vet J 34:72, 1986.
|
Persani L, Beck-Peccoz P: Central hypothyroid- Reimers TJ, etal.: Effects of reproductive Scott-Moncrieff JCR, Nelson RW: Change
ism. In Braverman LE, etal, editors: Werner state on concentrations of thyroxine, in serum thyroid-stimulating hormone
and Ingbars the thyroid, ed 10, Philadel- 3,5,3-triiodothyronine, and cortisol in concentration in response to administra-
phia, 2013, Lippincott Williams &Wilkins. serum of dogs, Biol Reprod 31:148, 1984. tion of thyrotropin-releasing hormone
Peruccio C: Incidence of hypothyroidism in Reimers TJ, etal.: Effect of fasting on thyrox- to healthy dogs, hypothyroid dogs, and
dogs affected by keratoconjunctivitis ine, 3,5,3-triiodothyronine, and cortisol euthyroid dogs with concurrent disease,
sicca, Las Vegas, 1982, Proceedings of concentrations in serum of dogs, Am J JAm Vet Med Assoc 213:1435, 1998.
the American Society of Veterinary Oph- Vet Res 47:2485, 1986. Scott-Moncrieff JCR, etal.: Measurement of
thalmology. p 47. Reimers TJ, etal.: Effects of age, sex, and serum free thyroxine by modied equi-
Peterson ME, Ferguson DC: Thyroid diseases. body size on serum concentrations of librium dialysis in dogs (abstract), J Vet
In Ettinger SJ, editor: Textbook of veteri- thyroid and adrenocortical hormones in Intern Med 8:159, 1994.
nary internal medicine, ed 3, Philadelphia, dogs, Am J Vet Res 51:454, 1990. Scott-Moncrieff JCR, etal.: Comparison of
1989, WB Saunders, p 1632. Reimers TJ, etal.: Effects of hemolysis, and serum concentrations of thyroid-stimulating
Peterson ME, Gamble DA: Effect of non- storage on quantification of hormones hormone in healthy dogs, hypothyroid dogs,
thyroidal illness on serum thyroxine in blood samples from dogs, cattle, and and euthyroid dogs with concurrent dis-
concentrations in cats: 494 cases (1988), horses, Am J Vet Res 52:1075, 1991. ease, J Am Vet Med Assoc 212:387, 1998.
J Am Vet Med Assoc 197:1203, 1990. Reusch CE, etal.: Serum fructosamine con- Scott-Moncrieff JCR, etal.: Evaluation of
Peterson ME, etal.: Effects of spontaneous centrations in dogs with hypothyroidism, antithyroglobulin antibodies after routine
hyperadrenocorticism on serum thyroid Vet Res Commun 26:531, 2002. vaccination in pet and research dogs, J
hormone concentrations in the dog, Am J Rogers JS, etal.: Factor VIII activity and thyroid Am Vet Med Assoc 221:515, 2002.
Vet Res 45:2034, 1984. function, Ann Intern Med 97:713, 1982. Scott-Moncrieff JCR, etal.: Lack of associa-
Peterson ME, etal.: Pretreatment clinical and Rogers WA, etal.: Lipids and lipoproteins in tion between repeated vaccination and
laboratory ndings in dogs with hypoadre- normal dogs and in dogs with secondary thyroiditis in laboratory beagles, J Vet
nocorticism: 225 cases (1979-1993), hyperlipoproteinemia, J Am Vet Med As- Intern Med 20:818, 2006.
J Am Vet Med Assoc 208:85, 1996. soc 166:1092, 1975. Scott-Moncrieff JCR, etal.: Accuracy of
Peterson ME, etal.: Measurement of serum Rossmeisl JH: Resistance of the peripheral serum free thyroxine concentrations
total thyroxine, triiodothyronine, free thy- nervous system to the effects of chronic determined by a new veterinary chemilu-
roxine, and thyrotropin concentrations for canine hypothyroidism, J Vet Intern Med minescent immunoassay in euthyoid and
diagnosis of hypothyroidism in dogs, J Am 24:875, 2010. hypothyroid dogs (abstract), J Vet Intern
Vet Med Assoc 211:1396, 1997. Rossmeisl JH, etal.: Longitudinal study of the Med 25:1493, 2011.
Pettigrew R, etal.: CNS hypomyelination in effects of chronic hypothyroidism on skeletal Seavers A, etal.: Evaluation of the thyroid
rat terrier dogs with congenital goiter muscle in dogs, Am J Vet Res 70:879, 2009. status of Basenji dogs in Australia, Aus-
and a mutation in the thyroid peroxidase Roti E, Vagenakis AG: Effect of excess iodide: tralian Vet J 86:429, 2008.
gene, Vet Pathol 44:50, 2007. clinical aspects. In Braverman LE, Cooper Seelig DM, etal.: Goitrous hypothyroidism
Phillips DE, Harkin KR: Hypothyroidism and DS, editors: The thyroid: a fundamental associated with treatment with trime-
myocardial failure in two Great Danes, J and clinical text, ed 10, Philadelphia, thoprim-sulfamethoxazole in a young dog,
Am Vet Med Assoc 39:133, 2003. 2013, WB Saunders, p 242. J Am Vet Med Assoc 232:1181, 2008.
Piechotta M, etal.: Autoantibodies against Salvatore D, etal, editors: Thyroid physiology Segalini V, etal.: Thyroid function and infer-
thyroid hormones and their influence on and diagnostic evaluation of patients with tility in the dog: a survey of five breeds,
thyroxine determination with chemilumi- thyroid disorders. In Melmed S, etal.: Reprod Dom Anim 44:211, 2009.
nescent immunoassay in dogs, J Vet Sci Williams textbook of endocrinology, ed 12, Shiel RE, etal.: Thyroid hormone concentra-
11:191, 2010. Philadelphia, 2011, Elsevier/Saunders. tions in young healthy pretraining grey-
Pinilla M, etal.: Quantitative thyroid scintig- Saunders HM, Jezyk PK: The radiographic hounds, Vet Rec 161:616, 2007a.
raphy in greyhounds suspected of primary appearance of canine congenital Shiel RE, etal.: Tertiary hypothyroidism in a
hypothyroidism, Vet Radiol Ultrasound hypothyroidism: skeletal changes with dog, Irish Vet J 60:88, 2007b.
50(2):224, 2009. delayed treatment, Vet Radiol 32:171, Shiel RE, etal.: Assessment of criteria used
Post K, etal.: Lack of effect of trimethoprim 1991. by veterinary practitioners to diagnose
and sulfadiazine in combination in mid- to Sauv F, etal.: Effects of oral administration hypothyroidism in sighthounds and
late gestation on thyroid function in neo- of meloxicam, carprofen, and a nutra- investigation of serum thyroid hormone
natal dogs, J Reprod Fertil 47(Suppl):477, ceutical on thyroid function in dogs with concentrations in healthy Salukis, J Am
1993. osteoarthritis, Can Vet J 44:474, 2003. Vet Med Assoc 236:302, 2010.
Pullen WH, Hess RS: Hypothyroid dogs Schachter S, etal.: Compariosn of serum-free Shiel E, etal.: Qualitative and semi-
treated with intravenous levothyroxine, thyroxine concentrations determined by quantitative assessment of thyroxine
J Vet Intern Med 20:32, 2006. standard equilibrium dialysis, modified binding globulin in the greyhound and
Radosta LA, etal.: Comparison of thyroid equilibrium dialysis, and five radioim- other dog breeds (abstract), J Vet Intern
analytes in dogs aggressive to familiar munoassays in dogs, J Vet Intern Med Med 25:1494, 2011.
people and in non-aggressive dogs, Vet J 18:259, 2004. Shiel RE, etal.: Assessment of the value of
192:472, 2012. Schoeman JP, etal.: Serum cortisol and quantitative thyroid scintigraphy for deter-
Ramsey IK, etal.: Thyroid-stimulating hor- thyroxine concentrations as predictors mination of thyroid function in dogs,
mone and total thyroxine concentrations in of death in critically ill puppies with J Small Anim Pract 53:278, 2012.
euthyroid, sick euthyroid and hypothyroid parvoviral diarrhea, J Am Vet Med Assoc Siegmund W, etal.: Replacement therapy
dogs, 231:1534, 2007. with levothyroxine plus triiododthyronine
J Small Anim Pract 38:540, 1997. Schuff KG, etal.: Psychiatric and cognitive (bioavailable molar ratio 14:1) is not
Reese S, etal.: Thyroid sonography as an effects of hypothyroidism, In Braverman LE, superior to thyroxine alone to improve
effective tool to discriminate between Cooper DS, editors: The thyroid, a funda- well-being and cognitive performance
euthyroid sick and hypothyroid dogs, J Vet mental and clinical text, ed 10, Philadel- in hypothyroidism, Clinical Endocrinol
Intern Med 19:491, 2005. phia, 2013, WB Saunders, p 596. 60:750, 2004.
Skopek E, etal.: Detection of autoantibodies Valdermarsson S, etal.: Relations between Jones BR, etal.: Preliminary studies on con-
against thyroid peroxidase in serum samples thyroid function, hepatic and lipoprotein genital hypothyroidism in a family of Abys-
of hypothyroid dogs, Am J Vet Res 67:809, lipase activities and plasma lipoprotein sinian cats, Vet Rec 131:145, 1992.
2006. concentrations, Acta Endocrinologica Mazrier H, etal.: Goiterous congenital hypo-
Slade E, etal.: Serum thyroxine and triiodothy- 104:50, 1983. thyroidism caused by thyroid peroxidase
ronine concentrations in canine pyoderma, van Geffen C, etal.: Serum thyroid hormone deficiency in a family of domestic shorthair
J Am Vet Med Assoc 185:216, 1984. concentrations and thyroglobulin autoanti- cats, J Vet Intern Med 17:395, 2003.
Sullivan P, etal.: Altered platelet indices in bodies in trained and non-trained healthy Mellanby RJ, etal.: Secondary hypothyroidism
dogs with hypothyroidism and cats with whippets, Vet J 172:135, 2006. following head trauma in a cat, J Feline
hyperthyroidism, Am J Vet Res 54:2004, Vitale CL, etal.: Neurologic dysfunction in hy- Med Surg 7:135, 2005.
1993. pothyroid hyperlipidemic labrador retriev- Miller PE, Panciera DL: Effects of experimen-
Sunthornthepvarakui T, etal.: Brief report: ers, J Vet Intern Med 21:1316, 2007. tally induced hypothyroidism on the eye
Resistance to thyrotropin caused by muta- von Klopmann T, etal.: Euthyroid sick syn- and ocular adnexa in dogs, Am J Vet Res
tions in the thyrotropin-receptor gene, drome in dogs with idiopathic epilepsy 55:692, 1994.
N Engl J Med 332:155, 1994. before treatment with anticonvulsant drugs, Mooney CT, etal.: Effect of illness not as-
Taeymans O, OMarra SK: Imaging diagnosis: J Vet Intern Med 20(3):516, 2006. sociated with the thyroid gland on serum
acquired goitrous hypothyroidism following Wartofsky L, Burman KD: Alterations in thyroid total and free thyroxine concentrations
treatment with trimethoprim sulfamethoxa- function in patients with systemic illness: in cats, J Am Vet Med Assoc 208:2004,
zole, Vet Radiol Ultrasound 50:443, the euthyroid sick syndrome, Endocrinol 1996a.
2009. Rev 3:164, 1982. Nykamp SG, etal.: Association of the risk of
Taeymans O, etal.: Thyroid imaging in the dog: Wenzel KW: Pharmacological interference with development of hypothyroidism after iodine
current status and future directions, J Vet invitro tests of thyroid function, Metabo- 131 treatment with the pretreatment
Intern Med 21:673, 2007a. lism 30:717, 1981. pattern of sodium pertechnetate Tc 99m
Taeymans O, etal.: Pre- and post-treatment Wiesinga WM, Van den Berghe G: Nonthyroi- uptake in the thyroid gland in cats with
ultrasonography in hypothyroid dogs, Vet dal illness syndrome. In Braverman LE, hyperthyroidism. 165 cases (1990-2002),
Rad and Ultrasound 48:262, 2007b. Cooper DS, editors: The thyroid: a funda- J Am Vet Med Assoc 226:1671, 2005.
Tani H, etal.: Proliferative responses to canine mental and clinical text, ed 10, Philadel- Peterson ME, Gamble DA: Effect of nonthyroi-
thyroglobulin of peripheral blood mono- phia, 2013, WB Saunders, p 596. dal illness on serum thyroxine concentra-
nuclear cells from hypothyroid dogs, J Vet Wilbe M, etal.: Increased genetic risk or pro- tions in cats: 494 cases (1988), J Vet
Med Sci 67:363, 2005. tection for canine autoimmune lymphocyt- Intern Med 197:1203, 1990.
Thacker EL, etal.: Prevalence of autoan- ic thyroiditis in Giant Schnauzers depends Peterson ME, etal.: Measurement of serum
tibodies to thyroglobulin, thyroxine, on DLA class II genotype, Tissue Antigens concentrations of free thyroxine, total
or triiodothyronine and relationship of 75:712, 2010. thyroxine, and total triiodothyronine in
autoantibodies and serum concentrations Williams DA, etal.: Validation of an immunoassay cat with hyperthyroidism and cats with
of iodothyronines in dogs, Am J Vet Res for canine thyroid-stimulating hormone and nonthyroidal illness, J Am Vet Med Assoc
53:449, 1992. changes in serum concentration following 218:529, 2001.
Tidholm A, etal.: Effect of thyroid hormone induction of hypothyroidism in dogs, J Am Quante S, etal.: Congenital hypothyroidism
supplementation on survival of euthyroid Vet Med Assoc 209:1730, 1996. in a kitten resulting in decreased IGF-1
dogs with congestive heart failure due to Williams DL, etal.: Reduced tear production concentration and abnormal liver function
systolic myocardial dysfunction: a double in three canine endocrinopathies, J Small tests, J Feline Med Surg 12:487, 2010.
blind placebo-controlled trial, Res Vet Sci Anim Pract 48:252, 2007. Rand JS, etal.: Spontaneous adult-onset
75:195, 2003. Williamson NL, etal.: Effects of short-term hypothyroidism in a cat, J Vet Intern Med
Torres SM, etal.: Comparison of colloid, trimethoprim-sulfamethoxazole administra- 7:272, 1993.
thyroid follicular epithelium, and thyroid tion on thyroid function in dogs, J Am Vet Schumm-Draeger PM, etal.: Spontaneous
hormone concentrations in healthy and Med Assoc 221:802, 2002. Hashimoto-like thyroiditis in cats, Verh
severely sick dogs, J Am Vet Med Assoc Woltz HH, etal.: Effect of prednisone on thy- Dtsch Ges Path 80:297, 1996.
222:1079, 2003. roid gland morphology on plasma thyroxine Sjollema BE, etal.: Congenital hypothyroidism
Torres SMF, etal.: Hypothyroidism in a dog and triiodothyronine concentrations in the in two cats due to defective organication:
associated with trimethoprim-sulfadiazine dog, Am J Vet Res 44:2000, 1984. Data suggesting loosely anchored thyroper-
therapy, Vet Derm 7:105, 1996. Yen PM, Brent GA: Genomic and non-genomic oxidase, Acta Endocrinol 125:435, 1991.
Tuohy JL, etal.: Outcome following simultane- actions of thyroid hormones. In Braver- Stegeman JR, etal.: Use of recombinant
ous bilateral thyroid lobectomy for treat- man LE, Cooper DS, editors: The thyroid: human thyroid-stimulating hormone for
ment of thyroid gland carcinoma in dogs: a fundamental and clinical text, ed 10, thyrotropin-stimulation testing of euthyroid
15 cases (1994-2010), J Am Vet Med Philadelphia, 2013, WB Saunders, p 127. cats, Am J Vet Res 64:149, 2003.
Assoc 241:95, 2012. Feline Hypothyroidism Tanase H, etal.: Inherited primary hypothy-
Turrel JM, etal.: Sodium iodide I 131 treat- Arnold U, etal.: Goitrous hypothyroidism and roidism with thyrotrophin resistance in
ment of dogs with nonresectable thyroid dwarsm in a kitten, J Am Anim Hosp As- Japanese cats, J Endocrinology 129:245,
tumors: 39 cases (1990-2003), J Am Vet soc 20:753, 1984. 1991.
Med Assoc 229:542, 2006. Blois SL, etal.: Use of thyroid scintigraphy Thoday KL, etal.: Radioimmunoassay of
Utiger RD: Decreased extrathyroidal triiodothy- and pituitary immunohistochemistry in serum total thyroxine and triiodothyronine
ronine production in nonthyroidal illness: the diagnosis of spontaneous hypothyroid- in healthy cats: Assay methodology and
benet or harm? Am J Med 69:807, ism in a mature cat, J Feline Med Surg effects of age, sex, breed, heredity and
1980. 12:156, 2010. environment, J Small Anim Pract 25:457,
Vail DM, etal.: Thyroid hormone concentra- Hoenig M, Ferguson DC: Assessment of thy- 1984.
tions in dogs with chronic weight loss with roid functional reserve in the cat by the Traas AM, etal.: Congenital thyroid hypoplasia
special reference to cancer cachexia, J Vet thyrotropin-stimulation test, Am J Vet Res and seizures in 2 littermate kittens, J Vet
Intern Med 8:122, 1994. 44:1229, 1983. Intern Med 22:1427, 2008.
|
Van Hoek IM, etal.: Effect of recombinant Wakeling J, etal.: Diagnosis of hyperthyroidism Zerbe CA, etal.: Thyroid proles in healthy
human thyroid stimulating hormone on in cats with mild kidney disease, J Small kittens from birth to 12 weeks of age,
serum thyroxin and thyroid scintigraphy in Anim Pract 49:287, 2008. Proc Annu Meet American College of
euthyroid cats, J Feline Med Surg 11:309, Wakeling J, etal.: Evaluation of predictors for Veterinary Internal Medicine 16:702,
2009. the diagnosis of hyperthyroidism in cats, 1998.
Van Hoek IM, etal.: Thyroid stimulation with J Vet Intern Med 25:1057, 2011.
recombinant human thyrotropin in healthy Williams TL, etal.: Association of iatro-
cats, cats with non-thyroidal illness, and in genic hypothyroidism with azotemia and
cats with low serum thyroxin and azotae- reduced survival time in cats treated
mia after treatment of hyperthyroidism, for hyperthyroidism, J Vet Intern Med
J Feline Med Surg 12:117, 2010. 24:1086, 2010.
CHAPTER 4 Feline Hyperthyroidism
CHAPTER CONTENTS Differential Diagnosis, 154

Definition, 137 Serum Thyroid Hormone Concentrations, 154
History of Hyperthyroidism, 137 Basal Total Serum Thyroxine Concentration, 154
Pathology, 137 Approach to Cats with Suspected Hyperthyroidism That Have a
Background, 137 Thyroxine Concentration Within the Reference Range, 156
Benign Thyroid Tumors, 137 Basal Total Serum Triiodothyronine Concentrations, 157
Malignant Thyroid Tumors, 138 Basal Free Thyroxine Concentration, 157
Etiology, 138 Baseline Serum Thyrotropin Concentration, 158
Evidence for Primary Thyroid Dysfunction, 138 Triiodothyronine Suppression Test, 158
Genetic Cause of Thyroid Autonomy, 138 Thyroid-Stimulating Hormone Response Test, 159
Epidemiological Studies, 139 Thyrotropin-Releasing Hormone Stimulation Test, 160
Nutritional Deficiencies or Excesses, 140 Summary of Diagnostic Testing for Hyperthyroidism, 160
Goitrogens (Thyroid Disrupters), 141 Radionuclide Imaging: Thyroid Scintigraphy, 161
Clinical Features of Feline Hyperthyroidism, 142 Choice of Radionuclide, 161
Signalment, 142 Clinical Indications for Scintigraphy, 163
Clinical Signs and Pathophysiology, 142 Cervical (Thyroid) Ultrasonography/Computed Tomography, 167
Weight Loss, 142 Nonfunctional Thyroid Nodules, 169
Polyphagia, 142 General Concepts in Treatment, 169
Nervousness, Hyperactivity, Aggressive Behavior, 144 Background, 169
Polydipsia and Polyuria, 144 Treatment of Hyperthyroidism and Renal Function, 170
Gastrointestinal Dysfunction, 144 Treatment with Anti-Thyroid Drugs (Thioureylenes), 172
Hair Loss/Unkempt Coat, 144 Mode of Action, 172
Panting and Respiratory Distress, 145 Propylthiouracil, 172
Decreased Appetite, 145 Methimazole (Tapazole), 172
Weakness and Lethargy, 145 Carbimazole, 177
Heat and Stress Intolerance, 145 Treatment with Surgery, 177
Concurrent Nonthyroidal Illness, 145 Presurgical Management, 177
Subclinical Hyperthyroidism, 145 Anesthesia, 178
Physical Examination, 145 Surgical Techniques, 178
General, 145 Postsurgical Management, 179
Palpable Cervical Mass (Goiter), 145 Results of Surgery, 181
Cardiac Disturbances, 146 Treatment with Radioactive Iodine, 181
Ventroflexion of the Head, 147 Goal of Therapy, 181
Ocular Lesions, 147 Dose Determination, 181
Thyroid Storm, 148 Route of 131-Iodine Administration, 183
In-Hospital Diagnostic Evaluation, 148 Prior Treatment with Methimazole, 183
Background, 148 Prior Treatment with Limited Iodine Diets, 183
Complete Blood Count, 148 Radiation Safety, 183
Serum Chemistry Prole, 148 Need for Retreatment, 185
Blood Glucose, 149 Recurrence, 185
Cholesterol, 150 Nutritional Management of Feline Hyperthyroidism, 185
Blood Urea Nitrogen and Creatinine, 150 Role of Dietary Iodine in the Pathogenesis of Disease, 185
Urinalysis, 150 Iodine-Limited Diets for Management of Feline Hyperthyroidism, 185
Plasma Cortisol/Urine Cortisol:Creatinine Ratio, 150 Clinical Experience, 186
Serum Fructosamine, 151 Indications for Nutritional Management, 186
Blood Pressure and Hypertension, 151 Expected Outcome, 186
Radiography, 151 Long-Term Nutritional Management, 186
Electrocardiography, 151 Transitioning from Methimazole to a Limited-Iodine Diet, 187
Echocardiography, 152 Transitioning from a Limited-Iodine Diet to Other Treatments, 187
136
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CHAPTER 4 Feline Hyperthyroidism 137
Recommended Monitoring, 187 Percutaneous Ethanol and Heat Ablation Injection

Feline Thyroid Carcinoma, 187 for Treatment of Feline Hyperthyroidism, 188
Clinical Features, 187 Beta Blockers, 189
Diagnosis, 187 Stable Iodine, 189
Treatment, 187 Iodinated Radiographic Contrast Agents, 190
Thyroid Cysts, 188 Treatment of Hypertension in Hyperthyroid Cats, 190
Miscellaneous Therapies, 188 Prognosis, 190
Hyperthyroidism, caused by autonomous growth and function substantially by geographic region. For example, the prevalence
of the thyroid follicular cells, was initially described in humans of hyperthyroidism in an urban area of Germany was estimated to
by Henry Plummer in 1913. Clinical observations led him to be 11.4% (Sassnau, 2006), whereas the prevalence rate in Hong
characterize two types of hyperthyroidism: exophthalmic goiter Kong was estimated to be 3.9% (De Wet etal, 2009). It has been
(Graves disease) and toxic adenomatous goiter. In Graves disease, proposed that the emergence of clinical hyperthyroidism is related
the hyperthyroidism was associated with diffuse hyperplasia of to the gradual introduction of commercially-prepared cat foods by
the thyroid glands. Toxic adenomatous goiter was associated with different cultures around the world. It is interesting that commer-
either single or multiple nodules and variable histologic patterns. cial cat foods were rst test-marketed on both coasts of the United
The latter disease involved the slow growth of autonomous func- States in the mid-1960s. This means that the rst generation of
tioning follicles. Toxic adenomatous goiter is very similar to the cats raised and maintained almost entirely on commercial foods
disorder seen in hyperthyroid cats, initially described as a clinical was reaching middle and old age in the late 1970s and early 1980s,
entity in 1979 by Peterson and colleagues and in 1980 by Holz- which coincides with the recognition of feline hyperthyroidism in
worth and colleagues. For detailed information on the anatomy Boston, New York, Philadelphia, Los Angeles, and San Francisco.
and physiology of the normal thyroid gland, see Chapter 3. Factors that have contributed to the increased recognition of
feline hyperthyroidism since the 1980s include increased aware-
ness by owners and veterinarians, inclusion of total T4 measure-
DEFINITION
ment on routine biochemical profiles for geriatric cats, improved
Naturally occurring hyperthyroidism (thyrotoxicosis) is a clini- feline health care, and increased feline life spans; however, there
cal condition that results from excessive production and secre- is little doubt that the true prevalence of the disease has also
tion of thyroxine (T4) and triiodothyronine (T3) by the thyroid increased from the time the rst reports in 1979 and 1980 were
gland. Hyperthyroidism in cats is almost always the result of a published until today. Unfortunately although there have been a
primary autonomous condition of the thyroid gland itself, most number of epidemiological studies investigating the risk factors
commonly due to adenomatous hyperplasia or a benign ade- for feline hyperthyroidism, no single risk factor has been identi-
noma. Adenomatous hyperplasia is the most common pathologic fied and it is thus believed that the cause is likely multifactorial.
change. Feline hyperthyroidism may also be caused by functional
thyroid carcinoma. Thyroid-stimulating hormone (also known as PATHOLOGY
thyrotropin; TSH) secreting pituitary adenoma is a rare cause of
hyperthyroidism in people (Beck-Peccoz etal, 2009), but has yet Background
to be described in cats. Other causes of hyperthyroidism, such as
ingestion of excessive quantities of exogenous thyroid hormone A thorough review of feline thyroid pathology has not been pub-
(Khler etal, 2012) or acute destruction of thyroid tissue causing lished in the 20 to 25 years since clinical feline hyperthyroidism
excessive release of thyroid hormone, have also not been reported became common. However, reviews of surgically removed tissue
in cats. and necropsy specimens have confirmed that multinodular ade-
nomatous goiter is the most common pathologic abnormality.
Benign tumors are much more common than malignant tumors.
HISTORY OF HYPERTHYROIDISM
Veterinary clinicians were not aware of the clinical syndrome Benign Thyroid Tumors
of feline hyperthyroidism until the publication of three clinical
reports by Peterson, etal., in 1979, Holzworth, etal., 1980, and Multinodular Adenomatous Goiter
Jones and Johnstone, 1981. After these publications, practitio- Follicular cell adenoma and multinodular adenomatous hyper-
ners increasingly started to recognize cats with signs suggestive plasia are the most common thyroidal histological abnormalities
of hyperthyroidism (thyrotoxicosis). From 1980 to 1985, 125 described in the thyroid glands from hyperthyroid cats. Both
hyperthyroid cats were identied at the University of California. histopathologic abnormalities are benign changes, and both may
During a similar period, hyperthyroid cats were being recognized occur together within the same thyroid gland. In both thyroid
at a rate of three per month at the Animal Medical Center in adenoma and adenomatous hyperplasia, the follicular cells are
New York City (Peterson etal, 1983). By 1993, hyperthyroidism uniform and cuboidal to columnar in shape with occasional pap-
was a common disease in both the United States and the United illary infoldings that form follicles containing variable amounts
Kingdom (Thoday and Mooney, 1992; Broussard etal, 1995). By of colloid (Maxie, 2007). Thyroid adenomas are grossly visible,
2004, a retrospective study suggested that the prevalence of feline have a thin fibrous capsule, and may compress the surrounding
hyperthyroidism in the United States was 3% of hospital visits normal thyroid tissue. In thyroid adenomatous hyperplasia, one
(Edinboro et al, 2004). Feline hyperthyroidism is now recog- or more nodules of hyperplastic follicular cells are present within
nized as a common clinical problem of cats in many countries the thyroid gland. The nodules of hyperplastic tissue range in size
in the world including Europe, Australia, New Zealand, Japan, from less than 1 mm to greater than 3 cm in diameter (Fig. 4-1).
and Hong Kong. Interestingly prevalence rates appear to vary There is no clinically relevant difference between an adenoma
A B
FIGURE 4-1 A, Multinodular adenomatous goiter, which has the gross appearance of a compressed cluster of
grapes. This is an example of bilaterally asymmetric thyroid enlargement. B, After the larger mass is cut in half,
cystic changes are revealed.
and adenomatous hyperplasia, and the two can coexist within

ETIOLOGY
the same thyroid gland. Adenomatous hyperplasia and adenomas
are bilateral in approximately 70% of cats and unilateral in the
Evidence for Primary Thyroid Dysfunction
remaining 30% of cats. Focal areas of necrosis, mineralization,
and cystic degeneration are often present in larger adenomas and Early studies of hyperthyroid cats in the 1980s suggested feline
rarely may form large fluid filled cystadenomas. Normal follicu- hyperthyroidism was due to a primary abnormality of the thyroid
lar cells surrounding adenomas and hyperplastic nodules are low gland rather than the result of thyroid stimulation by a circulating
cuboidal or atrophied with little evidence of endocytotic activity hormone, such as TSH, thyrotropin-releasing hormone (TRH),
(Maxie, 2007). or thyroid stimulating immunoglobulins. Thyroid tissue from
hyperthyroid cats was transplanted subcutaneously into nude
Malignant Thyroid Tumors mice that had endogenous TSH secretion suppressed by adminis-
tration of levothyroxine (also known as L-thyroxine; L-T4). It was
Thyroid Carcinoma demonstrated that the thyroid cells retained their cuboidal shape,
Malignant neoplasia is recognized to be the cause of hyperthyroid- high growth potential, and functional autonomy in the nude mice
ism in approximately 1% to 3% of hyperthyroid cats and may (Peter et al, 1987). Furthermore administration of serum from
involve one or both thyroid lobes. There are a variety of clini- hyperthyroid cats failed to stimulate iodine uptake in either nor-
cal presentations ranging from tumors that are well encapsulated, mal or hyperplastic thyroid tissue. Similar findings have more
freely moveable, and clinically indistinguishable from benign thy- recently been demonstrated in cells transfected with the feline
roid neoplasia, to thyroid masses that are very large, locally inva- TSH receptor (Nguyen etal, 2002).
sive, attached to overlying and underlying tissues, and metastatic
to local lymph nodes. There may be multiple masses throughout
Genetic Cause of Thyroid Autonomy
the cervical region and may also be distant metastases. In cats, thy-
roid carcinomas are usually well differentiated adenocarcinomas Stimulation of thyroid follicular cells by TSH results in thyroid
that are composed of a uniform pattern of small follicles contain- follicular cell growth as well as synthesis and secretion of thyroid
ing variable amounts of colloid (Maxie, 2007). Mixed compact hormone via the receptor G proteincyclic adenosine monophos-
and follicular morphologic patterns are most common although phate (cAMP) signal transduction system. The normal feline thy-
primary follicular and papillary patterns have also been reported roid gland contains subpopulations of follicular cells with high
(Turrel etal, 1988). There may be neoplastic invasion of blood ves- growth potential and TSH receptors that have detectable basal
sels and the connective tissue capsule. The neoplastic cells may be constitutive activity (Nguyen et al, 2002). In the thyroid gland
subdivided into small lobules by strands of connective tissue with of a cat that is destined to become hyperthyroid, subpopula-
an abundant capillary network. Nonfunctional thyroid tumors in tions of follicular cells begin replicating autonomously. Once
cats are rare (Turrel etal, 1988; Guptill etal, 1995). In one case these subpopulations are present in sufficient numbers, growth
series, the nonfunctional thyroid tumor was of the papillary type and thyroid hormone synthesis becomes autonomous (Peter etal,
(Turrel etal, 1988). 1991). It has been hypothesized that chronic stimulation of cells
Distinguishing between well-differentiated thyroid follicular with a high growth potential ultimately causes them to become
carcinoma and benign proliferation of thyroid follicular epithe- autonomous due to development of follicular cell mutations
lium on the basis of histologic features alone is not always possible (Ward et al, 2005a). In humans, gain-of-function mutations of
(Guptill et al, 1995). Criteria used to diagnose follicular carci- the TSH receptor or the alpha subunit of stimulatory G proteins
noma include evidence of capsular and vascular invasion, cellu- have been described. Altered expression of the alpha subunits of
lar pleomorphism, extracapsular extension or distant metastasis. the stimulatory and inhibitory G proteins has also been reported.
Clinical behavior of the tumor must be taken into consideration Eleven TSH receptor mutations were detected in 134 hyperplastic
when interpreting the histopathology findings. nodules from 50 hyperthyroid cats (Watson etal, 2005). Five of
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TABLE 4-1 RISK FACTORS FOR FELINE HYPERTHYROIDISM IDENTIFIED IN CASE CONTROL STUDIES
NUMBERS OF CASES
STUDY LOCATION (CONTROLS) STUDY DATES DIET STUDIED REPORTED RISK FACTORS
New York State College of 56 (117) 1982-1985 Diet for past 5 years Non-Siamese breeds
Veterinary Medicine, USA More than 50% canned food
Partial or complete indoor housing
Exposure to lawn or flea control products
University of California, 379 (351) 1986 Current and one previous diet Non-Siamese or Himalayan breeds
Davis, and Animal Medical More than 50% canned food
Center, New York, USA Exposure to cat litter
Seattle, WA, USA 100 (163) 1996-1997 Diet for past 5 years Increasing age
Preference for certain canned food flavors
New Zealand 125 (250) 1996-1998 Current diet* Increasing age
Female sex
Domestic Short-Hair
Canned food of multiple flavors
Sleeping on the floor
Contact with flea and fly control products
Drinking puddle water and exposure to organic
fertilizers
Purdue University, IN, USA 109 (173) 1998-2000 Lifetime diet until 1 year Increasing age
before presentation Female sex
More than 50% canned food
Food from pop-top cans
Baby food in regular kitten diet or as treat
Lack of iodine supplement in label ingredients
Increasing frequency of carpet cleaning
Increasing years of exposure to well water
Increasing years to exposure of gas fireplaces
Hong Kong 12 (293) 2006-2007 Not stated Increasing age
Non-domestic Short-Hair breed
United Kingdom 109 (196) 2006-2007 Diet for past 5 years Increasing age
Non-purebred
Litter box use
More than 50% wet (canned/pouched) food
Canned foods
Fish in diet
Lack of deworming medication
From Edinboro CH, etal.: Feline hyperthyroidism: potential relationship with iodine supplement requirements of commercial cat foods, J Feline Med Surg 12(9):672-679, 2010.
*This was not explicitly reported but apparent from the context.
the mutations that were identified have also been associated with these studies suggest that multiple mutations in thyroid follicular
human hyperthyroidism. Interestingly of the 41 cats for which cells may ultimately result in thyroid cell autonomy. What is still
more than one nodule was available, 14 had nodules with differ- unclear is the underlying cause of these mutations and why clini-
ent mutations. In an invitro study of thyroid adenomas obtained cal feline hyperthyroidism has become more common in the last
from hyperthyroid cats, a decreased amount of an inhibitory G 30 years.
protein was identied (Hammer etal, 2000). Decreased expres-
sion of this G protein in thyroid follicular cells could reduce the Epidemiological Studies
inhibitory effect on the cAMP cascade, leading to autonomous
growth and hypersecretion of thyroxine (Ward etal, 2005b). A Risk Factors
further study suggested that decreased expression of certain sub- Numerous epidemiological studies have been performed in the
sets of inhibitory G proteins, rather than a change in TSH-stimu- last 25 years in an attempt to elucidate the cause of feline hyper-
lated G protein activity, contributes to the molecular pathogenesis thyroidism (Table 4-1). The first study published in 1988 sug-
of feline hyperthyroidism (Ward etal, 2010). In another study, gested that feeding of canned cat foods, living strictly indoors,
overexpression of the product of the oncogene c-Ras was detected being a non-Siamese breed, and having reported exposure to
in areas of nodular hyperplasia/adenoma in thyroid tissue from flea sprays, fertilizers, insecticides, and herbicides increased the
18 hyperthyroid cats (Merryman et al, 1999). Taken together risk of developing hyperthyroidism (Scarlett et al, 1988). In
another study, two genetically related cat breeds (Siamese and in the diet can result from overt supplementation, or be naturally
Himalayan) were found to have a diminished risk of developing present in the diet from both plant and animal sourcesespecially
hyperthyroidism. In addition, there was a twofold to threefold ocean fish. Thus the lack of explicit iodine supplementation in
increase in risk of developing hyperthyroidism among cats fed a diet does not necessarily equate with iodine deficiency. Studies
mostly canned cat food. There was also a threefold increase in have documented that the iodine content of commercial diets,
risk among cats using cat litter (Kass et al, 1999). In a more especially canned diets, is extremely variable with some commer-
recent study, there was no breed association with risk for devel- cial diets being deficient in iodine while others contain iodine
oping hyperthyroidism. Exposure to fertilizers, herbicides, plant in excess (Johnson etal, 1992; Edinboro etal, 2013). There has
pesticides, or flea control products or the presence of a smoker been a recent trend toward less iodine supplementation of com-
in the home was not signicantly associated with an increased mercial cat foods, because recommended dietary requirements of
risk for developing hyperthyroidism. Cats that preferred sh- iodine for cats have decreased over the last 30 years (Edinboro
flavored or liver and gibletsflavored canned cat food had an etal, 2010). In a study of urinary iodide concentrations in hyper-
increased risk of hyperthyroidism (Martin etal, 2000). Finally thyroid cats, before and after treatment with radioactive iodine, it
in a study published in 2004, Edinboro et al. identified con- was demonstrated that iodine concentrations were lower in hyper-
sumption of canned cat food (especially food consumed from thyroid cats compared to euthyroid cats (Wakeling etal, 2009a).
pop top cans) as a risk factor for developing hyperthyroidism. Although it is possible that these findings indicate decreased
In this study, female cats were at increased risk of developing iodine intake during development of hyperthyroidism, there are
hyperthyroidism. Other identified risk factors were consump- many complex influences on iodine metabolism in cats and fur-
tion of baby food, lack of iodine supplement in label ingredi- ther studies are necessary to establish a cause and effect relation-
ents, and increasing frequency of carpet cleaning; increasing ship. Although it is unlikely that iodine deficiency is the sole cause
years of exposure to well water and increasing years of exposure of feline hyperthyroidism, it is possible that dramatic fluctuations
to gas fireplaces were also identified as risk factors (Edinboro in iodine intake or chronic iodine deficiency may contribute to
etal, 2010). Similar risk factors have been identified in widely the current increase in feline thyrotoxicosis.
diverse geographic locations, such as the United Kingdom, Ger-
many, New Zealand, and Hong Kong (Wakeling etal, 2009b) Soy Isoflavones
(Table 4-1). These studies collectively suggest that the cause of Dietary soy is a potential dietary goitrogen that is commonly
feline hyperthyroidism is probably multifactorial; however the used as a source of high-quality vegetable protein in commercial
consistent identification of canned cat food as a risk factor sug- cat food. In one study, soy isoflavones were identified in in 24
gests that diet likely plays a major role. Candidate dietary candi- of 42 commercial cat foods with concentrations ranging from 1
date risk factors fall into two categories; nutritional deficiencies to 163 g/g of food; these amounts are predicted to have a bio-
or excesses and consumption of goitrogens (Peterson, 2012). logic effect (Court and Freeman, 2002). Although soy is more
commonly used as an ingredient in dry food, it is also present in
some canned diets. The soy isoflavones genistein and daidzein are
Nutritional Deficiencies or Excesses
known to inhibit thyroid peroxidase, which is an enzyme essen-
Iodine tial to thyroid hormone synthesis (Doerge and Sheehan 2002),
Iodine deficiency causes hypothyroidism and goiter in humans and also inhibit 5-deiodinase activity, resulting in decreased con-
and other species. Low thyroid hormone concentrations cause version of T4 to T3. These compounds may also induce hepatic
increased TSH concentrations, which lead to thyroid hyperpla- enzymes that are responsible for hepatic clearance of T3 and T4
sia and goiter. Mild or moderate iodine deficiency increases the (White etal, 2004). In a study of normal cats fed either soy or
risk of toxic nodular goiter in elderly humans (Laurberg et al, soy-free diets for 3 months, soy fed cats had a measurable increase
1991; Pedersen et al, 2002). In some individuals, correction of in total T4 and free T4 (fT4) concentrations with no change in
iodine deficiency or administration of excess iodine can lead to total T3 concentrations (White etal, 2004). These changes were
thyrotoxicosis, which may be transient or persistent. Causes of hypothesized to be due to deiodinase inhibition and resulted in
iodine-induced thyrotoxicosis in humans include iodine supple- some cats having a fT4 concentration above the reference range.
mentation for endemic iodine deficiency goiter, iodine adminis- These finding are consistent with the hypothesis that decreased
tration to patients with euthyroid Graves disease or underlying total T3 concentrations cause increased TSH, which stimulates the
nodular or diffuse goiter, and administration of radiographic con- thyroid gland to increase thyroid hormone synthesis and normal-
trast material to patients with underlying thyroid disease. In areas ize total T3 concentrations. These compounds, therefore, could
of mild to moderate iodine deficiency, iodide administration can potentially cause chronic thyroid gland hyperplasia and play an
cause thyrotoxicosis in patients with no underlying thyroid disease etiologic role in feline thyrotoxicosis. Although compelling, this
(Roti and Vagenakis, 2013). It is therefore possible that iodine theory does not explain the increased risk of hyperthyroidism
excess or deficiency could contribute to the pathogenesis of feline in cats fed canned food, because soy is less commonly found in
hyperthyroidism. Although acute changes in iodine intake result canned diets. Interestingly the effects of soy on thyroid function
in inverse changes in thyroid hormone concentrations in cats, lon- are exacerbated in the presence of iodine deficiency (Doerge and
ger-term studies suggest that cats are able to auto regulate thyroid Sheehan, 2002). It is conceivable that soy diets contribute to the
hormone synthesis and maintain thyroid hormone concentrations pathogenesis of feline hyperthyroidism by interacting with other
within reference range despite variable iodide intake (Mumma factors that impact the thyroid gland such as iodine deficiency.
etal, 1986; Johnson etal, 1992; Edinboro etal, 2013). Longer- Further studies are necessary to confirm this hypothesis.
term effects of variation in iodide intake however are unknown.
In a case control study of cats with hyperthyroidism, cats consum- Selenium
ing diets that did not have iodine supplementation identified as a The thyroid gland contains more selenium per gram than any
labeled ingredient were four times more likely to be hyperthyroid other tissue, which suggests an important role for this trace ele-
than those that did; however it should be recognized that iodine ment in thyroid homeostasis. Selenium modifies thyroid hormone
|
metabolism through the activity of selenoproteins, such as glu- large number of chemicals that have the potential to disrupt thy-
tathione peroxidases and thioredoxin reductase, which protect roid function in cats, recently most attention has focused on BPA
thyrocytes from oxidative damage. In cats, the type I deiodinase and the PBDE flame retardants.
is a selenium dependent enzyme, and selenium deficiency may
impair thyroid function. In kittens fed a low selenium diet, total Bisphenol A
T4 increased and total T3 decreased (Yu etal, 2002). There was no BPA is a chemical used to make epoxy resins and polycarbonate
difference in plasma selenium concentrations of either euthyroid plastics. It has estrogenic activity and has been demonstrated to
or hyperthyroid cats from two geographic areas with an allegedly disrupt thyroid function both by inhibiting thyroid peroxidase
high incidence of hyperthyroidism (UK, Eastern Australia) and and by binding to the thyroid hormone receptor, inhibiting TR
two regions with a lower incidence (Denmark, Western Austra- mediated transcription. Epoxy resins are widely used for lining
lia); however, cats had higher concentrations of selenium in their the interior of metal cans to prevent corrosion and maintain flavor
plasma than do other species such as rats and humans (Foster etal, and shelf life. BPA has been demonstrated to migrate from food
2001). In another study, selenium concentrations were not differ- can linings into human and pet food products during the cook-
ent between hyperthyroid cats and control cats (Sabatino et al, ing process (Kang and Kondo, 2002). It is hypothesized that BPA
2013). The role, if any, of selenium in the pathogenesis of feline migration into canned cat food could explain the increased risk of
hyperthyroidism remains to be determined. hyperthyroidism in cats fed canned food (Edinboro etal, 2004).
Further studies are needed to establish the relationship between
BPA and hyperthyroidism in cats.
Goitrogens (Thyroid Disrupters)
A large number of environmental chemicals are known to disrupt Polybrominated Diphenyl Ether Flame Retardants
thyroid function in various species, including humans (Boas etal, PBDEs are a group of synthetic brominated compounds that
2012). Known endocrine disrupting chemicals include polychlori- are widely used as flame retardants in many consumer products.
nated biphenyls, dioxins, polybrominated diphenyl ether (PBDE) These chemicals interfere with thyroid function at multiple levels
flame retardants, perfluorinated chemicals, phthalates, bisphe- including binding with the TR, interacting with thyroid hormone
nol A (BPA), and perchlorate. Many of these compounds have a binding proteins, inhibition of deiodinases, and increasing hepatic
high degree of structural similarity to T4 (Fig. 4-2) and most are clearance of thyroid hormone. Studies have demonstrated that
metabolized via glucuronidation, a process that is unusually slow house cats have high plasma concentrations of a variety of PBDEs,
in cats (Court and Greenblatt, 2000). The mechanisms by which although concentrations do not differ between euthyroid and
goitrogens disrupt thyroid function are many and complex and hyperthyroid cats. In a recent study, although the serum concentra-
include binding to the TSH receptor, stimulation or inhibition tions of PBDEs did not differ between euthyroid and hyperthyroid
of the sodium iodide symporter, inhibition of thyroid peroxidase, cats, there were higher concentrations of PBDEs in dust collected
binding to thyroid hormone plasma binding proteins, interference from the households of hyperthyroid cats than from the households
with other receptors on the thyrocyte, interference with mem- of euthyroid cats (Mensching et al, 2012). Clearly domestic cats
brane thyroid hormone transporters, changes in thyroid receptor have a significant burden of PBDEs presumably due to ingestion
(TR) expression or binding, and stimulation of hepatic enzymes of household dust during grooming; however a causal association
responsible for thyroid hormone clearance. Although there are a between PBDEs and feline hyperthyroidism has yet to be proven.
CH3
HO OH
O
CH3
(Br)n (Br)n
Bisphenol (BPA)
Polybrominated diphenyl ethers (PBDEs)
I I
H2N O
HO O
OH (Cl)n (Cl)n
I I Polychlorinated biphenyls (PCB)
Thyroxine (T4)
I I I I
H2N O H2N O
HO O HO O
OH OH
I I I
Triiodothyroxine (T3) Thyroxine (T4)
FIGURE 4-2 Chemical structure of bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), polychlorinated
biphenyls (PCB), thyroxine (T4), and triiodothyronine (T3). (From Peterson ME: Hyperthyroidism in cats: whats
causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 14[11]:804-818, 2012.)
CLINICAL FEATURES OF FELINE iodine treatment at our institution did not have clinical signs recog-
HYPERTHYROIDISM nized by the owner prior to diagnosis of hyperthyroidism.
Signalment Weight Loss

Hyperthyroidism is the most common endocrinopathy affecting Weight loss is the most common clinical sign observed in cats with
cats (Edinboro etal, 2004). The reported age range is 4 to 22 years hyperthyroidism. Approximately 90% of hyperthyroid cats have
with a mean of 13 years. Interestingly the mean age of onset has evidence of mild to severe weight loss documented at the time
not changed over the time period of 1983 to 2004 (Peterson etal, of diagnosis. Some hyperthyroid cats become severely cachectic
1983; Broussard etal, 1995; Edinboro etal, 2004). A small num- (Fig. 4-4), but this is less common now than previously because
ber of cats younger than 4 years has been diagnosed with hyper- of the increased awareness of the disease and resultant earlier diag-
thyroidism, although the disorder remains rare in this age group nosis. The weight loss typically occurs gradually over a period of
(Gordon et al, 2003). Fewer than 5% of cats diagnosed with months to years. Owners may comment that the weight loss was
hyperthyroidism are younger than 8 years of age. Pure bred cats, not recognized until someone who had not seen the cat for several
particularly Siamese and Himalayan cats, have a decreased risk of months noticed the change.
developing hyperthyroidism (Scarlett etal, 1988; Kass etal, 1999;
Olczak etal, 2005).
Polyphagia
Clinical Signs and Pathophysiology Polyphagia and weight loss are quite common in feline hyperthy-
roidism. This is an extremely important historical nding, because
Overview the combination of polyphagia and weight loss has fewer differen-
Most hyperthyroid cats have a range of clinical signs that reflect tial diagnoses than anorexia and weight loss (Box 4-1). Cats previ-
the effects of thyroid hormone on almost every organ in the body. ously thought to be nicky eaters may develop excellent appetites,
Feline hyperthyroidism is a chronically progressive and insidious which is a change that may not initially be perceived as a prob-
disease, and the clinical effects can vary from mild to severe. Early lem by the owner. In severe cases of polyphagia, cats can become
in the disease process, the clinical signs are subtle enough to be aggressive in obtaining food.
missed by both the owner and the veterinarian and the diagnosis Polyphagia and weight loss occur due to the increased meta-
may only be made when routine thyroid hormone testing is per- bolic rate and increased energy expenditure of the hyperthyroid
formed. Even if the diagnosis is made by routine testing, clinical state, which results in reduced efciency of physiologic functions.
signs (e.g., weight loss) can often be identified retrospectively. In
some cases, weight loss is ignored because it occurs after inten-
TABLE 4-2 H
ISTORICAL AND PHYSICAL
tional calorie restriction to manage obesity, but the weight loss
EXAMINATION FINDINGS
continues even after calorie restriction is discontinued. In other
FROM THE FIRST LARGE CASE
cases, subtle clinical changes (e.g., tachycardia and increased activ-
SERIES OF 131 CATS WITH
ity) are blamed on stress during the office visit. Clinical signs may
HYPERTHYROIDISM
be present for months to 1 to 2 years prior to the diagnosis being
made (Thoday and Mooney, 1992). Because hyperthyroid cats SIGN PERCENT OF CATS
usually have a good to ravenous appetite and are active or even
overactive, the owners often perceive that an elderly cat has a new Weight loss 98
lease on life and do not initially worry about the clinical signs. Polyphagia 81
Only when the signs worsen or other more serious clinical signs Increased activity/restless 76
appear do owners seek veterinary help. The most common rea-
Tachycardia 66
sons for owners to seek veterinary care are weight loss, polyphagia,
polydipsia/polyuria, vomiting, and/or diarrhea. The spectrum of Polydipsia/polyuria 60
clinical signs reported in the first large case series reported in the Vomiting 55
veterinary literature is shown in Table 4-2. Cardiac murmur 53
Because owner and veterinary awareness of the clinical syndrome
of feline hyperthyroidism is now very high and measurement of Diarrhea 33
serum thyroxine concentration is a routine component of geriat- Increased fecal volume 31
ric feline serum biochemistry proles, cats with hyperthyroidism Anorexia 26
are being diagnosed earlier in the course of the disease. This means
Polypnea 25
that the clinical signs observed by owners and veterinarians are less
severe than those which were described when the disease was first Muscle weakness 25
recognized in the 1980s; thus diagnosis of feline hyperthyroidism Muscle tremor 18
has become more challenging particularly in cats with other con- Congestive heart failure 12
current illness (Broussard etal, 1995; Bucknell, 2000). There was a
Increased nail growth 12
dramatic decrease in the frequency and severity of clinical findings
in cats diagnosed with hyperthyroidism from 1983 to 1993 (Brous- Dyspnea 11
sard etal, 1995; Fig. 4-3). Unfortunately studies evaluating the fre- Alopecia 7
quency of clinical signs in hyperthyroid cats have not been published Ventroflexion of neck 3
in the peer reviewed literature since 2000, but subjectively the trend
for decreasing severity of clinical signs at the time of diagnosis has Modified from Peterson ME, etal.: Feline hyperthyroidism: pretreatment clinical and
continued. A significant percentage of cats presented for radioactive laboratory evaluation of 131 cases, J Am Vet Med Assoc 183(1):103-110, 1983.
|
100 100
1983
1983 1993
1993
80 80
% ABOVE NORMAL
% OF CATS
60 60
40 40
20 20
0 0
Wt Loss Tachycardia Polyphagia Vomiting PU/PD Hyperactive ALT AST ALP BUN PCV MCV
FIGURE 4-3 Percentage of cats with common clinical findings in 1983 (n = 131) compared to 1993 (n = 202).
(From Broussard JD, etal.: Changes in clinical and laboratory ndings in cats with hyperthyroidism from 1983 to
1993, J Am Vet Med Assoc 206[3]:302-305, 1995.) ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; BUN, blood urea nitrogen; MCV, mean corpuscular volume; PCV, packed cell volume;
PD, polydipsia; PU, polyuria.
A B
C D
FIGURE 4-4 A, Hyperthyroid 13-year-old cat showing severe emaciation due to severe hyperthyroidism B, Same cat
as in A 2 months after return to a euthyroid condition. C, Hyperthyroid cat choosing the cool cage floor rather than
a warm fleece pad. D, Hyperthyroid cat with marked ventroflexion of the head, a finding suggestive of concomitant
thiamine or potassium deficiency. (D, Courtesy of Dr. Jane Turrel, Pacifica, CA.)
BOX 4-1 D
ifferential Diagnosis for Cats with Polyphagia TABLE 4-3 PHYSICAL EXAMINATION
and Weight Loss FINDINGS ASSOCIATED WITH
HYPERTHYROIDISM IN CATS
Hyperthyroidism
Diabetes mellitus FINDING PERCENT OF CATS
Poor quality or insufficient diet Palpable thyroid 91
Gastrointestinal disease Thin 71
Malabsorption (inflammatory bowel disease, gastrointestinal lymphoma,
Tachycardia (more than 240 beats/min) 48
gastrointestinal parasitism)
Maldigestion (exocrine pancreatic insufficiency) Hyperactive/difficult to examine 48
Hyperadrenocorticism Heart murmur 41
Skin changes (patchy alopecia, matting, dry coat, 36
greasy seborrhea, thin skin)
Increased food intake and utilization of stored energy can initially Small kidneys 26
compensate for the increased energy expenditure; however, ulti-
mately chronic caloric and nutritional deficiency occurs. Although Increased rectal temperature 14
both synthesis and degradation of proteins are increased, the net Gallop cardiac rhythm 12
effect is protein catabolism. In addition to weight loss, negative Easily stressed 12
nitrogen balance is evidenced by muscle wasting and weakness. Dehydrated/cachectic appearance 11
The exact mechanism for the increase in appetite associated with
hyperthyroidism is poorly understood but studies suggest that sup- Aggressive behavior 8
pression of leptin, increased hypothalamic neuropeptide Y, and Premature cardiac beats 8
enhanced phosphorylation of adenosine monophosphate (AMP)- Increase nail growth 2
activated protein kinase may play a role (Ptervri etal, 2005; Ishii
Depressed/weak 2
etal, 2008). Although polyphagia is one of the most common clini-
cal signs of hyperthyroidism, a small percentage of hyperthyroid Ventroflexion of the neck <1
cats exhibit periods of decreased appetite (see Decreased Appetite).
specific gravity (USG), it is difficult to assess true renal func-

Nervousness, Hyperactivity, Aggressive Behavior
tion in hyperthyroid cats. After resolution of hyperthyroidism
Approximately 50% of humans with thyrotoxicosis exhibit trem- (regardless of the treatment method), renal perfusion typically
bling, nervousness, emotional lability, and depression and anxiety, decreases, which in some cats may unmask occult renal failure (see
which are presumably due to a direct effect of thyroid hormone Treatment of Hyperthyroidism and Renal Function).
concentrations on the nervous system (Burch, 2013). In cats, these
signs are characterized by restlessness, irritability, and/or aggres- Gastrointestinal Dysfunction
sive behavior (see Table 4-2; Table 4-3). Many hyperthyroid cats
appear to have an intense desire to move about constantly. Owners The most common clinical signs of hyperthyroidism referable to
may note that their cats wander, pace, sleep for only brief periods, the gastrointestinal tract are polyphagia and weight loss (see ear-
and waken easily. Many hyperthyroid cats appear anxious and lier). Other signs of gastrointestinal dysfunction include anorexia,
cannot be held for the short time required to complete a physical vomiting, diarrhea, increased fecal volume, increased frequency of
examination. Some become aggressive if an attempt is made to defecation, and foul smelling feces. Vomiting is relatively common,
further restrain them. The cause of these clinical signs is multifac- occurring in approximately 50% of hyperthyroid cats. Anorexia and
torial; however some of the signs are due to increased adrenergic watery diarrhea are less common but when present are usually seen in
activity, because a degree of improvement occurs during treatment cats with severe hyperthyroidism or in those with coexistent primary
with adrenergic antagonists. intestinal problems. Reasons for diarrhea and increased frequency
of defecation in hyperthyroidism include hypermotility of the gas-
trointestinal tract, leading to rapid gastric emptying, and shortened
Polydipsia and Polyuria
intestinal transit times (Papasouliotis etal, 1993; Schlesinger etal,
Polyuria and polydipsia are commonly reported in feline hyper- 1993). Rapid eating or overeating leading to gastric distension and
thyroidism. Although the two clinical signs invariably occur direct action of thyroid hormone on the chemoreceptor trigger zone
together, it is common for owners to report polydipsia in the are potential causes of vomiting. Steatorrhea is also reported in cats
absence of polyuria, or vice versa. Polyuria and polydipsia occur with severe hyperthyroidism; however, fat malabsorption may be due
in 30% to 40% of hyperthyroid cats, and changes in the amount to other concurrent illness, such as exocrine pancreatic insufficiency.
of water consumed and urine excreted are highly variable. There
are a number of mechanisms involved in the pathogenesis of poly- Hair Loss/Unkempt Coat
dipsia and polyuria in hyperthyroidism. Primary (psychogenic)
polydipsia increases water and solute intake, and down regulation Nonspecific hair coat changes (e.g., unkempt hair, matted hair,
of Aquaporin 1 and Aquaporin 2 channels may contribute to the and a lusterless coat) occur commonly in hyperthyroid cats. Less
polyuria (Wang etal, 2007). Occult renal disease may also play commonly, patchy alopecia may occur due to excessive grooming
a role. Polyuria and polydipsia may be present in hyperthyroid activity. Some cats may pull hair out in clumps. Heat intolerance
cats without evidence of renal disease, but because hyperthyroid- is a classic sign of thyrotoxicosis in humans, and hair pulling may
ism increases glomerular ltration rate (GFR) and decreases urine also be a result of heat intolerance in cats.
|
Panting and Respiratory Distress demonstrated in thyrotoxicosis, evidence of increased sensitivity

to catecholamines in thyrotoxicosis is lacking (Liggert etal, 1989).
Open-mouth breathing (panting) is rare in cats and is usually asso-
ciated with heart or respiratory disease. Some hyperthyroid cats
Concurrent Nonthyroidal Illness
exhibit panting, dyspnea, or hyperventilation at rest; these signs
are most common in hyperthyroid cats that are stressed by physi- Because feline hyperthyroidism is a geriatric disease, concurrent
cal restraint or transportation. Dyspnea on exertion is common nonthyroidal illness is common and often complicates the clinical
in thyrotoxic people and is due to respiratory muscle weakness, picture. Because the clinical signs of hyperthyroidism are so vari-
enhanced ventilatory drive, decreased pulmonary compliance, able and overlap with those of many other concurrent illnesses,
and concurrent cardiovascular complications (Burch, 2013). Thy- the presence or absence of any one clinical sign cannot be used to
rotoxicosis is associated with shallow rapid breathing, enhanced diagnose or exclude hyperthyroidism. In some cases, the only way
oxygen utilization and carbon dioxide output, and a low anaerobic to determine whether all the clinical signs exhibited by a particular
threshold (Burch, 2013). patient can be explained by hyperthyroidism is to treat the hyper-
thyroidism and determine if the clinical signs resolve.
Decreased Appetite
Subclinical Hyperthyroidism
Although most hyperthyroid cats are polyphagic, some hyperthy-
roid cats exhibit inappetence, anorexia, or a waxing and waning Subclinical hyperthyroidism is defined in humans as the pres-
appetite. Potential causes of a poor appetite include congestive ence of hormone test results indicating hyperthyroidism (usually
heart failure, severe debilitation and muscle weakness, thiamine or decreased TSH) in a person without clinical signs of hyperthyroid-
cobalamine deficiency, hypokalemia, or other concurrent nonthy- ism (Biondi etal, 2005). It is likely that a similar condition exists
roidal illness (e.g., inflammatory bowel disease, pancreatitis, renal in cats; however, documentation of this condition is hampered
disease, and neoplasia) (Cook etal, 2011). by the lack of a sensitive assay for TSH in cats. In one study of
104 geriatric cats with normal thyroid hormone concentrations,
Weakness and Lethargy 7.5% of cats became hyperthyroid during 12 months of follow up
(Wakeling etal, 2011). Cats with undetectable TSH at baseline
Decreased activity, weakness, fatigability, and lethargy occur in were more likely to become hyperthyroid, but not all cats with
some cats with severe hyperthyroidism. Some cats progress from a suppressed TSH became hyperthyroid. Furthermore, geriatric
over-activity and restlessness to listlessness and weakness. Weak- cats with a low TSH are more likely to have histologic evidence of
ness and fatigability are also frequent complaints in humans with nodular thyroid disease (Wakeling etal, 2007).
thyrotoxicosis. In one study, 67% of hyperthyroid people had
complaints of muscle weakness, mainly in the proximal muscles
PHYSICAL EXAMINATION
of the legs, and 19% had symmetrical distal sensory abnormalities
and depressed distal tendon reflexes (Duyff etal, 2000). The bio-
General
chemical basis of the muscular weakness is uncertain; it may sim-
ply be caused by weight loss and the catabolic state. Hypokalemia, Although many cats with mild hyperthyroidism appear asymp-
cobalamine deficiency, and thiamine deficiency may also contrib- tomatic to the owner, in the vast majority of cases abnormalities
ute to muscle weakness and weight loss (Ruaux etal, 2005). consistent with a diagnosis of hyperthyroidism can be detected by
a careful physical examination. Weight loss and tachycardia are
Heat and Stress Intolerance usually present and support a diagnosis of hyperthyroidism. Most
importantly, a palpable cervical mass is detected in over 90% of
Heat intolerance is a subtle sign that may be observed by cat own- hyperthyroid cats at the time of diagnosis.
ers. Most normal cats seek warm, sunny places to sleep. Hyperthy-
roid cats may reverse this heat-seeking behavior and sleep in cool
Palpable Cervical Mass (Goiter)
places, such as the bath tub or a cool tile floor (see Fig. 4-4, C). In
addition to heat intolerance, some hyperthyroid cats have an obvi- In healthy cats, the thyroid lobes are positioned just below the
ous impaired tolerance for stress. Brief car rides, bathing, and vis- cricoid cartilage and extend ventrally over the rst few tracheal
its to boarding kennels or veterinary hospitals may cause marked rings; they lie dorsolateral to and on either side of the trachea. The
clinical deterioration, respiratory distress, weakness, or even car- thyroid lobes are not palpable in normal cats. Hyperthyroidism
diac arrest. The clinician should always take into consideration is invariably associated with enlargement of one or both thyroid
this inability to cope with stress when diagnostic or therapeutic lobes (goiter)an enlargement that is palpable in more than 90%
procedures are being planned. of hyperthyroid cats. Careful palpation is required to identify
Heat intolerance and an inability to cope with stress are classic small goiters, which can be challenging in a stressed cat.
clinical signs of human thyrotoxicosis. Many of these effects are Palpation of a cervical mass is not pathognomonic for hyperthy-
similar to those induced by epinephrine, including heat intoler- roidism; some cats with palpable thyroid glands are clinically nor-
ance, excessive sweating (in humans), tremor, and tachycardia. mal, and some cervical masses arise from structures other than the
Because these signs are partly alleviated by adrenergic antago- thyroid gland. In one study of euthyroid geriatric cats (more than
nists, it has been hypothesized that a state of increased adrener- 9 years of age) a palpable goiter was present in 27 of 104 (26%)
gic activity exists in thyrotoxicosis; however investigators have of cats. Sixteen percent of these cats ultimately became hyperthy-
been unable to demonstrate increased catecholamine production, roid over 4 years of follow up (Wakeling etal, 2011). Causes
increased concentrations of serum catecholamine concentrations, of thyroid gland enlargement, other than adenomatous hyper-
or excretion of urinary catecholamine metabolites. Furthermore, plasia or adenoma, include thyroiditis, and thyroid cystadenoma
although increased numbers of adrenergic receptors have been (Norsworthy etal, 2002). Other causes of palpable cervical masses
Alternative Palpation Technique

An alternative semi-quantitative palpation technique has been
described in which the clinician stands behind the cat and ele-
vates the head at a 45-degree angle while turning the head to the
right and left (Norsworthy et al, 2002). The size of the thyroid
gland is scored from 0 to 6 with 0 being a non-palpable thyroid
gland, 1 being a barely palpable thyroid gland and 6 being a lobe
measuring 2.5 cm or greater in length. Using this technique, an
enlarged thyroid gland was detected in 96% of hyperthyroid cats
and 59% of euthyroid cats (Norsworthy etal, 2002); however, the
technique was not compared to the standard palpation technique.
None of the enlarged thyroid glands detected in euthyroid cats
had a score of 3 or more, whereas 18 of the 23 hyperthyroid cats
had a score of 4 or greater.
FIGURE 4-5 The clipped ventrocervical area of a cat with an obvious goiter.
Cardiac Disturbances
Tachycardia, Murmurs, Premature Beats, and Gallop Rhythm
include salivary mucoceles, parathyroid gland masses or cysts, The heart is very sensitive to the effects of thyroid hor-
thyroglossal cysts, dermoid cysts, and pharyngeal (branchial) cysts mone, and many hyperthyroid cats have clinical evidence of
(Norsworthy etal, 2002; Phillips etal, 2003; Lynn etal, 2009; heart disease. Common cardiovascular abnormalities include
Tolbert etal, 2009; Nelson etal, 2012). tachyarrhythmias, heart murmurs, and gallop rhythms. Less
Because the thyroid lobes are only loosely attached to the trachea, commonly, clinical signs of congestive heart failure (e.g., dys-
the increased weight associated with thyroid enlargement causes pnea, muffled heart sounds, and ascites) may be present. In a
migration of the lobes ventrally in the neck. Sometimes the abnor- study of approximately 200 hyperthyroid cats evaluated from
mal lobe (or lobes) descends through the thoracic inlet and into 1992 to 1993, 8% of cats had evidence of congestive heart fail-
the anterior mediastinum. This may be one explanation for being ure compared to 20% of cats evaluated between 1979 and 1982
unable to palpate a goiter in a hyperthyroid cat. In cats with thy- (Fox etal, 1999). Congestive heart failure due to feline hyper-
roid carcinoma, thyroid gland palpation may be similar to that of thyroidism is even less common now that it was in the 1990s
a hyperthyroid cat with benign disease; however, in other cases the (Connolly etal, 2005).
masses associated with thyroid carcinoma are large, fixed rather than Tachycardia is the most common cardiovascular abnormal-
freely moveable and attached to underlying or overlying tissues. ity present in hyperthyroid cats, but it is sometimes difficult to
distinguish tachycardia due to thyrotoxicosis from other causes
Palpation Technique of tachycardia, such as stress, hypovolemia, and primary cardiac
Evaluation of the thyroid area should be part of the physical disease. Sinus tachycardia is the most common cause of tachy-
examination of every cat seen by a veterinarian. This allows the cardia and is reported in about 30% of hyperthyroid cats. Other
clinician to develop expertise and condence when palpating a cat less common arrhythmias include atrial extrasystoles, atrial tachy-
suspected of having hyperthyroidism, and it occasionally allows cardia, ventricular extrasystoles, first degree atrioventricular block,
identication of a mass that would otherwise go undetected. left anterior fascicular block, right bundle branch block, and left
For the evaluation, the cats head should be gently extended. bundle branch block.
The thumb and index nger of one hand are gently placed on The tachycardia present in the majority of hyperthyroid cats
either side of the trachea in the jugular furrows at the level of the is due to both an increase in sympathetic tone and a decrease
larynx. The area is gently compressed, and the ngers are smoothly in parasympathetic tone (Fig. 4-6; Klein and Ojamaa, 2001).
slid down to the thoracic inlet and back up again to the larynx. Cardiac output is increased due to tachycardia, increased ejec-
The ngertips should remain within the jugular furrows. Thyroid tion fraction, increased blood volume, and decreased vascular
enlargement is usually felt as a somewhat movable, subcutaneous resistance (Klein and Ojamaa, 2001). The direct vasodilatory
(SC) nodule that may vary between the size of a lentil and the size effect of T3 on smooth muscle results in decreased peripheral
of a lima bean. Success in this maneuver depends on not squeezing resistance that leads to activation of the renin-angiotensin-
too hard; the pressure exerted must be gentle enough to allow the aldosterone system (RAAS) and increased blood volume. Thy-
abnormal nodule to slide under the ngertips but rm enough to roid hormones also directly activate genes that encode structural
detect the mass. Sometimes it is possible for owners to visualize a and regulatory cardiac proteins (Box 4-2), which ultimately
goiter by moistening the neck with alcohol; the enlarged thyroid results in an increase in contractile function (Connolly et al,
glands can often be visualized as the fingers palpating the neck 2005; Klein and Ojamaa, 2001). The increased metabolic rate
slide toward the thoracic inlet. Occasionally a large cervical mass of the hyperthyroid state increases peripheral oxygen demand
can be directly direct visualized if the ventrocervical area is clipped and also contributes to the high-output state. The normal heart
free of hair (Fig. 4-5). If thyroid enlargement is not palpated after compensates for these changes by cardiac dilation and hyper-
two or three attempts in a cat with compatible clinical signs, the trophy. Although the increased heart rate and increased cardiac
cats head and neck should be extended further and the palpation output of the hyperthyroid state resemble a state of increased
repeated. This maneuver will sometimes result in an intrathoracic adrenergic activity and various components of the adrener-
nodule moving back out into the neck where it can be palpated. gic receptor complex in the plasma membrane are altered by
Alternatively gradual pressure applied just below the thoracic inlet changes in thyroid hormone concentrations, there is no net
may move a thyroid mass located just inside the thoracic inlet effect on the sensitivity of the heart to adrenergic stimulation
back into the neck. (Klein and Ojamaa, 2001).
|
Increased Decreased
tissue systemic vascular
thermogenesis resistance
Decreased
effective arterial
filling volume
Thyroid hormones Increased

(T3 and T4) renal sodium
reabsorption
Increased blood
volume
Increased Increased cardiac

cardiac output inotropy and chronotropy
FIGURE 4-6 Effects of thyroid hormone on cardiovascular dynamics. The diagram shows the way that thyroid hor-
mones increase cardiac output by affecting tissue oxygen consumption, vascular resistance, blood volume, cardiac
contractility, and heart rate. T3, Triiodothyronine; T4, thyroxine. (Adapted from Klein I, Ojamaa K: Thyroid hormone
and the cardiovascular system, N Engl J Med 344[7]:501-509, 2001.)
BOX 4-2 R
egulation of Genes Coding for Cardiac Proteins the myocardium to cellular hypoxia. The serum troponin con-
by Thyroid Hormone centrations normalize in most cats after effective treatment of
hyperthyroidism.
Positive Regulation
-Myosin heavy chain Ventroflexion of the Head
Sarcoplasmic reticulum Ca2+-ATPase
1-Adrenergic receptors Early reports of hyperthyroid cats included occasional
Guanine-nucleotide-regulatory proteins cats exhibiting pronounced ventroflexion of the head (see
Na+/K+-ATPase Fig. 4-4, D). The head of an affected cat could be lifted without
Voltage-gated potassium channels (Kv1.5, Kv4.2, Kv4.3) difculty, but the cat immediately resumed the abnormal pos-
ture when released. Clinical signs usually seen in association with
Negative Regulation cervical ventroflexion were anorexia, mild ataxia, and mydriasis.
-Myosin heavy chain There have been no published reports of this syndrome since
Phospholamban 1994 (Nemzek etal, 1994). It has been hypothesized that either
Adenylyl cyclase types V and VI thiamine deficiency or hypokalemia could be the cause of cer-
Triiodothyronine (T3) nuclear receptor 1 vical ventroflexion; but because it is now so rare, there have
Na+/Ca2+ exchanger been no further investigations of the pathogenesis. Potassium
From Klein I, Ojamaa K: Thyroid hormone and the cardiovascular system, N Eng J depletion may occur in hyperthyroidism secondary to vomit-
Med 344(7):504, 2001. ing, diarrhea, anorexia, or excess urine loss. Vitamin deficiencies
ATPase, Adenosine triphosphatase. (e.g., thiamine and cobalamine deciency) occur in hyper-
thyroidism secondary to polyuria, malabsorption, diarrhea,
vomiting, and anorexia.
Some cats with hyperthyroidism develop secondary hypertro-
phic cardiomyopathy, which may result in heart failure. In a study Ocular Lesions
of 103 hyperthyroid cats, the most common echocardiographic
findings were ventricular or interventricular hypertrophy; only Systolic hypertension is documented in approximately 10% to
four cats had subnormal cardiac performance and ventricular dila- 15% of hyperthyroid cats at the time of diagnosis (Williams
tation, and all of these cats had clinical and radiographic evidence et al, 2010). Despite this, retinopathy secondary to hyperten-
of congestive heart failure (Bond etal, 1988). Severe heart failure sion is uncommonly detected in feline hyperthyroidism. In a
appears to be more common among hyperthyroid cats with the study of 100 hyperthyroid cats and 30 control cats, there were
dilated form of cardiomyopathy (Jacobs etal, 1986; Jacobs and no ophthalmologic abnormalities that were more commonly
Panciera, 1992). Dilated cardiomyopathy in hyperthyroid cats identified in hyperthyroid cats than in euthyroid cats (van der
may be due to concurrent primary heart disease rather than sec- Woerdt and Peterson, 2000). Two hyperthyroid cats had reti-
ondary to hyperthyroidism. Approximately 50% of hyperthyroid nal changes consistent with hypertensive retinopathy, including
cats have detectable concentrations of serum troponin I, which retinal hemorrhage and focal retinal detachment with subretinal
is a sensitive and specific marker of myocardial cellular damage effusion. The authors concluded that ocular abnormalities are
(Connolly etal, 2005); this would be expected in a systemic dis- uncommon in hyperthyroid cats (see also Blood Pressure and
ease that increases myocardial oxygen demand and predisposes Hypertension).
Heinz body formation in hyperthyroid cats (Christopher, 1989;

Thyroid Storm
Branter etal, 2012).
Thyroid storm is the term used in humans to describe an acute
exacerbation of clinical signs of thyrotoxicosis in conjunction with Leukon
varying degrees of organ decompensation. The cause is believed to Hyperthyroid cats usually have a normal leukogram or may have
be an increased cellular response to thyroid hormone in conjunc- nonspecific changes, such as a stress response characterized by leu-
tion with increased or abrupt availability of free thyroid hormones. kocytosis, neutrophilia, lymphopenia, and eosinopenia.
Thyroid storm is usually precipitated by a superimposed insult,
such as infection, thyroid surgery, other nonthyroidal illness, or Platelets
withdrawal of anti-thyroid drugs (Chiha etal, 2013). The diagno- Hyperthyroid cats have been demonstrated to have larger plate-
sis is based on documentation of four major clinical signs: fever, lets than normal control cats, but platelet counts were similar
central nervous system (CNS) manifestations, gastrointestinal or (Sullivan etal, 1993).
hepatic dysfunction, and cardiovascular effects, such as tachycar-
dia, atrial fibrillation, and congestive heart failure. Although cats Serum Chemistry Prole
with hyperthyroidism may have an acute exacerbation of clinical
signs either due to complications of thyrotoxicosis (e.g., conges- Liver Enzyme Activities
tive heart failure, hypertension) or presence of concurrent non- Increased liver enzymes are among the most frequently observed
thyroidal illness, thyroid storm as defined in humans has yet to be screening test alterations seen in hyperthyroid cats (Table 4-4). More
described (Ward, 2007; Tolbert, 2010). than 75% of hyperthyroid cats have abnormalities in both serum ala-
nine aminotransferase (ALT) and serum alkaline phosphatase (ALP)
activities, and more than 90% show increases of at least one of these
IN-HOSPITAL DIAGNOSTIC EVALUATION
enzymes. The increases are usually only mild to moderate (less than
500 IU/L), although higher values are noted occasionally. The influ-
Background
ence of underlying concurrent hepatic disease should be considered
Cats with hyperthyroidism are usually geriatric, and therefore in hyperthyroid cats with more markedly increased liver enzyme
abnormalities identified on the diagnostic evaluation may be due activities (more than 500 IU/L), although not all hyperthyroid cats
either to thyrotoxicosis or other underlying concurrent disease. with higher increases in ALT have concurrent hepatic dysfunction.
It can sometimes be difficult to distinguish which abnormalities Hepatic hypoxia is thought to be the major cause of abnormalities in
are due to hyperthyroidism and which are due to other concur-
rent illness. In addition, hyperthyroidism increases the metabolic
rate and GFR and can mask underlying chronic kidney disease TABLE 4-4 LABORATORY ABNORMALITIES
(CKD). The goals of the diagnostic evaluation in a cat with sus- ON ROUTINE TESTING OF
pected hyperthyroidism are to confirm the diagnosis, identify HYPERTHYROID CATS
complications of hyperthyroidism (e.g., hypertension and heart
failure that require either further evaluation or specific treatment), TEST PERCENTAGE OF CATS
and evaluate for the presence of other disorders that require treat- Complete Blood Count
ment or whose presence may influence the choice of treatment Erythrocytosis 39
for hyperthyroidism. Minimum diagnostic testing should include
Increase in MCV 27
a complete blood count (CBC), serum biochemistry prole, uri-
nalysis, serum T4 concentration, thoracic radiography, and mea- Lymphopenia 22
surement of indirect blood pressure. Electrocardiography and Leukocytosis 19
echocardiography are indicated if clinically significant heart dis- Eosinopenia 13
ease is suspected. Further diagnostic testing may be necessary in
cats in which the diagnosis of hyperthyroidism cannot be con- Serum Chemistry Profile
firmed by measurement of serum T4 concentration alone, and in Increased ALT 85
those cats in which the initial evaluation reveals abnormalities that Increased serum ALP 62
cannot be explained by hyperthyroidism alone.
Azotemia (increased BUN) 26
Increased creatinine 23
Complete Blood Count
Hyperphosphatemia 18
Erythron
Electrolyte abnormalities 11
Approximately 40% to 50% of hyperthyroid cats have a mild ele-
vation in the packed cell volume (PCV) (Broussard etal, 1995). Hyperglycemia 5
The increase in the red blood cell count may be directly related Hyperbilirubinemia 3
to thyrotoxicosis, because thyroid hormone stimulates secretion Urinalysis
of erythropoietin (Klein and Ojamaa, 2001). Additionally, 20%
Specific gravity > 1.035 63
of hyperthyroid cats have macrocytosis (Broussard et al, 1995).
Heinz bodies are a more common finding on evaluation of the Specific gravity < 1.015 4
blood film in hyperthyroid cats than in control cats. Although Glucosuria 4
cats with Heinz bodies tend to have a lower hematocrit than those Inflammation/infection 2
without Heinz bodies, anemia is a rare finding in hyperthyroid
cats (Christopher, 1989). Depletion of antioxidants and excessive ALP, Alkaline phosphatase; ALT, alanine aminotransferase; BUN, blood urea nitrogen;
fat and protein catabolism has been proposed as the reason for MCV, mean cell volume.
|
ALT but increased hepatic enzyme activity may also be due in part Hyperthyroid cats also have evidence of increased bone turn-
to malnutrition, congestive heart failure, infection, and direct toxic over as evidenced by increased activity of the bone isoenzyme of
effects of thyroid hormones on the liver. Separation of the different serum ALP and osteocalcin concentrations (Archer and Taylor,
isoenzymes of serum ALP has demonstrated that 50% to 80% of the 1996; Foster and Thoday, 2000). In a study of 36 hyperthyroid
increased serum ALP in hyperthyroid cats is the bone isoenzyme of cats, 44% of cats had increased osteocalcin concentrations. There
serum ALP, presumably because of increased bone turnover (Archer were no correlations between magnitude of serum ALP bone iso-
and Taylor, 1996; Foster and Thoday, 2000). Increased AST and enzyme, osteocalcin, and serum thyroxine concentrations (Archer
creatine kinase (CK) have also been reported in some hyperthyroid and Taylor, 1996). Derangements in calcium homeostasis also
cats (Archer and Taylor, 1996). Increases in gamma glutamyl trans- occur in hyperthyroid cats. Hyperthyroid cats have been reported
ferase (GGT) have not been reported in hyperthyroid cats (Archer to have increased serum phosphate concentrations and decreased
and Taylor, 1996; Berent etal, 2007). ionized calcium concentrations (Archer and Taylor, 1996; Wil-
liams etal, 2012; Barber and Elliott, 1996). The mechanism for
Liver Dysfunction ionized hypocalcemia in hyperthyroid cats is unknown but does
In addition to increased hepatic enzymes, cats with hyperthyroid- not appear to be due to concurrent CKD or reduced plasma cal-
ism have significantly higher fasting serum ammonia concentrations citriol concentrations (Williams etal, 2013). In a study of 30 cats
than euthyroid cats; these values return to normal with effective with untreated hyperthyroidism, hyperthyroid cats had lower
treatment of the hyperthyroidism (Berent et al, 2007). The rea- blood ionized calcium concentrations and higher phosphate con-
son for increased ammonia concentrations is unknown, but it may centrations than a group of age matched controls; 43% of the
be secondary to accelerated protein catabolism and deamination cats were hyperphosphatemic, and 27% of the cats had an ion-
due to the increased metabolic rate. Pre and post prandial bile acid ized calcium concentration below the reference range (Barber and
concentrations and results of hepatic ultrasonography were normal Elliott, 1996). Hyperparathyroidism was documented in 77% of
in all hyperthyroid cats with increased ammonia concentrations. the cats with parathyroid hormone (PTH) concentrations reach-
Four of the 19 hyperthyroid cats evaluated had ALT concentra- ing up to 19 times the upper limit of the reference range. Other
tions greater than 500 I/L; however, the ALT returned to normal in studies also suggest that 60% to 80% of hyperthyroid cats have
all cats after treatment. This implies that there were no functional increased serum concentrations of PTH (Williams et al, 2012;
or clinically relevant hepatic changes in these hyperthyroid cats and Barber and Elliott, 1996). This finding is very different from thy-
that a high ALT with no other indication of hepatic dysfunction rotoxic human patients that typically have hypoparathyroidism.
should not necessarily prompt further hepatic evaluation in a cat The changes usually normalize after treatment of hyperthyroid-
whose clinical signs are consistent with hyperthyroidism. Other ism (Williams etal, 2012), although some cats with underlying
indicators of hepatic dysfunction may include hypoglycemia, CKD have persistent increases in PTH presumably due to second-
hypocholesterolemia, hypoalbuminemia, and decreased blood urea ary renal hyperparathyroidism. Although indications of increased
nitrogen (BUN). In the cats studied by Berent etal., (2007), none of bone turnover have been documented in hyperthyroid cats, clini-
the hyperthyroid cats were hypoglycemic or hypocholesterolemic, cal consequences (e.g., increased fracture risk) are very rare.
although the hyperthyroid cats had lower concentrations of glucose
and cholesterol than age matched control cats. These changes also Blood Glucose
normalized after treatment of the hyperthyroidism. Serum albu-
min and BUN concentrations did not differ between hyperthyroid Cats have a remarkable ability to increase their blood glucose con-
cats and age matched control cats and did not change after treat- centrations in response to acute stress. Acutely stressed cats can have
ment. The differences likely relate to the increased metabolic rate blood glucose concentrations as high as 300 mg/dL (17 mmol/l)
of hyperthyroid cats, but the changes do not appear to be clinically (Rand etal, 2002). This hyperglycemia is believed to result from
relevant or supportive of hepatic dysfunction. There have been no an acute release of epinephrine. Blood glucose concentrations may
published studies evaluating hepatic histopathology in cats with become even higher (400 to 500 mg/dL, 22-28 mmol/L) due to
hyperthyroidism. One author reported that liver biopsies typically the stress of chronic illness, although it is difficult to assess the con-
reveal increased pigment within hepatocytes, aggregates of mixed tribution of concurrent beta cell dysfunction in clinically ill cats.
inflammatory cells in the portal regions, and focal areas of fatty Surprisingly the majority of hyperthyroid cats have normal blood
degeneration; and some cats have mild hepatic necrosis (Feldman glucose concentrations, and as a group, hyperthyroid cats have
and Nelson, 2004). In severe cases of thyrotoxicosis, it was reported lower blood glucose concentrations than age matched controls.
that centrilobular fatty inltration may occur together with patchy In humans, the increased energy expenditure of thyrotoxico-
portal brosis, lymphocytic inltration, and proliferation of bile sis is compounded by the inefcient maintenance of basic physi-
ducts (Feldman and Nelson, 2004). Liver enzyme activities, regard- ologic functions. To compensate for increased energy expenditure,
less of their origin, usually return to normal with successful man- increases in food consumption, utilization of stored energy, and
agement of the hyperthyroidism (Berent etal, 2007). enhanced oxygen expenditure alter the metabolism of carbohy-
drate, lipid, and protein. Intestinal absorption of glucose and the
Altered Bone Metabolism rate of glucose production from glycogen, lactate, glycerol, and
People with hyperthyroidism have decreased bone mineral den- amino acids are increased. Hepatic glycogen stores are decreased,
sity and increased concentrations of bone resorption markers and owing to increased glucose utilization by muscle and adipose tis-
bone formation markers such as ALP and osteocalcin (Williams, sue. It is likely that multiple factors influence the blood glucose
2013). There is believed to be an increased risk of fracture in peo- concentration in hyperthyroid cats with factors such as deple-
ple with either overt or subclinical hyperthyroidism, but studies tion of hepatic glycogen stores tending to decrease the blood
are confounded by multiple other factors that influence fracture sugar, whereas stress and peripheral insulin resistance tend to
risk, such as age, sex, use of hormone therapy, and other factors. increase the blood glucose. Diabetes mellitus and hyperthyroid-
Increased bone metabolism is attributed to the direct effects of ism are both common diseases of the geriatric cat and occasion-
thyroid hormones on osteoclasts and osteoblasts. ally can occur together. This scenario should be considered in
hyperthyroid cats with persistent mild hyperglycemia (more than intrinsic progression of CKD in the cat. Further epidemiological
200 mg/dL; 11 mmol/l) (Hoenig and Ferguson, 1989). studies are required to determine whether CKD is more common
in hyperthyroid cats than in the population at large.
Cholesterol
Urinalysis
Serum cholesterol concentration is usually within the reference
range in hyperthyroid cats. The synthesis and especially clearance Urine abnormalities that may be present in hyperthyroid cats
of cholesterol and triglycerides are increased in hyperthyroidism, include a decreased USG, proteinuria, evidence of urinary tract
resulting in modest reductions in both the serum cholesterol and infection, and ketonuria. As discussed earlier, concurrent CKD is
triglyceride concentrations, although the cholesterol concentra- common in hyperthyroid cats and may result in a decreased USG.
tions do not typically decrease below the reference range. Lipoly- Polyuria and polydipsia may also occur in hyperthyroid cats with-
sis is also accelerated, resulting in increased plasma free fatty acid out CKD by mechanisms that are poorly understood. Mechanisms
concentrations. that have been proposed include disturbances in the vasopres-
sin axis and primary polydipsia possibly due to heat intolerance
Blood Urea Nitrogen and Creatinine (Feldman and Nelson, 2004). In one study of 21 hyperthyroid
cats treated with radioactive iodine, USG did not change after
CKD is estimated to be present in 15% of cats older than 15 years treatment in most cats (van Hoek et al, 2009a) suggesting that
of age and is therefore a common concurrent disorder in hyper- CKD was the most common reason for a low USG. Proteinuria is
thyroid cats. Recent studies suggest that approximately 10% of detected in 75% to 80% of hyperthyroid cats and usually resolves
hyperthyroid cats are azotemic at the time of diagnosis of hyper- following treatment (Berent etal, 2007; van Hoek etal, 2009a;
thyroidism based on measurement of a serum creatinine above the Williams etal, 2010b). Studies suggest that the proteinuria associ-
laboratory reference range (Williams etal, 2010). Increased serum ated with hyperthyroidism is primarily due to increased excretion
BUN is found in a slightly larger number (10% to 20%) of hyper- of proteins other than albumin (Williams etal, 2010b). Reasons for
thyroid cats. It is important to recognize, however, that merely proteinuria in hyperthyroid cats could include glomerular hyper-
including the proportion of cats with azotemia underestimates tension and hyperfiltration, changes in tubular protein handling,
the prevalence of CKD in hyperthyroid cats because of physi- and changes in the structure of the glomerular barrier (van Hoek
ologic changes in hyperthyroidism that lead to an increased GFR. etal, 2009a). Although proteinuria usually resolves after treatment
Untreated hyperthyroid cats have a higher GFR, as measured by of hyperthyroidism, its presence prior to treatment is correlated
iohexol clearance or scintigraphy, than the same cats after reestab- with reduced survival but not development of azotemia (Williams
lishment of the euthyroid state (Adams etal, 1997; Graves etal, etal, 2010b). Urinary tract infection is relatively common in cats
1994; DiBartola etal, 1996; van Hoek etal, 2008a). Hyperthy- with hyperthyroidism. In one study urine culture was positive in
roidism increases renal blood flow due to increased cardiac output 11 of 90 (12%) of hyperthyroid cats, and 17 of 77 (22%) cats with
and intra-renal vasodilation. Changes in afferent and efferent arte- CKD. Only two of the hyperthyroid cats had clinical signs of lower
riolar resistance increases the glomerular transcapillary hydraulic urinary tract disease (Mayer-Roenne etal, 2007). Interestingly in
pressure, which increases GFR. Activation of the RAAS possi- one study, trace ketonuria was detected in 9 of 19 hyperthyroid
bly via changes in -adrenergic activity has been implicated as a cats (Berent etal, 2007). This had not been previously reported in
mechanism for this alteration in renal hemodynamics. Despite the hyperthyroid cats but has been described in humans with hyper-
increase in renal perfusion pressure in hyperthyroidism, resorp- thyroidism. Potential reasons for ketonuria in hyperthyroidism
tion of sodium and chloride from the proximal tubule and loop of include -adrenergic induced lipolysis, which results in increased
Henle is increased rather than decreased due to impairment of the fatty acid delivery to the liver, or increased hepatic ketogenesis due
pressure-diuresis-natriuresis response (Syme, 2007), which may to carnitine deficiency (Wood and Kinlaw, 2004). A number of
explain how plasma volume can increase and sodium excretion recent studies have investigated urinary markers of renal tubular
can decrease. In addition to the renal hemodynamic changes in injury such as urinary retinol binding protein and N-acetyl-D-
hyperthyroidism, weight loss and muscle atrophy further decrease glucosaminidase that might be useful in prediction of azotemia
serum creatinine concentrations in hyperthyroid cats. For these after treatment of hyperthyroid cats. Although these markers are
reasons, it may be difficult or impossible to diagnose CKD in cats present in the urine of hyperthyroid cats, they have not proved
with concurrent hyperthyroidism. useful in predicting which cats are likely to become azotemic after
The increased GFR normalizes after treatment of hyperthyroid- treatment (Lapointe etal, 2008; van Hoek etal, 2009b).
ism, so from 15% to 49% of cats that are non-azotemic at the time
of diagnosis of hyperthyroidism become azotemic after treatment. Plasma Cortisol/Urine Cortisol:Creatinine Ratio
The variability in the percentage of cats becoming azotemic likely
reflects variability in adequacy of control of hyperthyroidism (Wil- Adrenocortical hyperplasia is an uncommon nding in cats, but it
liams etal, 2010b). Numerous studies have failed to identify pre- was found in one-third of hyperthyroid cats in one study (Liu etal,
treatment parameters other than measurement of GFR that allow 1984). Increased cortisol secretion due to increased pituitary secre-
prediction of which cats will have clinically significant worsening tion of adrenocorticotropic hormone (ACTH) also occurs in hyper-
of azotemia after treatment. The fact that cats with hyperthy- thyroid humans, although it does not result in hypercortisolemia,
roidism and CKD may have similar clinical signs (e.g., polyuria, because hyperthyroidism in humans is also associated with increased
polydipsia, and weight loss) and that the two diseases commonly metabolic clearance of cortisol. In a study of 17 hyperthyroid cats,
occur together compounds the problem of establishing the sever- 18 healthy geriatric cats, and 18 cats with concurrent nonthyroidal
ity of CKD in hyperthyroid cats. Whether the long-term effects of illness, basal and ACTH stimulated cortisol concentrations were
hyperthyroidism actually contribute to progression of renal disease higher in hyperthyroid cats than in control cats, but the urinary cor-
in cats is still unclear. Glomerular hypertension, proteinuria, and tisol creatinine ratio (UCCR) and adrenal size as measured by ultra-
hyperparathyroidism have all been proposed as mechanisms for sound were not different between the groups (Ramspott etal, 2012).
|
Other studies have documented mild adrenomegaly in hyperthyroid Radiography

cats compared with healthy euthyroid cats, and higher UCCR in
hyperthyroid cats compared to healthy cats (de Lange etal, 2004; Thoracic radiographs should ideally be performed as part of the
Combes etal, 2012). Taken together, these studies suggest that there diagnostic evaluation of all hyperthyroid cats to assess for evi-
is some degree of hypercortisolemia and adrenal gland hyperplasia dence of heart disease or concurrent illness. Even if there are no
in hyperthyroid cats. These findings are important because although clinical signs of heart disease, thoracic radiographs allow detec-
hyperadrenocorticism is rare in cats, there are some similarities tion of occult concurrent illness, such as pulmonary or cranial
between the clinical signs of the two diseases. thoracic neoplasia. Abnormalities on physical examination that
increase the importance of obtaining thoracic radiographs include
respiratory distress, tachypnea or panting, muffled heart sounds,
Serum Fructosamine
tachycardia, arrhythmias, or a heart murmur. The most com-
Fructosamine is produced by an irreversible reaction between glu- mon findings on thoracic radiographs include mild cardiomeg-
cose and plasma proteins. Serum fructosamine concentrations in aly. Signs of congestive heart failure such as pulmonary edema,
cats are thought to reflect the mean blood glucose concentration enlarged pulmonary vessels, and pleural effusion are uncommon
during the preceding 1 to 2 weeks (Link and Rand, 2008). How- in hyperthyroid cats (Jacobs et al, 1986). In a study reporting
ever, fructosamine concentrations are also affected by the concen- radiographic abnormalities in hyperthyroid cats diagnosed from
tration and metabolism of serum proteins, and hyperthyroidism 1992 to 1993, 8% of cats had radiographic evidence of conges-
increases protein metabolism. Serum fructosamine concentrations tive heart failure compared to 20% in cats evaluated from 1979
in hyperthyroid cats have been documented to be signicantly to 1982 (Fox et al, 1999). The prevalence of congestive heart
lower than in healthy control cats (Reusch and Tomsa, 1999). failure in hyperthyroid cats is now likely even lower than it was
Fifty percent of hyperthyroid cats had serum fructosamine con- in the 1990s.
centrations less than the reference range. Serum fructosamine
concentrations in hyperthyroid, normoproteinemic cats did not Electrocardiography
differ from values in hypoproteinemic cats. During treatment for
hyperthyroidism, an increase in serum fructosamine concentra- Electrocardiographic changes are common in hyperthyroid cats
tion was documented. It was concluded that the concentration but rarely require specific treatment. The electrocardiographic
of serum fructosamine in hyperthyroid cats may be low because changes seen in cats with thyrotoxicosis are listed in Table 4-5
of accelerated protein turnoverindependent of blood glucose and are illustrated in Figs. 4-7 to 4-9. Tachycardia (heart rate
concentration. For these reasons, the serum fructosamine con- above 240/min) and an increased R-wave amplitude in lead II
centration should not be considered a reliable monitoring tool in (greater than 1.0 mv) are the abnormalities most frequently seen,
hyperthyroid cats with concurrent diabetes mellitus. Additionally, although each is now detected less commonly than in the 1980s
serum fructosamine concentrations should not be considered reli- (Broussard etal, 1995). Other less common arrhythmias include
able for differentiating between diabetes mellitus and stress-related atrial extrasystoles, atrial tachycardia, ventricular extrasystoles,
hyperglycemia in hyperthyroid cats (Reusch and Tomsa, 1999). first degree atrioventricular block, left anterior fascicular block,
right bundle branch block, and left bundle branch block. In a
study of hyperthyroid cats evaluated in 1993, evidence of right
Blood Pressure and Hypertension
or left atrial enlargement was present on the electrocardiogram
Although in earlier studies systolic hypertension was reported to be (ECG) in 42% of cats (Fox et al, 1999). Most electrocardio-
common in hyperthyroid cats (Kobayashi etal, 1990), more recent graphic abnormalities resolve with successful management of the
studies suggest that only 10% to 20% of hyperthyroid cats have thyrotoxicosis.
hypertension diagnosed at the time of diagnosis of hyperthyroidism;
end-organ damage due to hypertension (e.g., retinal detachment)
appears to be extremely uncommon (van der Woerdt and Peterson, TABLE 4-5 PRETREATMENT
2000; Syme, 2007; Williams etal, 2010). Reasons for the lower prev- ELECTROCARDIOGRAM
alence of hypertension in more recent studies include earlier diagno- FINDINGS IN 131 CATS WITH
sis of feline hyperthyroidism, more conservative cut-offs for diagnosis HYPERTHYROIDISM PRESENTING
of hypertension (blood pressure of more than170 mm Hg on a least IN 1992-1993
two occasions, or more than170 mmHg and evidence of hyperten-
sive retinopathy), and increased recognition of the white coat effect FINDING PERCENTAGE OF CATS
(Belew etal, 1999; see also Ocular Lesions). The low prevalence of
Sinus tachycardia 66
hypertension is similar to findings in humans and is likely because
the decrease in systemic vascular resistance results in a decrease in Increased R-wave amplitude (lead II) 29
diastolic resistance, and the increase in cardiac output results in only Left anterior fascicular block 8
modest increases in systolic blood pressure (Syme, 2007). Inter- Atrial asystoles 7
estingly a recent report found that approximately 20% to 25% of
Ventricular asystoles 2
cats that were normotensive prior to treatment of hyperthyroidism
became hypertensive several months (median 5 months) after treat- First degree atrioventricular block 2
ment of hyperthyroidism (Syme and Elliott, 2003). Whether this is Right bundle branch block 2
due to a decline in renal function after treatment or other undeter- Atrial tachycardia 1
mined mechanism is unclear. Posttreatment hypertension was not
limited to cats that became azotemic after therapy, and no differences Data modified from Fox PR, etal.: Electrocardiographic and radiographic changes in cats
were detected between cats that developed hypertension and those with hyperthyroidism: comparison of populations evaluated during 1992-1993 vs. 1979-
that did not in regard to RAAS activation (Syme, 2007). 1982, J Am Anim Hosp Assoc 35(1):27-31, 1999.
I I III
CV6LU
aVR aVL aVF
19 64 31
FIGURE 4-7 Electrocardiogram (ECG) from a thyrotoxic cat show-

ing R waves of increased amplitude in all leads and deviation of
the mean electrical axis to 30 degrees, suggestive of left heart
enlargement.
I II III aVR aVL aVF V4
II 20 06 18
FIGURE 4-8Electrocardiogram (ECG) from a thyrotoxic cat

showing normal P-QRS-T complex amplitudes. However, three
atrial premature contractions can be seen in the rhythm strip
(arrows), and an abnormal heart rate of 300 beats per minute
is present.
Echocardiography The radiographic, electrocardiographic, and echocardiographic

changes observed in feline hyperthyroidism occur due to the
Echocardiographic abnormalities frequently identied in hyper- marked cardiovascular effects of thyroid hormone on the heart.
thyroid cats include left ventricular caudal wall hypertrophy and Increased cardiac output, decreased systemic vascular resis-
hypertrophy of the interventricular septum; these changes are tance, direct positive chronotropic and inotropic stimulation,
largely reversible after treatment of the hyperthyroidism state -adrenergic stimulation, and underlying cardiomyopathy all
(Bond et al, 1988). Hyperthyroid cats also may have increased may contribute to the abnormalities detected. In a study of 91
left atrial diameter, aortic end-diastolic diameter, and left atrial to cats that were studied before and 2 to 3 months after treatment
aortic root ratio. Myocardial hypercontractility is also common with radioiodine, 37% of cats had one or more echocardiographic
as evidenced by increased percentage of shortening of the minor variables outside the reference range prior to treatment. The most
axis and velocity of circumferential shortening (Bond etal, 1988). common findings were primarily increases in interventricular
Less commonly, a dilated form of cardiomyopathy is observed. septal and left ventricular wall thickness; the findings were con-
Echocardiographic abnormalities in these cats include subnormal sidered clinically relevant in less than 10% of cats (Table 4-6)
myocardial contractility and marked ventricular dilation. These (Weichselbaum etal, 2005). Interestingly 32% of the cats studied
cats usually have radiographic evidence of congestive heart failure had one or more echocardiographic abnormalities present follow-
(Jacobs etal, 1986; Bond etal, 1988). ing treatment; almost half of these cats had been normal before
|
I II III aVR aVL aVF V4 V2 V1 V10
II 19 93 97
FIGURE 4-9 Electrocardiogram (ECG) from a thyrotoxic cat showing both increased amplitude in the R waves and
an atrial premature contraction (arrow).
TABLE 4-6 N
ORMAL FELINE REFERENCE, PRE-RADIOIODINE, AND POST-RADIOIODINE M-MODE
ECHOCARDIOGRAPHIC VALUES FOR 91 HYPERTHYROID CATS
Feline Normal Reference Values Feline Pre- and Post-Radioiodine Treatment Values (2.2 to 8.9 kg*)
(2.7 to 8.2 kg*)
Observed Range Observed Range Observed Range
ECHOCARDIOGRAPH PRERADIOIODINE POSTRADIOIODINE
VARIABLE (UNIT) MEAN SD MINIMUM MAXIMUM MEAN SD MINIMUM MAXIMUM MEAN SD MINIMUM MAXIMUM
Number of cats 76-79 91 91
IVSED (cm) 0.42 0.07 0.30 0.60 0.44 0.07 0.27 0.72 0.43 0.13 0.27 0.55
IVSES (cm) 0.67 0.12 0.40 0.90 0.78 0.12 0.41 1.14 0.72 0.11 0.34 1.08
LVEDD (cm) 1.50 0.20 1.08 2.14 1.63 0.22 0.64 2.09 1.64 0.22 1.17 2.22
LVESD (cm) 0.72 0.15 0.40 1.12 0.80 0.15 0.42 1.13 0.87 0.19 0.55 1.73
LVWED (cm) 0.41 0.07 0.25 0.60 0.47 0.10 0.28 0.89 0.42 0.56 0.29 0.59
LVWES (cm) 0.68 0.11 0.43 0.98 0.78 0.10 0.49 1.02 0.69 0.80 0.53 0.90
A0 (cm) 0.95 0.14 0.60 1.21 0.99 0.11 0.72 1.21 1.02 0.13 0.72 1.36
LA (cm) 1.17 0.17 0.70 1.70
LA Max (cm) 1.34 0.15 0.99 1.82 1.32 0.18 0.99 2.14
FS (%) 52.1 7.11 40.00 66.70 50.60 7.29 34.00 66.00 46.60 7.24 21.00 62.90
From Weichselbaum RC, etal.: Relationship between selected echocardiographic variables before and after radioiodine treatment in 91 hyperthyroid cats, Vet Radiol Ultrasound
46(6):506-513, 2005.
Ao, Aortic root maximum dimension (from M-mode); FS, LV fractional shortening, i.e.,((LVEDDLVESD)/LVEDD) 100); IVSED, interventricular septum at end-diastole (from M-mode);
IVSES, interventricular septum at end-systole (from M-mode); LA, left atrium dimension (from M-mode); LA Max, left atrium maximum dimension (from two-dimensional long-axis);
LVEDD, left ventricular end-diastolic dimension (from M-mode); LVESD, left ventricular end-systolic dimension (from M-mode); LVWED, left ventricular posterior wall thickness at end-diastole
(from M-mode); LVWES, left ventricular posterior wall thickness at end-systole (from M-mode).
*Body weight range.
treatment. The conclusions of the authors were that changes in or incomplete recovery from the effects of hyperthyroidism or
echocardiographic variables in hyperthyroid cats are less common possibly the effects of iatrogenic hypothyroidism. These findings
than previously reported, presumably due to earlier diagnosis. underscore the complexity of the interactions between hyperthy-
The emergence of new abnormalities after treatment of hyper- roidism and the heart. There was no correlation between the total
thyroidism may reflect underlying cardiac disease unrelated to T4 concentration and the presence of clinically relevant echocar-
hyperthyroidism, permanent hyperthyroidism related damage, diographic changes. The heart rate of hyperthyroid cats rather
than presence of echocardiographic changes may be a more useful total T4 is typically 1 to 4.5 g/dL for healthy cats, although the
parameter for determining which cats require medical manage- reference ranges of individual laboratories vary. The total T4 con-
ment with cardiac drugs during and after treatment of hyperthy- centration has both high sensitivity and specificity for diagnosis of
roidism (Weichselbaum etal, 2005). feline hyperthyroidism. In a study of 917 untreated hyperthyroid
cats, 221 cats with nonthyroidal illness, and 172 normal cats, 91%
of the hyperthyroid cats had high serum total T4 concentrations,
DIFFERENTIAL DIAGNOSIS
whereas none of the cats with nonthyroidal illness had high total
Because hyperthyroidism is a disease of geriatric cats and because T4 concentrations, giving an assay sensitivity of 91% and assay
the clinical signs of hyperthyroidism often mimic those of other specificity of 100% (Peterson etal, 2001; Fig. 4-10). Similar find-
disorders, the differential diagnosis for hyperthyroidism is exten- ings have been reported in other smaller studies. Commercial vet-
sive (Table 4-7). The most common disorders that should be con- erinary laboratories now include serum total T4 concentrations as
sidered in the differential diagnosis include CKD, gastrointestinal a component of most geriatric feline chemistry proles, which has
disorders, heart disease, and diabetes mellitus. resulted in the diagnosis of feline hyperthyroidism being made
much earlier in the disease process. This approach to screening
is appropriate for diagnosis of feline hyperthyroidism because
SERUM THYROID HORMONE CONCENTRATIONS
of the high specificity of total T4 for diagnosis of hyperthyroid-
For an overview of thyroid hormone physiology and the assays ism; however the cautions that apply to evaluation of a low total
used for diagnosis of thyroid disorders in dogs and cats, see T4 concentration in the dog also apply to the cat because of the
Chapter 3. Thyroid hormone measurements commonly used influence of nonthyroidal illness on the measured total T4 con-
to confirm the diagnosis of feline hyperthyroidism include the centration. Despite the high specificity of total T4 concentration
serum total T4 and fT4 concentrations. Measurement of serum for diagnosis of feline hyperthyroidism, if the total T4 is increased
T3 concentration is rarely useful for diagnosis of feline hyper- in a cat with no reported clinical signs of hyperthyroidism, it
thyroidism, and serum TSH concentrations have limited utility is important to rule out laboratory and other sample handling
because of poor sensitivity of the current commercial assays for errors before confirming the clinical diagnosis; in most cats with
measurement of feline TSH.
300 23
Basal Total Serum Thyroxine Concentration
The initial screening test of choice for diagnosis of feline hyperthy- 260 20
roidism is the basal serum T4 concentration. Reference range for
160
TABLE 4-7 D
IFFERENTIAL DIAGNOSIS FOR 12
HYPERTHYROIDISM IN CATS
140
MAJOR CLINICAL AREAS OF OVERLAP 10
DIFFERENTIAL DIAGNOSIS WITH HYPERTHYROIDISM
Serum T4 (nmol/L)
Serum T4 (g/dL)
120
Nonthyroid endocrine disease
Diabetes mellitus PD, PU, polyphagia, weight loss 8
100
Hyperadrenocorticism (rare) PD, PU, polyphagia, weight loss
Diabetes insipidus (rare) PD, PU, mild weight loss
Acromegaly (uncommon) PD, PU, polyphagia 80 6
Renal disease PD, PU, anorexia, weight loss,
elevated BUN
60
Heart disease and failure 4
Hypertrophic cardiomyopathy Respiratory distress, weight loss,
Congestive cardiomyopathy tachycardia, murmur, arrhythmia: 40
Idiopathic arrhythmia radiography, ECG, echocardio-
2
gram abnormalities are not 20
specific for hyperthyroidism
Gastrointestinal disease
Pancreatic exocrine insufficiency Bulky, foul-smelling stool, weight 0 0
Normal Hyperthyroid Other illness
loss, polyphagia
Diffuse gastrointestinal disorders FIGURE 4-10 Box plots of serum total thyroxine (T4) concentrations in 172 clini-
Inflammatory Diarrhea, vomiting, anorexia, chronic cally normal cats, 917 cats with untreated hyperthyroidism, and 221 cats with
weight loss nonthyroidal disease. The box represents the interquartile range (i.e., 25th to
Cancer (including 75th percentile range, or the middle half of the data). The horizontal bar in the
lymphosarcoma) box represents the median value. For each box plot, the T bars represent the main
Hepatopathy Elevated liver enzymes body of data, which in most instances is equal to the range. Outlying data points
Inflammatory are represented by open circles. The shaded area indicates the reference range
Cancer for the serum T4 concentration. (From Peterson ME, etal.: Measurement of serum
Pulmonary disease Respiratory distress, panting concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats
with hyperthyroidism and cats with nonthyroidal disease, J Am Vet Med Assoc
BUN, Blood urea nitrogen; ECG, electrocardiogram; PD, polydipsia; PU, polyuria. 218[4]:529-536, 2001).
|
apparent asymptomatic hyperthyroidism, there are usually some measured total T4 decreases (Mooney etal, 1996a; Peterson etal,
subtle clinical signs detected once a more detailed history is col- 2001). Diseases that are commonly associated with a decreased
lected and a physical examination is performed. total T4 concentration include diabetes mellitus, hepatopathy,
Although the total T4 concentration is a relatively sensitive CKD, gastrointestinal disease, and systemic neoplasia; however,
assay, in some cats with early hyperthyroidism and those with severity of disease has more significant effect than does disease cat-
concurrent nonthyroidal illness, the initial measured total T4 con- egory (Peterson etal, 1990b; 2001). The presence of concurrent
centration may be within the reference range (usually within the
upper 50% of the reference range). 50
Fluctuations in Serum Thyroxine Concentrations

In a study in which blood samples were collected from hyperthyroid
cats hourly during the day and daily over a 15 day period, there
were hourly and daily fluctuations in the measured serum total T4 40
concentration that sometimes exceeded the expected coefficient of 3
variation of the assay (Peterson etal, 1987), although another study
showed less variability (Broome etal, 1988a). Despite fluctuations
in total T4, the measured total T4 concentration in most hyperthy-
roid cats is usually persistently above the reference range (Fig. 4-11);
30
Serum T4 (nmol/L)
Serum T4 (g/dL)
however, in cats with only mild increases in the total T4 concentra-
tion, the serum T4 concentration may fluctuate in and out of the
reference range. For this reason, in a cat that has appropriate clinical 2
signs and physical examination findings, a diagnosis of hyperthy-
roidism should not be excluded on the basis of one normal total
T4 measurement (especially if there is a palpable thyroid gland). 20
Effect of Nonthyroidal Illness on Serum Total Thyroxine

Concentrations
1
As in dogs, the presence of concurrent illness can influence the
measured total T4 concentration. In a study of 98 euthyroid cats 10
with concurrent illness, 76 cats had values within the reference
range, 21 cats had values below the reference range, and one cat
had a very mild increase in serum total T4 concentration (less
than 3 SD from the reference mean) (Mooney etal, 1996a). In
another study that included 221 euthyroid ill cats, none had an 0 0
abnormally increased serum total T4 concentration, whereas 38% Mild Moderate Severe
of the cats had a low concentration (Peterson etal, 2001; see Fig. FIGURE 4-12 Box plots of serum total T4 concentration in 221 cats with nonthy-
4-10). These studies demonstrate that illness can lower serum T4 roidal illness grouped according to severity of illness. Of the 221 cats, 65 had
concentrations in euthyroid cats with the severity of the decrease mild disease, 83 had moderate disease, and 73 had severe disease (see Fig.
correlated with the severity of the disease (Fig. 4-12). In fact the 4-10 for key). (Peterson ME, etal.: Measurement of serum concentrations of free
total T4 concentration is a good prognostic indicator in cats with thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism
nonthyroidal illness syndrome (NTIS); mortality increases as the and cats with nonthyroidal disease, J Am Vet Med Assoc 218[4]:529-536, 2001.)
10
8
Serum T4 (g/dL)
4
FIGURE 4-11Serum thyroxine (T4) concentrations fluctuate
in normal and hyperthyroid cats. This figure demonstrates the
amount of fluctuation typical of cats with hyperthyroidism. Cats
2
with significantly increased serum T4 concentrations usually
have persistently abnormal results (dashed line), whereas cats
with borderline values have serum T4 concentrations that can
0 be non-diagnostic and occasionally abnormally increased
1 2 3 4 5
(dotted line) or (solid line). Light gray area is the reference
Days range. T4 laboratory reference range: 2.4 to 4.6 g/dL.
illness also decreases the measured total T4 in cats with hyperthy- axis in cats. It is presumed that most of the medications that
roidism. In one study of 110 cats with hyperthyroidism, systemic influence thyroid hormone concentrations in dogs have similar
disease was diagnosed in 36% of the cats, and the serum total effects in cats, but the data is lacking to confirm this. Drugs
T4 was significantly lower in the cats with nonthyroidal illness that are known to influence thyroid hormone concentrations in
than in those without (McLoughlin et al, 1993). Fourteen of cats include thioureylene drugs, iodinated contrast agents, and
the hyperthyroid cats in this study had serum T4 concentrations glucocorticoids.
within or below the reference range with total T4 concentrations
ranging from 1.3 to 4.0 g/dL. Ten of these 14 cats had evidence APPROACH TO CATS WITH SUSPECTED
of nonthyroidal illness. For this reason, the history and physi- HYPERTHYROIDISM THAT HAVE A THYROXINE
cal examination findings are critical in determining whether the CONCENTRATION WITHIN THE REFERENCE RANGE
diagnosis of hyperthyroidism should be pursued further in a cat
with a normal or subnormal total T4 concentration. Although in If hyperthyroidism is suspected in a cat based on the history and
most hyperthyroid cats with NTIS, the total T4 is in the upper physical examination, but the total T4 concentration is within
half of the reference range, as in the study discussed above with the upper half of the reference range, it is possible that the cat
severe concurrent illness the T4 can occasionally be below the either has mild disease in which the total T4 is fluctuating in
reference range in a cat with confirmed hyperthyroidism (Tomsa and out of the reference range, or that the cat has hyperthyroid-
etal, 2001). The effect of nonthyroidal illness on the total serum ism and concurrent nonthyroidal illness (Fig. 4-13). The clini-
T4 concentration in hyperthyroid cats was further evaluated in a cal approach to diagnosis depends upon the severity of clinical
study of cats with hyperthyroidism and concurrent CKD. In 16 signs. If the signs are mild and early hyperthyroidism is consid-
cats with a normal serum total T4 that were later confirmed to be ered likely, the most appropriate approach is to repeat the total
hyperthyroid, the total T4 ranged from 1.8 to 3.6 g/dL whereas T4 at later date. Because thyroid hormone concentrations vary
the total T4 in cats with CKD alone ranged from 0.4 to 2.3 g/dL. more over a period of days than over a period of several hours,
Most of the hyperthyroid cats with CKD had a total T4 greater repeat measurement of the serum T4 concentration should be
than 2.3 g/dL, whereas all the cats with CKD alone had a total performed days to weeks after the initial result was obtained
T4 less than 2.3 g/dL (Wakeling etal, 2008). (Peterson et al, 1987). This also allows for disease progression
such that there is less likely to be fluctuation into the reference
Other Factors Affecting Serum Total Thyroxine Concentrations range. If the cat has more severe clinical signs and it is therefore
Factors other than NTIS that are believed to influence serum important that a diagnosis be made in a more timely fashion,
total T4 concentrations in cats include age and concurrent medi- further diagnostic testing such as measurement of serum fT4
cation administration. There is little published information on concentration, a T3 suppression test, or thyroid scintigraphy
how thyroid hormone concentrations change with age in cats. In should be considered. TRH stimulation tests have also been rec-
a group of more than 13,000 cats of varying ages that had total ommended in this situation; however, they are rarely performed
T4 concentrations either within or below the reference range, because they are expensive and do not perform well in the pres-
there was no decline in total T4 with age (Table 4-8). There is ence of concurrent nonthyroidal illness (Tomsa et al, 2001).
also limited information on the effect of drugs on the thyroid Administration of TRH also causes adverse clinical signs in cats.
If concurrent NTIS is diagnosed and the disease is amenable to
treatment, the most appropriate course of action is to reassess
TABLE 4-8 M
EAN AND MEDIAN SERUM thyroid function after resolution of any nonthyroidal illness if
TOTAL THYROXINE immediate treatment of hyperthyroidism is not required.
CONCENTRATION OF SAMPLES
SUBMITTED TO A REFERENCE
LABORATORY FOR CATS
OF DIFFERENT AGES 70 3.0 2.0 150 12
5
MEAN THYROXINE, MEDIAN THYROXINE, NUMBER OF 60 2.5 130 10
76.61 PT G/DL G/DL PATIENTS 1.5

4 110
Serum T4 (nmol/L)
Serum T3 (nmol/L)
0-2 1.93 2.0 414 8

Serum T3 (ng/mL)
50 2.0
Serum T4 (g/dL)
3-5 2.01 2.1 733 90

6-8 2.02 2.1 2183 40 3 1.5 1.0 6
70
9-11 2.08 2.1 2480
30 1.0 4
12-14 2.12 2.1 3644 50
2 0.5
> 14 2.13 2.1 4477
20 0.5 30
All ages 2.08 2.1 13,931 2
1
Total T4 0.8-4.7 10 0 0 10
reference
FIGURE 4-13 Box plots of serum total thyroxine (T4), triiodothyronine (T3), and
range
free T4 (fT4) concentrations in 205 cats with mild hyperthyroidism (defined
Data provided by IDEXX Laboratories, Inc.; From Scott-Moncrieff JC: Thyroid disorders in as total T4 concentration less than 66 nmol/L; see Fig. 4-10 for key.) (From
the geriatric veterinary patient, Vet Clin North Am Small Anim Pract 42(4):707-725, 2012. Peterson ME, etal.: Measurement of serum concentrations of free thyroxine, total
Patients with an age listed as 0 were excluded. Samples from cats in which the thyroxine thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with
(T4) concentration was greater than 4.7 g/dL were excluded from the analysis. nonthyroidal disease, J Am Vet Med Assoc 218[4]:529-536, 2001.)
|
Basal Total Serum Triiodothyronine Concentrations intracellular binding. For these reasons, measurement of serum
free thyroid hormone concentrations (fT4) should provide a more
T3 is the most biologically active thyroid hormone; however, the consistent assessment of thyroid gland function than measure-
primary hormone secreted from the canine and feline thyroid ment of the total thyroid hormone concentration.
gland is T4, which is metabolized to T3. Studies suggest that as Although the gold standard technique for measurement of fT4
many as 25% to 33% of cats with conrmed hyperthyroidism is equilibrium dialysis, this technique is expensive and time con-
have serum T3 concentrations within the reference range (Brous- suming and is usually only performed in research laboratories.
sard etal, 1995; Peterson etal, 2001; Fig. 4-14). For this reason In commercial laboratories feline serum fT4 is measured by one
routine measurement of T3 concentration for diagnosis of feline of three methods: modied equilibrium dialysis (MED), analog
hyperthyroidism is not recommended and is rarely performed. radioimmunoassay (RIA), or analog chemiluminescent assay. In
A small percentage (< 5%) of human patients with hyperthyroid- MED assays, a short dialysis step is used to separate free from
ism have a normal total and fT4 but an increased T3 concentration protein-bound T4 followed by radioimmunoassay for fT4. MED
(so-called T3 thyrotoxicosis; Ladenson 2013). This syndrome has techniques have been regarded as the gold standard technique for
not been reported in cats, although as noted earlier T4 thyrotoxi- determining serum fT4 concentrations in cats. In one study, the
cosis (high total T4 and normal T3) is relatively common in cats sensitivity and specicity of fT4 concentration for diagnosis of
(Peterson etal, 2001). hyperthyroidism in cats measured using the MED technique was
98.5% and 93%, respectively (Peterson etal, 2001; Fig. 4-15). It is
Basal Free Thyroxine Concentration important to note that in this study, although the sensitivity of fT4
measurement was higher than measurement of total T4, specificity
The total T4 concentration includes both the protein-bound frac- was lower, because some euthyroid cats with nonthyroidal illness
tion (more than 99% of the total) and the free, unbound fraction had a fT4 that was above the reference range. Other studies have
of thyroid hormone (< 1% of the total). Only the free fraction of confirmed that approximately 6% to 12% of euthyroid cats with
thyroid hormone is available for entry into cells and is biologically nonthyroidal illness may have fT4 concentrations above the refer-
active. Measured serum thyroid hormone concentrations can be ence range using the MED assay. Other commercial assays have
altered by many illnesses that do not directly affect the thyroid now been validated for measurement of fT4 in cats (Table 4-9).
gland (NTIS; see Effect of Nonthyroidal Illness on Serum Total Although the specificity and sensitivity of the assays vary, over-
Thyroxine Concentrations and also Chapter 3). Total T4 concen- all diagnostic accuracy is remarkably similar and all of the assays
trations can also be affected by alterations in metabolism, hor- listed in the table appear to have acceptable performance for the
mone binding to plasma carrier proteins, transport into cells, and
200 15.5
2.0
1.25 14
1.8 175
1.6 12
150
1.0
1.4
10
125

Serum T3 (nmol/L)
1.2
Serum T3 (ng/mL)
0.75
8
100
1.0
0.8 75 6
0.5
0.6
50 4
0.4 0.25
25 2
0.2
0 0 0 0
Mild Moderate Severe Normal Hyperthyroid Other illness
FIGURE 4-14 Box plots of serum T3 concentrations in 221 cats with nonthy- FIGURE 4-15 Box plots of serum free T4 (fT4) concentrations in 172 clinically
roidal illness grouped according to severity of illness. Of the 221 cats, 65 cats normal cats, 917 cats with untreated hyperthyroidism, and 221 cats with nonthy-
had mild disease, 83 had moderate disease, and 73 had severe disease. (From roidal disease (see Fig. 4-10 for key). (From Peterson ME, etal.: Measurement of
Peterson ME, et al.: Measurement of serum concentrations of free thyroxine, total serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine
thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with in cats with hyperthyroidism and cats with nonthyroidal disease, J Am Vet Med
nonthyroidal disease, J Am Vet Med Assoc 218[4]:529-536, 2001.) Assoc 218[4]:529-536, 2001.)
TABLE 4-9 P
ERFORMANCE OF FREE in the follow-up time period of up to 54 months (Wakeling
THYROXINE ASSAY IN DIAGNOSIS etal, 2011). It should be noted however that not all cats with
OF FELINE HYPERTHYROIDISM an undetectable TSH became hyperthyroid during the study
period.
ASSAY SENSITIVITY (%) SPECIFICITY (%) ACCURACY (%)
Analog free 87 100 89 Triiodothyronine Suppression Test
T4 (fT4) Traditionally, humans suspected of having hormonal deciencies
MED IVD 87 100 89 are tested with provocative (stimulation) tests, and those sus-
MED AN 92 67 89 pected of having hormonal excesses are tested with suppression
tests. Administration of thyroid hormone to an individual with
Two step 89 100 91
a normal pituitary-thyroid axis should suppress pituitary TSH
Diasorin
secretion and in turn suppress endogenous thyroid hormone
From Peterson ME, etal.: Accuracy of serum free thyroxine concentrations determined secretion. Administration of T3 to normal cats should suppress
by a new veterinary chemiluminescent immunoassay in euthyroid and hyperthyroid cats pituitary TSH secretion, causing a subsequent decrease in the
[abstract]. Proceedings of the 21st ECVIM-CA Congress. Seville (Spain), September 8-10, serum T4 concentration. Measurement of serum T4 is a valid
2011. marker of thyroid gland function, because exogenous T3 cannot
Sensitivity, sensitivity, and accuracy of four assays for fT4 in cats. The cat population be converted to T4.
included 53 clinically healthy cats and 45 cats with clinical signs of hyperthyroid- Cats with hyperthyroidism have autonomous secretion of
ism (6 euthyroid, 39 hyperthyroid). Assays included the Immulite 2000 Veterinary thyroid hormone (i.e., hormone secretion is independent of
fT4 (analog fT4), Direct fT4 by dialysis (IVD technologies; MED IVD), fT4 by equilib-
pituitary control). Thus administration of T3 to hyperthyroid
rium dialysis (Antech Diagnostics; MED AN), and the Gammacoat fT4 (two step)
Radioimmunoassay (Diasorin).
cats has no effect on the serum T4 concentration, because pitu-
itary TSH secretion has already been chronically suppressed
and T3 administration has no further suppressive effect. The T3
suppression test should therefore allow discrimination between
diagnosis of hyperthyroidism in cats (Peterson et al, 2011). It cats with a normal pituitary-thyroid axis from those with
should be noted however that none of the assays evaluated in this autonomous thyroid secretion resulting in hyperthyroidism.
study, including the MED assays, had as good sensitivity as was The protocol for T3 suppression testing in cats involves mea-
originally reported in the first study evaluating performance of surement of serum T3 and T4 concentration and takes advan-
the MED assay by Peterson and colleagues in 2001. Because of tage of the relatively short (6 to 8 hours) serum half-life of T3
the problem of specificity of the fT4 measurement, an increased in cats (Broome et al, 1987; Hays et al, 1988; Peterson et al,
fT4 concentration must never be used alone for diagnosis of feline 1990a; Refsal etal, 1991).
hyperthyroidism; rather it should be interpreted in conjunction
with the history, physical examination, and total T4 concentra- Protocol
tion. Measurement of fT4 concentration is most useful for evalu- Initially, serum is obtained for determination of both serum T3
ation of cats with suspected hyperthyroidism that have a total T4 and T4 concentrations. Owners are then instructed to adminis-
concentration in the upper half of the normal reference range. ter T3 (liothyronine [Cytomel]; King Pharmaceuticals) begin-
In cats with a high fT4 and a low normal or low total T4 con- ning the next morning at a dosage of 25 g given orally three
centration, other diagnostic testing (e.g., scintigraphy) should be times daily for 2 days. On the morning of day 3, a seventh 25
utilized for confirmation of the diagnosis if hyperthyroidism is g dose should be administered and the cat returned to the
suspected clinically. hospital so that a second blood sample can be obtained. This
blood sample, for measurement of both serum T3 and T4 con-
centrations, should be obtained 2 to 4 hours after administra-
Baseline Serum Thyrotropin Concentration
tion of the seventh dose of liothyronine (Peterson etal, 1990a;
TSH is a highly glycosylated glycoprotein hormone that has an Table 4-10). The pretreatment and posttreatment serum sam-
alpha and beta subunit. The alpha subunit is identical to that of ples should be submitted to the laboratory together to elimi-
the alpha subunit of the related glycoprotein hormones lutein- nate any concern about a possible effect of interassay variation
izing hormone (LH), follicle-stimulating hormone (FSH), and on the results.
chorionic gonadotrophin, whereas the beta chain is unique and
confers the unique biologic properties of TSH. Human TSH Change in Serum Thyroxine
assays cannot be used to measure TSH in other species. The first Normal cats demonstrate a marked reduction in the serum
assay for canine TSH was validated in 1996, and since that time T4 concentration after seven doses of synthetic T3. Cats with
there have been a number of commercial assays developed. A hyperthyroidism, however, demonstrate minimal or no decrease
canine TSH assay (Immulite canine TSH assay, DPC) has been in serum T4 concentrations (Fig. 4-16). This is true even for
validated for use in cats (Wakeling etal, 2008; 2011). Although cats with mild hyperthyroidism and high-normal or marginally
the sensitivity of the assay is suboptimal, a high TSH concentra- increased resting T4 concentrations. Normal cats consistently
tion in a cat with a low total T4 concentration is highly specific have post-pill serum T4 concentrations of less than 1.5 g/dL
for a diagnosis of hypothyroidism. Because of the extremely poor (20 nmol/l). Hyperthyroid cats have post-pill T4 concentra-
sensitivity of this TSH assay in cats, measurement of TSH has tions greater than 1.5 g/dL. Values close to the cut-off of 1.5
a limited role in diagnosis of feline hyperthyroidism; however g/dL should be considered nondiagnostic. The percentage of
in one study of 104 geriatric cats evaluated for a routine health decrease in the serum T4 concentration is not as reliable a crite-
evaluation, cats with an undetectable TSH at baseline were sig- rion as the absolute value, although suppression of greater than
nificantly more likely to be diagnosed with hyperthyroidism 50% below the baseline value was observed only in euthyroid
|
TABLE 4-10 COMMONLY USED PROTOCOLS FOR DYNAMIC THYROID FUNCTION TESTS IN CATS*
THYROID-STIMULATING HORMONE THYROTROPIN-RELEASING HORMONE

TRIIODOTHYRONINE SUPPRESSION STIMULATION STIMULATION
Drug Liothyronine (Cytomel) Human recombinant TSH TRH
Dose 25 g every 8 hours 7 doses 0.025 to 0.2 mg 0.1 mg/kg
Route Oral IV IV
Sampling times Before and 2 to 4 hours after last dose 0 and 6 to 8 hours 0 and 4 hours
Assays Total T3 and T4 Total T4 Total T4
Interpretation
a) Euthyroid < 1.5 g/dL (20 nmol/L) with > 50% suppression > 100% > 60%
b) Hyperthyroid > 1.5 g/dL (20 nmol/L) < 50% suppression Minimal or no increase from baseline < 50%
Reference Peterson etal, 1990a Mooney etal, 1996b Peterson etal, 1994
IV, Intravenous; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
*Values quoted are guidelines only. Each laboratory should furnish its own reference ranges.
100 100
80 80
Serum T4 (nmol/L)
60 60
FIGURE 4-16Box plots of the serum
thyroxine (T4) concentrations before
(A) and after (B) administration of lio-
40 40
thyronine to 44 clinically normal cats,
77 cats with hyperthyroidism, and 22
cats with nonthyroidal disease. Data
20 20 plotted as described in Fig. 4-10. (From
Peterson ME, etal.: Triiodothyronine
[T3] suppression test: an aid in the
diagnosis of mild hyperthyroidism in
0 0 cats, J Vet Intern Med 4[5]:233-238,
A Normal Hyperthyroid Other illness B Normal Hyperthyroid Other illness
1990.)
cats (Peterson etal, 1990a; Refsal etal, 1991). As for any endo- owners to administer the drug seven times (Peterson etal, 1990a;
crine test, it is important for laboratory to establish laboratory Refsal etal, 1991).
specific reference ranges.
Change in Serum Triiodothyronine Thyroid-Stimulating Hormone Response Test

Assay results for the serum T3 concentration are not used to The TSH response test is the gold standard for diagnosis of canine
evaluate the status of the pituitary-thyroid axis. Rather, serum hypothyroidism and may have value for evaluating cats suspected
T3 results are used to determine whether the owner success- of having hypothyroidism (see Chapter 3). The TSH stimulation
fully administered the T3. The serum T3 concentration should test has also been evaluated for diagnosis of hyperthyroidism in cats
increase in all cats that are successfully medicated, regardless of (see Table 4-10). The test involves obtaining serum for determina-
the status of thyroid gland function (Fig. 4-17). If the serum tion of the T4 level before and after TSH administration. The most
T4 concentration fails to decline in a cat that does not demon- recently reported protocol evaluated in healthy cats used intrave-
strate an increase in the serum T3 concentration, problems with nous (IV) administration of 0.025 to 0.2 mg recombinant human
owner compliance could explain these results, and the test results thyrotropin (rhTSH) with total T4 concentration measured prior
should not be trusted. to injection and 6 to 8 hours later (Stegeman etal, 2003).
The T3 suppression test is particularly useful in distinguishing
euthyroid from mildly hyperthyroid cats with borderline resting Interpretation
serum T4 concentrations. The disadvantages of the test are the Euthyroid cats have greater responsiveness to TSH than hyper-
3 days required to complete the regimen and the need to rely on thyroid cats; however, hyperthyroid cats with a normal or
4 6
5
3
Serum T3 (nmol/L) 4
Serum T3 (nmol/L)
2 3
2
1
0 0
A Normal Hyperthyroid Other B Normal Hyperthyroid Other
illness illness
FIGURE 4-17 Box plots of the serum triiodothyronine (T3) concentrations before (A) and after (B) administration
of liothyronine to 44 clinically normal cats, 77 cats with hyperthyroidism, and 22 cats with nonthyroidal disease.
Data plotted as described in Fig. 4-10. (From Peterson ME, etal.: Triiodothyronine [T3] suppression test: an aid in
the diagnosis of mild hyperthyroidism in cats, J Vet Intern Med 4[5]:233-238, 1990.)
borderline T4 concentration are indistinguishable from euthy- The TRH stimulation test has been reported to be as reli-
roid cats. Therefore the TSH stimulation test is not recom- able as the T3 suppression test for diagnosis of hyperthyroid-
mended for diagnosing feline hyperthyroidism (Mooney et al, ism in cats and has the advantage of being less time-consuming
1996b). and less dependent on owner compliance (Sparkes etal, 1991;
Peterson and Becker, 1995). However, in the most recent study
investigating this test, the TRH stimulation test did not reli-
Thyrotropin-Releasing Hormone Stimulation Test
ably distinguish between sick euthyroid and sick hyperthy-
Protocol roid cats (Tomsa et al, 2001). Because this is the population
In cats, the TRH stimulation test (see Table 4-10) is per- of cats that is most likely to need additional testing beyond
formed by evaluating changes in the serum T4 concentration in measurement of the total T4 and the fT4, the TSH stimula-
response to TRH (Peterson etal, 1994). Blood is collected for tion test currently has little place in diagnostic evaluation for
serum T4 determination before and 4 hours after IV adminis- hyperthyroidism.
tration of TRH at a dosage of 0.1 mg/kg body weight. Adverse
reactions (e.g., salivation, vomiting, tachypnea, defecation) are Summary of Diagnostic Testing for Hyperthyroidism
common with IV administration of TRH. Side effects usu-
ally begin immediately after TRH administration and may The clinician should gain a suspicion of hyperthyroidism based
continue as long as 4 hours. Side effects are reported to be on careful review of the history and physical examination
the result of activating central cholinergic and catecholamin- ndings. Careful palpation of the cats neck, especially in the area
ergic mechanisms and direct neurotransmitter effects of TRH of the thoracic inlet, is very important. Most cats with hyperthy-
on specic binding sites (Holtman etal, 1986; Beleslin etal, roidism have a palpable thyroid mass. If a thyroid mass is not
1987a; 1987b). palpable, the clinician should consider that the abnormal thyroid
tissue might be in the mediastinum, but other possible causes of
Interpretation the clinical signs observed by the owners should be considered
Healthy cats and those with nonthyroidal illness usually have a (see Table 4-7).
twofold increase in the serum T4 concentration 4 hours after IV The diagnosis of hyperthyroidism can usually be conrmed
administration of TRH. Cats with mild hyperthyroidism have by evaluating a single, random, serum total T4 concentration
little or no increase in the serum T4 concentration (see Fig. 4-18; (Fig. 4-20). If a cat that appears to be hyperthyroid does not
Fig. 4-19). Serum T3 assessments have been less consistent and are have a diagnostic baseline serum total T4 concentration and no
not recommended. A percentage increase in the post-TRH serum other cause for the clinical signs is identified, the test should be
T4 concentration of less than 50% above basal values was also con- repeated days to weeks later, together with a serum fT4 concen-
sistent with the diagnosis of hyperthyroidism. Post-TRH T4 values tration. If the serum T4 concentrations (total and free) fail to
greater than 60% above basal concentrations were observed only conrm hyperthyroidism at the time of the second evaluation,
in normal cats and in those with nonthyroidal illness. Increases of the T3 suppression test or a radionuclide imaging (scintigra-
50% to 60% should be considered nondiagnostic (Peterson etal, phy) should be considered. Trial therapy with methimazole as a
1994; Tomsa etal, 2001). means to confirm the diagnosis is not recommended.
|
120 120
100 100
Post-TRH serum T4 (nmol/L)

Basal serum T4 (nmol/L)
80 80
60 60
FIGURE 4-18 Box plots of the serum thyroxine

40 40
(T4) concentrations before (A) and after (B)
thyrotropin-releasing hormone (TRH) stimula-
tion in 31 clinically normal cats, 35 cats with
20 20 hyperthyroidism, and 15 cats with nonthyroidal
illness. Data plotted as described in Fig. 4-10.
(From Peterson ME, etal.: Use of the thyrotropin
0 0 releasing hormone stimulation test to diagnose
A Normal Hyperthyroid Other B Normal Hyperthyroid Other mild hyperthyroidism in cats, J Vet Intern Med
illness illness 8[4]:279-286, 1994.)
(310) (275) determining the functional status of the thyroid gland, estab-
250
lishing whether thyroid disease is unilateral or bilateral, iden-
tifying ectopic tissue or metastatic thyroid tissue and may give
insight into differentiation of malignant from benign thyroid
200 disease. Thyroid scintigraphy can also be used to determine
the dose of radioactive iodine for treatment of a hyperthy-
roid cat (see Dose Determination). Several radionuclides are
Percent increase in serum T4
150
available for thyroid scintigraphy in cats. The iodine isotopes
(iodine-131 [131I] and iodine-123 [123I]) are both trapped and
concentrated within thyroid follicular cells in a similar man-
ner to stable iodine and are incorporated into the tyrosine
100 groups of thyroglobulin and then into T3 and T4. Radioactive
technetium-99m pertechnetate (99mTcO4) is referred to as a
pseudohalogen because it mimics the biologic behavior of iodine
50 and chloride. It is therefore trapped and concentrated within
thyroid follicular cells, although it is not incorporated into
thyroid hormone and therefore is not retained in the thyroid
gland. Some other epithelial structures (salivary glands, gastric
0 mucosa) also concentrate iodine and pertechnetate without
organic binding or storage within the tissue (Nap etal, 1994).
Both iodine and pertechnetate are primarily excreted in the
50 urine, so the bladder is also visible on whole body scintigraphy.
Normal Hyperthyroid Other
illness
Choice of Radionuclide
FIGURE 4-19 Box plots of the relative change in serum thyroxine (T4) concen-
trations after thyrotropin-releasing hormone (TRH) administration (percent All three radionuclides (131I, 123I, and pertechnetate) provide
increase) in 31 clinically normal cats, 35 cats with hyperthyroidism, and 15 cats excellent thyroid images, but pertechnetate, for several reasons,
with nonthyroidal disease. Data plotted as described in Fig. 4-10. (From Peterson is the most commonly used radionuclide for thyroid scintig-
ME, etal.: Use of the thyrotropin releasing hormone stimulation test to diagnose raphy (Table 4-11). 131I is inexpensive and readily available,
mild hyperthyroidism in cats, J Vet Intern Med 8[4]:279-286, 1994.) but it has a long physical half-life (8 days) and emits a high-
energy -photon (364 keV) that is inefciently collimated by
the camera. 131I also emits beta-particles that are not detected
by the camera but that increase total body and thyroid radia-
RADIONUCLIDE IMAGING: THYROID
tion exposure. The increased risk to technicians administering
SCINTIGRAPHY 131I makes this material less suitable for routine use (Beck etal,
Thyroid scintigraphy provides both anatomic and functional 1985). In contrast to 131I, 123I has a short physical half-life
information about the thyroid gland. Scintigraphy is useful for (13.3 hours), emits low-energy -rays (159 keV) that are well
FELINE HYPERTHYROIDISM SUSPECTED
SERUM TOTAL T4
LOW OR BORDERLINE HIGH DIAGNOSIS

LOWER HALF CONFIRMED
REFERENCE
RANGE
REPEAT SERUM
TOTAL T4
DIAGNOSIS REFUTED
(IF STILL SUSPECT
HYPERTHYROIDISM
CLINICALLY, BORDERLINE HIGH DIAGNOSIS
CONSIDER THYROID CONFIRMED
SCINTIGRAPHY)
FREE T4
BORDERLINE HIGH DIAGNOSIS

LOW DIAGNOSIS
CONFIRMED
REFUTED (IF STILL
SUSPECT
HYPERTHYROIDISM
CLINICALLY, CONSIDER
CONSIDER THYROID T3 SUPPRESSION TEST
SCINTIGRAPHY) OR
THYROID SCINTIGRAPHY
FIGURE 4-20 Algorithm for the diagnosis of hyperthyroidism in cats.
suited for scanning, and has no -emission. The imaging probe acquired any time from 20 minutes to 2 hours after isotope
cedure can begin as soon as 4 hours after administration. For administration (Broome et al, 2006). At the time of scanning,
these reasons, 123I is a good agent for thyroid scanning; until the cat is placed over a gamma scintillation camera, using a low
recently the high cost of 123I limited its use, but it has recently energy all purpose (LEAP) collimator that interfaces with a dedi-
become more affordable. cated nuclear imaging computer. Ventral, dorsal, and right and
Pertechnetate, a widely available and relatively inexpensive left lateral images are acquired of the cervical region and ventral
radionuclide, is considered by most investigators to be the best and right and left lateral views of the thorax (after shielding the
choice for routine imaging of thyroid glands in humans and cats activity arising from the stomach and thyroid area to increase the
(Broome etal, 2006). Pertechnetate has a short physical half-life count density within the thoracic region). Some protocols also use
(6 hours), and imaging procedures can begin as soon as 20 min- a pin-hole collimator that acquires a magnified image to acquire a
utes after administration because of its rapid uptake by the thy- more detailed image of the thyroid gland(s). Although many facil-
roid. Pertechnetate emits low-energy -particles (140 keV), has no ities perform scintigraphy without sedation or anesthesia, sedation
-emission, and gives the lowest radiation dose to the thyroid of is required when using a pinhole collimator, because the effect of
all available scanning agents. patient motion is exacerbated when using a pin-hole collimator.
In one of our hospitals all scintigraphy in small animal patients is
Protocol for Technetium-99m Pertechnetate done under general anesthesia to minimize exposure of personnel
Thyroid scanning using pertechnetate is accomplished after IV to radiation; in other hospitals anesthesia is not used.
administration of radiolabeled pertechnetate (37 to 185 MBq [1
to 5 mCi]). One report described successful thyroid scintigraphy Protocol for Iodine-123
in cats after SC administration of the isotope; however, a direct Thyroid scanning using 123I is accomplished after oral or IV admin-
comparison between IV and SC administration was not made istration of 200 to 400 Ci 123I. The image is typically acquired 8
(Page et al, 2006). The image is typically acquired 60 minutes and 24 hours after isotope administration (Nieckarz and Daniel,
after isotope administration; however, good quality scans can 2001; van Hoek etal, 2008b).
|
TABLE 4-11 RADIONUCLIDES USED IN THYROID IMAGING STUDIES
PRINCIPAL GAMMA TIME FROM INJECTION TO

ISOTOPE EXPENSE/AVAILABILITY ENERGY (KEV) SCANNING PROCEDURE PHYSICAL HALF-LIFE RISK TO TECHNICIANS
Iodine-131 Inexpensive/available 364 24 hours 8.1 days Yes
Iodine-123 More expensive/less 159 8, 24 hours 13.3 hours Low
available
99mTcO (pertechnetate) Inexpensive/available 140 20 minutes 6.0 hours Low
4
certain circumstances other tissues can concentrate pertechnetate.

In one study, in addition to concentrating in the tissues previously
described, the imaging radionuclides accumulated in broncho-
genic carcinomas in two cats (Cook etal, 1993).
Clinical Indications for Scintigraphy

Clinical indications for performing thyroid scintigraphy in cats
are shown in Box 4-3.
Determine Whether Thyroid Autonomy Is Unilateral or Bilateral

Approximately 30% of hyperthyroid cats have unilateral hyperthy-
roidism, whereas in 70% of cats there is autonomous tissue pres-
ent within both thyroid lobes. In either case, the normal thyroid
tissue is atrophic due to lack of stimulation by TSH. In cats with
unilateral disease, surgical thyroidectomy is a straightforward and
simple procedure, whereas in cats with bilateral disease it may be
complicated by postoperative hypothyroidism and/or hypopara-
thyroidismso other modes of therapy may be more appropriate.
Unfortunately it is not always possible to determine the functional
activity of the thyroid glands by palpation or by visual inspection
FIGURE 4-21 Thyroid scan (radioactive technetium-99m [99mTc]) of a normal at surgery. In some cases, both glands are grossly enlarged and both
cat. Note the similar size and density of the thyroid lobes (straight arrow) and the are clearly abnormal, but in other cases, a small lobe may contain
salivary glands (curved arrow). small numbers of adenomatous cells but be grossly indistinguish-
able from an atrophic normal thyroid gland. Scintigraphy allows
determination of the functional status of both thyroid glands
prior to thyroidectomy so that treatment planning can be opti-
Tissue Identified mized (see General Concepts in Treatment for more information
Scintigraphy identifies all functional thyroid tissue in the body on treatment choice for hyperthyroid cats). In cats with unilateral
and allows determination of whether the abnormal thyroid tissue disease, only one thyroid lobe is detected on the scan, because
is unilateral, bilateral, or ectopic. In a study of 120 hyperthyroid there is no uptake of isotope into the contralateral atrophic thy-
cats, 12% had ectopic thyroid tissue identified on scintigraphy roid gland (see Fig. 4-22). If any isotope uptake is visualized in the
(Harvey etal, 2009). Pertechnetate also concentrates in the gastric contralateral thyroid gland, bilateral disease should be assumed to
mucosa, the salivary glands, and the bladder; the relative uptake be present (see Figs. 4-23 to 4-25). It is important to review all
of technetium by the thyroid glands and the salivary glands is the cervical views of the scintigram in order to determine whether
used to subjectively assess thyroid gland function. A euthyroid the disease is unilateral or bilateral, because particularly on the
cat should have close to a 1:1 ratio of salivary gland to thyroid lateral views, one thyroid gland may overlie the other, leading to
lobe uptake (Fig. 4-21). In most hyperthyroid cats, the thyroid the appearance of unilateral disease when actually both thyroid
lobe(s) have much more intense uptake than the salivary glands, glands are abnormal.
and this is usually easily determined by subjective visual inspec-
tion of the images (Figs. 4-22 to 4-25) (Broome et al, 2006; Determine Presence of Mediastinal or Ectopic Thyroid Tissue
Harvey et al, 2009). The relative uptake of the thyroid lobe(s) and In some hyperthyroid cats, an enlarged thyroid lobe may descend
the salivary tissue can be also be quantified by drawing regions of into the thoracic cavity where it is not palpable. In addition, addi-
interest around the thyroid lobe(s) and the ipsilateral zygomatic/ tional ectopic thyroid tissue may be present anywhere from the
molar salivary gland. The percentage uptake of radioisotope by base of the tongue to within the thoracic cavity (Knowles etal,
the thyroid gland, the thyroid-to-salivary (T:S) ratio, and rate 2010; Reed etal, 2011). A study of 120 hyperthyroid cats under-
of isotope uptake by the thyroid gland are all significantly cor- going scintigraphy documented that 12% of hyperthyroid cats
related with the T4 concentration, indicating that scintigraphy is had more than two areas of increased radionuclide uptake (IRU)
a good indicator of the metabolic activity of the thyroid gland with the number of areas of IRU ranging from 1 to 5 (Harvey
(Daniel etal, 2002). The best correlation is obtained by using the etal, 2009). Areas of IRU were located in the neck in 61% of cats,
20 minute T:S ratio using only the most intense of the thyroid the thoracic inlet in in 53% of cats, and the thorax in in 22% of
lobes (Daniel et al, 2002). It is important to remember that in cats. Most of the cats with more than two areas of IRU had IRU
FIGURE 4-22 Thyroid technetium-99m (99mmTc) scan from a thyrotoxic cat with a unilateral thyroid tumor. Note the
density of the thyroid (straight arrow) compared with that of the salivary glands (curved arrow).
A B
FIGURE 4-23 A and B, Thyroid technetium-99m (99mTc) scan from a thyrotoxic cat with bilaterally symmetric
adenomatous hyperfunctional thyroids.
in the thorax. Although thyroid scintigraphy is an excellent diag- Determine Presence of Functional Thyroid Carcinoma
nostic tool for locating ectopic or intra-thoracic thyroid tissue, it The incidence of thyroid malignancy in hyperthyroid cats is
can be difficult to distinguish benign ectopic thyroid tissue from believed to be approximately 3%, although it may be more com-
metastasis of thyroid carcinoma by scintigraphy (Figs. 4-26 to mon in hyperthyroid cats treated with medical therapy for long
4-29). There are no scintigraphic features that by themselves can periods of time. Thyroid carcinoma should be suspected in hyper-
distinguish benign from malignant disease (see discussion later), thyroid cats with large cervical masses, particularly when the
and in some cats with thyroid carcinoma, scintigraphic studies are masses are fixed or are attached to underlying or overlying tis-
identical to those of cats with benign disease. sues. Thyroid carcinoma should also be considered in cats with
|
FIGURE 4-24 Thyroid technetium-99m (99mTc) scan from a thyrotoxic cat with bilaterally asymmetric adenomatous
hyperfunctional thyroids. Note that on the lateral view one thyroid lobe overlies the other.
FIGURE 4-25 Thyroid technetium-99m (99mTc) scan from a thyrotoxic cat with bilaterally asymmetric adenomatous
hyperfunctional thyroids. Note that this scan shows the larger thyroid below the smaller rather than the side-by-
side location seen in Fig. 4-24.
ectopic tissue or a mediastinal mass on scintigraphy (see Figs. to identify the presence of metastatic disease in cats with known
4-27 to 4-29). Scintigraphic features such as distortion of the thyroid carcinoma both before and after surgical resection.
thyroid lobe, multiple foci of radionuclide uptake, heterogenous
or irregular uptake with spiculated margins, extension caudally Scintigraphy as a Diagnostic Aid in Cats with Nonthyroidal Illness
into the thoracic inlet, and the presence of linear multifocal pat- The thyroid scan may be used as a diagnostic test for cats with
terns suggesting tumor extension along fascial planes, are consid- clinical signs of hyperthyroidism but normal or borderline serum
ered suspicious for carcinoma, but definitive diagnosis requires total T4 and fT4 concentrations. Scintigraphy is particularly useful
histopathology (see Feline Thyroid Carcinoma). Some cats with in suspected hyperthyroid cats with concurrent illness in which
thyroid carcinoma do not display these features, and some cats other tests do not perform well. The thyroid gland to salivary gland
with benign thyroid disease have multifocal or irregular uptake ratio in euthyroid cats should normally be 1:1 (see Fig. 4-21), but
of isotope (Harvey etal, 2009). Scintigraphy is also very helpful in hyperthyroid cats the ratio is higher (Broome etal, 2006). In
this setting the thyroid scan has the potential for both diagnosing has been documented to increase iodine trapping as measured by
hyperthyroidism and locating the abnormal tissue. technetium and 123I uptake in euthyroid cats (Nieckarz and Daniel,
2001). This effect was documented after 3 weeks of methimazole
Scintigraphy as an Aid to Planning Treatment treatment, and iodine uptake was maximal 4 days after methima-
Scintigraphy can be useful in planning treatment, especially in cases in zole withdrawal. Uptake of radioisotope returned to baseline by
which thyroidectomy would be an option if the thyroid dysfunction 15 days after methimazole withdrawal. No effect of methimazole
was unilateral (see Treatment with Surgery). Some investigators have on pertechnetate uptake was documented in hyperthyroid cats
used scintigraphy to estimate thyroid mass volume and then utilized after 30 days of methimazole treatment (Fischetti etal, 2005), pre-
this information to determine the dose of radioactive iodine to be sumably because TSH suppression was not relieved by methima-
administered for treatment (Forrest etal, 1996). Unfortunately this zole treatment; in most of the cats, TSH concentration remained
approach has not proved to be reliable in predicting radioactive iodine suppressed during methimazole treatment. Two cats with mild
uptake (RAIU) after treatment, because the biologic half-life of 131I hyperthyroidism that had unilateral uptake before methimazole
determined by tracer studies does not correlate well with the biologic treatment developed bilateral uptake after methimazole treat-
half-life after administration of therapeutic doses of radioactive iodine. ment. For these reasons, when nuclear scintigraphy is used as a
This is probably because of cellular necrosis and resultant changes in diagnostic tool to confirm hyperthyroidism, it is very important
thyroid physiology after administration of large doses of 131I. that methimazole treatment should be withdrawn at least 2 weeks
prior to scintigraphy. Methimazole should also be discontinued
Drugs That Cause Interference with Scintigraphy prior to scintigraphy when it is used to identify the location of
Compounds that interfere with iodine uptake or thyroid hormone ectopic tissue, because it may cause errors in distinguishing uni-
synthesis can influence the results of scintigraphy. Methimazole lateral from bilateral disease (Fischetti et al, 2005). Iodine and
iodinated contrast agents (e.g., iohexol) may decrease uptake of
radioiodine into the thyroid gland. Iohexol is often used to deter-
mine GFR in hyperthyroid cats prior to treatment with radio-
BOX 4-3 Indications for Thyroid Scintigraphy
active iodine. Studies suggest that treatment with iohexol within
24 hours of radioactive iodine administration decreases iodine
1 . Evaluation of the functional status of the thyroid glands
uptake in the thyroid gland, although the effect was relatively small
2. Determination of unilateral or bilateral thyroid lobe involvement
and the clinical outcome did not appear to be affected (Peremans
3. Detection and localization of ectopic thyroid tissue
etal, 2008). In a similar study, thyroid scintigraphy was performed
4. Differentiation between benign and malignant thyroid diseases
in euthyroid cats before and after administration of iohexol
5. Determination of the origin of a cervical mass
(Lee etal, 2010). There was a significant decrease in technetium
6. Detection of functional metastasis
uptake on days 1, 3, and 14 after iohexol administration; however,
7. Evaluation of the efficacy of therapy
uptake did not fall below the published reference ranges for euthy-
8. Evaluation for residual tissue after thyroidectomy
roid cats (Lee etal, 2010). Ideally concurrent administration of
From Daniel GB, Neelis DA: Thyroid scintigraphy in veterinary medicine, Semin Nucl iohexol or other iodine containing compounds should be avoided
Med 44(1):24-34, 2014. prior to scintigraphy or treatment with 131I. The protocol used
A B
FIGURE 4-26Dorsoventral (A) and lateral (B) views of a large intrathoracic anterior mediastinal thyroid mass with
a small active gland just cranial to it (arrow in A). Also note that a small amount of pertechnetate leaked into the
subcutaneous (SC) space during administration (arrow in B).
|
for sedation or anesthesia can also influence the results of scintig- anesthesia is used when scintigraphy is performed and that each
raphy, because drugs used commonly for sedation may increase facility develop appropriate reference ranges for T:S ratios for the
or decrease salivation and thus influence the T:S ratio (Schaafsma protocols used.
et al, 2006). For example in a study of euthyroid cats, the T:S
ratio for technetium was significantly higher at 40 minutes when CERVICAL (THYROID) ULTRASONOGRAPHY/
ketamine-midazolam was used than when propofol or ketamine- COMPUTED TOMOGRAPHY
midazolam-atropine protocols were used. Unfortunately this
study did not include a control group without sedation. Although Although scintigraphy is the imaging procedure of choice for eval-
statistically significant changes were identified between the differ- uation of the feline thyroid gland, cervical ultrasonography can
ent sedation protocols, in most cats the T:S ratio was still within also be used to evaluate feline thyroid glands and estimate thyroid
or close to the typical range of the normal T:S ratio of 0.8 to gland volume. Cervical ultrasound usually requires no anesthesia
1.2. It is recommended that a consistent protocol for sedation or or sedation, although more consistent positioning can be achieved
A B
C D
FIGURE 4-27Lateral (A) and dorsoventral (B) views of a pertechnetate scan performed on a hyperthyroid cat. Note
the large thyroid in the neck (large curved arrow on lateral view); the small, adenomatous thyroid tissue in the
anterior mediastinum (small curved arrow); the salivary glands and the saliva, which concentrates pertechnetate
(small straight arrow); and the gastric mucosa, which concentrates pertechnetate (large straight arrow). In the lat-
eral (C) and dorsoventral (D) views of the pertechnetate scans from another cat, note the large intracervical mass
(curved arrows) that does not concentrate pertechnetate displacing the normal thyroid glands (straight arrows).
This mass was a salivary carcinoma, demonstrating that not all cervical masses are thyroid.
if cats are sedated for the procedure. As with any ultrasound evalu- ultrasonographically were hyperfunctional on scintigraphy in two
ation, the value of cervical studies depends heavily on the skill of cats. Ultrasound cannot replace scintigraphy for locating ectopic
the operator. or metastatic tissue, but it is considerably more available and less
In a study of six healthy cats and 14 cats with conrmed hyper- expensive.
thyroidism, a signicant difference in the mean estimated thy- Normal thyroid lobes are thin, fusiform-shaped structures
roid volume of hyperthyroid cats compared with healthy cats that are moderately and uniformly echogenic (Fig. 4-30). The
was identified (Wisner et al, 1994). Although in most cases, lobes are located adjacent and medial to the common carotid
there was good correlation between thyroid scintigraphy and arteries and are surrounded by a thin, hyperechoic fascia. The
ultrasound in regard to identifying unilateral versus bilateral cranial and caudal ends of each thyroid lobe usually taper
thyroid dysfunction; thyroid lobes that could not be identified within this sheath, which sometimes makes the exact mar-
gins difcult to discern. Linear measurements of each lobe are
easiest to make in the long axis plane. Normal thyroid lobes
are usually 15 to 25 mm long with calculated volumes of 40
to 140 mm3 (Wisner et al, 1994; Table 4-12). Thyroid lobe
parenchyma ranges from low to moderate echogenicity com-
pared with surrounding tissue. Thyroid lobes from hyperthy-
roid cats are usually uniformly enlarged and are less echogenic
than normal thyroid lobes. Some lobes have mildly or mod-
erately lobulated outer margins and/or poor delineation from
surrounding tissue. Although most abnormal glands are uni-
formly echogenic, a mottled echogenicity occasionally is seen.
Cystic structures within the thyroid gland can be identified on
ultrasound in a significant number of hyperthyroid cats. Cysts
vary in shape and structure, some being unicameral and others
containing one or several internal septae. It is not unusual for
abnormal thyroid lobes to be normal in length but obviously
rounder and thicker; this accounts for the abnormal volume,
which usually ranges from 140 to 1000 mm3 despite a length
similar to that of the thyroid lobes of a healthy cat (see Fig.
4-30 and Table 4-12) (Wisner et al, 1994; Goldstein et al,
2001; Wells etal, 2001; Barberet etal, 2010).
Computed tomography (CT) has also been used to evaluate
feline thyroid glands. Although the thyroid glands can be iden-
FIGURE 4-28 Lateral view of a thyroid technetium-99m (99mTc) scan from a thy- tified on CT and an estimate of thyroid lobe size obtained, CT
rotoxic cat with multiple functioning hyperactive thyroid masses within the cervi- is not able to reliably distinguish unilateral versus bilateral thy-
cal region. This could be either ectopic adenomatous neoplasia or metastasis of roid gland dysfunction and ectopic tissue cannot be identified
thyroid carcinoma. (Lautenschlaeger etal, 2013).
A B
FIGURE 4-29 A, Thyroid technetium-99m (99mTc)scan from a thyrotoxic cat with multiple functioning hyperactive
thyroid masses. This may be representative of a cat with a functioning thyroid carcinoma that has undergone mas-
sive local invasion throughout the neck and anterior mediastinum. This also could represent multiple adenomatous
tissuesome of which is ectopic. B, Thyroid 99mTc scan from a thyrotoxic cat with multiple functioning thyroid
masses. This cat had a thyroid carcinoma with massive local invasion throughout the neck (straight arrow) and
diffuse functional carcinoma throughout the pulmonary parenchyma (curved arrows).
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Nonfunctional Thyroid Nodules GENERAL CONCEPTS IN TREATMENT

In older cats, it is not uncommon to palpate an enlarged thyroid Background
gland in an apparently healthy euthyroid cat. Possible differen-
tial diagnoses include early hyperthyroidism in which a goiter is There are four methods of managing feline hyperthyroidism (Fig.
present but the thyroid gland is not fully autonomous, thyroid 4-31). Each treatment modality has advantages and disadvantages
cyst, thyroid cystadenoma, or nonfunctional thyroid adenoma (Table 4-13). Thyroid hormone synthesis can be inhibited by either
or carcinoma (see Feline Thyroid Carcinoma). Nonfunctional anti-thyroid drugs or iodine restricted diets. Neither of these treat-
thyroid carcinoma is very rare in the cat. If an obvious cervical ment methods results in permanent resolution of hyperthyroidism;
nodule is palpated in a cat with a normal T4 concentration, a fine however, medical therapy permits trial resolution of hyperthyroid-
needle aspirate should be considered to determine the tissue of ism while the effect of reestablishing the euthyroid state on renal
origin. Unfortunately, thyroid cytology is not accurate for dif- function is assessed. Definitive therapy includes either surgical thy-
ferentiation of benign from malignant thyroid disease. roidectomy or administration of radioactive iodine.
A B
C
FIGURE 4-30 A, Cervical ultrasound of normal feline thyroid (T, thyroid; C, carotid artery). B, Abnormal enlarged
thyroid in a cat with hyperthyroidism. C, Abnormal enlarged cystic thyroid in a cat with hyperthyroidism.
INEAR MEASUREMENTS (MM) AND VOLUMETRIC ESTIMATIONS (MM3) FOR LEFT AND RIGHT
TABLE 4-12 L
THYROID LOBES OF CONTROL AND HYPERTHYROID CATS
Left Lobe Mean Standard Deviation Right Lobe Mean Standard Deviation
LENGTH HEIGHT WIDTH VOLUME* LENGTH HEIGHT WIDTH VOLUME*
Control (n = 6) 20.5 1.6 3.3 0.8 2.5 89 23 20.3 1.6 3.0 0.6 2.5 80 19
Hyperthyroid (n = 14) 20.2 3.6 5.5 2.4 5.7 2.1 382 312 21.9 4.4 8.1 3.0 7.7 2.4 782 449
*Volume estimation calculated using the formula for a prolate ellipsoid, /6 (length x height x width).
Width measurements for normal thyroid lobes defaulted to 2.5 mm because they could not be seen ultrasonographically.
FELINE HYPERTHYROIDISM CONFIRMED
NORMAL RENAL BORDERLINE OR ABNORMAL

PARAMETERS BUN OR CREATININE
THYROID SCAN
(OPTIONAL BUT IDEAL) METHIMAZOLE THERAPY
LIMITED
TRIAL THERAPY WITH (6-12 wks, increasing dose
OR IODINE
METHIMAZOLE slowly starting at 1.25 MG
DIET
Q 12 HOURS )
MORE THAN TWO UNILATERAL BILATERAL

THYROID MASSES DISEASE DISEASE RENAL PARAMETERS
SERUM T4 DECREASES
REMAIN NORMAL ABNORMAL
NEAR TO OR INTO
AND CLINICAL RENAL PARAMETERS
REFERENCE RANGE
IMPROVEMENT
THYROID
CARCINOMA OR TREATMENT TREATMENT
OPTIONS OPTIONS
ECTOPIC THYROID
1) SURGERY 1) RADIOACTIVE
TISSUE
2) RADIOACTIVE IODINE TREAT: NO
IODINE 2) SURGERY METHIMAZOLE TREATMENT
3) METHIMAZOLE 3) METHIMAZOLE
CONSIDER 4) LIMITED IODINE 4) LIMITED IODINE
SURGICAL DIET DIET
BIOPSY
OR
BALANCE:
RADIOACTIVE
1) ENOUGH
IODINE
METHIMAZOLE TO RENAL
WORSENING
DECREASE SIGNS PARAMETERS
IN RENAL
2) NOT ENOUGH BORDERLINE
PARAMETERS
METHIMAZOLE TO OR NORMAL
SIGNIFICANTLY WORSEN
RENAL PARAMETERS
FIGURE 4-31 Algorithm for the treatment of cats with hyperthyroidism, emphasizing the potential negative effects
of therapy on renal function.
The treatment chosen for an individual cat depends on various Pathophysiology

factors, including owner preference and financial constraints, the Hyperthyroidism increases cardiac output and decreases peripheral
presence of nonthyroidal illness, the age of the cat, and availability vascular resistance, leading to increased renal plasma flow (RPF)
of a skilled surgeon or a facility with nuclear medicine capability and an increase in the GFR. Numerous studies have documented
for administering radioactive iodine. that GFR is increased in feline hyperthyroidism (Boag et al, 2007;
Vandermeulen etal, 2008; van Hoek etal, 2008a; 2009a). In a
Treatment of Hyperthyroidism and Renal Function study of 21 cats before and after treatment of hyperthyroidism
using radioactive iodine, GFR was above the reference range for
Background healthy cats in 80% of hyperthyroid cats (van Hoek etal, 2009a).
Clinical evaluation and management of geriatric cats with con- In a study of geriatric cats followed until they became hyperthy-
current hyperthyroidism and CKD is challenging. The tendency roid, a decrease in creatinine was documented at the time of diag-
of nonthyroidal illnesses such as CKD to lower serum T4 con- nosis of hyperthyroidism (Wakeling etal, 2011).
centrations may mask hyperthyroidism. On the other hand,
hyperthyroidism can increase the GFR and thereby decrease the Worsening Renal Function after Resolution of Hyperthyroidism
serum creatinine and BUN concentrations, masking underlying Because restoration of euthyroidism normalizes the GFR, treat-
renal disease. The progressive weight loss and reduction in muscle ment of cats for hyperthyroidism usually results in an increase in
mass associated with hyperthyroidism may further contribute to serum creatinine, resulting in azotemia and overt renal failure in
the reduction of serum creatinine concentrations, also obscur- some cats (Graves et al, 1994; DiBartola et al, 1996; van Hoek
ing evidence of concurrent renal disease. Finally if treatment of etal, 2009a; Williams etal, 2010). Of 216 non-azotemic hyper-
hyperthyroidism results in hypothyroidism, renal function may thyroid cats, 41 (15%) developed azotemia within 240 days of
deteriorate further and exacerbate CKD. It has been estimated diagnosis and treatment; the severity of azotemia and whether it
that as many as 40% of hyperthyroid cats have CKD. Whether was associated with clinical signs were not reported (Williams etal,
CKD is more common in hyperthyroid cats than in the gen- 2010). As would be expected, a higher percentage of cats with well
eral geriatric cat population is unknown. Mechanisms by which controlled hyperthyroidism became azotemic than cats that were
hyperthyroidism could contribute to progression of renal disease poorly controlled (Williams etal, 2010). Pretreatment BUN and
in geriatric cats include induction of proteinuria, activation of the creatinine was positively correlated with development of azotemia,
renin-angiotensin-aldosterone axis, hypertension and aberrations but posttreatment azotemia was not associated with decreased sur-
in calcium, and phosphate homeostasis. vival in this group of cats. The clinical effect of decreased GFR
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TABLE 4-13 ADVANTAGES AND DISADVANTAGES OF DIFFERENT TREATMENTS FOR FELINE HYPERTHYROIDISM
THERAPY ADVANTAGES DISADVANTAGES

Surgery 1 . Usually corrects the thyrotoxicosis 1 . Risk of anesthesia in elderly and fragile cats
2. Thyroids easily accessible 2. Anesthesia may decompensate other abnormal organ systems
3. Relatively inexpensive 3. Iatrogenic hypoparathyroidism
4. Sophisticated equipment not required 4. Iatrogenic hypothyroidism
5. Definitive treatment 5. Risk of surgical complications (recurrent laryngeal nerve damage)
6. Rapid reduction in thyroid hormone concentrations 6. Failure to remove all abnormal thyroid tissue
7. Effect on GFR irreversible
Oral anti-thyroid drugs 1 . Usually corrects the thyrotoxicosis 1. Side effects of the medication:
2. Inexpensive a. Anorexia
3. Small tablet size b. Vomiting
4. No anesthesia or surgery c. Depression/lethargy
5. No expensive facilities d. Thrombocytopenia
6. No hospitalization required e. Granulocytopenia
7. Effect on GFR reversible f. Hepatopathy
2. Daily to twice daily medication required
3. Iatrogenic hypothyroidism (reversible)
4. Not definitive treatment
5. Does not resolve underlying thyroid pathology
Radioactive iodine 1 . Usually corrects the thyrotoxicosis 1 . Need for sophisticated facilities
2. Only one treatment for most cats; no pills 2. Radiation exposure to personnel and owners
3. No anesthesia or surgery 3. Hospitalization after treatment to decrease risk of human exposure
4. Rapid reduction in thyroid hormone concentrations 4. Possibility of iatrogenic hypothyroidism
5. Definitive therapy 5. Re-treatment may be necessary in 2% to 5%
6. Irreversible
Nutritional management 1 . Usually corrects the thyrotoxicosis 1 . Cat can only eat one diet
with iodine limited diets 2. Inexpensive 2. Difficult to limit dietary intake in multi-cat households
3. No anesthesia or surgery required 3. Outdoor cats may have access to other dietary sources of iodine
4. No expensive facilities 4. Not palatable to all cats
5. No hospitalization required 5. Not definitive treatment
6. Effect on GFR reversible 6. Does not resolve underlying thyroid pathology
7. Long-term consequences of limited iodine diet unknown
after treatment of hyperthyroidism is variable. Most cats have a abnormalities. In addition, BUN and serum creatinine are affected
modest increase in creatinine after treatment that may or may not by factors other than functional renal mass and blood flow.
be severe enough to result in azotemia. A smaller subset of cats has Methods to assess GFR include inulin or exogenous creatinine
a clinically significant worsening of azotemia and developed overt clearance, nuclear scintigraphy (using radiolabelled diethylene-
signs of renal failure after treatment. Unfortunately there are no triamine penta-acetic acid [DTPA] or 51Cr- ethylenediaminetet-
routine pretreatment clinical parameters that allow prediction of raacetic acid [51Cr-EDTA]), or measurement of plasma clearance
which cats will develop clinically significant failure. It has been of iohexol. Iohexol is an iodinated radiographic contrast agent, and
stated that cats with a normal BUN and creatinine and a USG the iohexol clearance test has been validated for determination of
more than1.035 are unlikely to have clinically significant renal fail- GFR in cats (van Hoek etal, 2008a). An IV catheter must be placed
ure after treatment, but other studies and our clinical experience for administration of the iohexol. The research protocols that have
suggest that this is not always the case (Riensche etal, 2008). Cats been described require collection of blood samples at 0, 15, and 30
that develop azotemia after treatment are likely to be older and minutes and then at 1, 2, 3, 6, 8, and 10 hours after iohexol admin-
have a higher total T4, BUN, and creatinine; but measurement of istration for measurement of either iodine or iohexol by high perfor-
GFR is believed to be a more sensitive predictor of renal failure mance liquid chromatography (HPLC). An abbreviated protocol
after treatment (Adams etal, 1997; van Hoek etal, 2009a). with collection of samples at 3, 4, and 5 hours after iohexol admin-
istration is recommended for clinical use, and the iohexol assay
Predicting Emergence of Renal Failure by Determining the is commercially available (http://www.animalhealth.msu.edu).
Glomerular Filtration Rate After assay of the iohexol concentration at these three time points,
Serum creatinine and BUN concentrations vary inversely with the the diagnostic laboratory reports a calculated GFR.
GFR and are used as indirect measures of the GFR. However, these In a study of 21 hyperthyroid cats in which GFR was measured
two commonly used parameters are relatively insensitive indica- before and 1, 4, 12, and 24 weeks after treatment of hyperthy-
tors of renal disease, because at least 75% of functional renal mass roidism by radioactive iodine therapy, decreases in GFR occurred
must be lost before changes are noted. Signicant renal disease, within 4 weeks of treatment and did not change thereafter.
therefore, can be present in the absence of serum biochemical Maximum decrease in GFR could only be partially predicted by
O inhibiting oxidation of iodide, organication of iodide, and cou-

pling of iodothyronines to form T4 and T3 (Manna etal, 2013).
CH3 H CH2CH2CH3
N Most studies suggest that the mode of action is via inhibition of
N SH
thyroid peroxidase, although PTU also inhibits the type-I iodothy-
ronine deiodinase (ID-I) thus impairing peripheral deiodination
S N of T4 to T3 (Cooper, 2013). None of the anti-thyroid drugs affects
N the iodide pump, which concentrates iodide in the thyroid cells, or
H Propylthiouracil
Methimazole the secretion of thyroid hormone formed prior to treatment (Peter-
son and Becker, 1995). Although thioureylenes decrease thyroid
hormone concentrations and thereby control the clinical signs of
CH3 hyperthyroidism, they are not cytotoxic to the thyroid gland and
N do not resolve the underlying cause of hyperthyroidism.
S
When administered orally, anti-thyroid drugs are rapidly
absorbed and have a volume of distribution close to that of total
N body water. Methimazole has a plasma half-life of 1.4 to 10 hours
COOC2H5 in cats; although because the drug is concentrated in the thyroid
gland and the intrathyroidal turnover is low, the duration of the
Carbimazole biologic effect exceeds the plasma half-life.
FIGURE 4-32Chemical structures of the anti-thyroid drugs (thioureylenes),
which inhibit thyroidal iodide organification. Propylthiouracil
Although PTU is effective in blocking the synthesis of thyroid
a formula using the pretreatment GFR, serum total T4, serum hormones in cats and controlling hyperthyroidism, it has been
creatinine, BUN, and USG (van Hoek et al, 2009a). Although reported to cause an unacceptable rate of mild to severe adverse
some studies have suggested that cats with a GFR more than 2.25 effects. These include anorexia, vomiting, lethargy, immune-
mL/kg/minute are unlikely to develop clinically significant renal mediated hemolytic anemia, and thrombocytopenia (Peterson
failure after treatment of hyperthyroidism, other studies do not etal, 1984; Aucoin etal, 1985; 1988). Because of these side effects,
support this contention (Graves et al, 1994; Adams etal, 1997; PTU is not recommended for use in cats. It has been hypothesized
Riensche etal, 2008). that taurine deficiency, which impairs drug elimination, may have
exacerbated the side effects of PTU when it was first used, but the
Summary drug is not currently recommended for use in cats.
There are no routine pretreatment parameters that reliably predict
development of azotemia in cats after treatment of hyperthyroid- Methimazole (Tapazole)
ism. Although measurement of pretreatment GFR is helpful, such
studies do not consistently predict the development of renal fail- Indications
ure after euthyroidism is restored. Therefore a methimazole trial Methimazole has three indications in the treatment of hyperthy-
with follow-up serum biochemical and urine analyses should be roidism. First, it can be used to normalize serum T4 concentrations
considered prior to definitive treatment of hyperthyroid cats with and allow assessment of the effect of resolution of hyperthyroid-
either thyroidectomy or radioactive iodine (Riensche etal, 2008). ism on clinical signs, renal function, and other laboratory param-
It is important to recognize that not all increases in serum cre- eters prior to definitive treatment (see Fig. 4-31). Second, it can be
atinine concentration result in clinical signs of renal failure; mild used for short-term stabilization of hyperthyroidism in cats with
increases in creatinine after treatment should be expected. Such severe clinical manifestations of hyperthyroidism prior to surgery
changes do not preclude definitive treatment of hyperthyroidism. or radioactive iodine treatment. Lastly, it can be used for long-
For cats that develop marked azotemia and overt clinical signs of term treatment of hyperthyroidism (Fig. 4-33 and Fig. 4-34).
renal failure after euthyroidism is established, medical therapy
rather than definitive therapy is recommended long term, and the Advantages
treatment should be tailored to balance the two disorders. Alterna- The advantages and disadvantages of oral methimazole therapy
tively thyroid supplementation after definitive treatment of hyper- are shown in Table 4-13. Methimazole is relatively inexpensive
thyroidism can be considered; however, most owners decline this and readily available, and it does not require sophisticated train-
option due to financial considerations. ing, facilities, or prolonged hospitalization. The medication can
be administered by owners, is relatively safe, and can be given to
the oldest of hyperthyroid cats. Furthermore, the drug can also be
TREATMENT WITH ANTI-THYROID DRUGS
administered topically (Hoffman etal, 2002; Sartor etal, 2004;
(THIOUREYLENES)
Hill etal, 2011).
Methimazole reversibly inhibits thyroid hormone synthesis,
Mode of Action
and therefore there is no risk of permanent hypothyroidism. In
The structures of the three available anti-thyroid drugs methima- general, the adverse effects are reversible after discontinuation.
zole, carbimazole, and propylthiouracil (PTU) are shown in Fig. Methimazole is considered the anti-thyroid drug of choice in cats
4-32. After oral administration, carbimazole is rapidly converted to in the United States and is reported to be effective for control of
methimazole and has identical properties to methimazole. Ten mil- hyperthyroidism in approximately 90% of hyperthyroid cats.
ligrams of carbimazole is approximately equivalent to 6 milligrams Oral Dosage Protocol.Methimazole is available as 2.5 mg
methimazole. Methimazole and PTU are concentrated within the and 5 mg sugar-coated tablets in a veterinary labelled product
thyroid gland and inhibit the synthesis of thyroid hormones by and in 5, 10, and 15 mg tablets in a human labelled product.
|
METHIMAZOLE TREATMENT FOR

CATS WITH HYPERTHYROIDISM
INITIATE METHIMAZOLE
(1.25 TO 2.5 mg PO q 12 to 24 hours
IF Gastrointestinal signs switch to transdermal
administration)
AFTER 2-3 WEEKS IF DEVELOPMENT OF: STOP METHIMAZOLE.

AGRANULOCYTOSIS CONSIDER ALTERNATIVE
MONITOR SERUM T4, CBC, PLATELET THROMBOCYTOPENIA TREATMENT.
COUNT, & SERUM CHEMISTRY PROFILE ANEMIA CONSIDER LIMITED IODINE
HEPATOPATHY DIET IN AZOTEMIC CATS
CLINICALLY
SIGNIFICANT AZOTEMIA
T4 LOW T4 HIGH-NORMAL TO HIGH
T4 LOW-NORMAL,
NOT AZOTEMIC
1) SURGICAL
THYROIDECTOMY OR CONFIRM OWNER COMPLIANCE,
DECREASE METHIMAZOLE
2) RADIOACTIVE IODINE INCREASE METHIMAZOLE
DOSAGE BY 1.25 to 2.5 mg/day
3) CONTINUE METHIMAZOLE DOSAGE BY 1.25 TO 2.5 MG PER DOSE
INDEFINITELY
AFTER 2-3 WEEKS AFTER 2-3 WEEKS
MONITOR T4, CBC, & T4 MONITOR T4, CBC, & PLATELET COUNT T4 MONITOR T4, CBC, &
PLATELET COUNT LOW-NORMAL, CHEMISTRY PROFILE EVERY 2-3 LOW-NORMAL, PLATELET COUNT
CHEMISTRY PROFILE NOT AZOTEMIC WEEKS FOR FIRST 3 MONTHS NOT AZOTEMIC CHEMISTRY PROFILE
T4 LOW-NORMAL AFTER 3 MONTHS T4 LOW-NORMAL,

NOT AZOTEMIC NOT AZOTEMIC
1) SURGICAL MONITOR T4 EVERY 3-6 MONTHS; ADMINISTER 1) SURGICAL

THYROIDECTOMY OR LOWEST EFFECTIVE DOSE TO MAINTAIN T4 IN LOW- THYROIDECTOMY OR
2) RADIOACTIVE IODINE NORMAL RANGE; MONITOR OTHER LABORATORY 2) RADIOACTIVE IODINE
TESTS AS NEEDED
FIGURE 4-33 Algorithm for the treatment and monitoring of hyperthyroid cats during methimazole therapy. CBC,
Complete blood count; T4, thyroxine.
40
36
28
20
Serum T4 (g/dL)
12
10
4
Normal
range
2
0
0 0.5-1 1-2 2-4 4-6 6-12 12-18 18-24 24-30 30-36
(64) (64) (64) (64) (46) (33) (18) (7) (2) (2)
Time (months)
FIGURE 4-34 Serum thyroxine (T4) concentrations in 64 cats with hyperthyroidism before and during long-term
treatment with methimazole. The horizontal lines indicate mean values. The numbers in parentheses indicate the
number of cats treated during each time period. (From Peterson ME, etal.: Methimazole treatment of 262 cats with
hyperthyroidism, J Vet Intern Med 2[3]:150-157, 1988.)
The veterinary labelled sugar-coated tablets do not have the bitter transdermal application is usually dispensed in tuberculin syringes
taste of the uncoated human products, which reduces the risk of and can be formulated in a variety of concentrations (typically
excessive salivation associated with methimazole administration in 2.5 or 5 mg/0.1 mL). The gel is applied to the non-haired pinna
some cats. Whether oral methimazole can be absorbed through of the ear by the owners using a finger-cot. Dosing is alternated
human skin has not been determined, but the sugar-coated tablets between ears and, if necessary, residual gel is removed from the
are less likely to result in systemic absorption. ear prior to the next application using a cotton ball. In a study
The usual recommended starting dose for methimazole is of 47 cats with newly diagnosed hyperthyroidism, randomized
1.25 to 2.5 mg every 12 hours, with the more conservative dose to receive either oral or transdermal methimazole, significantly
recommended in very small and debilitated cats or those con- more cats treated with oral methimazole were euthyroid than
sidered at high risk for adverse effects. The methimazole dose those treated with transdermal methimazole after 2 weeks of treat-
should be titrated every 2-3 weeks until the serum thyroid ment, but by 4 weeks the difference was no longer significant.
hormone concentration is within the lower half of the refer- Nine of 11 cats treated with oral methimazole were euthyroid at
ence range (see Fig. 4-33). The total T4 usually decreases within 4 weeks, versus 14 of 21 cats receiving methimazole transdermally
1 week of treatment with oral methimazole, and the clinical signs (Trepanier et al, 2003). Although the difference in efficacy at
improve within 2 to 3 weeks. Because the risk of adverse drug 4 weeks was not statistically significant, this may have been due to
effects are highest during the initial 2 to 3 months of treatment, the smaller number of cats remaining in the study after 4 weeks.
cats should be reassessed every 2-3 weeks with a history and physi- There is no difference in the incidence of hepatic, hematologic,
cal examination, and blood should be obtained for a CBC, plate- or dermatologic side effects in cats treated with oral versus trans-
let count, serum biochemistry prole (BUN, creatinine, hepatic dermal methimazole, but significantly fewer gastrointestinal side
enzymes), and serum T4 concentration in order to monitor for effects are observed with the transdermal form of treatment
signs of toxicity and deterioration of renal function. Cats should (Sartor etal, 2004). Some cats have mild inflammation and ery-
be assessed in a similar way if they become clinically ill during thema of the pinnae where the drug is applied, and rarely these
treatment. Studies suggest that the length of time between drug result in discontinuation of the drug. Other studies have con-
administration and blood sample collection does not influence firmed that transdermal methimazole therapy can be very effec-
the serum thyroid hormone concentration during methimazole tive for long-term treatment of feline hyperthyroidism at doses
treatment; therefore a blood sample for therapeutic monitoring ranging from 2.5 mg every 24 hours to 5 mg every 12 hours (Hill
can be collected at any time of day (Rutland etal, 2009; Boretti et al, 2011; Boretti etal, 2013a). In a long-term study of 60 cats
etal, 2013a). If the serum T4 concentration is within the lower treated with transdermal methimazole at doses ranging from 1 to
half of the reference range, the dose should be maintained for an 15 mg per day, clinical improvement was seen in all cats although
additional 2 to 6 weeks to allow determination of the need for higher doses were required after prolonged treatment, and several
any further dosage adjustments. If the serum T4 concentration cats repeatedly had T4 concentrations above or below the refer-
is below the reference range, the dose should be reduced. If the ence range during the study (Boretti etal, 2013b). Although most
hyperthyroidism is not controlled, the dosage should continue to studies have evaluated transdermal methimazole administered
be increased every 2 weeks in increments of 2.5 mg a day until every 12 hours, some cats are effectively managed with once daily
the measured total T4 concentration is within the lower half of administration (Fig. 4-35) (Boretti etal, 2013a).
the reference range. If adverse effects are identified, methimazole The advantages of topical methimazole include the ease of
should be discontinued. A decision can then be made to choose administration and the decreased risk of gastrointestinal side
an alternative therapy, switch to transdermal methimazole, or effects. Disadvantages include the added expense, slightly slower
reinitiate treatment using a lower dose of oral methimazole. onset of control of hyperthyroidism, and slightly lower efficacy.
Most cats require 2.5 to 5 mg of methimazole every 12 hours Care should be taken to ensure that children are not exposed to
to control hyperthyroidism, and total T4 concentrations increase the methimazole gel. It is important to remember that there is
to pretreatment levels within 48 hours of discontinuing treatment little regulation of compounding pharmacies and care should be
(Peterson etal, 1988). Methimazole is more effective when admin- taken when choosing a pharmacy. Studies suggest that methima-
istered twice a day than once a day at least for the first 4 weeks of zole compounded in an organogel should be stored at room tem-
treatment (Trepanier etal, 2003). Most cats require long-term twice perature and should be discarded after 60 days or earlier if there
daily treatment, but in some cats the frequency of dosing can be is visible separation of the components in the dosing syringe
reduced to every 24 hours after a few weeks of treatment. The dose (Pignato etal, 2010).
range of methimazole reported in the literature for long-term con-
trol of hyperthyroidism is 2.5 to 20 mg methimazole total mg dose Trial Methimazole Therapy to Assess Renal Function After
per day. The most common reasons for treatment failure include Reestablishment of Euthyroid State
problems with owner compliance and occurrence of adverse effects. As discussed earlier, because it is not possible to accurately pre-
Cats with very large goiters and those with thyroid carcinoma may dict which cats will develop a clinically significant exacerbation
be more resistant to treatment with methimazole. of azotemia after therapy for hyperthyroidism, a clinical trial with
methimazole is recommended in most cats prior to definitive
Topical (Transdermal) Methimazole treatment (see Figs. 4-31 and 4-33).
Methimazole can also be administered to hyperthyroid cats as a The recommended treatment protocol for a methimazole trial is
topical gel. Methimazole is usually compounded in a pluronic to administer methimazole at an initial dose of 1.25 to 2.5 mg. A
lecithin organogel, which is a permeation enhancer that disrupts CBC, serum chemistry profile, and total T4 is measured every 2 to
the stratum corneum and allows absorption into the systemic 3 weeks, and the dose of methimazole adjusted until euthyroidism
circulation (Sartor et al, 2004). Some methimazole may also be is achieved. If after 4 weeks of euthyroidism, the renal parameters
ingested by the oral route during grooming. Another novel lipo- are stable or only mildly increased, definitive treatment can be
philic formulation has also been reported to result in effective pursued. However, if the renal parameters worsen when the euthy-
absorption of methimazole (Hill et al, 2011). Methimazole for roid state is reestablished, long-term treatment with a conservative
|
a Cat number b Cat number

1 1
15 15
2 2
10 3 3
10
4 4
5 5
8 6 8 6
7 7
8 8
T4 [g/dL]
T4 [g/dL]
9 6 9
6
10 10
4 4
2 2
0 0
0 2 4 6 8 10 0 2 4 6 8 10
Time [hours] Time [hours]
A
a Cat number b Cat number

50 11 50 11
45 13 45 12
40 40 13
12
35 35
14 14
30 30
25 15
25 16
20 16 20
15 17
17 15
10
10
T4 [g/dL]
T4 [g/dL]
18
19
19 8
8 20
20
6
6
4 4
2 2
0 0
0 2 4 6 8 10 0 2 4 6 8 10
Time [hours] Time [hours]
B
FIGURE 4-35 A, Change in serum T4 concentrations during a 10-hour sampling period before and after twice daily
transdermal methimazole application. Sustained T4 suppression is evident during the whole observation period for
most cats. Dark gray shaded (horizontal area) reference range T4 concentrations, light gray shaded (vertical area)
in A: T4 concentrations before starting treatment. a) Week 1; b) Week 3. B, Change in serum T4 concentrations
during a 10-hour sampling period before and after once daily transdermal methimazole application. Sustained
T4 suppression is evident during the whole observation period for most cats. Gray shaded (horizontal area) refer-
ence range T4 concentrations, light-gray shaded (vertical area) in B: T4 concentrations before starting treatment.
a) Week 1; b) Week 3. (From Boretti FS, etal.: Duration of T4 suppression in hyperthyroid cats treated once and
twice daily with transdermal methimazole, J Vet Intern Med 27[2]:377-381, 2013.)
TABLE 4-14 A
DVERSE REACTIONS ASSOCIATED WITH DRUGS USED THERAPEUTICALLY IN FELINE
HYPERTHYROIDISM
APPROXIMATE PERCENTAGE
DRUG REACTION OF CATS AFFECTED TIME AT OCCURRENCE TREATMENT REQUIRED
Methimazole Vomiting, anorexia, depression 15 < 4 weeks Usually transient, decrease
dose
Eosinophilia, leukopenia, lymphocytosis 15 < 8 weeks Usually transient
Self-induced excoriations 2 < 4 weeks Withdrawal and glucocorti-
coid therapy
Agranulocytosis, thrombocytopenia <5 < 3 months Withdrawal and symptom-
atic therapy
Hepatopathy (anorexia,alanine <2 < 2 months Withdrawal and symptom-
aminotransferase, alkaline phosphatase) atic therapy
Positive antinuclear antibody > 50 > 6 months Decrease daily dosage
Acquired myasthenia gravis Rare < 16 weeks Withdrawal and appropriate
treatment
Carbimazole Vomiting, anorexia, depression 10 < 3 weeks Usually transient, decrease
dose
Eosinophilia, leukopenia, lymphocytosis 5 < 2 weeks Usually transient
Self-induced excoriations Rare < 4 weeks Withdrawal and glucocorti-
coid therapy
Stable iodine Salivation and anorexia Occasional Immediate Change formulation
dose of methimazole or alternatively nutritional management of These changes are common in methimazole treated cats but do not
hyperthyroidism should be considered. The goal is to minimize usually require discontinuation of treatment. More severe hemato-
the clinical signs of hyperthyroidism as much as possible without logic reactions are much less common (3% to 9% cats) and include
causing escalation in renal failure. severe thrombocytopenia associated with bleeding (platelet count less
than 75,000/L), and neutropenia (less than 500/L) associated with
Adverse Effects of Methimazole fever, anorexia, lethargy, and localized or systemic infections (Peter-
Adverse effects of treatment with methimazole are common in son etal, 1988). Any severe blood dyscrasia should prompt imme-
cats (Table 4-14) and can occur whether methimazole is adminis- diate cessation of treatment, and resolution usually occurs within 1
tered orally or transdermally. week. The mechanism for blood dyscrasias due to methimazole is
Clinical Side Effects. Relatively mild clinical side effects from unknown, but in humans these adverse effects are believed to be
methimazole therapy are common, occurring in approximately immune-mediated (Trepanier, 2006). Aplastic anemia was reported
10% to 25% of cats (Peterson et al, 1988; Sartor et al, 2004). in a cat that had been treated with methimazole for 3 years, but the
Most side effects are observed during the rst 4 to 8 weeks of cat also had a mast cell tumor (Weiss 2006). In the largest case series
treatment; it is rare for a cat to develop methimazole-induced side of cats treated with methimazole, approximately 20% had had posi-
effects after 2 to 3 months of treatment. The most common side tive antinuclear antibody (ANA) test results, and 2% developed a
effects include anorexia, vomiting, and lethargy (Peterson et al, positive direct Coombs test (Peterson etal, 1988). The risk of a posi-
1988). These adverse reactions may be transient or may resolve tive antinuclear antibody (ANA) increased with duration of treat-
after the dose is decreased. Gastrointestinal signs are managed by ment and dose of methimazole. The importance of this nding is not
discontinuing the drug until all signs of toxicity have resolved for known, because methimazole is not associated with development of
at least a week and then restarting the medication at a lower dose. lupus erythematosus or immune mediated hemolytic anima in cats.
The gastrointestinal side effects may result from direct gastric irri- Bleeding tendencies unassociated with thrombocytopenia have
tation, because they are much less common in cats treated with been rarely reported in methimazole treated cats, and in humans
transdermal methimazole (Sartor etal, 2004). methimazole is reported to interfere with the vitamin Kdependent
Self-induced excoriation of the face and neck is an unusual reac- coagulation factors. In a study of 20 cats treated with methimazole,
tion to methimazole seen in 2% to 3% of cats treated with methim- three cats had abnormal coagulation profiles characterized by pro-
azole. Like most of the drugs adverse effects, this problem usually longation of protein induced by vitamin K absence or antagonism
occurs within the rst 4 to 8 weeks of therapy. The characteristic (PIVKA) prior to treatment, and one cat developed prolongation
scabbed lesions at the base of the pinna may improve after treat- of PIVKA bleeding time, unassociated with clinical signs of bleed-
ment with glucocorticoids, although drug discontinuation is usually ing, 2 to 6 weeks after treatment (Randolph etal, 2000). No cats
necessary for complete resolution. Alternative treatment should be developed prolongation of prothrombin time (PT) or activated
considered for these cats. Lymphadenopathy has also been reported partial thromboplastin time (APTT). If a coagulopathy is sus-
in a cat treated with methimazole (Niessen etal, 2007), although pected in a hyperthyroid cat treated with methimazole, testing of
other causes of lymphadenopathy were not completely ruled out. PIVKA may be more sensitive than the standard PT and APTT.
Blood Dyscrasias. Mild hematologic changes caused by methim- Hepatic toxicity occurs in a small number of cats treated with
azole include eosinophilia, lymphocytosis, and mild leukopenia. methimazole. The hepatopathy is characterized by systemic signs
|
of illness (anorexia, vomiting, and lethargy), icterus, and marked suggestion that there are fewer side effects associated with carbim-
increases in serum ALT and ALP activities. Days to weeks may azole administration, carbimazole is rapidly converted to methim-
be required for all clinical and biochemical abnormalities to azole, so its use in cats that have adverse reactions to methimazole
resolve after discontinuation of the drug. Alternative therapies for is probably unwise (Trepanier, 2007).
hyperthyroidism should be considered for cats that develop these
adverse reactions. TREATMENT WITH SURGERY
Myasthenia gravis has been reported to develop in hyperthy-
roid cats treated with methimazole (Shelton et al, 2000; Bell etal, Although surgical thyroidectomy is an effective and usually perma-
2012) and may be caused by the immunomodulatory effects of the nent treatment for feline hyperthyroidism, over the last 20 years
drug. Methimazole has been associated with a number of differ- it has become less commonly performed because of the increasing
ent immune mediated diseases in humans, but the precise mecha- availability of radioiodine treatment facilities, the potential for recur-
nism is unknown. Myasthenia gravis was reported to resolve in the rence due to residual ectopic thyroid tissue, and the risk of adverse
two cats in which methimazole was withdrawn; interestingly one postoperative clinical consequences, such as hypoparathyroidism
cat that was subsequently treated with carbimazole did not have and hypothyroidism. These complications can occur because the
recurrence of signs, but it was also treated with pyridostigmine functional status of the thyroid gland cannot be determined by visual
(Bell etal, 2012). An adverse drug effect should be suspected in inspection, and therefore it not always possible to determine at sur-
cats treated with methimazole that develop myasthenia gravis and gery whether one or both thyroid glands should be removed. Other
potentially other immune mediated disorders. less common complications of thyroidectomy include Horners syn-
Hypothyroidism.Although cats treated with methimazole drome and damage to the laryngeal nerve. Despite these limitations,
rarely show clinical signs of hypothyroidism, overtreatment thyroidectomy is a very effective treatment for feline hyperthyroid-
resulting in biochemical hypothyroidism is relatively common ism, and the concerns discussed earlier can be minimized by preop-
(Williams etal, 2010). Cats with iatrogenic hypothyroidism are erative scintigraphy and good surgical technique. The advantages of
at increased risk of azotemia and have a shorter survival time than thyroidectomy include a short hospital stay provided treatment for
euthyroid azotemic cats so it is important to avoid hypothyroid- hypoparathyroidism is not required, and the opportunity to evalu-
ism by appropriate dose adjustment (Williams etal, 2010). ate thyroid tissue by histopathology, which is important in cats with
Methimazole administration should be discontinued and appro- suspected thyroid carcinoma. In our opinion, scintigraphy should
priate supportive care provided to any cat in which a clinically always be performed prior to surgical thyroidectomy to determine
significant adverse effect of methimazole is suspected. Adverse reac- whether thyroid disease is unilateral or bilateral and to rule out the
tions typically resolve within 7 days after discontinuation of the presence of ectopic thyroid tissue. Unfortunately many practitioners
drug (Peterson etal, 1988). For severe or life-threatening adverse do not have ready access to scintigraphy, but understanding the ben-
effects, alternative treatment should be considered rather than risk- efit of this procedure and knowing when to refer for it is important.
ing reexposure to the drug. It is unclear whether treatment with For cats that are determined to have unilateral thyroid disease, thy-
methimazole can interfere with response to treatment with 131I; roidectomy is a simple and speedy surgical procedure that results in
therefore it is recommended that treatment should be discontinued rapid resolution of hyperthyroidism. For cats with bilateral thyroid
1 to 2 weeks prior to treatment (see Treatment with Radioactive disease, thyroidectomy should be performed only if there are good
Iodine for more on this topic). reasons for avoiding radioactive iodine treatment. If bilateral thy-
roidectomy is chosen, owners need to be warned about the possibil-
Carbimazole ity of postoperative complications, such as hypoparathyroidism or
hypothyroidism. In cats with ectopic tissue identified by scintigra-
Background phy, surgical treatment is not recommended because it is not always
Carbimazole is a pro-drug of methimazole that is used in Europe possible to readily identify the location of ectopic tissue at the time
and Australia for treatment of feline hyperthyroidism. Carbima- of surgery. Even if ectopic tissue is identified and removed surgically,
zole is rapidly and almost completely converted to methimazole, recurrence is common (Naan etal, 2006). Thyroidectomy is most
either in the gastrointestinal tract or immediately after absorption, appropriate for cats that do not tolerate hospitalization and for own-
because drug concentrations of methimazole but not carbimazole ers who are concerned about use of radioactive iodine for treatment.
are detected in the serum and thyroid gland after ingestion (Peter-
son etal, 1993). Carbimazole has a higher molecular weight than
Presurgical Management
methimazole, so 5 mg of carbimazole is equivalent to 3 mg of
methimazole. The starting dose for carbimazole is 5 mg every 8 to In an attempt to minimize perisurgical and postsurgical com-
12 hours. There is also a controlled release tablet formulation that plications, hyperthyroid cats must be thoroughly evaluated for
can be administered once a day at a starting dose of 10 to 15 mg concurrent illness prior to surgery. Problems such as congestive
every 24 hours. In one study, the dose range required to achieve heart failure, cardiac arrhythmias, hypertension, renal failure, and
euthyroidism ranged from 10 mg every other day to 25 mg per electrolyte abnormalities (e.g., hypokalemia) should be identied
day (Frnais etal, 2009). There have been no studies directly com- and treated prior to surgery (Naan etal, 2006). Depending on the
paring the efficacy and adverse effects associated with carbimazole severity of the thyrotoxicosis and the needs of the individual case,
versus methimazole; however, anecdotally carbimazole is associ- consideration should be given to controlling thyrotoxicosis with
ated with a lower rate of adverse effects than methimazole, and medical therapy prior to surgery, both to decrease risk of anesthetic
severe blood dyscrasias have not yet been reported in association complications and assess the effect of euthyroidism on renal func-
with carbimazole. The most common adverse effects associated tion (see Treatment of Hyperthyroidism and Renal Function). The
with carbimazole administration are gastrointestinal signs (Buck- goal is to make the cat as stable as possible prior to surgery.
nell, 2000). Other adverse effects that have been reported include Treatment with beta blockers may be useful prior to surgery to
excoriations of the head and neck, lymphadenopathy, pruritus, control severe tachycardia and supraventricular tachyarrhthmias
lymphocytosis, and leucopenia (Mooney etal, 1992). Despite the in cats that do not tolerate anti-thyroid drugs.
Surgical Techniques
General Guidelines
Exploratory surgery of the ventrocervical region is relatively simple,
quick, and inexpensive. The thyroid gland in the cat is divided into
two lobes, which are usually located adjacent to the trachea and dis-
tal to the larynx, in close proximity to the carotid artery, jugular vein,
and recurrent laryngeal nerve (Fig. 4-36). Normal thyroid lobes are
Cranial thyroid artery
pale tan, whereas a thyroid adenoma or adenomatous hyperplasia
Parathyroid gland
is typically brown to reddish brown. The area from above the nor-
mal location of the thyroids (hyoid region) down to the thoracic
inlet should be examined with careful attention to hemostasis. After
Thyroid gland exposure and inspection of all visible thyroid tissue, the external
parathyroid gland or glands should be identied (see Fig. 4-36).
The external parathyroid glands are usually located in the loose fas-
cia at the cranial pole of each lobe. The external parathyroids are
much smaller than the thyroid lobes and can be distinguished from
Carotid artery thyroid tissue by their lighter color and spherical shape (Birchard,
2006). The internal parathyroid glands are usually embedded in the
thyroid lobe parenchyma and are variable in location.
Unilateral Versus Bilateral Involvement

Bilateral lobe involvement is present in more than 70% of hyper-
FIGURE 4-36 Anatomy of the thyroid and parathyroid glands in the cat. (From thyroid cats; however, in many cats, lobe enlargement is not sym-
Panciera DL, Peterson ME, Birchard SJ: Diseases of the thyroid gland. In Birchard metric. In unilateral cases, there is atrophy of the contralateral
SJ, Sherding RG [eds]: Saunders Manual of Small Animal Practice, ed 3, St. Louis, lobe, but the distinction between a small but hyperfunctional lobe
2006, Elsevier.) and an atrophic lobe is not always obvious. For this reason, it is
ideal to perform scintigraphy prior to surgery. If scintigraphy is not
possible and a decision about whether to perform a unilateral or
Anesthesia
bilateral thyroidectomy has to be made at the time of surgery, the
The anesthetic protocol should be individualized based on the surgeon should determine whether the risk of persistence/recur-
unique needs of each patient. Most cats undergoing anesthesia rence of hyperthyroidism or the risk of hypoparathyroidism (and
for thyroidectomy are fragile geriatric cats with concurrent medi- potentially hypothyroidism) are of the most concern. The decision
cal problems. Particular attention should be paid to the renal and depends upon the skill of the surgeon, the wishes of the owner,
cardiovascular systems when planning anesthesia. Adequate fluid and whether or not the owners are able to administer oral medica-
therapy is critical but overhydration must be avoided. Factors that tion for treatment of hypoparathyroidism and hypothyroidism.
should be taken into account include the body condition score,
presence of concurrent illness, whether hyperthyroidism has been Intracapsular Versus Extracapsular Thyroidectomy
controlled with medical therapy prior to surgery, and how difficult Two surgical techniques have been described, and both have been
the patient is to handle. The increased metabolic rate associated successfully modied to enhance success rates for resolving hyper-
with hyperthyroidism increases the absorption, distribution, tis- thyroidism and to preserve parathyroid tissue. The original intra-
sue uptake, and inactivation of anesthetic agents. capsular technique involved incision through the thyroid capsule
and blunt dissection to separate and remove the thyroid lobe,
Premedication and Anesthesia Induction leaving the capsule in situ. This technique did help preserve para-
Drugs that stimulate or potentiate adrenergic activity capable of thyroid tissue but was associated with recurrence due to regrowth
inducing tachycardia and arrhythmias should be avoided. Anti- of tissue adherent to the capsule (Swalec and Birchard, 1990). The
cholinergic agents (e.g., atropine) should also be avoided because original extracapsular technique involved removal of the intact
they cause sinus tachycardia and enhance anesthetic-induced car- thyroid lobe with its capsule, after ligation of the cranial thyroid
diac arrhythmias. The most common anesthetic protocol in our artery, while attempting to preserve blood supply to the adjacent
hospital is premedication with butorphanol (0.2 mg/kg) followed parathyroid gland. This technique reduced the recurrence rate
by induction with isoflurane in an anesthesia induction chamber. but increased the risk of postsurgical hypoparathyroidism. Both
Induction with IV propofol (3 to 6 mg/kg to effect) with or with- these techniques have been modied (Fig. 4-37). The intracapsu-
out premedication is also an effective approach in cats in which lar modication involves removing most of the capsule after the
an IV catheter can be placed prior to induction. Once anesthe- thyroid tissue has been excised. The extracapsular modification
tized, the cat is intubated and inhalation anesthesia continued. In involves use of bipolar electrocautery rather than ligatures, which
cats that are too fractious for placement of an IV catheter before minimizes blunt dissection around the parathyroid glands. The
induction, the catheter can be placed after use of an anesthesia modied extracapsular technique is usually preferred, because it is
induction chamber. It is important to minimize anesthesia/sur- quicker and is associated with less hemorrhage that could obscure
gery time, and continuous monitoring of blood pressure, oxygen the surgical eld (Birchard, 2006; Welches etal, 1989).
saturation, and the ECG is essential. Postoperative pain control
should be routine. Buprenorphine (0.01 to 0.03 mg/kg every 6-8 Postsurgical Recurrence of Hyperthyroidism
hours IM IV or buccal) is a good choice for postoperative control Failure to remove all abnormal, adenomatous thyroid cells
of mild pain in cats. results in postsurgical recurrence of hyperthyroidism. In a study
|
A B
FIGURE 4-37 A, Intracapsular thyroidectomy. The thyroid capsule is incised and the thyroid lobe removed.
(The modified technique involves excision of the capsule.) B, Extracapsular thyroidectomy. The thyroid lobe and
capsule are removed, and the vascular supply to the external parathyroid glands is preserved. (The modified tech-
nique involves bipolar cautery rather than ligatures.) (From Mooney CT: Hyperthyroidism in cats, Veterinary Practice
22:103, 1990.)
of 101 cats undergoing thyroidectomy using a modified intra- days. The use of parathyroid transplantation in cats in which the
capsular technique, recurrence was reported in five cats (Naan parathyroid gland is accidentally removed or completely devas-
etal, 2006). Three of these cats had had a previous thyroidec- cularized during surgery has been reported (Padgett etal, 1998).
tomy performed by the referring veterinarian, and four of the The parathyroid gland is cut into small 1 mm pieces and inserted
five cats had scintigraphic evidence of ectopic thyroid tissue into a pocket in the cervical musculature. This procedure may
that was removed at the time of surgery. Hyperthyroid cats with not prevent severe hypocalcemia from occurring in the rst week
ectopic thyroid tissue had a significantly higher chance of recur- after surgery but may prevent a long-term need for treatment of
rence even when the ectopic tissue was identified and removed hypoparathyroidism.
at surgery. Recurrence of hyperthyroidism is uncommon in the
absence of ectopic thyroid tissue (Swalec and Birchard, 1990; Postsurgical Management
Naan etal, 2006).
Management of Postoperative Hypocalcemia
Iatrogenic Hypoparathyroidism (Hypocalcemia) The frequency of clinically significant hypocalcemia after bilat-
One of the most serious complications associated with bilateral eral thyroidectomy is variable and dependent upon the skills of
thyroidectomy is postsurgical hypocalcemia. Hypocalcemia has the surgeon. If a bilateral thyroidectomy is performed, serum
been reported in 6% to 82% of cats, depending on the surgical total or ionized calcium concentration should be assessed at least
method (Birchard etal, 1984; Flanders etal, 1987; Welches etal, once daily for 4 to 7 days. As discussed earlier, it is common
1989; Naan etal, 2006). In most cats undergoing thyroidectomy, for mild and transient hypocalcaemia to develop after surgery.
postoperative hypocalcemia is mild, transient, and attributed Clinically important hypocalcemia is usually associated with
to local edema of the parathyroid gland and chronic depletion serum total calcium concentrations less than 7.0 mg/dL (ion-
of bone calcium due to thyrotoxicosis. With successful surgery ized calcium less than 0.8 mmol/L). Cats should be carefully
(even after unilateral tumor removal), the serum calcium con- observed for clinical signs of hypocalcaemia (Box 4-4). Ideally,
centration may decline below the reference range for several days hypocalcemia should be documented by measurement of total
as skeletal reserves are restored. This mild hypocalcemia (serum or ionized calcium concentration before therapy is begun. If
calcium concentration of 7.0 to 9.0 mg/dL) must be differen- an acute crisis with clinical signs of tetany develops, a blood
tiated from the severe hypocalcemia associated with iatrogenic sample should be obtained for later evaluation and immediate
hypoparathyroidism. In a study of 86 cats undergoing bilat- treatment with IV calcium should be instituted. Management
eral thyroidectomy using the modified intracapsular technique, with oral vitamin D and calcium supplementation is initiated
postoperative hypocalcemia required treatment in only five cats immediately after normalization of serum calcium by parenteral
(Naan etal, 2006). Hypocalcemia in these five cats resolved after administration (see Chapter 16 for further discussion of man-
treatment with calcium and dihydrotachysterol within 3 to 6 agement of hypocalcemia).
parathyroid tissue has begun to compensate for glands damaged

BOX 4-4 Signs Associated with Hypocalcemia in Cats or removed at surgery. It is possible that accommodation of cal-
cium-regulating mechanisms may occur despite absence of PTH
Anorexia (Flanders etal, 1991).
Restlessness Replacement vitamin D therapy can suppress recovery of endog-
Irritability enous PTH secretion and cause hypercalcemia. After starting
Abnormal behavior vitamin D therapy in any cat, the serum calcium concentration
Muscle cramping or muscle pain should be monitored prior to each planned dose reduction (every
Muscle tremors, especially of face and ears 2 weeks) and the dose gradually decreased if possible based on
Tetany the results of these measurements. The tapering process can begin
Convulsions days to weeks after the start of vitamin D therapy and may take as
long as 2 to 4 months. The goal is to maintain the serum calcium
concentration within the low-normal range (8.5 to 9.5 mg/dL). In
Calcitriol (Rocaltrol; Roche, Nutley, NJ) is an analogue of this range, clinical signs of hypocalcemia do not occur, but there is
activated vitamin D3 (1,25 dihydroxycholecalciferol) and is the stimulation of growth and function of any atrophied parathyroid
most effective vitamin D product for treatment of hypoparathy- tissue. If accessory parathyroid tissue is present and functional,
roidism. The advantages include quick onset of action, quick the medications may be completely discontinued within weeks to
dissipation from the body if overdose occurs, and consistent months of surgery. If hypocalcemia recurs, therapy with vitamin
effect. The recommended dose in cats is 0.02 to 0.03 g/kg/day D and calcium must be reinstituted and is likely to be necessary
for 2 to 4 days; the dose is then tapered based on the serum cal- lifelong.
cium concentration. The maintenance dose is typically 0.005 to
0.015 g/kg/day. Reformulation by a compounding pharmacy Hypothyroidism
may be required for accurate dosing of calcitriol in cats. Subtotal Thyroidectomy. Cats that have undergone unilateral
Ergocalciferol (vitamin D2) is a less expensive form of vitamin thyroidectomy may transiently develop low serum T4 values.
D that has to be converted to active vitamin D3 and is not rec- Thyroid hormone supplementation is not indicated in these
ommended for treatment of cats with postsurgical hypocalcemia. cats. The remaining atrophied thyroid regains normal function
Ergocalciferol is available in a liquid solution suitable for adminis- within 1 to 3 months. Replacement thyroid medication only
tration to cats. Usually 10,000 IU given orally once daily increases delays the growth and functional return of atrophied thyroid
serum calcium concentrations, but it can take from 5 to 21 days tissue.
before an effect is seen. Because this vitamin preparation is fat Total Thyroidectomy. Plasma thyroid hormone concentrations
soluble, tissue accumulation and subsequent hypercalcemia can decline, often to subnormal levels, within 24 to 72 hours of total
occur. The ultimate dosage interval may be as infrequent as once thyroidectomy. However, not all cats become permanently hypo-
every 7 to 14 days. thyroid, probably because of growth of accessory thyroid tissue
Dihydrotachysterol.Dihydrotachysterol is a synthetic ana- in the neck or anterior mediastinum. Thyroid supplementation
logue of vitamin D that has a more rapid onset of action than should only be initiated in the first few weeks after surgery if clini-
ergocalciferol and a shorter duration of activity; this reduces the cal signs of hypothyroidism (e.g., lethargy and obesity) are noted
risk of tissue accumulation and prolonged iatrogenic hypercalce- (see Chapter 3) or if there is a decline in renal function. Cats that
mia. The starting dose is 0.03 mg/kg given orally once daily for are persistently hypothyroid 3 to 6 months after thyroidectomy
1 to 7 days until the serum calcium concentration increases into should also be supplemented.
the reference range. The dose should then be decreased to 0.02 If thyroid replacement therapy is deemed necessary, L-T4
mg/kg and further dose adjustments made based on the serum at a dose of 0.05 mg to 0.1 mg once or twice a day is recom-
calcium concentration. Unfortunately this product is currently mended. Not all cats will require thyroid supplementation long
not available commercially, although it can be obtained from some term, because some may recover endogenous thyroid func-
compounding pharmacies. tion. Whether this represents the recovery of cellular function
Calcium Supplementation. To control clinical signs of tetany, of cells left in situ or developing function in accessory tissue is
IV calcium gluconate should be administered slowly to effect (5 not clear. Regardless, thyroid replacement therapy can suppress
to 15 mg/kg), using ECG monitoring for detecting bradycardia endogenous secretion of thyroid hormone; therefore the need for
or arrhythmias. Calcium gluconate mixed in an equal volume of long-term treatment can only be determined after 8 to 12 weeks
saline can then be given subcutaneously two to four times a day, at following discontinuation of thyroid replacement therapy.
a dose equal to that initially given intravenously, to control clini- Recurrence of Hyperthyroidism. Because of the potential for
cal signs of hypocalcemia. Calcium chloride should never be given recurrence of hyperthyroidism, all cats treated surgically should
subcutaneously, because it causes tissue irritation. Oral calcium have their serum thyroid hormone status monitored once or twice
supplementation can be accomplished with several over the coun- yearly (Welches etal, 1989; Swalec and Birchard, 1990). In cats
ter calcium lactate or carbonate preparations. The dose is 0.5 to 1 g with recurrence of hyperthyroidism, treatment with oral anti-
of calcium per cat/day. thyroid medication or with radioactive iodine is recommended,
Duration of Hypoparathyroidism. The persistence of hypo- because the incidence of surgical complications is considerably
parathyroidism after thyroidectomy is variable and difficult to higher among cats undergoing a second surgery than among those
predict. Some cats may need medication for only a few days, undergoing their rst surgery (Welches et al, 1989; Naan et al,
whereas others require therapy for the rest of their lives. Recov- 2006). Scintigraphy may be useful in these cats to document the
ery of parathyroid function may occur after days, weeks, or location of functioning thyroid tissue and investigate for evidence
months of vitamin D and calcium supplementation. Whenever of thyroid carcinoma.
resolution of hypoparathyroidism is observed, it is assumed Persistence of Hyperthyroidism. Rarely, clinical signs of hyper-
that reversible parathyroid damage occurred or that accessory thyroidism persist despite unilateral or bilateral thyroidectomy.
|
30 persist for years. Care must thus be taken in interpreting thyroid

cytology after radioiodine treatment.
Because beta particles travel only a short distance (1 to 2 mm)
Serum thyroxine concentration (g/dL)
25
in tissue, surrounding tissues (e.g., the parathyroid glands) are
spared the effects of 131I. In addition because atrophic thyroid tis-
20 sue does not concentrate iodine, only functional thyroid tissue is
affected by treatment. Thus, once hyperthyroidism is resolved and
the normal feedback loops are reestablished, previously atrophic
15 thyroid follicular cells return to function and long-term hypothy-
roidism is avoided.
10 Radioactive iodine therapy is now considered the treatment
of choice for managing feline hyperthyroidism and is available
in numerous locations throughout the United States and other
5 countries. High dose treatment with 131I is also effective for treat-
ment of cats with functional thyroid carcinoma (see Feline Thy-
0
roid Carcinoma).
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time after 131I administration (days) Goal of Therapy
FIGURE 4-38Serum thyroxine (T4) concentrations in 10 hyperthyroid cats
sampled every 12 hours following iodine-131 (131I) therapy. Note how quickly The goal of 131I therapy is to resolve hyperthyroidism and avoid
the T4 concentrations decline. Shaded region represents the normal reference hypothyroidism. In most cats, thyroid hormone concentrations
range. (From Meric S, etal.: Serum thyroxine concentrations after radioac- normalize over a period of days to a few weeks (Meric etal, 1986;
tive iodine therapy in cats with hyperthyroidism, J Am Vet Med Assoc 188[9]: Peterson and Becker, 1995; Figs. 4-38 to 4-40). Various methods
1038-1040, 1986.) have been evaluated to determine a dose that results in a high suc-
cess rate but does not induce hypothyroidism. Ideally the lowest
effective dose should be used to minimize exposure to hospital
This is most common in cats undergoing thyroidectomy without personnel and family members.
prior scintigraphy and implies that not all abnormal thyroid tis-
sue was removed surgically. Such ectopic tissue is most likely to
Dose Determination
be in the mediastinum, cranial to the heart. This complication
can usually be avoided by preoperative thyroid scintigraphy. The radiation dose received by the thyroid gland is dependent
on the dose administered, the thyroidal uptake of the isotope,
Results of Surgery and the duration of iodine retention by the thyroid gland. Three
methods have been used to determine the appropriate dose of
In most veterinary hospitals, the results of surgery are excellent. 131I for treatment of hyperthyroidism in cats. The dose can
Most treated cats respond well with resolution of the hyper- be determined by tracer studies, use of a scoring system, or a
thyroidism. Exceptions include cats with concurrent disease predetermined fixed dose can be administered. Interestingly all
(e.g., renal failure), cats with unrecognized ectopic thyroid tis- methods appear to result in the same clinical outcome in regard
sue, and cats that undergo unilateral thyroidectomy but that to both efficacy and rate of posttreatment hypothyroidism.
have adenomatous tissue in the contralateral gland. The major
advantages of surgery are that the procedure can be performed Iodine-131 Dose Determined by Tracer Studies
by most practitioners; it is relatively inexpensive; it can result Prior to administration of therapeutic 131I, tracer studies can
in a permanent cure; and morbidity and mortality can be mini- be performed to calculate RAIU and effective half-life of the
mized by appropriate presurgical and postsurgical management radionuclide using a tracer dose of 131I (Broome, 1988b). The
protocols. radiation dose is calculated based on the RAIU, tracer half-
life, and estimated size of the thyroid gland based on tech-
TREATMENT WITH RADIOACTIVE IODINE netium scans and digital palpation (Turrel etal, 1984; Meric
et al, 1986; Theon et al, 1994). Using this approach, 94%
Thyroid cells concentrate radioactive iodine as they do stable of cats were euthyroid 1 year after treatment, and 84% were
iodine. Treatment with the radioisotope 131I is an effective and euthyroid 4 years after treatment, whereas 6% of cats became
well-established treatment for hyperthyroidism in both cats and hypothyroid (Theon etal, 1994). Subsequent studies however
humans with a success rate of about 95% in both species. After have shown that the biologic half-life of 131I determined by
IV or SC administration, radioactive iodine is transported into tracer studies does not correlate well with the biologic half-life
hyperplastic and neoplastic thyroid follicular cells and incorpo- after administration of therapeutic doses of radioactive iodine,
rated into thyroglobulin. The percentage uptake of iodide by probably because of the changes in thyroid physiology after
the thyroid gland in hyperthyroid cats ranges from 10% to 60% administration of large doses of 131I and resultant follicular cell
(Broome etal, 1987; van Hoek etal, 2008b). The remainder of necrosis.
the administered iodine is excreted in the urine and feces. The
isotope 131I emits both gamma rays and beta particles. It is the Iodine-131 Dose Determined by Serum Thyroxine Concentration
ionizing effects of the beta particles that are responsible for follicu- and Severity of Disease
lar cell death, manifested histopathologically as cell necrosis and This method of 131I dose determination uses a variety of scoring
inflammation. In humans, bizarre nuclear changes reminiscent of systems that use the severity of clinical signs, the subjective size
carcinoma are present cytologically after 131I treatment and may of the abnormal thyroid(s), and the serum T4 concentration
60 500
50
400
40
300
30
Serum thyroxine concentration (g/dL)
Serum thyroxine (nmol/L)

250
20
14 200
12
150
10
100
8
50
6
4 0
Pretreatment 7-25 days 2-3 months 6-12 months
(524) (524) (519) (502)
2
FIGURE 4-40 Box plots of serum thyroxine (T4) concentrations in 524 cats before
0 and at various times after administration of radioiodine for treatment of hyper-
Pre 131I Day 4 Day 8 1 Month thyroidism (see Fig. 4-10 for key). (From Peterson ME, Becker DV: Radioiodine
treatment of 524 cats with hyperthyroidism, J Am Vet Med Assoc 207[11]:1422,
FIGURE 4-39 Serum thyroxine (T4) concentrations in 31 hyperthyroid cats treat-
1995.)
ed with iodine-131 (131I). These cats were studied before therapy, 4 and 8 days
after therapy, at the time of hospital discharge (variable), and 1 month after
treatment. Note how quickly the T4 concentrations decline. Open circles represent TABLE 4-15 S
CORING SYSTEM USED
the three cats that remained hyperthyroid 1 month after treatment. Shaded area TO DETERMINE DOSE OF
represents the normal reference range. (From Meric S, etal.: Serum thyroxine RADIOACTIVE IODINE IN CATS
concentrations after radioactive iodine therapy in cats with hyperthyroidism,
J Am Vet Med Assoc 188[9]:1038-1040, 1986.) FACTOR CLASSIFICATION SCORE
Clinical Signs* Mild 1
Moderate 2
to determine the dose administered (Jones et al, 1991;
Severe 3
Mooney,1994; Peterson and Becker, 1995; Table 4-15). In the
largest such study, a low (2.5 to 3.5 mCi), moderate (3.5 to 4.5 Serum T4 concentration < 125 nmol/L (10 g/dL) 1
mCi), or high (4.5 to 6.5 mCi) dose of 131I was administered 125-250 nmol/L (10-20 g/dL) 2
to hyperthyroid cats (Peterson and Becker, 1995). The median > 250 nmol/L (20 g/dL) 3
dose administered was 3 mCi. The response to treatment was
considered good in 94% of cats. Fewer than 2% of more than Thyroid tumor size < 1.0 0.5 cm 1
500 cats remained hyperthyroid at 6 months and required a 1.0 0.5 to 3.0 1.0 cm 2
second dose of iodine (see Fig. 4-40). Only 2% developed signs > 3.0 1.0 cm 3
and laboratory data consistent with a diagnosis of hypothy-
roidism. A similar number of cats (2%) had a relapse of hyper- From Peterson ME, Becker DV: Radioiodine treatment of 524 cats with hyperthyroidism,
thyroidism within 1 to 6 years of treatment. J Am Vet Med Assoc 207(11):1422-1428, 1995.
Cats with a total score of 3, 4, or 5 were treated with a low dose (2.0 to 3.4 mCi; 74 to
Administration of a Fixed Dose Iodine-131 130 megabecquerels [MBq]), cats with a total score of 6 or 7 were treated with a moderate
dose (3.5 to 4.4 mCi; 130 to 167 MBq), and cats with a total score of 8 or 9 were treated
Other investigators have evaluated the efficacy of administration with a high dose (4.5 to 6.0 mCi; 167 to 222 MBq) of radioiodine.
if a fixed dose of 131I for treatment of feline hyperthyroidism *Severity of clinical signs determined on the basis of number and magnitude of clinical
(Meric and Rubin, 1990; Chun, 2002; Forrest etal, 1996; Craig, signs and the duration of illness.
1993). The most commonly utilized dose reported was 4 mCi. Thyroid tumor size estimated from digital palpation of the thyroid gland; if both thyroid
Of 321 cats treated with 4 mCi, a good response to treatment lobes were enlarged, the sizes of both lobes were added together to determine the score.
was reported in 96% of cats and 7% were reported to become
hypothyroid (Chun, 2002; Meric and Rubin, 1990; Craig, 1993). performed. Whether dose estimation using a scoring system is
There have been no studies that have directly compared superior to a fixed dose method requires further study. In theory,
these three methods of radioactive iodine dose estimation. All such an approach should decrease incidence of hypothyroidism,
approaches have resulted in a high success rate and low incidence decrease hospitalization time, and decrease radiation exposure to
of hypothyroidism and therefore tracer studies are now rarely personnel.
|
Treatment of Thyroid Carcinoma either failure rate or rate of hypothyroidism (Andrade etal, 2001;
Fewer than 2% to 3% of hyperthyroid cats are diagnosed Shi etal, 2009). The reasons for radioresistance due to treatment
with thyroid carcinoma. Findings that increase the likelihood with anti-thyroid drugs are poorly understood. PTU may neutral-
of thyroid carcinoma include recurrence after surgery or low ize iodinated free radicals produced by radiation exposure. Both
dose radioactive iodine treatment, a thyroid mass that is very drugs may also decrease retention of radioactive iodine in the thy-
large or irregular, fixed or attached to underlying tissues, roid gland by inhibiting organification of iodine. Withdrawal of
or documentation of metastatic disease. On thyroid scintig- methimazole increases iodine uptake in the thyroid gland for up to
raphy, some cats with thyroid carcinoma have scans indistin- 2 weeks. This could result in increased uptake of 131I and mitigate
guishable from adenomatous hyperplasia or an adenoma, and the previous effects. Most clinical studies in cats have not dem-
some cats have large, irregular masses, more than two masses, onstrated a difference in radioiodine efficacy in cats treated with
or obvious distant metastases on scintigraphy. Confirma- methimazole prior to 131I treatment (Peterson and Becker, 1995;
tion of thyroid carcinoma requires histopathology; however, Chun, 2002); however, most treatment centers still recommend
because some thyroid carcinomas are well differentiated, the that methimazole be withdrawn 1 to 2 weeks prior to treatment.
diagnosis can be difficult to confirm unless there is evidence
of metastasis or capsular or vascular invasion (Guptill et al, Prior Treatment with Limited Iodine Diets
1995). If thyroid carcinoma is conrmed, higher doses of
radioactive iodine are required for effective treatment (10 to Treatment with iodine-limited diets increases iodine uptake into
30 mCi) (Turrel, 1988; Guptill etal, 1995; Hibbert, 2009). In the thyroid gland by 60% to 600% (Scott-Moncrieff, unpub-
our experience, the best outcomes are achieved with a com- lished data). Theoretically this could increase thyroidal sensitivity
bination of surgical debulking followed by administration of to radioiodine treatment and increase the risk of hypothyroid-
a high dose of radioactive iodine (Turrel et al, 1988; Guptill ism. Alternatively pretreatment with these diets could improve
etal, 1995). Other investigators have relied on treatment with treatment response and, perhaps, reduce the dose of radioiso-
high dose radioactive iodine without prior debulking surgery tope required for a cure. This might reduce radiation exposure
with a good outcome reported in the majority of cases (Hibbert to the cat and personnel, and reduce cost. The increased iodine
etal, 2009). The decision as to whether to perform debulking uptake returns to baseline by 2 weeks after withdrawal of the diet.
surgery depends on whether prior surgery has been performed, Thus iodine limited diets should be discontinued 2 weeks prior
whether there is histopathologic confirmation of thyroid car- to radioiodine treatment until further studies have evaluated this
cinoma, and the location of the neoplastic tissue. Risks of sur- interaction.
gery include hypoparathyroidism, injury to structures (e.g., the
recurrent laryngeal nerve), and the additional expense. Risks of Radiation Safety
treatment without surgery include the consequences of exten-
sive tissue necrosis if there is a large volume of neoplastic tissue, In-Hospital
especially if the thyroid tissue is intrathoracic, and the possibil- Radioactive iodine is a hazardous material with a long half-life
ity of variable uptake of iodine by cells within the tumor such (8 days). As such, 131I-treated cats are a potential source of haz-
that not all neoplastic cells are destroyed. Ultimately the deci- ardous radiation to humans and to other animals due to gamma
sion should be made on a case by case basis. Longer hospital- radiation released from 131I trapped in the thyroid gland of the
ization can be anticipated if cats receive high doses of 131I due cat, as well as surface contamination of the cats coat and paws by
to the additional time required for isotope excretion. Most cats urine and feces containing radioactive iodine (so called removable
treated with such high doses of radioactive iodine will become activity; Chalmers, 2006). Any facility using radioactive iodine
permanently hypothyroid. must adhere to national and state regulations regarding its use to
minimize human exposure. Isolation of treated cats in an approved
131-Iodine facility is required for a variable period that depends upon the
Route of Administration
dose administered and state regulations. Each animal is kept in an
Although most early studies utilized the IV route of administra- individual cage, and all urine and feces are disposed of as radioac-
tion, 131I can be safely administered subcutaneously, and studies tive waste until the cat has a radioactivity level that is considered
have demonstrated that administration of radioactive iodine IV appropriate for release. Release criteria are based on measurement
or SC is equally effective. Use of the SC route is safer for per- of gamma emissions measured with a survey meter either at the
sonnel and, subjectively, less stressful for the cat (Thon et al, patient surface or at a specified distance from the neck (Chalm-
1994). Although commonly used in humans, oral 131I is not rec- ers, 2006). Surface emissions are correlated with urine concentra-
ommended because of the increased risk of exposure to radiation tions of 131I (Feeney, 2003). The principles of as low as reasonably
by the personnel dosing the cats and the risk of vomiting after achievable (ALARA) should be followed. Contact with hospital
administration. Vomiting of the isotope not only results in inad- personnel should be limited to that required for adequate care of
equate dose administered but also could result in contamination the cat. Attending personnel must wear protective clothing and
of the nuclear medicine facility. gloves, be well trained in principles of radiation safety, and are
required to carry regularly monitored dosimeters. The duration of
hospitalization varies between facilities and ranges from 3 days to
Prior Treatment with Methimazole
3 weeks.
Methimazole inhibits synthesis of thyroid hormones but does not
interfere with iodine trapping by follicular cells. In people, PTU After Release from the Hospital
lowers the efficacy of subsequent radioactive iodine treatment, Owners should be given instructions on the proper care of their
and continuous treatment with methimazole during treatment pet for the rst few weeks after therapy (Fig. 4-41). Each cat
decreases the final cure rate. Pretreatment with methimazole up should wear a collar with a Caution Radioactive Material label
to 7 days prior to radioactive iodine treatment does not influence for 2 weeks and must be strictly conned to the home or kept on
RELEASE CRITERIA AND OWNER PRECAUTIONS

FOR ANIMALS TREATED WITH RADIOACTIVE IODINE-131
IN HOMES WITHOUT PREGNANT WOMEN AND WITHOUT CHILDREN UNDER 12 YEARS OF AGE
The maximum exposure rate (dorsal to thyroid) at one foot from the pet shall not exceed 1 mR/hr.
Animals released to their owners will contain a small amount of radioactivity and will continue to excrete low levels of
radioactivity for a period. The amount of radiation exposure you may receive is well below levels that result in significant risk of
harmful effects. The owners must sign a consent form to protect themselves and other members of the public. In this consent
they will agree to the following:
Keep cats in their carriers for the drive home.

A. Maintain a distance of six feet between you and your pet except for brief periods of necessary care.
B. Children and pregnant or nursing women should have NO contact with the pet until the collar with radioactive label is
removed.
C. Minimize contact with the pet, including arrangement for a separate sleeping room away from people.
D. The pet must wear a collar or tag with a Caution Radioactive Material label attached for 2 weeks.
Date for collar removal ____________________.
E. Ensure that if the pet is a cat, it will remain indoors and use its litter box. The box should be lined with plastic.
Change the litter frequently, disposing of it in the outside trash or by flushing it down the toilet.
F. Care must be taken to wash hands after handling the animal, its food dishes, or litter pans.
G. Ensure that your cat uses a litter box and line it with plastic.
H. These restrictions will remain in force until the levels of activity decrease to insignificant levels.
This time period will be 2 weeks.
Measured exposure
(mR/hr at 1 foot): Date: Measured by:
As a condition for release of my pet following radioiodine therapy, I agree to the restrictions above:
I also understand the animal contains a small level of radioactivity and will excrete low-level radioactivity for a period of time.
Minimizing contact with the pet, washing hands after contact, and arranging for the pet to sleep in another area will minimize
my radiation exposure.
____________________________________________ ______________________
Signed Date
FIGURE 4-41 Example of a form used to inform cat owners about release criteria and owner precautions for
animals treated with radioactive iodine.
a leash. Adults are recommended to stay 6 feet or farther away the litter pan with plastic. The used litter should be disposed of
from the cat except for brief periods needed for necessary care, in the outside trash or by flushing flushable litter down the toilet.
including arrangement for a separate sleeping area away from peo- The hands should be washed thoroughly after handling of the cat,
ple. Children and pregnant women should have no contact with its food dishes, or the litter pan.
the cat until the collar has been removed. To further reduce any Rechecks and Hypothyroidism.Recheck evaluations are
chance of unwanted exposure, it is recommended that owners line recommended 1, 3, 6, and 12 months following treatment for
|
a complete history, physical examination (including weight and hypothyroidism and goiter. Published guidelines for iodine require-
blood pressure measurement), serum biochemical profile, and ments for healthy cats have changed over the years, but current rec-
measurement of serum T4 concentrations. Most cats are euthyroid ommendations are that healthy cats should consume at least 0.46
or have a serum T4 concentration below the reference range at the mg/kg of dry food (Wedekind etal, 2010). There are no published
time of hospital discharge. A small percentage of cats (15%) are guidelines for iodine requirements of hyperthyroid cats. Dietary
still hyperthyroid at the time of discharge but become euthyroid iodine restriction to less than 0.3 mg/kg reduces the circulating thy-
within 6 months after treatment (Peterson and Becker, 1995). roid hormone concentrations to the normal range in hyperthyroid
Some cats treated with radioactive iodine become transiently or cats (Melendez etal, 2011a; 2011b; Yu etal, 2011; van der Kooij
permanently hypothyroid after radioactive iodine treatment. Per- etal, 2013), suggesting that dietary iodine restriction has potential
sistent hypothyroidism after treatment is a risk factor for azotemia. as an alternative management strategy for feline hyperthyroidism.
Measurement of total T4 together with TSH can help distinguish Commercial cat foods are commonly supplemented with iodine
true hypothyroidism from NTIS (see Baseline Serum Thyrotro- using calcium iodate or potassium iodide. Studies suggest that there
pin Concentration). Cats that are still hypothyroid 6 months after is huge variability in the concentration of iodine in commercial
treatment, those that develop clinical signs of hypothyroidism, cat foods because of the variability of iodine content of individual
and those that have progressive azotemia and a low serum T4 con- ingredients. Ingredients that typically contain high concentrations
centration should be supplemented with L-T4 at a dose of 0.05 to of iodine include fish, shellfish, and fresh meats. The range of iodine
0.1 mg of L-T4 given orally once or twice daily. Cats that continue content in commercial cat foods varies by a factor of 30, with the
to have abnormally increased serum T4 concentrations 6 months largest variation being found in canned cat food (Ranz etal, 2002;
after radioiodine therapy may need to be retreated with 131I. These Mumma etal, 1986; Johnson etal, 1992; Edinboro etal, 2013).
cats are at higher risk of thyroid carcinoma, and this possibility
should be investigated so that a higher dose of isotope can be
Role of Dietary Iodine in the Pathogenesis of Disease
administered if appropriate (see Feline Thyroid Carcinoma).
Prognosis for Resolution of Hyperthyroidism.More than The variability in iodine content of commercial cat food and the
93% of cats treated with radioactive iodine become euthyroid after similarities between feline hyperthyroidism and toxic nodular goi-
one treatment. Failure to respond to the first treatment is most ter in humans have prompted hypotheses, so far unsupported by
common in cats that have large tumors, severe clinical signs, and research, that low iodine intake, high iodine intake, or wide vari-
very high serum T4 concentrations (Peterson and Becker, 1995). ability in iodine content has contributed to the current increased
Cats with thyroid carcinoma also fail to become euthyroid after prevalence of feline hyperthyroidism. Whether or not iodine con-
low dose 131I treatment. There are no reports of adverse effects on tent of the diet is important in the pathogenesis of feline hyper-
organs other than the thyroid glands after low dose 131I therapy. thyroidism, it is likely only one of many potential contributing
factors. It is also clear that the final common pathway in the patho-
Need for Retreatment genesis of feline hyperthyroidism is the presence of mutations in
subsets of thyroid follicular cells that lead to autonomous thy-
Approximately 2% to 5% of 131I-treated hyperthyroid cats require roid hormone synthesis. Once thyroid follicular cells have become
a second treatment (Peterson and Becker, 1995). Several factors, autonomous, the cellular changes are not reversible or likely to be
such as dose administered, thyroid gland size, thyroid gland pathol- influenced by dietary change. In other words, limiting the iodine
ogy (adenoma, adenomatous hyperplasia, or carcinoma), and content of the food can lead to normalization of thyroid hormone
iodine excretion rate, may contribute to an incomplete response synthesis whether or not the iodine content of the diet is a factor
to an initial therapeutic dose of 131I. Errors in radioisotope admin- in the underlying pathogenesis of feline hyperthyroidism.
istration can also occur and explain a treatment failure. Prior to
administration of a second treatment, the reason for failure should
Iodine-Limited Diets for Management of Feline
be evaluated. Although a second standard dose is effective in most
Hyperthyroidism
cats, consideration should be given to obtaining an incisional or
excisional thyroid biopsy in cats in which thyroid carcinoma is sus- In a series of studies involving 33 cats with naturally occurring
pected. In cats with thyroid carcinoma, high dose radioactive iodine hyperthyroidism, the effects of feeding diets containing from 0.15
treatment may be necessary (see Feline Thyroid Carcinoma). mg/kg to 1.9 mg/kg dietary iodine concentration were investigated
(Melendez etal, 2011a; 2011b; Yu et al, 2011). All cats studied
Recurrence were consuming commercial diets containing 1.9 mg/kg iodine at
the time of diagnosis and were confirmed to be hyperthyroid by
A small percentage of cats (less than 3%) develop recurrence of standard methods. The iodine content of the control and experi-
hyperthyroidism at a median time of 3 years (range 1 to 6 years) mental diets was confirmed by epiboron neutron atomic activa-
after treatment with radioactive iodine. No predictors of relapse tionan extremely sensitive assay method. Four to 8 weeks after
have been identified. There was no difference between the T4 con- consumption of a diet containing 0.17 mg/kg or less of dietary
centration or the dose of radioactive iodine used between cats that iodine, all cats had a total T4 within the reference range. Eight of
did and did not relapse (Peterson and Becker, 1995). It is likely nine cats consuming a diet of 0.28 mg/kg iodine were euthyroid
that relapse in these cats is due to development of new foci of within 3 to 12 weeks, whereas the proportion of cats becoming
autonomous tissue arising from new mutations. euthyroid was lower when consuming diets containing higher
concentrations of iodine (0.39 mg/kg [7 of 9 cats] or 0.47 mg/kg
[4 of 5 cats]). More extensive thyroid profiles were performed in
NUTRITIONAL MANAGEMENT OF FELINE
14 of the cats; fT4, total T3, free T3, and TSH concentrations were
HYPERTHYROIDISM
within the laboratory reference range while consuming the iodine-
In mammals, the only known function of iodine is incorpo- restricted diet. There was no change in renal parameters after res-
ration into thyroid hormones; diets deficient in iodine cause toration of euthyroidism, which is surprising because decreased
TABLE 4-16 R
ESPONSE TO TREATMENT of hyperthyroidism in cats that are not good candidates for
WITH AN IODINE-LIMITED DIET definitive treatment of their hyperthyroidism. As with methim-
IN 10 HYPERTHYROID CATS azole, limiting the intake of dietary iodine limits thyroidal
synthesis of thyroid hormone, but the autonomous thyroid
4-8 WEEK PRE POST adenoma is still present. Therefore definitive treatment with
131I or thyroidectomy should be recommended if possible;
PRE THYROXINE THYROXINE G/DL CREATININE CREATININE
CAT G/DL (RR 2.5-4.6) (RR 2.5-4.6) MG/DL MG/DL however, for cats that have concurrent nonthyroidal illness, for
cats that have adverse effects of methimazole, for owners with
1 13.3 2.8 1.2 1.4
financial constraints, or for owners who are unable to medi-
2 6.4 1.7 1.0 0.7 cate their cats, nutritional management is a feasible alternative.
3 12.4 6.5* 0.8 0.6 Nutritional management is not a good option for cats that do
4 8.7 4.4 0.7 0.7 not find the food to be palatable, for outdoor cats with access
to other sources of dietary iodine, or for cats that need to be
5 8.0 4.3 0.6 on a controlled diet to manage other concurrent illnesses, such
6 8.9 3.4 0.6 0.4 as inflammatory bowel disease, allergic dermatitis, or heart dis-
7 13 2.6 0.8 0.7 ease. For cats in early renal failure, Prescription Diet y/d may
be an acceptable diet because it is supplemented with omega-3
8 8.7 2.8
fatty acids and contains controlled amounts of phosphorus,
9 5.9 3.1 1.4 1.0 sodium, and high-quality protein (36% dry matter basis). Cats
10 9.4 2.9 with more severe renal failure may need to be fed a diet for-
mulated for management of renal failure. Hyperthyroid cats in
RR, Reference range. multicat households need to be fed individually, and access to
food of other pets in the household must be prevented. Alter-
14 natively the iodine-limited diet can be fed to all cats in the
12 household providing the euthyroid cats are supplemented daily
with a food with higher iodine content.
10
Expected Outcome
TT4 g/dL
6 More than 90 percent of hyperthyroid cats become euthyroid

4 when fed a limited-iodine diet exclusively (Table 4-16; Fig. 4-42).
The most common reason for failure to control the hyperthyroid-
2 ism is access to iodine-containing food, such as treats, human
0 food, or other pet foods. Even small amounts of other iodine-con-
Time 0 Week 4 Week 8 taining foods can result in an increase in the T4 concentration. For
FIGURE 4-42 Change in total thyroxine (T4) and free T4 (fT4) in six cats consum-
this reason, cats being managed with an iodine-limited food need
ing an iodine-limited diet over an 8 week period (unpublished data).
to be indoor cats, and the owner needs to feed the diet exclusively.
For owners who consider it important to give their cats treats,
one strategy is to feed the dry Prescription Diet y/d diet predomi-
GFR associated with reestablishment of euthyroidism results in nantly and give the canned Prescription Diet y/d as a treat. In cats
azotemia in 15% to 49% of previously non-azotemic cats treated that do not become euthyroid within 4 to 8 weeks of starting the
by other methods (Williams etal, 2010). limited-iodine diet, a detailed history should be investigated for
evidence of other sources of iodine. Possible sources in addition
to access to other pet foods include well water, medications or
Clinical Experience
supplements, contaminated food bowls, and human food.
There is now a commercially available iodine-limited diet marketed
for management of feline hyperthyroidism (Prescription Diet y/d). Long-Term Nutritional Management
The diet is similar in formulation to Prescription g/d but has an
iodine content of 0.2 mg/kg or less and is available as both canned Nutritional management of feline hyperthyroidism is an entirely
and dry food. In a retrospective study of 49 client-owned hyperthy- new approach that does not have a parallel in people. In human med-
roid cats fed this diet exclusively, serum total T4 became normal in icine, low-iodine diets are only used for short periods of time prior
71% of cats between 21 and 60 days and 96% of cats between 61 to nuclear imaging to screen for metastasis in patients with thyroid
and 180 days respectively. Cats with a higher starting total T4 took carcinoma. For this reason the long-term consequences of dietary
longer to become euthyroid. The median heart rate, body weight, restriction of iodine are unknown. Iodine may have anti-oxidant and
and serum creatinine did not change over the 6 months of the anti-inflammatory properties as well as playing a role in prevention of
study (Scott-Moncrieff, unpublished data). The reasons for a lack breast cancer and fibrocystic breast disease (Patrick, 2008). One con-
of weight gain in these cats may reflect the influence of concurrent cern is that cats managed long-term with iodine-limited diets might
disease or subclinical hyperthyroidism in some cats. develop a clinically significant goiter due to continued follicular cell
hyperplasia; additionally, management using an iodine-limited diet
could increase the risk of transformation of adenomatous nodules
Indications for Nutritional Management
into thyroid carcinoma. In a report of eight cats with thyroid carci-
Nutritional management is an alternate option for short-term noma, two cases had both adenomatous changes and carcinoma cells
management of hyperthyroidism or longer-term management contained within one gland, suggesting that the carcinoma could
|
have arisen from a background of benign neoplasia (Hibbert etal, cats have a history of prior thyroidectomy, and in addition to the
2009). These potential risks are also of concern in cats treated chroni- typical clinical signs of hyperthyroidism, voice change has been
cally with methimazole. For these reasons, the thyroid gland should reported. Palpable cervical mass masses are present in 71% of
be palpated routinely in cats on a limited-iodine diet, and definitive cases. In cats with thyroid carcinoma, thyroid gland palpation may
therapy with radioactive iodine treatment should be recommended if be similar to that of a hyperthyroid cat with benign disease; how-
clinically significant thyroid gland enlargement is identified. ever, in other cases, the masses associated with thyroid carcinoma
are large and fixed rather than freely moveable and attached to
underlying or overlying tissues.
Transitioning from Methimazole to a Limited-Iodine Diet
Iodine-limited diets should not be used concurrently with Diagnosis
methimazole for management of feline hyperthyroidism because
of the risk of severe hypothyroidism. Methimazole should be dis- Common abnormalities on the minimum data base are similar to
continued immediately prior to starting an iodine-limited diet. cats with benign thyroid disease with the exception of occasional
Transient hyperthyroidism may occur during the transition, but hypercalcemia. Radiographic abnormalities may include cardio-
this is preferable to hypothyroidism because of the deleterious megaly, evidence of congestive heart failure, mediastinal masses,
influence of hypothyroidism on the GFR. and evidence of pulmonary metastasis. The majority of cats with
thyroid carcinoma have increased basal serum T4 concentrations.
No differences have been identified in the range of serum T4 con-
Transitioning from a Limited-Iodine
centrations in cats with benign and malignant thyroid tumors. A
Diet to Other Treatments
nonsecretory or nonfunctional tumor should be suspected if a thy-
If nutritional management fails to control hyperthyroidism despite roid tumor is identified but T4 concentration is normal and there
investigation for other sources of iodine, another diet should be rein- are no clinical signs of hyperthyroidism. Nuclear scintigraphy
stituted and alternative treatment of the hyperthyroidism considered. using sodium pertechnetate (technetium-99m [99mTc]) is valu-
A washout period is not necessary in cats started back on methima- able in the evaluation of cats with suspected malignant thyroid
zole treatment, because thyroid hormone synthesis increases very tumors. In cats with thyroid carcinoma, a 99mTc scan may dem-
rapidly once the limited iodine diet is discontinued. Little is known onstrate patchy or irregular uptake of isotope, extension of isotope
about the effect of a limited-iodine diet on response to radioactive uptake down the neck and into the mediastinum, and evidence
iodine. In theory, increased iodine trapping by the thyroid gland due of distant metastasis (see Fig. 4-29); however, in some cats with
to the lack of iodine could make the normal atrophic thyroidal tissue thyroid carcinoma scintigraphic findings may be similar to the
more susceptible to the effects of radioactive iodine and increase the scans of cats with thyroid adenomatous hyperplasia or adenoma.
risk of hypothyroidism after 131I treatment. Conversely consumption Conversely, scans that reveal uptake by multiple masses in the cer-
of a limited iodine diet could be used to decreased the required dose vical region or masses extending into the cranial mediastinum in
of 131I needed to reestablish a euthyoid state. In eight hyperthyroid some cases may be benign ectopic tissue. Thus scintigraphy alone
cats that were euthyroid after consumption of an iodine limited diet, cannot definitively distinguish between adenomatous hyperpla-
radioisotope scans using 123I revealed increased radio-isotope uptake sia and thyroid carcinoma. Bronchogenic carcinoma may have
of 60% to 600% (Scott-Moncrieff, unpublished data). scintigraphic findings that may be confused with those of thyroid
tumors. Nonfunctional thyroid tumors may or may not take up
99mTc depending upon the degree of differentiation of the tumor.
Recommended Monitoring
Definitive diagnosis of thyroid carcinoma requires histopatho-
It is recommended that cats being managed with an iodine-limited logic examination of excised tissue. Because the majority of feline
diet be reevaluated by physical examination and measurement of a thyroid tumors are benign, thyroid carcinoma may not be suspected
BUN, creatinine, USG, and total T4 monthly until establishment on the initial evaluation. Factors that should increase the index of
of euthyroidism. As for methimazole treated cats the ideal range suspicion for thyroid carcinoma include recurrence of hyperthy-
for the total T4 is within the lower half of the reference range. Cats roidism after previous thyroidectomy(ies), failure to respond to low
should then be monitored every 6 months if otherwise healthy; cats dose radioactive iodine treatment, presence of multiple palpable
with concurrent illnesses may require more frequent monitoring. cervical nodules, and cervical nodules that are firmly attached to
underlying or overlying structures. Large, palpable, thyroid masses
that compress surrounding structures may be due either to thyroid
FELINE THYROID CARCINOMA
carcinoma or benign thyroid cyst. Thyroid carcinoma should also
Malignant thyroid neoplasia is diagnosed in approximately 1% be suspected if scintigraphy reveals multiple areas of radionuclide
to 3% of cats with hyperthyroidism (Peterson and Becker, 1995). uptake and irregular or patchy isotope uptake.
Most malignant thyroid tumors in the cat are functional tumors Cytologic characteristics are usually unhelpful in differentia-
with follicular carcinomas being most common. Nonsecretory tion of benign from malignant thyroid tumors, because pleomor-
thyroid tumors (tumors that do not produce excess concentrations phism, anaplasia, and increased mitotic rate are not consistent
of thyroid hormone but do concentrate iodine) and nonfunctional features. Features that distinguish malignant from benign tumors
thyroid tumors (tumors that neither secret thyroid hormone nor include local tissue invasion, regional lymph node involvement,
concentrate iodine) have been described in cats but are rare (Turrel and distant metastasis. Metastasis has been reported to occur in
etal, 1988; Guptill etal, 1995). up to 71% of cats with thyroid carcinoma.
Clinical Features Treatment

The signalment and clinical signs of cats with thyroid carcinoma Although cats with thyroid carcinoma may show clinical improve-
are similar to those of cats with benign hyperthyroidism. Many ment when treated with anti-thyroid drugs, these drugs are not
A B
FIGURE 4-43 A, Thyroid carcinoma at time of cervical exploratory. Note the large size of the tumor and the irregular
appearance. B, Photomicrograph of a thyroid follicular carcinoma in a different cat demonstrating extracapsular
foci and possible lymphatic or blood vascular invasion (arrows).
recommended for several reasons. Anti-thyroid drugs may increase effectively and because there is often a larger mass of thyroid tis-
release of TSH from the anterior pituitary gland by decreasing sue present. A combination of surgical resection and postopera-
secretion of T4 and exacerbate tumor growth due to the tropic tive treatment with high doses of 131I is an effective approach to
effects of TSH. Furthermore, anti-thyroid drugs are not cyto- treatment. Surgical removal followed by administration of 30 mCi
toxic and will neither slow progression of local tumor growth nor 131I in seven cats with thyroid carcinoma resulted in survival times
metastasis to distant organs. The only indication for using anti- ranging from 10 to 41 months (Guptill et al, 1995), and none
thyroid drugs in the management of thyroid carcinoma is for the of the cats died due to thyroid carcinoma. Higher doses of 131I
purpose of initial clinical stabilization prior to 131I therapy or thy- necessitate a longer hospitalization time to allow the isotope time
roidectomy. Beta blockers (e.g., propranolol or atenolol) are useful to decay to activity levels compatible with discharge to the home
in hyperthyroid cats that require stabilization of cardiac disease environment. The majority of cats treated with higher doses of
prior to surgery or 131I therapy. 131I become permanently hypothyroid and require supplementa-
Thyroidectomy is the initial treatment of choice in cats with tion with L-T4. Treatment with 30 mCi 131I as the sole mode of
suspected thyroid carcinoma, because the diagnosis must be con- therapy has also been reported to result in a successful outcome in
firmed by histopathology (Fig. 4-43) and because complete exci- cats with feline thyroid carcinoma, although one of eight cats did
sion can be curative. Scintigraphy should always be performed not respond to treatment and one cat had recurrence 6 months
prior to thyroidectomy. As much tumor as possible should be after treatment (Hibbert etal, 2009). Adverse effects of high dose
excised. Thyroid biopsy, followed by adjunctive therapy, may be 131I may include transient dysphagia and hypothyroidism. In one
more appropriate in cats with invasive or infiltrative masses. Pres- study, pancytopenia was identified 6 months after high dose 131I
ervation of the parathyroid glands is more difficult in cats with treatment, but the relationship with the radioiodine treatment was
invasive thyroid carcinomas treated surgically, and postoperative unclear because the cat was also feline immunodeficiency virus
monitoring of serum calcium concentrations is essential for cats (FIV) positive.
undergoing bilateral thyroidectomy. A cat exhibiting signs of
hypocalcemia after thyroidectomy (e.g., muscle tremors, tetany, Thyroid Cysts
or convulsions) should be treated with appropriate calcium and
vitamin D supplementation (see Management of Postoperative Thyroid cysts may occur associated with thyroid adenomatous
Hypocalcemia for approach to treatment of hypocalcemia). hyperplasia, adenoma, or thyroid carcinomas. The cystic lesion
Even if all of the visible tumor is removed, many thyroid carci- may be palpated as a thin walled fluctuant mass that usually col-
nomas will recur within weeks to months. Thus, in histopatholog- lapses and is non-palpable once the fluid has been removed (Fig.
ically confirmed thyroid carcinoma, thyroid scintigraphy should 4-44). The total T4 concentration of the cystic fluid is typically
be repeated 4 to 8 weeks after thyroidectomy in order to evalu- high (Hofmeister etal, 2001). Diagnosis of thyroid cysts is best
ate the success of surgical removal. If tumor recurrence is con- made by a combination of palpation and aspiration. Ultrasound
firmed, treatment with high dose 131I is recommended. Following examination can be helpful in evaluation of thyroid glands with
treatment with 131I, reevaluation of serum T4 concentrations and cystic changes (Barberet, 2010). Treatment of large thyroid cysts is
99mTc scans should be performed every 3 to 6 months. If recur- best accomplished by surgical resection of the cyst and associated
rence is not detected in these follow-up evaluations after 1 year, thyroid tissue rather than radioactive iodine therapy.
the period between evaluations can progressively be lengthened.
Treatment with 131I is indicated in cats with non-resectable MISCELLANEOUS THERAPIES
thyroid carcinoma and in cats with evidence of metastasis or
recurrence after thyroidectomy, providing the neoplastic tissue Percutaneous Ethanol and Heat Ablation Injection
concentrates iodine or technetium on scintigraphy. Higher doses for Treatment of Feline Hyperthyroidism
of 131I (10 to 30 mCi) are required to successfully treat cats with
thyroid carcinoma than are required to treat cats with thyroid Both ultrasound guided ethanol injection and percutaneous radio-
adenoma, because the thyroid tissue may concentrate iodine less frequency heat ablation have been evaluated for treatment of feline
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A B
C
FIGURE 4-44 A, Photograph of a large thyroid cyst in a hyperthyroid cat during thyroidectomy and surgical resec-
tion of the thyroid cyst. B and C, Ventral and lateral thyroid technetium-99m (99mTc) scans from the same cat. Note
that the cyst appears as a large cold area surrounded by a thin rim of tissue that takes up 99mTc. The majority of
the thyroid gland is medial and dorsal to the cyst.
hyperthyroidism (Goldstein etal, 2001; Wells etal, 2001; Mallery The dose should be started at the lower end of the range and
etal, 2002). Problems with frequent recurrence and complications then slowly increased until the goals of controlling tachycardia
in cats with bilateral thyroid disease have limited the practical- and arrhythmias are achieved. Propranolol is a potent myocardial
ity of these approaches. For more information see Feldman and depressant and should be used with extreme caution if heart fail-
Nelson, Canine and Feline Endocrinology and Reproduction, ed 3. ure is present. In a study of induced hyperthyroidism, the half-life
of propranolol was not affected by hyperthyroidism (Jacobs etal,
Beta Blockers
1997). After oral administration, total body clearance was lower and
Beta blockers may be useful to control tachycardia and other the peak plasma propranolol concentration, fractional absorption,
supraventricular tachyarrhythmias especially in cats that do not and area under the curve were higher in hyperthyroid cats com-
tolerate anti-thyroid drugs. Beta blockade results in slowing of the pared with euthyroid cats. This indicated increased bioavailability in
heart rate, lowers the end-diastolic pressure of the left ventricle, thyrotoxicosis, which was calculated to exceed 100% and suggested
prolongs the ventricular lling time, decreases the oxygen demand enterohepatic recycling of the drug. The ndings of this study sup-
of the myocardium, acts as an antiarrhythmic agent, and reduces port starting at the lower end of the dose in hyperthyroid cats.
outflow pressure gradients. Beta blockers may also reduce the sys- Atenolol is a selective beta1 blocker with potential advantages
tolic blood pressure and have been recommended for control of over propranolol, including more selective 1-adrenoreceptor
hypertension in hyperthyroidism; however, studies suggest that blocking action and longer duration of action. Atenolol is rapidly
efficacy is limited in hyperthyroid cats with hypertension (Henik absorbed from the gastrointestinal tract in cats and has a half-life
etal, 2008). More potent anti-hypertensive drugs (e.g., amlodip- of 3 hours in cats. The duration of effect persists for at least
ine) should be utilized in hyperthyroid cats with clinically signifi- 12 hours in healthy cats (Quiones, 1996). Atenolol is used at a
cant hypertension. dosage of 6.25 to 12.5 mg per cat mg every 12 to 24 hours. The
Propranolol is a nonselective beta blocker that has the added starting dose should be at the low end of the range, and the dose is
advantage of also decreasing conversion of T4 to T3; however, then gradually increased depending upon the response.
propranolol can cause bronchospasm in cats with reactive airway
disease because of blockade of beta2 receptors in airway smooth Stable Iodine
muscle. Propranolol is rapidly absorbed from the gastrointestinal
tract, and the plasma half-life is approximately 3 to 6 hours. The rec- Although the thyroid gland requires small amounts of iodide
ommended dose of propranolol is 2.5 to 5 mg every 8 to 12 hours. for hormone synthesis, large amounts given over a brief period
(1 to 2 weeks) may result in transient hypothyroidism in nor- channel blockers (e.g., amlodipine), and angiotensin convert-
mal individuals due to the Wolff-Chaikoff effect. High doses ing enzyme (ACE) inhibitors (e.g., benazepril and enalapril).
of iodide inhibit organication of thyroid hormone, which As discussed earlier, beta blockers are effective at controlling
results in reduced secretion. Iodide can be rapidly effective in tachycardia in hyperthyroid cats but are not as effective at con-
ameliorating increased serum thyroid hormone concentrations trolling hypertension. In a study of 20 hyperthyroid cats with
associated with hyperthyroidism. Benecial effects are seen in systolic blood pressure more than 160 mmHg treated with
7 to 14 days and include improvement in clinical signs, as well 1 to 2 mg/kg orally every 12 hours atenolol, the tachycardia
as reduction in the size and vascularity of the thyroid gland. was successfully controlled in most cats but systolic blood pres-
Iodide has a role in the treatment of thyroid storm in humans. sure only decreased below 160 mmHg in 30% of cats (Henik
Unfortunately, it is rarely possible to achieve complete remis- etal, 2008). Amlodipine (0.625 to 1.25 mg per cat every 24
sion of hyperthyroidism or to maintain any degree of control hours) is a more effective antihypertensive drug in cats with
for more than a few weeks with iodide, but it may be useful hypertension and has the additional advantage of decreas-
when used in conjunction with beta-blockers to control the ing proteinuria in cats with CKD (Jepson et al, 2007). ACE
disease preoperatively in cats that do not tolerate methimazole inhibitors (e.g., benazepril) are less potent than amlodipine
(Foster and Thoday, 1999). Potassium iodate (KI) at a dose of for control of feline hypertension but have both systemic and
21 to 42 mg every 8 hours was administered daily beginning glomerular anti-hypertensive effects so are useful in cats with
10 days prior to surgery in conjunction with propranolol. The concurrent CKD. ACE inhibitors are typically used as a second
KI was placed in a small gelatin capsule to avoid the aftertaste drug in cats that do not have good control of systemic blood
that may bother some cats. The most common side-effect of pressure with amlodipine alone (Stepien, 2011). As mentioned
treatment with KI was gastrointestinal upset. earlier, some cats with hyperthyroidism develop hypertension
after control of the hyperthyroid state, so it is really important
Iodinated Radiographic Contrast Agents to continue to monitor blood pressure in all hyperthyroid cats
after treatment.
Oral cholecystographic agents (e.g., calcium ipodate and iopa-
noic acid) acutely inhibit peripheral conversion of T4 to T3
Prognosis
and may decrease T4 synthesis. Blocking of the conversion of
circulating thyroid hormone has been demonstrated in iat- A number of studies have evaluated the prognosis and pre-
rogenic feline hyperthyroidism, and the drug appears to be dictors of survival for hyperthyroid cats treated with radio-
well tolerated with few adverse side effects. In 12 cats with active iodine. In a study of more than 200 cats, male cats
naturally occurring hyperthyroidism treated with calcium ipo- were found to have a shorter life expectancy than females
date, eight exhibited a good response. The serum total T3 con- (Slater et al, 2001). Age at the time of treatment was also a
centrations decreased into the reference range within 2 weeks prognostic factor, because older cats did not survive as long
of the start of treatment and remained at those levels for a as younger cats. For example, 28% of 10-year-old male
14-week study period. In addition, improvement in clinical cats were alive 5 years after therapy and 4% of 16-year-old
signs, body weight, heart rate, and blood pressure were docu- male cats were alive 5 years after treatment, whereas 42% of
mented. Four of the eight responders continued to do well for 10-year-old female cats were alive 5 years after treatment.
as long as 6 months, but two of them had relapses of hyperthy- The mean age of death was 15 years of age, with a range of
roidism by week 14. The serum total T4 concentrations were 10 to 21 years. Clinical abnormalities documented just before
not affected by treatment, and cats with severe disease were death were renal disorders in 41% of cats and cancer in 16%
less likely to respond, even after the dose was doubled (Mur- of cats.
ray and Peterson, 1997). Unfortunately calcium ipodate is no In a retrospective study of 300 hyperthyroid cats treated with
longer commercially available. Iopanoic acid has been evalu- methimazole, thyroidectomy, or radioactive iodine, median
ated as an alternative agent and is also effective at decreasing survival was 417 days; increasing age, presence of proteinuria,
T3 concentration; however, in a study of 11 hyperthyroid cats, and hypertension were associated with decreased survival time
only five cats had partial and transient responses (Gallagher (Williams etal, 2010). In another study, median survival time
etal, 2011). for feline hyperthyroidism after radioactive iodine was reported
to be approximately 2 years (range 2 weeks to 7 years) (Peterson
etal, 2001). In a retrospective study of 167 cats treated with
Treatment of Hypertension in Hyperthyroid Cats
methimazole and/or radioactive iodine, cats with pre-existing
As discussed earlier, the prevalence of hypertension in hyper- renal disease had significantly shorter survival times than cats
thyroid cats is lower than previously believed, and only a small without pre-existing renal disease (Milner et al, 2006; Fig.
percentage of cats require specific treatment for hypertension. 4-45). When cats with pre-existing renal disease were excluded,
The criteria for initiating specific anti-hypertensive treatment cats treated with methimazole alone had a shorter median sur-
include documentation of systolic blood pressure more than vival time (2 years) than cats treated with radioactive iodine
160 mmHg on more than one occasion or evidence of end alone or methimazole followed by radioactive iodine (4 years).
organ damage, such as retinal lesions due to hypertension. It The reasons for the difference in survival between the treat-
is important that blood pressure is measured in as calm and ment groups may have been related to poorer control of the
non-stressful way as possible to minimize the white coat effect hyperthyroid state with long-term medical treatment as well as
that hyperthyroid cats seem particularly susceptible to. In addi- owner bias toward less aggressive management in methimazole
tion to specific management of the hypertension, underlying treated cats. The prognosis for hyperthyroid cats managed by
hyperthyroidism should be treated at the same time. Drugs dietary iodine restriction is currently unknown, although some
that are used to control hypertension in hyperthyroid cats cats have reportedly been managed with this strategy for up to
include beta-blockers (e.g., propranolol or atenolol), calcium 6 years.
|
1.0 Renal disease 1.0

Methimazole
No renal disease
Methimazole + 131I
0.8 0.8 I
131
Proportion surviving
Proportion surviving
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
A Time (y) B Time (y)
FIGURE 4-45 A, Kaplan-Meier curves of survival times for 167 hyperthyroid cats treated with methimazole, io-
dine-131 (131I), or methimazole followed by 131I, grouped according to whether they had evidence of renal disease
prior to treatment. B, Kaplan-Meier curves of survival times for 167 hyperthyroid cats treated with methimazole,
131I, or methimazole followed by 131I, and grouped according to treatment. (A, From Milner RJ, etal.: Survival times
for cats with hyperthyroidism treated with iodine 131, methimazole, or both: 167 cases [1996-2003], J Am Vet Med
Assoc 228[4]:559-563, 2006. [Fig. 3; p. 562])
REFERENCES
Adams WH, etal.: Changes in renal function in Beleslin DB, etal.: Nature of salivation pro- Boretti FS, etal.: Duration of T4 suppression
cats following treatment of hyperthyroidism duced by thyrotropin-releasing hormone in hyperthyroid cats treated once and twice
using 131I, Vet Radiol Ultrasound 38:231, (TRH), Brain Res Bull 18:463, 1987a. daily with transdermal methimazole, J Vet
1997. Beleslin DB, etal.: Studies of thyrotropin-re- Intern Med 27:377, 2013a.
Andrade VA, etal.: Methimazole pretreatment leasing hormone (TRH)induced defeca- Boretti FS, etal.: Transdermal application of
does not reduce the efcacy of radioiodine tion in cats, Pharmacol Biochem Behav methimazole in hyperthyroid cats: a long-
in patients with hyperthyroidism caused by 26:639, 1987b. term follow up study, J Feline Med Surg
Graves disease, J Clin Endocrinol Metab Belew AM, etal.: Evaluation of the white-coat [Epub ahead of print], 2013b.
86:3488, 2001. effect in cats, J Vet Intern Med 13:134, Branter E, etal.: Antioxidant status in hyperthy-
Archer FJ, Taylor SM: Alkaline phosphatase 1999. roid cats before and after radioiodine treat-
bone isoenzyme and osteocalcin in the Bell ET, etal.: Immune-mediated myasthenia ment, J Vet Intern Med 26:582, 2012.
serum of hyperthyroid cats, Can Vet J gravis in a methimazole-treated cat, J Broome MR, etal.: Peripheral metabolism of
37:735, 1996. Small Anim Pract 53:661, 2012. thyroid hormones and iodide in healthy
Aucoin DP, etal.: Propylthiouracil-induced Berent AC, etal.: Liver function in cats with and hyperthyroid cats, Am J Vet Res
immune-mediated disease in cats, hyperthyroidism before and after 131-I 48:1286, 1987.
J Pharmacol Exp Ther 234:13, 1985. therapy, J Vet Intern Med 21:1217, 2007. Broome MR, etal.: Serial determinations of
Aucoin DP, etal.: Dose dependent induction of Biondi B, etal.: Subclinical hyperthyroidism: thyroxine concentrations in hyperthyroid
anti-native DNA antibodies by propylthioura- clinical features and treatment options, cats, J Am Vet Med Assoc 192:49, 1988a.
cil in cats, J Arthr Rheum 31:688, 1988. Eur J Endocrinol 152(1):1, 2005. Broome MR, etal.: Predictive value of tracer
Barber PJ, Elliott J: Study of calcium hemosta- Birchard SJ: Thyroidectomy in the cat, Clin studies for 131I treatment in hyperthyroid
sis in feline hyperthyroidism, J Small Anim Tech Small Anim Pract 21(1):29, 2006. cats, Am J Vet Res 49:193, 1988b.
Pract 37:575, 1996. Birchard SJ, etal.: Surgical treatment of feline Broome MR, etal.: Thyroid scintigraphy in hy-
Barberet V, etal.: Pre- and posttreatment hyperthyroidism: results of 85 cases, perthyroidism, Clin Tech Small Anim Pract
ultrasonography of the thyroid gland in J Am Anim Hosp Assoc 20:705, 1984. 21(1):10, 2006.
hyperthyroid cats, Vet Radiol Ultrasound Boag AK, etal.: Changes in the glomerular Broussard JD, etal.: Changes in clinical and
51(3):324, 2010. filtration rate of 27 cats with hyperthyroid- laboratory ndings in cats with hyperthy-
Beck KA, etal.: The normal feline thyroid: ism after treatment with radioactive iodine, roidism from 1983 to 1993, J Am Vet Med
technetium pertechnetate imaging and Vet Rec 161:711, 2007. Assoc 206:302, 1995.
determination of thyroid to salivary gland Boas M, etal.: Thyroid effects of endocrine Bucknell DG: Feline hyperthyroidism: spectrum
radioactivity ratios in 10 normal cats, disrupting chemicals, Mol Cell Endocrinol of clinical presentations and response to car-
Vet Radiol 26:35, 1985. 355(2):240, 2012. bimazole therapy, Aust Vet J 78:462, 2000.
Beck-Peccoz P, etal.: Pituitary tumours: TSH- Bond BR, etal.: Echocardiographic ndings in Burch HB: Overview of the clinical manifesta-
secreting adenomas, Best Pract Res Clin 103 cats with hyperthyroidism, J Am Vet tions of hyperthyroidism. In Braverman LE,
Endocrinol Metab 23(5):597, 2009. Med Assoc 192:1546, 1988. Cooper DS, editors: Werner and Ingbars
the thyroid: a fundamental and clinical Duyff RF, etal.: Neuromuscular ndings in Gordon JM, etal.: Juvenile hyperthyroidism
text, ed 10, Philadelphia, 2013, Lippin- thyroid dysfunction: a prospective clini- in a cat, J Am Anim Hosp Assoc 39:67,
cott Williams and Wilkins, p 434. cal and electrodiagnostic study, J Neurol 2003.
Chalmers HJ, etal.: Identifying removalbe Neurosurg Psychiatry 68:750, 2000. Graves TK, etal.: Changes in renal function as-
radioactivity on the surface of cats during Edinboro CH, etal.: Epidemiologic study of sociated with treatment of hyperthyroidism
the first week after treatment with Iodine relationships between consumption of in cats, Am J Vet Res 55:1745, 1994.
131, Vet Rad Ultrasound 47:507, 2006. commercial canned food and risk of hy- Guptill L, etal.: Response to high-dose
Chiha M, etal.: Thyroid storm: an updated perthyroidism in cats, J Am Vet Med Assoc radioactive iodine administration in cats
review, J Intensive Care Med [Epub ahead 224:879, 2004. with thyroid carcinoma that had previously
of print], 2013. Edinboro CH, etal.: Feline hyperthyroidism: undergone surgery, J Am Vet Med Assoc
Christopher MM: Relation of endogenous Heinz potential relationship with iodine supple- 207:1055, 1995.
bodies to disease and anemia in cats: 120 ment requirements of commercial cat Hammer KB, etal.: Altered expression of G
cases (1978-1987), J Am Vet Med Assoc foods, J Feline Med Surg 12:672, 2010. proteins in thyroid gland adenomas
194:1089, 1989. Edinboro CH, etal.: Iodine concentration in obtained from hyperthyroid cats,
Chun R, etal.: Predictors of response to ra- commercial cat foods from three regions of Am J Vet Res 61:874, 2000.
dioiodine therapy in hyperthyroid cats, Vet the USA, 2008-2009, J Feline Med Surg Harvey AM, etal.: Scintigraphic findings in
Radiol Ultrasound 43:587, 2002. 15:717, 2013. 120 hyperthyroid cats, J Feline Med Surg
Combes A, etal.: Ultrasonographic measure- Feeney DA, etal.: Relationship between orally 11:96, 2009.
ments of adrenal glands in cats with administered dose, surface emission rate Hays MT, etal.: A multicompartmental model
hyperthyroidism, Vet Radiol Ultrasound for gamma irradiation, and urine radioac- for iodide, thyroxine, and triiodothyronine
53(2):210, 2012. tivity in radioiodine treated hyperthyroid metabolism in normal and spontane-
Connolly DJ, etal.: Serum troponin I levels in cats, Am J Vet Res 64:1242, 2003. ously hyperthyroid cats, Endocrinology
hyperthyroid cats before and after treat- Feldman EC, Nelson RW: Canine and feline 122:2444, 1988.
ment with radioactive iodine, J Feline Med endocrinology and reproduction, ed 3, St Henik RA, etal.: Efficacy of atenolol as a sin-
Surg 7:289, 2005. Louis, 2004, Saunders/Elsevier. gle antihypertensive agent in hyperthyroid
Cook AK, etal.: The prevalence of hypoco- Fischetti AJ, etal.: Effects of methimazole on cats, J Feline Med Surg 10:577, 2008.
balaminemia in cats with spontaneous thyroid gland uptake of 99mTC-pertechne- Hibbert A, etal.: Feline thyroid carcinoma:
hyperthyroidism, J Small Anim Pract tate in 19 hyperthyroid cats, Vet Radiol diagnosis and response to high-dose radio-
52:101, 2011. Ultrasound 46:267, 2005. active iodine treatment, J Feline Med Surg
Cook SM, etal.: Radiographic and scintigraph- Flanders JA, etal.: Feline thyroidectomy: a 11:116, 2009.
ic evidence of focal pulmonary neoplasia in comparison of postoperative hypocalcemia Hill KE, etal.: The efficacy and safety of a
three cats with hyperthyroidism: diagnos- associated with three different surgical novel lipophilic formulation of methima-
tic and therapeutic considerations, J Vet techniques, Vet Surg 16:362, 1987. zole for once daily transdermal treatment
Intern Med 7:303, 1993. Flanders JA, etal.: Functional analysis of of cats with hyperthyroidism, J Vet Intern
Cooper DS: Treatment of thyrotoxicosis. In ectopic parathyroid activity in cats, Am J Med 25:1357, 2011.
Braverman LE, Cooper DS, editors: Werner Vet Res 52:1336, 1991. Hoenig M, Ferguson DC: Impairment of glucose
and Ingbars the thyroid: a fundamental and Forrest LJ, etal.: Feline hyperthyroidism: tolerance in hyperthyroid cats, J Endocri-
clinical text, ed 10, Philadelphia, 2013, efcacy of treatment using volumetric nol 121:249, 1989.
Lippincott Williams and Wilkins, p 492. analysis for radioiodine dose calculation, Hoffman SB, etal.: Bioavailability of trans-
Court MH, Freeman LM: Identication and con- Vet Radiol Ultrasound 37:141, 1996. dermal methimazole in a pluronic lecithin
centration of soy isoflavones in commercial Foster DJ, Thoday KL: Use of propranolol organogel in healthy cats, J Vet Pharmacol
cat foods, Am J Vet Res 63:181, 2002. and potassium iodate in the presurgical Ther 25:189, 2002.
Court MH, Greenblatt DJ: Molecular genetic management of hyperthyroid cats, J Small Hofmeister E, etal.: Functional cystic thyroid
basis for decient acetaminophen gluc- Anim Pract 40:307, 1999. adenoma in a cat, J Am Vet Med Assoc
uronidation by cats: UGT1A6 is a pseudo- Foster DJ, Thoday KL: Tissue sources of serum 219:190, 2001.
gene, and evidence for reduced diversity alkaline phosphatase in 34 hyperthyroid Holtman JR Jr, etal.: Central respiratory stimu-
of expressed hepatic UGT1A isoforms, cats: a qualitative and quantitative study, lation produced by thyrotropin-releasing
Pharmacogenetics 10:355, 2000. Res Vet Sci 68:89, 2000. hormone in the cat, Peptides 7:207,
Craig A, etal.: A prospective study of 66 cases Foster DJ, etal.: Selenium status of cats in 1986.
of feline hyperthyroidism treated with a four regions of the world and comparison Holzworth J, etal.: Hyperthyroidism in the cat:
fixed dose of intravenous 131I, Aust Vet with reported incidence of hyperthyroid- ten cases, J Am Vet Med Assoc 46:345,
Practit 23:2, 1993. ism in cats in those regions, Am J Vet Res 1980.
Daniel GB, etal.: Quantitative thyroid scin- 62:934, 2001. Ishii S, etal.: Triiodothyronine (T3) stimu-
tigraphy as a predictor of serum thyroxine Fox PR, etal.: Electrocardiographic and radio- lates food intake via enhanced hypotha-
concentration in normal and hyperthyroid graphic changes in cats with hyperthyroid- lamic AMP-activated activity, Regul Pept
cats, Vet Radiol Ultrasound 43(4):374, ism: comparison of populations evaluated 151:164, 2008.
2002. during 1992-1993 vs. 1979-1982, J Am Jacobs G, Panciera D: Cardiovascular compli-
de Lange MS, etal.: High urinary corticoid/cre- Anim Hosp Assoc 35:27, 1999. cations of feline hyperthyroidism. In Kirk
atinine ratios in cats with hyperthyroidism, Frnais R, etal.: Clinical efficacy and safety of RW, Bonagura JD, editors: Kirks current
J Vet Intern Med 18(2):152, 2004. a once-daily formulation of carbimazole in veterinary therapy XI: small animal prac-
De Wet CS, etal.: Prevalence of and risk factors cats with hyperthyroidism, J Small Anim tice, Philadelphia, 1992, WB Saunders,
for feline hyperthyroidism in Hong Kong, Pract 50:510, 2009. p 756.
J Feline Med Surg 11(4):315, 2009. Gallagher AE, etal.: Efficacy of iopanic acid for Jacobs G, etal.: Congestive heart failure
DiBartola SP, etal.: Effects of treatment of treatment of spontaneous hyperthyroidism associated with hyperthyroidism in cats,
hyperthyroidism on renal function in cats, in cats, J Feline Med Surg 13:441, 2011. J Am Vet Med Assoc 188:52, 1986.
J Am Vet Med Assoc 208:875, 1996. Goldstein RE, etal.: Percutaneous ethanol Jacobs G, etal.: Pharmacokinetics of proprano-
Doerge DR, Sheehan DM: Goitrogenic and injection for treatment of unilateral hyper- lol in healthy cats during euthyroid and
estrogenic activity of soy isoflavones, plastic thyroid nodules in cats, J Am Vet hyperthyroid states, Am J Vet Res 58:398,
Environ Health Perspect 3:349, 2002. Med Assoc 218:1298, 2001. 1997.
|
Jepson RE, etal.: Effect of control of systolic Lynn A, etal.: Caudal mediastinal thyroglossal Mooney CT, etal.: Effect of illness not associ-
blood pressure on survival in cats with cyst in a cat, J Small Anim Pract 50:147, ated with the thyroid gland on serum total
systemic hypertension, J Vet Intern Med 2009. and free thyroxine concentrations in cats,
21:402, 2007. Mallery KF, etal.: Percutaneous ultrasound- J Am Vet Med Assoc 208:2004, 1996a.
Johnson LA, etal.: Iodine content of commer- guided radiofrequency heat ablation for Mooney CT, etal.: Serum thyroxine and
cially-prepared cat foods, NZ Vet J 40:18, treatment of hyperthyroidism in cats, J Am triiodothyronine responses of hyperthyroid
1992. Vet Med Assoc 223:1602, 2003. cats to thyrotropin, Am J Vet Res 57:987,
Jones BR, Johnstone AC: Hyperthyroidism in Manna D, etal.: Antithyroid drugs and their 1996b.
an aged cat, NZ Vet J 29:70, 1981. analogues: synthesis, structure, and Mumma RO, etal.: Toxic and protective
Jones BR, etal.: Radioiodine treatment of mechanism of action, Acc Chem Res constituents in pet foods, Am J Vet Res
hyperthyroidism in cats, NZ Vet J 39:71, 46(11):2706, 2013. 47:1633, 1986.
1991. Martin KM, etal.: Evaluation of dietary and Murray LA, Peterson ME: Ipodate treatment
Kang J-H, Kondo F: Determination of bisphe- environmental risk factors for hyperthyroid- of hyperthyroidism in cats, J Am Vet Med
nol A in canned pet foods, Res Vet Sci ism in cats, J Am Vet Med Assoc 217:853, Assoc 211(1):63, 1997.
73:177, 2002. 2000. Naan EC, etal.: Results of thyroidectomy in
Kass PH, etal.: Evaluation of environmental, Maxie MG: Neoplasms of the thyroid gland. 101 cats with hyperthyroidism, Vet Surg
nutritional, and host factors in cats with In Maxie MG, editor: Jubb, Kennedy, and 35:287, 2006.
hyperthyroidism, J Vet Intern Med 13:323, Palmers pathology of domestic animals, Nap AM, etal.: Quantitative aspects of thyroid
1999. ed 5, St Louis, 2007, Saunders/Elsevier, scintigraphy with pertechnetate (99mTcO4)
Kobayashi DL, etal.: Hypertension in cats with p 96. in cats, J Vet Intern Med 8:302, 1994.
chronic renal failure and hyperthyroidism, Mayer-Roenne B, etal.: Urinary tract infections Nelson LL, etal.: Pharyngeal pouch and cleft
J Vet Intern Med 4:58, 1990. in cats with hyperthyroidism, diabetes mel- remnants in the dog and cat: a case
Klein I, Ojamaa K: Thyroid hormone and the litus, and chronic kidney disease, J Feline series and review, J Am Anim Hosp Assoc
cardiovascular system, N Engl J Med Med Surg 9:124, 2007. 48:105, 2012.
344:501, 2001. McLoughlin MA, etal.: Influence of systemic Nemzek JA, etal.: Acute onset of hypokalemia
Knowles S, etal.: Intraperitoneal ectopic thy- nonthyroidal illness on serum concentra- and muscular weakness in four hyperthy-
roid carcinoma in a cat, J Vet Diagn Invest tions of thyroxine in hyperthyroid cats, roid cats, J Am Vet Med Assoc 205:65,
22:1010, 2010. J Am Anim Hosp Assoc 29:227, 1993. 1994.
Khler B, etal.: Dietary hyperthyroidism in Melendez LD, etal.: Titration of dietary Nguyen LQ, etal.: Serum from cats with
dogs, J Small Anim Pract 53:182, 2012. iodine for maintaining normal serum hyperthyroidism does not activate feline
Ladenson PW: Diagnosis of thyrotoxicosis. In thyroxine concentrations in hyperthyroid thyrotropin receptors, Endocrinology
Braverman LE, Cooper DS, editors: Werner cats (abstract), J Vet Intern Med 25:683, 143:395, 2002.
and Ingbars the thyroid: a fundamental and 2011a. Nieckarz JA, Daniel GB: The effect of methim-
clinical text, ed 10, Philadelphia, 2013, Melendez LM, etal.: Titration of dietary iodine azole on thyroid uptake of pertechnetate
Lippincott Williams and Wilkins, p 487. for reducing serum thyroxine concentra- and radioiodine in normal cats, Vet Radiol
Lapointe C, etal.: N-Acetyl-b-D-Glucosaminidase tions in newly diagnosed hyperthyroid Ultrasound 42:448, 2001.
index as an early biomarker for chronic cats (abstract), J Vet Intern Med 25:683, Niessen SJ, etal.: Generalized lymphadeno-
kidney disease in cats with hyperthyroidism, 2011b. megaly associated with methimazole treat-
J Vet Intern Med 22:1103, 2008. Mensching DA, etal.: The feline thyroid gland: ment in a hyperthyroid cat, J Small Anim
Laurberg P, etal.: High incidence of multinodu- a model for endocrine disruption by poly- Pract 48:165, 2007.
lar toxic goiter in the elderly population in a brominated dephenyl ethers (PBDEs)? Norsworthy GD, etal.: Palpable thyroid and
low iodine area vs. high incidence of Graves J Toxicol Environ Health A 75(4):201, parathyroid nodules in asymptomatic cats,
disease in the young in a high iodine area: 2012. J Feline Med Surg 4:145, 2002.
comparative surveys of thyrotoxicosis Meric SM, Rubin SI: Serum thyroxine concen- Olczak J, etal.: Multivariate analysis of risk
epidemiology in East-Jutland Denmark, and trations following xed-dose radioactive factors for feline hyperthyrodism in New
Iceland, J Int Med 229:415, 1991. iodine treatment in hyperthyroid cats: 62 Zealand, NZ Vet J 53:1, 2005.
Lautenschlaeger IE, etal.: Comparison between cases (1986-1989), J Am Vet Med Assoc Padgett SL, etal.: Efcacy of parathyroid gland
computed tomography and 99mTc-pertech- 197:621, 1990. autotransplantation in maintaining serum
netate scintigraphy characteristics of the Meric SM, etal.: Serum thyroxine concentra- calcium concentrations after bilateral
thyroid gland in cats with hyperthyroidism, tions after radioactive iodine therapy in thyroparathyroidectomy in cats, J Am Anim
Vet Radiol Ultrasound 54:666, 2013. cats with hyperthyroidism, J Am Vet Med Hosp Assoc 34:219, 1998.
Lee WR, etal.: The effects of iohexol adminis- Assoc 188:1038, 1986. Page RB, etal.: Accuracy of increased thyroid
tration on technetium thyroid scintigraphy Merryman JI, etal.: Overexpression of c-Ras activity during pertechnetate scintigraphy
in normal cats, Vet Radiol Ultrasound in hyperplasia and adenomas of the by subcutaneous injection for diagnosing
51(2):182, 2010. feline thyroid gland: An immunohisto- hyperthyroidism in cats, Vet Radiol Ultra-
Liggert SB, etal.: Increased fat and skel- chemical analysis of 34 cases, Vet Pathol sound 47(2):206, 2006.
etal muscle b-adrenergic receptors but 36(2):117, 1999. Papasouliotis K, etal.: Decreased orocaecal
unaltered metabolic and hemodynamic Milner RJ, etal.: Survival times for cats with transit time, as measured by the exhalation
sensitivity to epinephrine invivo in experi- hyperthyroidism treated with iodine 131, of hydrogen in hyperthyroid cats, Res Vet
mental human thyrotoxicosis, J Clin Invest methimazole, or both: 167 cases (1996- Sci 55:115, 1993.
83:803, 1989. 2003), J Am Vet Med Assoc 228:559, Patrick L: Iodine: deficiency and therapeutic
Link KR, Rand JS: Changes in blood glucose 2006. considerations, Altern Med Rev 13(2):116,
concentration are associated with relatively Mooney CT: Radioactive iodine therapy for 2008.
rapid changes in circulating fructosamine feline hyperthyroidism: effciacy and Pedersen IB, etal.: Large differences in
concentrations in cats, J Feline Med Surg administration routes, J Small Anim Pract incidences of overt hyper- and hypothyroid-
10(6):583, 2008. 35:289, 1994. ism associated with a small difference in
Liu S, etal.: Hypertrophic cardiomyopathy and Mooney CT, etal.: Carbimazole therapy of iodine intake: a prospective comparative
hyperthyroidism in the cat, J Am Vet Med feline hyperthyroidism, J Small Anim Pract register-based population survey, J Clin
Assoc 185:52, 1984. 33:228, 1992. Endocrinol Metab 87:4462, 2002.
Peremans K, etal.: Interference of iohexol with Phillips DE, etal.: Cystic parathyroid and para- Sassnau R: Epidemiological investigation on the
radioiodine thyroid uptake in the hyperthy- thyroid lesions in cats, J Am Anim Hosp As- prevalence of feline hyperthyroidism in an
roid cat, J Feline Med Surg 10:460, 2008. soc 39:349, 2003. urban population in Germany, Tierarztliche
Peter HJ, etal.: Autonomy of growth and of Pignato A, etal.: Stability of methimazole in Praxis 35:375, 2006.
iodine metabolism in hyperthyroid feline poloxamer lecithin organogel to determine Scarlett JM, etal.: Feline hyperthyroidism: a
goiters transplanted onto nude mice, beyond-use date, Int J Pharm Compd descriptive and case-control study, Prev
J Clin Invest 80:491, 1987. 14:522525, 2010. Vet Med 6:295, 1988.
Peter HJ, etal.: Autonomous growth and func- Quinones M, etal.: Pharmacokinetics of ateno- Schaafsma IA, etal.: Effect of four sedative
tion of cultured feline thyroid follicles from lol in clinically normal cats. Am J Vet Res and anesthetic protocols on quantitative
cats with spontaneous hyperthyroidism, 57:1050, 1996. thyroid scintigraphy in euthyroid cats,
Thyroid 1:331, 1991. Ramspott S, etal.: Adrenal function in cats Am J Vet Res 67:1362, 2006.
Peterson ME, Aucoin DP: Comparison of the with hyperthyroidism, J Feline Med Surg Schlesinger DP, etal.: Use of breath hydrogen
disposition of carbimazole and methima- 14:262, 2012. measurement to evaluate orocecal transit
zole in clinically normal cats, Res Vet Sci Rand SJ, etal.: Acute stress hyperglycemia time in cats before and after treatment
54:351, 1993. in cats is associated with struggling and for hyperthyroidism, Can Vet J 57:89,
Peterson ME, Becker DV: Radioiodine treat- increased concentrations of lactate and 1993.
ment of 524 cats with hyperthyroidism, norepinephrine, J Vet Intern Med 16:123, Scott-Moncrieff JC: Thyroid disorders in the
J Am Vet Med Assoc 207:1422, 1995. 2002. geriatric veterinary patient, Vet Clin Small
Peterson ME, Gamble DA: Effect of nonthyroi- Randolph JF, etal.: Prothrombin, activated Anim 42:707, 2012.
dal disease on serum thyroxine concentra- partial thromboplastin, and proteins Shelton GD, etal.: Risk factors for ac-
tions in cats: 494 cases (1988), J Am Vet induced by vitamin K absence or antago- quired myasthenia gravis on cats: 105
Med Assoc 197:1203, 1990b. nists: clotting times in 20 hyperthyroid cases (1986-1998), J Am Vet Med Assoc
Peterson ME, etal.: Spontaneous hyperthyroid- cats before and after methimazole treat- 216:55, 2000.
ism in the cat abstract, Am Coll Vet Intern ment, J Vet Intern Med 14:56, 2000. Shi G-M, etal.: Influence of propylthiouracil
Med 108, 1979. Ranz D, etal.: Estimation of iodine status and methimazole pre-treatment on the
Peterson ME: Hyperthyroidism in cats: whats in cats, J Nutr 132(Suppl 2):1751S, outcome of Iodine-131 therapy in hyper-
causing this epidemic of thyroid disease 2002. thyroid patients with Graves disease, J Int
and how can we prevent it? J Feline Med Reed TP, etal.: Cystic ectopic lingual thyroid Med Res 37(2):576, 2009.
Surg 14:804, 2012. tissue in a male cat, J Am Vet Med Assoc Slater MR, etal.: Long-term health and
Peterson ME, etal.: Feline hyperthyroidism: 239:981, 2011. predictors of survival for hyperthyroid cats
pretreatment clinical and laboratory evalu- Refsal KR, etal.: Use of the triiodothyronine treated with iodine-131, J Vet Intern Med
ation of 131 cases, J Am Vet Med Assoc suppression test for diagnosis of hyperthy- 15:47, 2001.
103:103, 1983. roidism in ill cats that have a serum con- Sparkes AK, etal.: Thyroid function in the cat:
Peterson ME, etal.: Propylthiouracil-associated centration of iodothyronines within normal assessment by the TRH response test and
hemolytic anemia, thrombocytopenia, and range, J Am Vet Med Assoc 199:1594, the thyrotropin stimulation test, J Small
antinuclear antibodies in cats with hyper- 1991. Anim Pract 32:59, 1991.
thyroidism, J Am Vet Med Assoc 184:806, Reusch CE, Tomsa K: Serum fructosamine Stegeman JR, etal.: Use of recombinant
1984. concentration in cats with overt hyperthy- human thyroid-stimulating hormone for
Peterson ME, etal.: Serum thyroid hormone roidism, J Am Vet Med Assoc 215:1297, thyrotropin-stimulation testing of euthyroid
concentrations fluctuate in cats with 1999. cats, Am J Vet Res 64(2):149, 2003.
hyperthyroidism, J Vet Intern Med 1:142, Riensche MR, etal.: An investigation of predic- Stepien RL: Feline systemic hypertension:
1987. tors of renal insufficiency following treat- diagnosis and management, J Feline Med
Peterson ME, etal.: Methimazole treatment ment of hyperthyroidism in cats, J Feline Surg 13:35, 2011.
of 262 cats with hyperthyroidism, J Vet Med Surg 10:160, 2008. Sullivan P, etal.: Altered platelet indices in
Intern Med 2:150, 1988. Roti E, Vagenakis G: Effect of excess iodide: dogs with hypothyroidism and cats with
Peterson ME, etal.: Triiodothyronine (T3) sup- clinical aspects. In Braverman LE, Cooper hyperthyroidism, Am J Vet Res 54:2004,
pression test: an aid in the diagnosis of DS, editors: Werner and Ingbars the 1993.
mild hyperthyroidism in cats, J Vet Intern thyroid: a fundamental and clinical text, Swalec KM, Birchard SJ: Recurrence of hyper-
Med 4:233, 1990a. ed 10, Philadelphia PA, 2013, Lippincott thyroidism after thyroidectomy in cats,
Peterson ME, etal.: Use of the thyrotropin- Williams and Wilkins, p 242. J Am Anim Hosp Assoc 26:433, 1990.
releasing hormone (TRH) stimulation test Ruaux CG, etal.: Early biochemical and clini- Syme HM, Elliott J: The prevalence of hyper-
to diagnose mild hyperthyroidism in cats, cal responses to cobalamin supplementa- tension in hyperthyroid cats at diagnosis
J Vet Intern Med 8:279, 1994. tion in cats with signs of gastrointestinal and following treatment, J Vet Intern Med
Peterson ME, etal.: Measurement of serum disease and severe hypocobalaminemia, 17:754, 2003.
concentrations of free thyroxine, total J Vet Intern Med 19:155, 2005. Syme HM: Cardiovascular and renal manifesta-
thyroxine, and total triiodothyronine in Rutland BE, etal.: Optimal testing for thyroid tions of hyperthyroidism, Vet Clin North
cats with hyperthyroidism and cats with hormone concentration after treatment Am Small Anim Pract 37(4):723, 2007.
nonthyroidal disease, J Am Vet Med Assoc with methimazole in healthy and hyper- Thon AP, etal.: A prospective randomized
218:529, 2001. thyroid cats, J Vet Intern Med 23:1025, comparison of intravenous versus subcu-
Peterson ME, etal.: Accuracy of serum free 2009. taneous administration of radioiodine for
thyroxine concentrations determined by a Sabatino BR, etal.: Amino acid, iodine, treatment of feline hyperthyroidism: a study
new veterinary chemiluminescent immu- selenium, and coat color status among of 120 cats, Am J Vet Res 55:1734, 1994.
noassay in euthyroid and hyperthyroid cats hyperthyroid Siamese, and age-matched Thoday KL, Mooney CT: Historical, clinical and
[abstract]. Proceedings of the 21st ECVIM- control cats, J Vet Intern Med 27(5):1049, laboratory features of 126 hyperthyroid
CA Congress. Seville (Spain), September 2013. cats, Vet Rec 131:257, 1992.
8-10, 2011. Sartor LL, etal.: Efficacy and safety of trans- Tolbert MK, Ward CR: Feline Thyroid storm.
Ptervri E, etal.: Hyperphagia of hyperthy- dermal methimazole in the treatment of :Rapid recognition to improve patient
roidism: is neuropeptide Y involved? Regul cats with hyperthyroidism, J Vet Intern survival, Compend Contin Educ Vet,
Pept 131:103, 2005. Med 18:651, 2004. Vol.32(12), p.E2-E2, 2010.
|
Tolbert K, etal.: Dermoid cysts presenting as J Vet Intern Med 23:1031, 2009b. conditions 1996-2004, J Feline Med Surg
enlarged thyroid glands in a cat, J Feline Wakeling J, etal.: Subclinical hyperthyroidism 8:203, 2006.
Med Surg 11:717, 2009. in cats: a spontaneous model of subclini- Welches CD, etal.: Occurrence of problems
Tomsa K, etal.: Thyrotropin-releasing hormone cal toxic nodular goiter in humans? Thyroid after three techniques of bilateral thyroid-
stimulation test to assess thyroid function 17:12, 2007. ectomy in cats, Vet Surg 18:392, 1989.
in severely sick cats, J Vet Intern Med Wakeling J, etal.: Diagnosis of hyperthyroidism Wells AL, etal.: Use of percutaneous ethanol
15:89, 2001. in cats with mild chronic kidney disease, injection for treatment of bilateral hyper-
Trepanier LA: Medical management of J Small Anim Pract 49:287, 2008. plastic thyroid nodules in cats, J Am Vet
hyperthyroidism, Clin Tech Small Anim Wakeling J, etal.: Urinary iodide concentra- Med Assoc 218:1293, 2001.
Pract 21(1):22, 2006. tion in hyperthyroid cats, Am J Vet Res White HL, etal.: Effect of dietary soy on serum
Trepanier LA: Pharmacologic management of 70:741, 2009a. thyroid hormone concentrations in healthy
feline hyperthyroidism, Vet Clin North Am Wakeling J, etal.: Risk factors for feline adult cats, Am J Vet Res 65:586, 2004.
Small Anim Pract 37(4):775, 2007. hyperthyroidism in the UK, J Small Anim Williams GR: The skeletal system in thyro-
Trepanier LA, etal.: Efcacy and safety of Pract 50:406, 2009b. toxicosis. In Braverman LE, Cooper DS,
once versus twice daily administration of Wakeling J, etal.: Evaluation of predictors for editors: Werner and Ingbars the thyroid:
methimazole in cats with hyperthyroidism, the diagnosis of hyperthyroidism in cats, a fundamental and clinical text, ed 10,
J Am Vet Med Assoc 222:954, 2003. J Vet Intern Med 25:1057, 2011. Philadelphia, 2013, Lippincott Williams
Turrel JM, etal.: Radioactive iodine therapy in Wang W, etal.: Polyuria of thyrotoxicosis: and Wilkins, p 468.
cats with hyperthyroidism, J Am Vet Med downregulation of aquaporin water chan- Williams TL, etal.: Association of iatrogenic
Assoc 184:554, 1984. nels and increased solute excretion, hypothyroidism with azotemia and reduced
Turrel JM, etal.: Thyroid carcinoma causing Kidney Int 72(9):1088, 2007. survival time in cats treated for hyper-
hyperthyroidism in cats: 14 cases (1981- Ward CR: Feline thyroid storm, Vet Clin thyroidism, J Vet Intern Med 24:1086,
1986), J Am Vet Med Assoc 193:359, North Am Small Anim Pract 37(4):745, 2010a.
1988. 2007. Williams TL, etal.: Survival and the develop-
van der Kooij M, etal.: Effects of an iodine- Ward CR, etal.: Thyrotropin-stimulated DNA ment of azotemia after treatment of hy-
restricted food on client-owned cats with synthesis and thyroglobulin expression in perthyroid cats, J Vet Intern Med 24:863,
hyperthyroidism, J Feline Med Surg [Epub normal and hyperthyroid feline thyrocytes 2010b.
ahead of print], 2013. in monolayer culture, Thyroid 15:114, Williams TL, etal.: Calcium and phosphate
Vandermeulen E, etal.: A single method for 2005a. homeostasis in hyperthyroid cats:
evaluating 51chromium-ethylene diaminic Ward CR, etal.: Expression of inhibitory G associations with development of azotemia
tetraacetic acid clearance in normal proteins in adenomatous thyroid glands and survival time, J Small Anim Pract
and hyperthyroid cats, J Vet Intern Med obtained from hyperthyroid cats, Am J Vet 53(10):561, 2012.
22:266, 2008. Res 66:1478, 2005b. Williams TL, etal.: Investigation of the
van der Woerdt A, Peterson ME: Prevalence of Ward CR, etal.: Evaluation of activation of pathophysiological mechanism for altered
ocular abnormalities in cats with hyper- G proteins in response to thyroid stimulat- calcium homeostasis in hyperthyroid cats,
thyroidism, J Vet Intern Med 14(2):202, ing hormone in thyroid gland cells from J Small Anim Pract 54:367, 2013.
2000. euthyroid and hyperthyroid cats, Am J Vet Wisner ER, etal.: Ultrasonographic examina-
van Hoek I, etal.: Plasma clearance of Res 71:643, 2010. tion of the thyroid gland of hyperthyroid
exogenous creatinine, exo-iohexol, and Watson SG, etal.: Somatic mutations of the cats: comparison to 99mTc scintigraphy,
endo-iohexol in hyperthyroid cats before thyroid-stimulating hormone receptor gene Vet Radiol Ultrasound 35:53, 1994.
and after treatment with radioiodine, J Vet in feline hyperthyroidism: parallels with Wood ET, Kinlaw WB: Nondiabetic ketoacidosis
Intern Med 22:879, 2008a. human hyperthyroidism, J Endocrinol caused by severe hyperthyroidism, Thyroid
van Hoek I, etal.: Recombinant human thyro- 186(3):523, 2005. 14:628, 2004.
tropin administration enhances thyroid up- Wedekind KJ, etal.: The feline iodine require- Yu S, etal.: A low selenium diet increases
take of radioactive iodine in hyperthyroid ment is lower than the 2006 NRC recom- thyroxine and decreases 3,5,3 triiodothy-
cats, J Vet Intern Med 22:1340, 2008b. mended allowance, J Anim Physiol Anim ronine in the plasma of kittens, J Anim
van Hoek I, etal.: Short- and long-term follow- Nutr 94(4):527, 2010. Physiol and Anim Nutr 86:36, 2002.
up of glomerular and tubular renal markers Weichselbaum RC, etal.: Relationship between Yu S, etal.: Controlled level of dietary iodine
of kidney function in hyperthyroid cats selected echocardiographic varaibles be- normalizes serum total thyroxine concen-
after treatment with radioiodine, Domest fore and after radioiodine treatment in 91 trations in cats with naturally occurring
Anim Endocrinol 36(1):45, 2009a. hyperthyroid cats, Vet Radiol Ultrasound hyperthyroidism, J Vet Intern Med 25:683,
van Hoek I, etal.: Retinol binding protein in 46(6):506, 2005. 2011.
serum and urine of hyperthyroid cats be- Weiss DJ: Aplastic anemia in cats-clinicopath-
fore and after treatment with radioiodine, ologic features and associated disease
CHAPTER 5 Canine Thyroid Tumors and Hyperthyroidism
CHAPTER CONTENTS account for 30% to 50% of thyroid masses identied in stud-
Tumor Classification, 196 ies published by veterinary pathologists (Brodey and Kelly, 1968;
Thyroid Adenoma/Carcinoma, 196 Leav et al, 1976). These benign tumors tend to be small, non-
Pathogenesis of Thyroid Tumors, 197 invasive, clinically silent, non-palpable tumors that involve one
Iodine Deficiency, 197 thyroid lobe and are incidental ndings on necropsy. However,
Ionizing Radiation, 197 almost all clinically significant thyroid tumors in dogs are malig-
Oncogenes, 197 nant and classified as carcinomas of varying types (Withrow and
Lymphocytic Thyroiditis/Hypothyroidism, 198 MacEwen, 2012). Malignant thyroid tumors in dogs are usually
Benign Thyroid Tumors, 198 large fixed masses that are easily palpable. About two thirds of
Malignant Thyroid Tumors, 198 carcinomas are located in one lobe, whereas one third involve
Clinical Approach to Thyroid Tumors, 198 both lobes of the thyroid. Thyroid carcinomas are usually poorly
Signalment, 198 encapsulated and commonly extend into or around the trachea,
Clinical Signs, 199 esophagus, and muscles of the neck. Thyroid tumors are usually
Physical Examination, 199 highly vascular and may invade local blood vessels with resultant
Minimum Data Base, 199 hemorrhage (Slensky etal, 2003).
Radiography, 202
Ultrasonography, 202 THYROID ADENOMA/CARCINOMA
Computed Tomography and Magnetic Resonance Imaging, 202
Scintigraphy, 202 Most thyroid tumors are adenomas or carcinomas that arise from
Basal Serum Thyroxine Concentrations, 205 the epithelial cells that line the thyroid follicles. In dogs, most
Thyroid Biopsy, 206 small solid thyroid adenomas are characterized by either small
Differential Diagnosis, 206 or large irregular follicles containing varying amounts of colloid
Treatment of Thyroid Tumors, 206 (Leav etal, 1976). The cystic structures noted in some tumors are
Surgical Resection, 208 lined by dense brous capsules from which project fronds of uni-
Postsurgical Monitoring, 209 form cells arranged in follicular and/or compact cellular patterns.
External Beam Radiation Therapy, 209 Thyroid follicular carcinomas are usually well differentiated
Radioactive Iodine, 209 and the distinction between benign and malignant is made based
Chemotherapy, 210 primarily on whether there is evidence of capsular or vascular
Treatment of Hyperthyroidism, 210 invasion. Criteria such as cellular atypia and mitotic activity are
Prognosis in Canine Thyroid Neoplasia, 211 not reliable markers of malignancy in thyroid tumors (Leav etal,
1976). Thyroid tumors of follicular cell origin may be further
subclassied into follicular, compact (solid), papillary, compact-
Estimates for the prevalence of thyroid tumors in dogs range from follicular, or undifferentiated (anaplastic) carcinomas depend-
1% to 4% of all canine neoplasms (Brodey and Kelly, 1968; Birchard ing on their pattern of growth (Box 5-1). In addition, veterinary
and Roesel, 1981; Harari et al, 1986). Although thyroid adenomas oncologists use a clinical staging classication system initially
do occur in the dog, they are usually nonfunctional and too small to developed by the World Health Organization Owen 1980 (Table
be palpable; they are therefore rarely identified clinically. Conversely 5-1). Most canine thyroid carcinomas contain both follicular and
thyroid carcinomas are usually large, nonfunctional, invasive, and compact cellular patterns and are classied as compact follicu-
malignant. For this reason approximately 90% of clinically detect- lar (mixed follicular-compact cellular) carcinomas. Slightly less
able thyroid tumors in dogs are carcinomas. The thyroid gland is common are pure follicular carcinomas. A smaller percentage of
not normally palpable in dogs, and a palpable thyroid gland is there- thyroid tumors are pure compact carcinomas. Undifferentiated
fore highly likely to be due to a malignant thyroid tumor. (anaplastic) tumors are recognized in about 10% of dogs with
thyroid tumors, whereas papillary carcinomas are rare (Leav etal,
1976). Although histologic subtype has prognostic significance in
TUMOR CLASSIFICATION
human thyroid tumors, it does not appear to influence outcome
Although most thyroid tumors arise in the thyroid gland, tumors for well-differentiated tumors in dogs; however, high grade and
may also develop in vestigial thyroid tissue that may be present anaplastic thyroid tumors do have a less favorable outcome.
anywhere from the base of the tongue to the base of the heart In addition to tumors arising from follicular cells, medullary thy-
(see Chapter 3; Capen, 2007). Benign thyroid tumors (adenomas) roid carcinomas may arise from the parafollicular C cells, which are
196
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CHAPTER 5 Canine Thyroid Tumors and Hyperthyroidism 197
BOX 5-1 H
istologic Classification of Thyroid Tumors
in Dogs
Follicular adenoma
Compact follicular carcinoma
Follicular carcinoma
Compact (solid) carcinomas
Undifferentiated (anaplastic) carcinomas
Papillary carcinomas
Parafollicular (C-cell) carcinomas
FIGURE 5-1 Genetic events in thyroid tumorigenesis. Activating point mutations
of the RAS gene are found with a high frequency in follicular adenomas and
TABLE 5-1 C
LINICAL STAGING OF CANINE carcinomas and are considered to be an early event in follicular tumorigenesis.
THYROID TUMORS The PPAR-PAX8 rearrangement is found only in follicular tumors. Rearrange-
ments of transmembrane receptors with tyrosine kinase activity (RET/PTC TRK
T: Primary Tumor genes) and activating point mutations of the BRAF gene are found only in papil-
T0 No evidence of tumor lary thyroid carcinomas (PTCs). Inactivating point mutations of the P53 gene are
found only in poorly-differentiated and anaplastic thyroid carcinomas. Activa-
T1 Tumor < 2 cm maximum diameter: T1a, not fixed; T1b, fixed
tion of the cyclic adenosine monophosphate pathway by point mutation of the
T2 Tumor 2 to 5 cm maximum diameter: T2a, not fixed; T2b, fixed thyrotropin receptor (TSH-R) or the alpha subunit of the G protein genes leads
T3 Tumor > 5 cm maximum diameter: T3a, not fixed; T3b, fixed to the appearance of hyperfunctioning thyroid nodules. Gs, Stimulatory guanyl
N: Regional Lymph Nodes* nucleotide protein; PPAR, peroxisome proliferator-activated receptor. (Modified
from Schlumberger M-J, etal.: Nontoxic diffuse and nodular goiter and thyroid
N0 No evidence of RLN involvement neoplasia. In Melmed S, etal., editors: Williams textbook of endocrinology, ed 12,
N1 Ipsilateral RLN involved: N1a, not fixed; N1b, fixed Philadelphia, 2011, Elsevier/Saunders, p. 452.)
N2 Bilateral RLN involved: N2a, not fixed; N2b, fixed
M: Distant Metastasis Iodine Deficiency
M0 No evidence of distant metastasis Early epidemiologic studies suggested that thyroid cancer
M1 Distant metastasis detected in humans was more frequent in iodine-decient areas of the
world. Although some of the evidence for an association between
STAGE GROUPING T N M
iodine intake and thyroid cancer is conflicting, the evidence for
I T1a, b N0 M0 an association of iodine deficiency with an increased risk of
II T0 N1 M0 follicular thyroid carcinoma (FTC) is quite strong (Schneider
and Brenner, 2013). Studies in humans have demonstrated that
T1a, b N1 M0
when iodine supplementation is introduced into an iodine defi-
T2a, b N0 or N1a M0 cient area, the ratio of papillary to follicular carcinoma increases.
III Any T3 Any N M0 These studies and others have suggested that iodine deficiency
Any T Any N M0 plays a role in the pathogenesis of follicular carcinoma, possi-
bly due to prolonged TSH stimulation. Experimental data and
IV Any T Any N M1
clinical experience have neither conrmed nor denied the role of
Modified from Owen LN, editor: TNM classification of tumours in domestic animals, iodine in the pathogenesis of canine thyroid tumors.
Geneva, 1980, World Health Organization.
*The regional lymph nodes (RLNs) are the mandibular and the superficial cervical lymph
Ionizing Radiation
nodes.
Involvement implies histologic evidence of tumor invasion.
The relationship between ionizing radiation and thyroid cancer
is well established in humans. Radiation therapy of the cervi-
part of the amine precursor uptake decarboxylation (APUD) system cal region and ingestion of radioactive iodine isotopes following
and produce calcitonin (see Chapter 15). Although the tumors arise nuclear accidents (e.g., at Chernobyl, Ukraine, in 1986) are associ-
from different progenitor cells, the clinical presentation and treat- ated with increased risk of thyroid neoplasia especially in children
ment options for follicular and medullary carcinomas are similar. and adolescents. Thyroid neoplasia due to radiation exposure is
usually well-differentiated thyroid papillary or papillary-follicular
carcinomas (Schneider and Brenner, 2013). Ionizing radiation has
PATHOGENESIS OF THYROID TUMORS
also been demonstrated to be a cause of thyroid neoplasia in dogs
As with most neoplastic conditions in dogs, the exact cause of thyroid (Benjamin etal, 1997).
tumors is not known. Studies in humans have suggested an associa-
tion between thyroid neoplasia and (1) iodine deciency or excess, Oncogenes
(2) chronic excesses in thyroid-stimulating hormone (also known
as thyrotropin; TSH) secretion, (3) ionizing radiation, and (4) gene Genetic and epigenetic mutations have been shown to play a fun-
abnormalities and oncogene expression. In dogs the only known risk damental role in the pathogenesis of thyroid neoplasia in humans
factors for thyroid neoplasia are hypothyroidism due to thyroiditis (Suarez etal, 2000; Schlumberger, 2011; Xing, 2013; Fig. 5-1).
(Benjamin etal, 1996) and ionizing radiation (Benjamin etal, 1997). The progression of thyroid cancer occurs due to an accumulation
of these mutations, which result in dysregulated activity of cel- TABLE 5-2 F

REQUENCY OF METASTATIC
lular signaling pathways that promotes the malignant transforma- DISEASE IN DOGS WITH THYROID
tion of normal tissue. Loss of radioiodine avidity of thyroid cancer CARCINOMA*
promoted by the BRAF-V600E mutation is a cause of failure of
radioiodine treatment in humans. ANATOMIC SITE PERCENTAGE OF ANIMALS
Studies investigating the molecular mechanisms of canine thy-
roid carcinoma are limited. In one study a p53 mutation was Lung 77
detected in one of 23 cases of thyroid carcinoma (Devilee etal, Regional lymph node 51
1994). Trisomy 18 was the sole clonal cytogenetic abnormality Local incision 49
found in a canine thyroid adenoma (Reimann etal, 1996). Aneu-
Adrenal 14
ploidy is a common feature of canine thyroid carcinomas with
hypoploidy being most common (Verschueren etal, 1991). Kidney 14
In a study of samples collected from 23 dogs with FTC, dif- Heart muscle 9
ferential expression of 489 characterized transcripts were identi- Liver 6
fied by microarray analysis between tissues from dogs with FTC
and histologically normal thyroid tissue. Differentially expressed Intestine 6
genes belonged to several gene categories including those regulat- Skin 6
ing cell shape, cell adhesion, mitogen-activated protein (MAP) Brain 3
kinase activity, angiogenesis, and cell migration (Metivier et al,
Spleen 3
2012). The expression of osteopontin was significantly increased in
follicular carcinoma compared to normal thyroid tissue (Metivier Mesentery 3
etal, 2012). Osteopontin (secreted phosphoprotein I) is a promis- Diaphragm 3
ing marker for cancer detection and monitoring in humans and
appears to also have potential in dogs. From Leav I, etal.: Adenomas and carcinomas of the canine and feline thyroid, Am J
Pathol 83:61, 1976.
*Data is based on 35 autopsied dogs with metastatic carcinoma of the thyroid.
Lymphocytic Thyroiditis/Hypothyroidism Includes invasion of thyroidal, jugular, and maxillary veins; esophagus; trachea; larynx;
omohyoid muscle; and vertebra.

Hypothyroidism due to lymphocytic thyroiditis was associated
with the development of thyroid tumors in a colony of 276
Beagles that were allowed to live out their full life span without trachea, is unusual. Distant metastasis is common and is most fre-
treatment of their thyroid disease. Lymphocytic thyroiditis was quent in the pulmonary parenchyma and the regional lymph nodes
present in 26% of the beagles at the time of death and resulted in (retropharyngeal, mandibular, and superficial cervical). Lymphatic
hypothyroidism in 16% of dogs in the colony. Hypothyroid dogs drainage of the thyroid gland is primarily in the cranial direction,
had an increased risk for thyroid follicular neoplasia, including so lymph node enlargement is most likely to be detected cranial
follicular carcinoma. Fifty four percent of hypothyroid dogs had and medial to the primary tumor. Occasionally, both ipsilateral and
one or more thyroid neoplasms, whereas only 23% of euthyroid contralateral cervical lymph nodes may be involved. Other sites of
dogs had similar neoplasms (Benjamin etal, 1996). The authors metastasis include the jugular vein, liver, adrenal gland, kidneys,
hypothesized that chronic excess stimulation of residual follicu- liver, heart base, spleen, bone and bone marrow, prostate, brain,
lar epithelium by TSH was responsible for the strong association skeleton, and spinal cord (Bentley et al, 1990; Harmelin et al,
between thyroiditis, hypothyroidism, and follicular neoplasia. 1993; Theon etal, 2000; Tamura et al, 2007; Nadeau and Kitchell,
2011; Table 5-2). Approximately 30% to 40% of dogs with thy-
BENIGN THYROID TUMORS roid tumors have detectable distant metastases at time of diagnosis
(Harari etal, 1986; Sullivan etal, 1987). Necropsy studies suggest
The majority of benign canine thyroid tumors (adenomas) are that 60% to 80% of thyroid carcinomas had metastasized at the
small, focal lesions that are not usually detected during life. When time of death (Leav etal, 1976). In one study, the risk of metas-
they are diagnosed, they are usually incidental findings identified tasis was correlated with the size of the tumor. In tumors with a
by cervical ultrasonography. Much less commonly, a dog with a volume of 20 cm3 or less, 14% of dogs had metastasis; whereas in
benign tumor may have a palpable mass or have clinical signs of tumors more than 100 cm3, 100% had metastasized (Leav et al,
hyperthyroidism (Leav etal, 1976; Lawrence etal, 1991). Canine 1976; Table 5-3). The relation of size to metastasis likely reflects
thyroid adenomas are usually solitary masses and may be solid or that larger or more aggressive tumors have escaped clinical detec-
cystic. Adenomas are typically round or ovoid and measure a few tion longer, allowing for a greater probability of metastasis.
millimeters to several centimeters in diameter. They are usually
cream to reddish brown in color and may compress adjacent nor-
CLINICAL APPROACH TO THYROID TUMORS
mal thyroid tissue. Cystic adenomas can be turgid and lled with
an amber or blood-tinged fluid (Leav etal, 1976).
Signalment
MALIGNANT THYROID TUMORS Thyroid tumors in the dog typically develop in middle-aged and
older individuals. The most common age range for dogs with thy-
Carcinomas of the canine thyroid are usually large solid masses that roid tumors is 10 to 15 years (Wucherer etal, 2010). One study
commonly invade into adjacent structures. Extension of malignant conducted within a small colony of Beagles demonstrated an age-
thyroid tumors into or around the esophagus, trachea, cervical specic incidence of thyroid tumors of 1.1% per year in dogs 8 to
musculature, nerves, and thyroidal vessels is fairly common. How- 12 years of age and 4.0 % per year in dogs 12 to 15 years of age
ever, invasion into the lumen of structures, such as the esophagus or (Haley etal, 1989).
|
TABLE 5-3 F
REQUENCY OF THYROID TABLE 5-4 O
WNER-OBSERVED SIGNS IN 237
CARCINOMA METASTASIS IN DOGS WITH THYROID TUMORS
RELATION TO SIZE OF PRIMARY
TUMOR SIGN PERCENT OF DOGS
Visible mass in neck 78
TUMOR VOLUME NUMBER OF ANIMALS
Coughing 34
(CU CM) AUTOPSIED* PERCENT WITH METASTASIS
Rapid breathing (even at rest) 32
1-20 14 14
Dyspnea (difficulty breathing-distress) 28
21-100 19 74
Trouble swallowing (dysphagia) 23
101-500 9 100
Change in bark (dysphonia) 14
501-1000 4 100
Weight loss 14
1001-1500 3 100
Listlessness/depression 13
From Leav I, etal.: Adenomas and carcinomas of the canine and feline thyroid, Am J No observed signs 12
Pathol 83:61, 1976.
*Measurements were not recorded in eight cases. Vomiting/regurgitation 11
Anorexia/decrease in appetite 11
There is no obvious gender predilection for thyroid neoplasia in Polydipsia/polyuria 10
the dog (Harari etal, 1986; Wucherer etal, 2010). By contrast, the Hyperactivity 9
incidence of human thyroid cancer is about four times greater in Diarrhea 9
women than in men at most ages (Schneider and Brenner, 2013).
Increased appetite 3
Breeds thought to be at increased risk include Boxers, Beagles,
Golden Retrievers, and Siberian Huskies (Leav etal, 1976; Harari Facial edema 2
etal, 1986; Verschueren etal, 1992; Wucherer etal, 2010). Apparent cervical discomfort 2
Clinical Signs
Physical Examination
Dogs with thyroid tumors that are not hyperthyroid are usually
presented to veterinarians because of detection of a mid-cervical Most thyroid masses are rm, irregular in shape, and non-painful. Most
mass or because of clinical signs resulting from compression or thyroid tumors are located close to the typical location of the normal
invasion of surrounding tissues. The length of time between owner thyroid glands (at the level of or ventral to the larynx) and are not as
observation of the mass or clinical sign(s) and presentation for vet- ventral in location or as freely movable in the subcutaneous space as
erinary care is highly variable (days to years). in cats (Fig. 5-2). Usually, the thyroid mass is non-moveable and obvi-
Because most benign thyroid tumors are clinically silent, it is very ously well embedded into surrounding tissue. It is usually not possible
likely that a palpable thyroid mass is malignant, especially if it is not to palpate the interior or medial surface of the mass because of local
freely moveable. Most thyroid tumors are identified at or just below invasion. An irregular shape is not always diagnostic of carcinoma, but
the level of the larynx, but larger tumors may extend closer to the an immovable mass usually implies local invasion and should raise a
thoracic inlet. Thyroid tumors are usually firm and non-painful and strong suspicion for malignancy. Submandibular lymph nodes may be
may be unilateral or bilateral. There is no predisposition for either enlarged as a result of tumor spread or lymphatic obstruction. Horners
the right or left thyroid lobes. In a study of 44 dogs with thyroid syndrome may occur due to encroachment on the vagosympathetic
carcinoma, the lesion was unilateral in 64% of dogs and bilateral in trunk (Melin etal, 1996). Unfortunately palpation is not accurate for
36% of dogs (Leav etal, 1976). In one study, bilateral tumors were assessing extent of tumor invasion (Taeymans etal, 2013).
much more likely to metastasize than unilateral tumors (Theon In addition to the presence of a palpable cervical mass, physical
etal, 2000). It is usually not possible to determine whether bilateral examination of dogs with functional thyroid tumors may reveal
tumors have arisen independently in each gland or whether metas- evidence of weight loss, muscle atrophy, or cachexia (Fig 5-3).
tasis from one lobe to the other has occurred. Other clinical signs of Tachycardia with or without cardiac arrhythmias is common.
thyroid carcinoma include coughing, dyspnea or tachypnea, stridor Affected dogs may pant excessively and may be restless during the
or stertor, dysphagia, dysphonia, weight loss, listlessness/depres- physical examination. Panting, respiratory distress, and swallow-
sion, vomiting, regurgitation, anorexia, facial edema, and appar- ing difculties may be the result of thyrotoxicosis or the tumor
ent cervical pain or discomfort (Table 5-4). In one report, erosion mass compressing the trachea and/or esophagus.
of arterial blood vessels by a thyroid carcinoma resulted in acute
severe hemorrhage into the tumor and rapid enlargement of the Minimum Data Base
mass (Slensky etal, 2003). Dyspnea may be due to upper airway
compression or pulmonary metastasis. The minimum data base is rarely helpful in diagnosis or manage-
Additional clinical signs in dogs with functional thyroid tumors ment of dogs with thyroid tumors. Leukocytosis and a mild normo-
include signs of hyperthyroidism, such as weight loss, polydipsia, cytic normochromic anemia are identified in some dogs. One report
polyuria, polyphagia, vomiting, voluminous soft stools, increased identied increased liver enzymes in 7 of 21 dogs, none of which were
activity or nervousness, weakness, poor hair coat, heat intolerance, thyrotoxic (Harari et al, 1986). The cause of the enzyme increases
panting, and shivering (Melin etal, 1996; Simpson and McCown, was not determined. Hypercalcemia has also been identied in dogs
2009). The clinical signs of hyperthyroidism may precede identifica- with thyroid carcinoma and is attributed to a paraneoplastic condi-
tion of a cervical mass and be the reason for initial patient evaluation. tion (Lane and Wyatt, 2012). The urinalysis is usually unremarkable.
A
B
D C
FIGURE 5-2 A, Photograph of the shaved ventral cervical area of a dog with a large, obvious goiter (arrows).
B, Lateral view of the dog with a large thyroid tumor. The mass is delineated ventrally by the leash. C, Large
thyroid tumor, at surgery, displacing the trachea. D, The thyroid tumor following excision. (A, Courtesy of
Dr. Jane Turrel.)
A B
FIGURE 5-3 A, A cachectic 9-year-old German Shepherd dog with hyperthyroidism caused by a functioning thy-
roid carcinoma. B, A thin 12-year-old Labrador-mix with mild hyperthyroidism secondary to a functioning thyroid
carcinoma.
|
Cranial thyroid
artery
Parathyroid gland
Thyroid lobe
Caudal thyroid
artery
Common carotid
artery
A
B C
FIGURE 5-4 A, Ultrasound of the canine thyroid gland. For initial localization of the thyroid in long axis, the
transducer is positioned on the jugular groove with the imaging plane directed midway between the frontal and
parasagittal planes. The ipsilateral common carotid artery serves as an anatomic landmark. B, Ultrasound image
of the normal canine thyroid gland (sagittal view). The normal canine thyroid lobe appears as a uniformly moder-
ately echoic ellipsoid structure (arrows). A thin hyperechoic fascial sheath surrounds and defines the thyroid lobe.
C, Ultrasound image of the normal canine thyroid gland. In the short-axis view, the thyroid lobe (large solid arrows)
appears as a roughly triangular structure adjacent and medial to the common carotid artery (small solid arrows).
The esophagus can be seen when imaging the left thyroid lobe and appears as an irregularly-shaped structure
medial and dorsal to the thyroid lobe (open arrows). (Modified from Wisner ER, Nyland TG: Ultrasonography of the
thyroid and parathyroid glands, Vet Clin N Amer Sm Anim Pract 28:973, 1998. Used with permission.)
Radiography and lateral to the thyroid lobes) and echogenicity. Salivary glands,
for example, are typically uniformly hypoechoic with character-
Radiographs of the thorax should always be evaluated in a dog istic internal linear arborization that likely represents the salivary
with a thyroid mass because of the high risk of pulmonary metas- duct system (Wisner and Nyland, 1998).
tasis. In clinical studies, pulmonary metastasis is identified in 30%
to 40% of dogs, which contrasts with histopathologic studies that Ultrasound Appearance of a Thyroid Carcinoma
report metastasis in up to 80% of dogs at time of death (Leav Thyroid carcinomas are typically large nonhomogeneous masses
et al, 1976; Brodey and Kelly, 1968; Sullivan et al, 1987; Marks et that that may be poorly delineated (Fig. 5-5). The parenchyma
al, 1994; Carver et al, 1995; Turrel et al, 2006). This discrepancy may be complex, sometimes containing multiple cysts, or may
is likely due to the relative insensitivity of pulmonary radiographs have foci of mineralization. Thyroid carcinomas are highly vas-
for detection of pulmonary metastasis and due to progression of cular, and a large arterial vascular plexus is often distributed in
disease between diagnosis and time of death. Computed tomogra- and around these masses. The vascular plexus can be veried by
phy (CT) is more sensitive for detection of pulmonary metastasis pulsed or color-flow Doppler ultrasonographic evaluation. Some
than is radiography (Armbrust etal, 2012) and should be done dogs develop arteriovenous malformations within the tumor; such
prior to treatment planning. Neoplastic transformation of ectopic abnormalities can also develop after surgery (Wisner etal, 1994;
thyroid tissue may result in identification of a cranial mediastinal Wisner and Nyland, 1998). Invasion of surrounding structures
mass on pulmonary radiographs (Liptak etal, 2008). (e.g., fascial sheaths, esophagus, and cervical vasculature) may
Radiography of the neck may identify a space-occupying mass also be detected by ultrasound. Although a tentative diagnosis of
caudal to the pharynx, which may contain areas of soft tissue thyroid carcinoma can be made in most dogs based on localiza-
mineralization (Taeymans et al, 2007). A mass in this location tion to one or both thyroid lobes and qualitative ultrasonographic
may cause an uneven or distorted laryngeal space and compress characteristics, the diagnosis must be confirmed by ne needle
or displace the trachea ventrally. Esophageal displacement or aspiration or biopsy. Because of the vascularity of thyroid tumors,
focal dilatation may indicate esophageal invasion. Metastasis to needle aspiration or biopsy should be performed with ultrasound
the retropharyngeal lymph nodes may cause displacement of the guidance to aid in avoiding larger blood vessels. Both aspiration
pharynx, decreased size of the pharyngeal airspace, and loss of the and needle biopsy of a vascular tumor may only retrieve peripheral
fascial planes in the retropharyngeal area (Taeymans etal, 2007). blood. Ultrasound may also be used to help stage a carcinoma, by
Abdominal radiographs are usually normal, although dogs with documentation of tumor extent, invasiveness, and local metasta-
hepatic metastasis may have an irregular hepatic silhouette. sis; however, it is less accurate for tumor staging than are either CT
or magnetic resonance imaging (MRI) (Taeymans etal, 2013).
Ultrasonography
Equipment and Positioning Computed Tomography and Magnetic Resonance Imaging
Because the thyroid glands are very superficial structures, high fre- Both CT and MRI have been used for preoperative diagnosis and
quency transducers of at least 10 MHz that result in high spatial staging of thyroid tumors. On CT, thyroid tumors have lower
resolution should be used to examine the thyroid glands (Taeymans attenuation value than normal thyroid tissue. On MRI, thyroid
etal, 2007). The ventral cervical area should be carefully clipped carcinomas are hyperintense compared to surrounding muscula-
and the dog positioned as symmetrically as possible on a padded ture in both T1 and T2 imaging sequences (Taeymans etal, 2013).
V-top table in dorsal recumbency. Dogs usually do not require seda- Characteristics that are important to evaluate by either modality
tion for cervical ultrasound; however, dogs that have cervical masses are origin of the mass, mass size, tumor capsule disruption, local
large enough to produce upper airway obstruction are at risk for tissue invasion, lymphadenopathy, presence of metastatic disease,
developing severe dyspnea after being placed in dorsal recumbency. and parathyroid involvement in the tumor. Both CT and MRI are
It may be safer to examine such dogs under general anesthesia with superior to ultrasound for establishing extent of invasion of thy-
an endotracheal tube in place (Wisner and Nyland, 1998). roid tumors. CT is also useful for diagnosis and staging of thyroid
tumors arising in ectopic locations (Rossi etal, 2013)
Normal Anatomy, Imaging Planes, and Indications
The thyroid lobes are normally located just caudal to the arch of
Scintigraphy
the cricoid cartilage. Healthy medium-sized dogs have flattened
lobes measuring approximately 6.0 cm 1.5 0.5 cm (Fig. 5-4). Thyroid gland scintigraphy in dogs is usually performed following
The common carotid arteries are lateral and slightly supercial intravenous (IV) administration of 2 to 4 mCi of technetium-99m
to the thyroid lobes, serving as an important internal landmark. pertechnetate (99mTcO4). Gamma camera imaging of the cervical
Ultrasonography is a useful non-invasive and inexpensive screen-
ing tool for evaluation of cervical masses and is most useful for
determining whether a mass is arising from the thyroid gland BOX 5-2 D
ifferential Diagnosis for Cervical Masses
and if one or both the thyroid lobes are involved. The differen- in Dogs
tial diagnosis of disorders resulting in a cervical mass is shown
in Box 5-2. Thyroid adenoma/carcinoma (see Box 5-1)
When evaluating a dog with a neck mass of unknown etiol- Secondary metastasis to thyroid gland
ogy, the ultrasonographer should begin by attempting to identify Carotid body tumor
both thyroid lobes. This usually allows quick identication of thy- Cellulitis/abscess/granuloma
roid masses; however, large cervical masses can distort the normal Lymphadenopathy (submandibular, medial retropharyngeal, or cervical)
anatomy and make identication of the origin of the mass more Salivary gland inflammation or neoplasia
difcult. Lymph nodes and salivary masses are usually not difcult Other neoplasia (e.g., rhabdomyosarcoma, leiomyosarcoma)
to distinguish from thyroid lobes based on location (usually cranial
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region and thorax is typically performed 20 to 60 minutes after of isotope uptake in the thyroid gland is approximately equal to
isotope administration. The 99mTcO4 is trapped by cells that con- that of the parotid salivary tissue (thyroid-to-salivary ratio at 20
centrate iodine, including the thyroid gland, salivary glands, and minutes 1.12:1 0.13) (Daniel and Neelis, 2014). When a cervical
gastric mucosa. Usually, static left lateral, right lateral, ventral, and mass arises from the thyroid gland, the scintigraphic appearance
dorsal images are acquired (Marks etal, 1994). The appearance of of the thyroid gland is abnormal (Fig. 5-7). If the mass arises from
the normal canine thyroid glands is of paired spherical to ovoid other tissues or ectopic thyroid tissue, the scintigraphic appear-
lobes that have symmetrical isotope uptake (Fig. 5-6). The intensity ance of the thyroid glands should be normal, although concurrent
A B
FIGURE 5-5 A, Cervical ultrasound of encapsulated thyroid carcinoma in a dog. The thyroid is grossly enlarged,
and the thyroid parenchyma is heterogeneous, but the lesion appears to be well-marginated. B, Cervical ultrasound
of poorly-marginated thyroid carcinoma in a dog. The thyroid is enlarged, and thyroid parenchyma is heterogeneous
(arrowheads). In addition, lesion margins are poorly defined and appear to extend into surrounding tissues (ar-
rows). (Modified from Wisner ER, Nyland TG: Ultrasonography of the thyroid and parathyroid glands, Vet Clin N Amer
Sm Anim Pract 28:973, 1998. Used with permission.)
A B C
FIGURE 5-6 Thyroid technetium-99m (99mTc) scan lateral (A) and ventral (B) from a normal dog. The thyroids
of a normal dog (straight arrow) are approximately the size of normal salivary glands (curved arrow). C, Thyroid
technetium-99m (99mTc) scan from a dog that had one thyroid lobe removed. One normal cervical thyroid and one
ectopic anterior mediastinal thyroid (curved arrows) are identified. Salivary glands (open arrow) and stomach
(straight arrow) are also visualized because these tissues concentrate pertechnetate.
A B
C D
E
FIGURE 5-7 A to D, Thyroid technetium-99m (99mTc) scans from three dogs, each with thyroid tumors demonstrat-
ing well-circumscribed, homogeneous uptake. In the first two dogs (B and D) the thyroid tissue (straight arrow) and
salivary tissue (curved arrow) are defined by uptake of the radioactive contrast. The first dog has bilateral thyroid
follicular carcinomas, which were large (lateral [A] and dorsoventral [B] view) with partial ability to concentrate
the radioactive material. The dog was euthyroid. Lateral (C) and dorsoventral (D) views of a pertechnetate thyroid
scan from a dog with one large functioning thyroid follicular carcinoma (straight arrow), which concentrated the
pertechnetate to a much greater degree than the salivary glands (curved arrow). This dog was hyperthyroid. E, Scan
from a hypothyroid dog with a thyroid carcinoma.
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A B
C
FIGURE 5-8 Thyroid technetium-99m (99mTc) scans from two dogs, each with thyroid carcinomas demonstrating
poorly circumscribed, heterogeneous uptake in the cervical area (thyroid, straight arrows; salivary tissue, curved ar-
rows). Lateral (A) and dorsoventral (B) views of a pertechnetate thyroid scan from a dog with typical local invasion
of neoplastic cells throughout the cervical area. The dog was euthyroid despite the appearance of the thyroid on the
scan. C, Thyroid technetium-99m (99mTc) scan (ventral view) from a dog with a thyroid tumor causing hyperthyroidism.
hypothyroidism can complicate interpretation of the scintigraphic the metastatic cells retain the ability to trap iodine (see Fig. 5-9;
image. The appearance of canine thyroid carcinoma on scintigraphy Fig. 5-10). Even if the metastatic cells concentrate iodine, detec-
varies both in intensity and size. With a unilateral nonfunctional tion of metastasis may be less sensitive when the primary tumor is
tumor, one thyroid lobe will appear abnormal and the other is usu- concentrating (stealing) the majority of the radioactive isotope. In
ally normal in appearance. Some tumors have homogenous dif- this situation, the metastatic lesion may only be visible after surgi-
fuse uptake of isotope, and some have diffuse but irregular uptake cal resection of the primary tumor. Scintigraphy can also identify
of isotope (see Fig. 5-7; Figs. 5-8, and 5-9). Poorly differentiated ectopic sites of thyroid tissue (neoplastic or normal) (see Fig. 5-6).
tumors have decreased uptake of isotope and are referred to as cold Because of these variables, dogs with normal thoracic radiographs
nodules. Some tumors have well-defined borders, whereas others may have scintigraphic evidence of metastasis, whereas some dogs
have ill-defined or spiculated borders (see Fig. 5-8). Studies suggest with pulmonary metastasis visible on radiography may not have
that tumors with homogenous uptake and well-defined margins scintigraphic evidence of metastasis (see Figs. 5-9 and 5-10).
are more likely to be surgically resectable than those with hetero-
geneous uptake and poorly circumscribed margins (Marks et al, Basal Serum Thyroxine Concentrations
1994). There is poor correlation between histologic type and scin-
tigraphic pattern of thyroid tumors; however, tumors with homog- The majority of dogs (55% to 60%) with thyroid tumors are
enous diffuse uptake are more likely to be functional tumors that euthyroid. Because most thyroid tumors are unilateral and more
cause hyperthyroidism (Marks etal, 1994). Whether or not pulmo- than 80% of both thyroid glands must be destroyed before clinical
nary metastasis is detected on scintigraphy depends upon whether hypothyroidism results, hypothyroidism is rarely caused by thyroid
A B
FIGURE 5-9Radiographic (A) and scintigraphic (B) views of a dog with thyroid adenocarcinoma and pulmonary
metastases. The location of the thorax is shown by dotted lines on the scintigraphic image.
tumors. In one study, 3 of 29 dogs with thyroid tumors were diag- can often be made based on the presence of neuroendocrine cells
nosed as hypothyroid; however, interpretation of thyroid hormone in the sample, but definitive diagnosis requires histopathology.
concentrations in dogs with thyroid tumors is complicated by the Samples for histopathology can be obtained by needle biopsy,
effects of concurrent illness on serum thyroid hormone concentra- incisional biopsy, or excisional biopsy. Large-bore needle biopsy is
tions and because hypothyroidism may be a pre-existing condition avoided when possible because of the risk of hemorrhage and the
(Benjamin et al, 1996). Hyperthyroidism has been reported in difficulty in obtaining a diagnostic biopsy sample. Incisional or
10% to 20% of dogs with thyroid tumors (Verschueren etal, 1992; excisional biopsy is preferred, and the choice is dependent upon
Marks etal, 1994; Rijnberk, 1996; Fig 5-11). Although functioning the characteristics of the mass. If surgical excision is possible, then
thyroid adenomas have been described, most tumors are malignant histopathology should be obtained at this time.
(Lawrence et al, 1991; Marks et al, 1994). A functional thyroid
tumor is the only naturally occurring cause of hyperthyroidism in Differential Diagnosis
the dog other than consumption of diets containing thyroid tissue.
Lymphocytic thyroiditis causing anti-triiodothyronine (T3) and Common differential diagnoses for ventral cervical masses in
thyroxine (T4) antibodies can result in the presence of spuriously dogs include thyroid adenoma or carcinoma, and submandibular,
increased thyroid hormone concentrations (see Chapter 3); but in medial retropharyngeal, or cervical lymphadenomegaly. Lymph-
dogs with thyroiditis, clinical signs of hyperthyroidism are absent adenomegaly may result from tonsillar squamous cell carcinoma
and there is no palpable cervical mass. or spread from other tumors or non-tumor disorders that origi-
nate in the oral cavity or the neck such as cellulitis, abscess or
Thyroid Biopsy granuloma or salivary gland tumor or inflammation (Wisner etal,
1994; see Box 5-2).
Thyroid tumors are highly vascular, and hemorrhage associated
with any biopsy procedure is common. The hemorrhagic poten-
TREATMENT OF THYROID TUMORS
tial of these masses precludes routine large-bore needle biopsy
procedures. Rather, we recommend ne-needle aspiration, using Treatment modalities used for treatment of thyroid tumors include
a 21- to 23-gauge needle ideally performed with ultrasound guid- surgical resection, radiation therapy, radioactive iodine treatment,
ance. This technique is usually adequate for differentiating thyroid and chemotherapy. In some cases, multiple treatment modalities
tumors from abscesses, cysts, salivary mucoceles, or lymph nodes. are used together or sequentially. The choice of treatment depends
The number of neoplastic cells obtained by needle aspiration upon a number of factors including size, vascularity, and mobil-
is variable, and the sample is almost always contaminated with ity of the tumor, functional status of the tumor, severity of clini-
blood. Because neoplastic follicular cells are fragile, many isolated cal signs particularly with regard to respiratory signs, presence
nuclei may be seen, but intact cells found in clusters resemble or absence of metastatic disease, and financial constraints of the
glandular structures. A presumptive diagnosis of thyroid neoplasia owner.
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E
FIGURE 5-10Radiographic (A) view of the thorax and scintiscan images of the thorax (B) and cervical region (C)
in a dog with an undifferentiated thyroid carcinoma and pulmonary metastases. A metastatic nodule can be seen
on the radiograph (arrow) but not on the thoracic scintiscan. The location of the thorax is shown by dotted lines
on the scintigraphic image. The primary tumor had minimal pertechnetate uptake (arrows). The dorsoventral area
(D), cervical area, and lateral thoracic area (E) on scintiscan of a hyperthyroid dog with a thyroid carcinoma and
pulmonary metastases that concentrate pertechnetate. In this scan (D and E), radioactive uptake is white. The
salivary tissue (straight arrow), stomach (open arrowheads), cervical thyroid (closed arrowheads), and pulmonary
metastases (curved arrows) can be visualized.
5010
60
50
% of dogs with thyroid carcinoma
3010
40
30
20
A
105
10
0
<1.0 g/dL 1.5-3.5 g/dL >5.0 g/dL
(hypothyroid) (euthyroid) (hyperthyroid)
FIGURE 5-11 Percentage of dogs with thyroid tumors detected clinically that
were hypothyroid, euthyroid, or hyperthyroid as determined from clinical signs
and serum thyroxine (T4) concentrations.
Surgical Resection
Surgical resection is most appropriate for the 25% to 50% of dogs
with freely moveable non-invasive thyroid tumors (Carver et al,
1995; Klein etal, 1995). Mobility can be determined by deep palpa-
tion ideally under general anesthesia; however, ultrasound and ide-
ally advanced imaging with CT or MR should be considered prior
to surgery, because attachment to deep structures may be either
under- or overestimated. Scintigraphy can also be useful to evalu-
ate the suitability of a thyroid tumor for surgical resection. Surgical B
thyroidectomy is most appropriate for well-circumscribed tumors
that have uniform uptake of pertechnetate (Fig. 5-12). Surgery is FIGURE 5-12Lateral (A) and dorsoventral (B) scintiscans from a dog with hy-
less likely to be a good choice in dogs with tumors that are poorly perthyroidism secondary to a solitary functioning thyroid follicular adenoma. Note
circumscribed or demonstrate patchy uptake of pertechnetate. the parotid salivary glands (curved arrows) and the thyroid adenoma (straight
In one study of 82 dogs with thyroid carcinoma, 24% of dogs arrows). Surgical excision resulted in complete resolution of all clinical signs.
met the criteria of a freely moveable tumor with no evidence of Five-year follow-up was unremarkable.
metastasis. In this study, tumor resection resulted in long-term
local control of the tumor with a median survival of more than
36 months and low incidence of metastasis (Klein et al, 1995). merits of adjunctive therapy (even in dogs with evidence of capsu-
Metastasis was documented after surgery in only 2 of 20 dogs, lar or vascular invasion or tumor thrombi) appear questionable in
suggesting that local tumor control had an impact on subsequent dogs with mobile tumors. Marginal resection at a plane adjacent
development of metastasis. Age, breed, and tumor histologic type to the tumor capsule does not appear to increase risk of recurrence
were not associated with survival time (Klein et al, 1995). In a and is associated with less postoperative complications than more
more recent study of 15 dogs with discrete mobile bilateral thy- aggressive approaches. Complications (e.g., hypocalcemia due to
roid carcinomas that underwent thyroidectomy, median survival hypoparathyroidism and hypothyroidism) do occur but are eas-
time was 38 months and de novo metastasis was not detected in ily treated and do not impact long-term survival. Approximately
any dog (Tuohy etal, 2012). In this study, tumor assessment of 50% of dogs require long-term calcitriol supplementation (Tuohy
tumor mobility was based on documentation of mobility more etal, 2012). If bilateral tumors are resected, iatrogenic hypopara-
than 1 cm in all planes by physical examination. Interestingly, in thyroidism is likely and should be treated with calcitriol and cal-
both of these studies, survival was not influenced by tumor histo- cium supplementation. In a study of 15 dogs undergoing bilateral
pathologic type, presence of bilateral thyroid gland involvement, thyroid tumor resection, 13 dogs required short-term calcitriol
tumor size, tumor volume, presence of gross tumor thrombi, histo- and calcium supplementation, 7 dogs required long-term cal-
pathologic evidence of capsular or vascular invasion, preservation citriol treatment, and 8 dogs required long-term thyroid hormone
of parathyroid glands, or use of adjuvant chemotherapy. Indeed supplementation (Tuohy et al, 2012). Interestingly dogs treated
many dogs with evidence of gross tumor thrombi at surgery had for hypothyroidism had longer survival than those that were not
long-term survival with no evidence of local tumor recurrence or supplemented. This could suggest that chronic stimulation by
metastasis, independent of whether adjuvant chemotherapy was TSH led to more aggressive tumor growth (Tuohy etal, 2012).
administered. Based on these two studies, it appears that surgical Other potential surgical complications associated with resection
resection alone may result in long-term survival for well-encap- of thyroid tumors include laryngeal paralysis, hemorrhage, and
sulated mobile thyroid tumors in dogs without metastasis; the need for short-term tracheostomy.
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In dogs with invasive thyroid tumors, complete excision is usu- et al, 2000). The thyroid tumors in this study were categorized as
ally not possible, and surgical thyroidectomy alone will not result compact-cellular (nine dogs), follicular (eight dogs), and follicular-
in a cure. In these cases the pros and cons of surgical debulking compact-cellular (eight dogs) adenocarcinomas. The dogs ranged in
should be carefully considered. In some dogs, careful tumor deb- age from 3 to 18 years (median, 10 years), and various breeds were
ulking may relieve clinical signs due to compression of the trachea represented. All had been referred for irradiation because the tumors
and esophagus; however, further adjunctive therapy is required in were considered unresectable on the basis of clinical ndings, such
such cases. Unless surgical debulking is required to relieve clinical as palpation, ultrasonography, and radiography (11 dogs), or after
signs due to cervical compression, consideration should be given unsuccessful attempts at resection (14 dogs). Of the 25 dogs, 6 had
to use of other non-surgical treatments (e.g., radiation therapy or been diagnosed as hypothyroid, whereas the other 19 dogs were
chemotherapy) as the primary mode of treatment. If debulking euthyroid. Imaging studies with sodium 99mTcO4 were performed
surgery is attempted, heroic attempts to remove all malignant tis- in 20 of the 25 dogs. Scintigraphy demonstrated that seven dogs had
sue are not recommended, because they result in a higher incidence unilateral lobe involvement, eight had bilateral lobe involvement,
of treatment related complications, such as hemorrhage, hypopara- and ve had ventral midline masses with invasion of the laryngeal
thyroidism, laryngeal paralysis, and the need for tracheostomy. cartilages. A well-circumscribed area of homogeneous uptake was
Median survival times ranging from 8 to 20 months have been observed in seven dogs. Poorly-circumscribed areas of uptake were
reported in studies that did not select for tumors that were freely demonstrated in 13 dogs; 9 of these dogs had diffuse uptake through-
mobile (Harari etal, 1986; Carver etal, 1995; Kent etal, 2002). out their masses, and 4 of them had mixed areas of no uptake together
with some areas of uptake. Each dog in this study was treated with
48 Gy administered in 12 fractions on a 3-day-per-week schedule.
Postsurgical Monitoring
The radiation treatment field included the primary thyroid tumor
In dogs undergoing bilateral tumor removal, serum calcium con- and the regional lymph nodes. Mean progression free survival time
centrations should be measured at least once daily for 5 to 7 days defined as time from completion of radiation therapy to local tumor
after surgery. Although most dogs with iatrogenic hypoparathy- recurrence or death from unrelated causes in the 25 dogs was 45
roidism develop hypocalcemia within the first week following months. The progression free survival rate was 80% at 1 year and
surgery, in some cases development of clinical hypocalcemia may 72% at 3 years. Age, sex, tumor histologic type, tumor stage, gland
be delayed by several weeks or precipitated by factors (e.g., che- involvement (right versus left), and pattern of 99mTcO4 uptake were
motherapy) that decrease oral calcium intake (Tuohy etal, 2012). not associated with response to therapy. Interestingly the tumors were
Vitamin D and calcium therapy should be instituted if clinical slow to regress, with time to maximum tumor size reduction ranging
evidence of hypoparathyroidism (hypocalcemia) is present (see from 8 to 22 months. For this reason, radiation therapy is not a good
Chapter 16). Serum T4 concentration should initially be assessed 4 choice when there is clinical evidence of cervical compression by the
weeks after surgery and, depending on clinical signs, replacement tumor. Patterns of failure were identied in 14 of the 25 dogs (11 did
therapy implemented accordingly. not have evidence of failure despite being followed for more than 4
It is important that the excised tumor is examined histopatho- years). In three dogs, local tumor progression was the rst cause of
logically. If the tumor is a benign adenoma and the resection is failure. In four dogs with no clinical evidence of tumor progression,
complete, there is an excellent chance of a surgical cure and adjunc- metastasis was the rst cause of failure. Pulmonary metastases were
tive treatment is unnecessary; however, follow up examinations detected in ve dogs, one of which also had bone metastasis. In two
should be scheduled 3, 6, and 12 months after surgery because dogs, metastases were found in abdominal viscera. Dogs with bilat-
of the possibility of missing a diagnosis of carcinoma. If the mass eral tumors had 16 times the risk for metastasis. Previous attempts at
is malignant but excision is apparently complete with clean mar- resection did not affect risk of metastasis (Theon etal, 2000). Adverse
gins reported by the pathologist, close follow up including physical effects of radiation therapy develop during or after therapy and are
examination, thoracic radiographs, cervical and abdominal ultra- usually reversible. Dry or moist desquamation of the skin, alopecia,
sonography, and possibly scintigraphy should be performed every and mucositis usually occur within the treatment field and are man-
3 months for the first year and every 6 months thereafter. If exci- aged by supportive care and pain management. Hypothyroidism
sion is not complete or there are tumor cells identified in the edges was reported in 2 of 19 hypothyroid dogs, 13 and 29 months after
of the surgical eld, adjunctive therapy with radiation or chemo- radiation, respectively, and 1 of these 2 dogs also developed hypo-
therapy should be considered. Although it makes intuitive sense parathyroidism. This latent period for induction of hypothyroidism
that radiation and chemotherapy are appropriate for treatment of was longer than that previously reported for one dog that was treated
dogs with histologic evidence of residual disease, the merits of such with both radiation and surgery (Kramer etal, 1994). Whether there
treatment for prolonging survival or quality of life have not yet was an association between radiation therapy and development of
been proven in dogs with thyroid carcinoma (Tuohy etal, 2012). hypothyroidism is unknown. In humans, subclinical hypothyroidism
is a common complication following irradiation of the head and neck
regions when the thyroid gland is in the radiation eld (Nishiyama
External Beam Radiation Therapy
etal, 1996). The benefits of postoperative irradiation of the surgical
Unfortunately there are limited prospective studies evaluating the effi- field in dogs with incompletely resected tumors or when tumor cells
cacy of radiation therapy for treatment of thyroid tumors in dogs. In are present in the surgical margins have not been conclusively dem-
a study of 13 dogs with thyroid tumors treated with palliative external onstrated. Nevertheless, it is a good idea to consult with a radiation
beam irradiation, the mean survival time was 96 weeks (range: 6 to oncologist to obtain the latest data regarding treatment of malignant
247 weeks; Brearley and Hayes, 1999). Another retrospective study thyroid tumors.
of eight dogs with thyroid carcinoma treated with external beam irra-
diation resulted in a median survival time of more than 2 years (Pack Radioactive Iodine
etal, 2001). The largest study of thyroid tumors treated with curative
intent external beam radiation therapy included 25 dogs with his- Until recently, radioactive iodine treatment has been reserved for
tologically conrmed thyroid carcinoma without metastasis (Theon dogs with functional thyroid tumors. Recent studies however have
reported good results after treatment of dogs with thyroid tumors In our clinical experience, the best outcome has been observed
that concentrated either 99mTcO4 or radioactive iodine indepen- in dogs that have homogenous uptake of isotope on scintig-
dent of the functional status of the tumor. In two retrospective raphy. This is likely because in dogs with heterogeneous iso-
studies that included a total of 82 dogs with thyroid carcinoma tope uptake, there are clones of cells with differing sensitivity
that were treated with either radioactive iodine alone or before or to radioactive iodine. Careful case selection is recommended
after incomplete thyroidectomy, median survival in dogs without when considering radioactive iodine treatment so that the last
documented metastasis ranged from 28 to 34 months (Worth etal, few weeks of a patients life are not spent in a radioactive iodine
2005; Turrel etal, 2006). Criteria for treatment with radioactive isolation facility.
iodine included thyroid tumors that were surgically non-resectable
or incompletely resected and documentation of 99mTcO4 uptake Chemotherapy
by the tumor. In one study, iodine-deficient diets were fed for
3 weeks prior to radioactive iodine treatment for those dogs that A number of different chemotherapeutic agents have been used
were not functionally hyperthyroid in an attempt to increase iodine with varying degrees of success in dogs with thyroid carcinoma.
uptake by the tumor (Turrel etal, 2006). The dose of iodine-131 Chemotherapeutic drugs are typically used in an adjunctive role for
(131I) was determined empirically and ranged from 11 to 191 mCi management of thyroid tumors. Chemotherapy is indicated when
(4.2 mCi/kg). Factors taken into consideration when determin- total surgical removal or destruction with external beam radia-
ing the treatment dose included body weight, technetium uptake, tion is not successful, when distant metastatic lesions have been
tumor size, and total T4 concentration. The number of treatments identied, or when local invasion or metastasis is suspected. Drugs
administered ranged from one to three per dog. The only adverse that have been evaluated either alone or in combination for treat-
effects documented were myelosuppression in three dogs in one ment of thyroid carcinoma include doxorubicin, cisplatin, carbo-
study and hypothyroidism, which was documented and treated platin, mitoxantrone, toceranib phosphate, and chlorambucil.
with T4 supplementation in the majority of dogs in both studies. The median survival time in 10 dogs with thyroid tumors treated
All of the dogs that developed myelosuppression were treated with with doxorubicin alone was 37 weeks (Jeglum and Whereat, 1983).
doses of radioactive iodine above the median dose of 4 mCi/Kg, In 13 dogs with thyroid carcinoma treated with cisplatin, one dog
but other dogs treated with similar doses did not show myelosup- had complete remission, six dogs had partial remissions, and three
pression. It is possible that transient myelosuppression unassoci- dogs had stable disease; however, the median survival time was
ated with clinical consequences occurred in other dogs in these only 98 days (Fineman et al, 1998). In a retrospective study of
studies. dogs treated with either surgery alone or surgery in combination
These studies together suggest that radioactive iodine has a place with chemotherapy using various combinations of carboplatin, cis-
in treatment of thyroid carcinomas that are not amenable to com- platin, gemcitabine, and doxorubicin, there was no difference in
plete surgical resection that concentrate iodine based on scintig- survival between the two groups, but the power to detect a differ-
raphy. Studies in humans suggest that assessment of tumor iodine ence was small (Nadeau and Kitchell, 2011). In a prospective trial
trapping by either iodine-123 (123I) or tracer 131I may be superior evaluating metronomic chlorambucil chemotherapy in dogs with
to assessment based on uptake of 99mTcO4, because iodine is not naturally occurring cancer, complete remission was documented in
only trapped by follicular cells but also incorporated into thyro- one dog with thyroid carcinoma and the duration of response was
globulin within follicular cells and thus is retained longer by the 114 weeks (Leach etal, 2011). The dosage of chlorambucil used in
tumor. Although the superiority of radioactive iodine for detec- this study was 4 mg/m2 daily. In a phase one study of the tyrosine
tion of metastatic lesions was demonstrated in a dog with thyroid kinase inhibitor toceranib phosphate, clinical benefit was reported
carcinoma, the higher cost of 123I and the long-half-life of 131I in 12 of 15 dogs with thyroid carcinoma (four with partial remis-
usually preclude their routine use for scintigraphy. In human stud- sion; eight with stable disease; London etal, 2012). Most of the
ies, administration of recombinant human thyrotropin (rhTSH) dogs in the study had been previously treated with a combination
prior to radioactive iodine treatment in patients with differenti- of surgery, other chemotherapeutic agents, and radiation therapy. A
ated thyroid cancer enhances iodine uptake and decreases whole primary tumor was present in 13 dogs, and 10 dogs had metastatic
body radiation exposure. Preliminary studies of TSH administra- disease. Dogs were treated with toceranib at a median dosage of 2.75
tion in dogs with thyroid carcinoma showed no significant effect mg/kg every 2 to 3 days. The median duration of treatment for the
on iodine uptake (Campos et al, 2012). Whether this was due 12 dogs that experienced a clinical benefit was 24 weeks. Studies
to the protocol used in the study (TSH dose, route of adminis- have demonstrated expression of potential targets for tyrosine kinase
tration, timing of injection) or due to differences in concentra- inhibitors, such as vascular endothelial growth factor receptor 2,
tion and affinity of TSH receptors in canine thyroid tumors is platelet-derived growth factor receptors alpha and beta, and stem
unknown. Advantages of radioactive iodine treatment include the cell factor receptor in canine thyroid carcinoma (Urie etal, 2012).
low risk of adverse effects and the potential to effectively simul- We urge consultation with a medical oncologist if chemotherapy
taneously treat both the primary tumor and metastatic lesions. is being considered.
The major disadvantage is the need for prolonged isolation after
radioactive iodine treatment and the limited number of facilities TREATMENT OF HYPERTHYROIDISM
that are licensed to administer the high doses required for treat-
ment of canine tumors. Approximately 10% to 20% of dogs with thyroid neoplasia are
There are many unanswered questions that remain with thyrotoxic based on measurement of serum T4 concentration
regard to radioactive iodine treatment in dogs with malignant (Marks et al, 1994; Nadeau and Kitchell, 2011). Most dogs with
thyroid neoplasia. It is still unknown whether there is an advan- thyrotoxicosis have clinical signs, such as weight loss, polyuria,
tage to surgical debulking or surgical resection either before or polydipsia, and polyphagia, but some are asymptomatic (Marks et
after radioactive iodine treatment. The ideal method for dose al, 1994; Kent et al, 2002; Worth etal, 2005; Tuohy etal, 2012).
determination to maximize the therapeutic effect and minimize In most cases, the clinical signs are mild and resolve with surgical
the risk of myelosuppression also still needs to be established. thyroidectomy. In dogs with functional thyroid carcinoma that is
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not amenable to surgical resection, therapeutic options are lim- factors in determining prognosis. In one older study, bilateral tumors
ited. Oral anti-thyroid drugs are not recommended as the primary were much more likely to metastasize than unilateral tumors (Theon
mode of therapy, because they are not cytotoxic. However, we etal, 2000); however in a more recent study of 15 dogs with discrete
have used anti-thyroid drugs as palliative therapy to control clini- mobile bilateral thyroid carcinomas that underwent thyroidectomy,
cal signs of hyperthyroidism in untreated dogs or those that had median survival time was 38 months and de novo metastasis was
recurrence of hyperthyroidism after surgery or treatment with 131I not detected in any dog (Tuohy etal, 2012).
or chemotherapy. Our therapeutic approach is similar to that used The influence of thyroid tumor size on prognosis is less clear.
in hyperthyroid catsthat is, 2.5 to 5 mg of methimazole twice One study, Leav, etal. (1976), demonstrated that the likelihood
daily with subsequent increases in the dosage as needed to control of metastasis was related to tumor size and that smaller tumors
clinical signs and maintain serum T4 concentrations between 1.0 carried a better prognosis. Other studies have not confirmed these
and 3.0 g/dL. In rare cases, we have managed hyperthyroidism in findings however (Klein et al, 1995; Theon et al, 2000; Kent et al,
dogs with thyroid neoplasia for prolonged periods of time with 2002; Tuohy et al, 2012).
this approach. Because thyroid neoplasms may retain a stimula- In general, the prognosis for dogs with malignant thyroid
tory response to TSH, it is important to avoid hypothyroidism in tumors is guarded to poor. Although long survival times have
dogs treated with methimazole. been reported for many dogs with mobile thyroid tumors follow-
ing surgical resection, in most other cases the long-term prognosis
is poor due to the invasiveness and high metastatic rate of most
PROGNOSIS IN CANINE THYROID NEOPLASIA
tumors. In humans, suppression of TSH by thyroid hormone
In dogs managed surgically, the degree of mobility of the tumor, supplementation is routinely recommended because differentiated
histomorphologic criteria of malignancy (including the presence thyroid tumors retain their response to TSH, and TSH is there-
of capsular and vascular invasion, degree of cellular and nuclear fore a potential growth factor for thyroid neoplasia. This approach
polymorphism, and frequency of mitoses), and tumor stage are has not been routinely advocated in euthyroid dogs with thyroid
the only identified prognostic factors (Klein et al, 1995; Theon et neoplasia. Interestingly in one study of dogs with bilateral thyroid
al, 2000; Turrel et al, 2006; Tuohy et al, 2012). Histologic tumor tumors, dogs that received thyroid supplementation after bilateral
classication, breed, gender, age, serum thyroid hormone concen- thyroidectomy had longer survival times (Tuohy etal, 2012). This
trations, and serum thyroglobulin concentrations are not signicant approach requires further study in dogs.
REFERENCES
Armbrust LJ, etal.: Comparison of three-view Carver JR, etal.: A comparison of medullary Kramer RW, etal.: Hypothyroidism in a dog
thoracic radiography and computed tomog- thyroid carcinoma and thyroid adenocarci- after surgery and radiation therapy for a
raphy for detection of pulmonary nodules noma in dogs: a retrospective study of 38 functional thyroid adenocarcinoma, Vet
in dogs with neoplasia, J Am Vet Med cases, Vet Surg 24:315, 1995. Radiol Ultrasound 35:132, 1994.
Assoc 240:1088, 2012. Daniel GB, Neelis DA: Thyroid scintigraphy Lane AE, Wyatt KM: Paraneoplastic hypercal-
Benjamin SA, etal.: Associations between lym- in veterinary medicine, Semin Nucl Med cemia in a dog with thyroid carcinoma,
phocytic thyroiditis, hypothyroidism, and 44:24, 2014. Can Vet J 53:1101, 2012.
thyroid neoplasia in beagles, Vet Pathol Devilee P, etal.: The canine p53 gene is Lawrence D, etal.: Hyperthyroidism associated
33:486, 1996. subject to somatic mutations in thyroid with a thyroid adenoma in a dog, J Am Vet
Benjamin SA, etal.: Non-neoplastic and carcinoma, Anticancer Res 14:2039, Med Assoc 199:81, 1991.
neoplastic thyroid disease in beagles 1994. Leach TN, etal.: Prospective trial of metro-
irradiated during prenatal and postnatal Fineman LS, etal.: Cisplatin chemotherapy for nomic chlorambucil chemotherapy in dogs
development, Radiat Res 147:422, 1997. treatment of thyroid carcinoma in dogs: with naturally occurring cancer, Vet Comp
Bentley JF, etal.: Metastatic thyroid solid- 13 cases, J Am Vet Med Assoc 34:109, Oncol 10:102, 2011.
follicular carcinoma in the cervical portion 1998. Leav I, etal.: Adenomas and carcinomas of
of the spine of a dog, J Am Vet Med Assoc Haley PJ, etal.: Thyroid neoplasms in a the canine and feline thyroid, Am J Pathol
197:1498, 1990. colony of beagle dogs, Vet Pathol 26:438, 83:61, 1976.
Birchard SJ, Roesel OF: Neoplasia of the 1989. Liptak JM, etal.: Cranial mediastinal carcino-
thyroid gland in the dog: a retrospective Harari J, etal.: Clinical and pathologic features mas in nine dogs, Vet Comp Oncol 6:19,
study of 16 cases, J Am Anim Hosp Assoc of thyroid tumors in 26 dogs, J Am Vet 2008.
17:369, 1981. Med Assoc 188:1160, 1986. London C, etal.: Preliminary evidence for
Brearley MJ, Hayes AM: Hypofractionated Harmelin A, etal.: Canine medullary thyroid biologic activity of toceranib phosphate
radiation therapy for invasive thyroid car- carcinoma with unusual distant metasta- (Palladia) in solid tumors, Vet Comp Oncol
cinoma in dogs: a retrospective analysis of ses, J Vet Diagn Invest 5:284, 10:194, 2012.
survival, J Am Anim Pract 40:206, 1999. 1993. Marks SL, etal.: 99mTc-pertechnetate imaging
Brodey RS, Kelly DF: Thyroid neoplasms in the Jeglum KA, Whereat A: Chemotherapy of of thyroid tumors in dogs: 29 cases (1980-
dog: a clinicopathologic study of 57 cases, canine thyroid carcinoma, Compend Contin 1992), J Am Vet Med Assoc 204:756,
Cancer 22:406, 1968. Educ Pract Vet 5:96, 1983. 1994.
Campos M, etal.: Effect of recombinant hu- Kent MS, etal.: Computer assisted image Melin C, etal.: Horners syndrome associated
man thyrotropin on the uptake of radio- analysis of neovascularization in thyroid with a functional thyroid carcinoma in a
active iodine (123I) in dogs with thyroid neoplasms from dogs, Am J Vet Res dog, J Small Anim Pract 37:591, 1996.
tumors, PLoS One 7:e50344, 2012. 63:363, 2002. Metivier KS, etal.: Gene expression profiling
Capen CC: The endocrine glands. In Maxie Klein MK, etal.: Treatment of thyroid carci- demonstrates differential expression of
MG, editor: Jubb, Kennedy, and Palmers noma in dogs by surgical resection alone: osteopontin in follicular thyroid carcinomas
pathology of domestic animals, ed 5, St 20 cases (1981-1989), J Am Vet Med compared to normal thyroid tissue in dogs,
Louis, 2007, Saunders/Elsevier, p 379. Assoc 206:1007, 1995. Vet Comp Oncol 12:181, 2014.
Nadeau M-E, Kitchell BE: Evaluation of the Simpson AC, McCown JL: Systemic hyperten- Urie BK, etal.: Evaluation of expression and
use of chemotherapy and other prognostic sion in a dog with a functional thyroid function of vascular endothelial growth
variables for surgically excised canine gland adenocarcinoma, J Am Vet Med factor receptor 2, platelet derived growth
thyroid carcinoma with and without metas- Assoc 235:1474, 2009. factor receptors-alpha and -beta, KIT, and
tasis, Can Vet J 52:994, 2011. Slensky KA, etal.: Acute severe hemorrhage RET in canine apocrine gland anal sac
Nishiyama K, etal.: A prospective analysis of secondary to arterial invasion in a dog with adenocarcinoma and thyroid carcinoma,
subacute thyroid dysfunction after neck thyroid carcinoma, J Am Vet Med Assoc BMC Vet Res 8:67, 2012.
irradiation, Int J Radiat Oncol Biol Phys 223:649, 2003. Verschueren CP, etal.: Flow-cytometric DNA
34:439, 1996. Suarez HG, etal.: Molecular basis of epithelial ploidy analysis in primary and metastatic
Owen LN: Clinical stages (TNM) of canine thyroid tumorigenesis, C R Acad Sci III canine thyroid carcinoma, Anticancer Res
tumours of the thyroid gland. In Owen LN, 323:519, 2000. 11:1755, 1991.
editor: TNM classication of tumours in Sullivan M, etal.: Thyroid tumours in the dog, Verschueren CP, etal.: Thyrotropin receptors in
domestic animals, Geneva, 1980, World J Small Anim Pract 28:505, 1987. normal and neoplastic (primary and meta-
Health Organization. Taeymans O, etal.: Thyroid imaging in the dog: static) canine thyroid tissue, J Endocrinol
Pack LA, etal.: Denitive radiation therapy for current status and future directions, J Vet 132:461, 1992.
inltrative thyroid carcinoma in dogs, Vet Intern Med 21:673, 2007. Wisner ER, Nyland TG: Ultrasonography of the
Radiol Ultrasound 42:471, 2001. Taeymans O, etal.: Comparison between clini- thyroid and parathyroid glands, Vet Clin N
Reimann N, etal.: Trisomy 18 in a canine cal, ultrasound, CT, MRI, and pathology Amer Sm Anim Pract 28:973, 1998.
thyroid adenoma, Cancer Genet Cytogenet findings in dogs presented for suspected Wisner ER, etal.: Ultrasonographic evaluation
90:154, 1996. thyroid carcinoma, Vet Radiol Ultrasound of cervical masses in the dog and cat, Vet
Rijnberk A: Thyroids. In Rijnberk A, editor: 54:61, 2013. Radiol Ultrasound 35:310, 1994.
Clinical endocrinology of dogs and cats, Tamura S, etal.: Multiple metastases of thyroid Withrow SJ, MacEwen EG: Tumors of the
Dordrecht, The Netherlands, 1996, Kluwer cancer in the cranium and pituitary gland in endocrine system. In Withrow SJ, etal.,
Academic, p 35. two dogs, J Small Anim Pract 48:237, 2007. editors: Withrow and MacEwens small
Rossi F, etal.: Computed tomographic features Theon AP, etal.: Prognostic factors and pat- animal clinical oncology, ed 5, St Louis,
of basihyoid ectopic thyroid carcinoma in terns of treatment failure in dogs with un- 2012, Saunders/Elsevier, p 423.
dogs, Vet Radiol Ultrasound 54:575, 2013. resectable differentiated thyroid carcino- Worth AJ, etal.: Radioiodide (131I) therapy for
Schlumberger MJ, etal.: Nontoxic diffuse and mas treated with megavoltage irradiation, the treatment of canine thyroid carcinoma,
nodular goiter and thyroid neoplasia. In J Am Vet Med Assoc 216:1775, 2000. Aust Vet J 83:208, 2005.
Melmed S, etal., editors: Williams text- Tuohy JL, etal.: Outcome following simultane- Wucherer KL, etal.: Thyroid cancer in dogs: an
book of endocrinology, ed 12, Philadel- ous bilateral thyroid lobectomy for treat- update based on 638 cases (1995-2005),
phia, 2011, Elsevier/Saunders. ment of thyroid gland carcinoma in dogs: J Am Anim Hosp Assoc 46:249, 2010.
Schneider AB, Brenner AV: Carcinomas of 15 cases (1994-2010), J Am Vet Med Xing M: Molecular pathogenesis and mecha-
follicular epithelium: epidemiology and Assoc 241:95, 2012. nisms of thyroid cancer, Nat Rev Cancer
pathogenesis. In Braverman LE, Cooper Turrel JM, etal.: Sodium iodide I131 treatment 13:184, 2013.
DS, editors: The thyroid: a fundamental of dogs with non-resectable thyroid tumors:
and clinical text, ed 10, Philadelphia, 39 cases (1990-2003), J Am Vet Med As-
2013, Saunders/Elsevier, p 665. soc 229:542, 2006.
SECTION 3 THE ENDOCRINE PANCREAS
CHAPTER 6 Canine Diabetes Mellitus

Richard W. Nelson
CHAPTER CONTENTS Single Blood Glucose Determination, 234

Classification and Etiology, 214 Serum Fructosamine Concentration, 234
Type 1 Diabetes Mellitus, 214 Blood Glycated Hemoglobin Concentration, 235
Type 2 Diabetes Mellitus, 214 Urine Glucose Monitoring, 236
Other Specific Types and Diabetic Remission, 215 Serial Blood Glucose Curve, 236
Pathophysiology, 216 Role of Serum Fructosamine in Aggressive, Excitable, or Stressed Dogs, 241
Signalment, 217 Insulin Therapy During Surgery, 242
Anamnesis, 217 Complications of Insulin Therapy, 242
Physical Examination, 218 Hypoglycemia, 242
Establishing the Diagnosis of Diabetes Mellitus, 218 Recurrence or Persistence of Clinical Signs, 243
Clinical Pathologic Abnormalities, 219 Insulin Underdosage, 244
Overview of Patient Evaluation, 219 Insulin Overdosing and Glucose Counterregulation (Somogyi Response), 244
Complete Blood Count, 220 Short Duration of Insulin Effect, 245
Serum Biochemical Panel, 220 Prolonged Duration of Insulin Effect, 246
Urinalysis, 220 Inadequate Insulin Absorption, 246
Serum Cholesterol and Triglyceride Concentrations, 220 Circulating Insulin-Binding Antibodies, 246
Pancreatic Enzymes, 220 Allergic Reactions to Insulin, 247
Serum Thyroxine Concentration, 221 Concurrent Disorders Causing Insulin Resistance, 248
Serum Insulin Concentration, 221 Chronic Complications of Diabetes Mellitus, 251
Treatment of Nonketotic Diabetes Mellitus, 221 Cataracts, 251
Goals of Therapy, 221 Lens-Induced Uveitis, 252
Insulin Therapy, 222 Corneal Ulceration, 252
Dietary Therapy, 229 Diabetic Retinopathy, 252
Exercise, 231 Diabetic Neuropathy, 252
Oral Hypoglycemic Drugs, 231 Diabetic Nephropathy, 253
Identification and Control of Concurrent Problems, 232 Systemic Hypertension, 253
Techniques for Monitoring Diabetic Control, 233 Prognosis, 253
History and Physical Examination, 234
The endocrine pancreas is composed of the islets of Langerhans, in either an excess or a deciency of the respective hormone in
which are dispersed as small islands in a sea of exocrine- the circulation. In the dog and cat, the most common disorder
secreting acinar cells. Four distinct cell types have been identied of the endocrine pancreas is diabetes mellitus, which results from
within these islets on the basis of staining properties and mor- an absolute or relative insulin deciency due to decient insulin
phologyalpha cells, which secrete glucagon; beta cells, which secretion by the beta cells, often in conjunction with concurrent
secrete insulin; delta cells, which secrete somatostatin; and pancre- insulin resistance. The incidence of diabetes mellitus in dogs varies
atic polypeptide (PP) cells, which secrete pancreatic polypeptide. between countries. The largest study, to date, involved 180,000
Dysfunction involving any of these cell lines ultimately results insured dogs in Sweden and researchers estimated the cumulative
213
214 SECTION 3 THE ENDOCRINE PANCREAS
proportion of dogs that would develop diabetes mellitus before TABLE 6-1 P
OTENTIAL FACTORS INVOLVED
12 years of age at 1.2% (Fall etal, 2007). Davison, etal., (2005) IN THE ETIOPATHOGENESIS OF
reported from a UK insurance cohort a diabetes mellitus preva- DIABETES MELLITUS IN DOGS
lence of 0.32%; Guptill, etal., (2003) reported a hospital preva- AND CATS
lence of 0.64% in the United States; and Fracassi, etal., (2004)
reported an Italian hospital prevalence of 1.33%. DOG CAT
Genetics Islet amyloidosis
CLASSIFICATION AND ETIOLOGY Immune-mediated insulitis Obesity
Pancreatitis Pancreatitis
Type 1 Diabetes Mellitus Obesity Concurrent hormonal disease
The most common clinically recognized form of diabetes melli- Concurrent hormonal disease Hyperadrenocorticism
tus in the dog resembles type 1 diabetes mellitus in humans. In Hyperadrenocorticism Acromegaly
our hospital, virtually all dogs are insulin dependent at the time Diestrus-induced excess of growth Hyperthyroidism
diabetes mellitus is diagnosed. Type 1 diabetes mellitus is char- hormone Drugs
acterized by permanent hypoinsulinemia, essentially no increase Hypothyroidism Progestagens
in endogenous serum insulin concentration following administra- Drugs Glucocorticoids
tion of an insulin secretagogue (e.g., glucose, glucagon), and an Glucocorticoids Infection
absolute necessity for exogenous insulin to maintain control of Progestagens Concurrent illness
glycemia, avoid ketoacidosis, and survive. The etiology of type 1 Infection Renal insufficiency
diabetes has been poorly characterized in dogs but is undoubt- Concurrent illness Cardiac disease
edly multifactorial (Table 6-1). Genetic predispositions have been Renal insufficiency Hyperlipidemia (?)
suggested by familial associations, pedigree analysis of Keeshonds, Cardiac disease Genetics (Burmese cat)
and genomic studies aimed at identification of susceptibility and Hyperlipidemia Immune-mediated insulitis (?)
protective major histocompatibility complex haplotypes in canine
diabetes (Hess et al, 2000a; Guptill et al, 2003; Fracassi et al,
2004; Kennedy etal, 2006; Fall etal, 2007; Table 6-2). A number diabetes more closely resembles latent autoimmune diabetes of
of genes linked with susceptibility to diabetes mellitus in humans adult humans (Andersen et al, 2010). Seemingly, autoimmune
are associated with an increased risk of diabetes mellitus in dogs mechanisms in conjunction with genetic and environmental fac-
(Catchpole etal, 2013). Diabetes mellitus in dogs has been associ- tors, insulin-antagonistic diseases and drugs, obesity, and pan-
ated with major histocompatibility complex class II genes, dog creatitis all play a potential role in the initiation and progression
leucocyte antigen (DLA), with similar haplotypes and genotypes of diabetes in dogs. The end result is a loss of beta-cell function,
being identified in the most susceptible breeds. A region contain- hypoinsulinemia, impaired transport of circulating glucose into
ing a variable number of tandem repeats and several polymor- most cells, and accelerated hepatic gluconeogenesis and glycoge-
phisms have been identified in the canine insulin gene with some nolysis. The subsequent development of hyperglycemia and gly-
alleles associated with susceptibility or resistance to diabetes in a cosuria causes polyuria, polydipsia, polyphagia, and weight loss.
breed-specific manner (Catchpole etal, 2013). Ketoacidosis develops as the production of ketone bodies increases
Common histologic abnormalities in dogs include a reduction to compensate for the underutilization of blood glucose. Loss of
in the number and size of pancreatic islets, a decrease in the num- beta-cell function is irreversible in dogs with type 1 diabetes, and
ber of beta cells within islets, and beta cell vacuolation and degen- lifelong insulin therapy is mandatory to maintain glycemic con-
eration. An extreme form of the disease may occur in juvenile trol of the diabetic state.
dogs, represented by an absolute deficiency of beta cells and pan- Clinically, pancreatitis is often seen in dogs with diabetes mel-
creatic islet hypoplasia or aplasia. Less severe changes of pancreatic litus and has been suggested as a cause of diabetes after destruction
islets and beta cells may predispose the adult dog to diabetes mel- of the islets (Watson etal, 2010; Bostrom etal, 2013). However,
litus after it has been exposed to environmental factors, such as the incidence of histologically identifiable pancreatitis in diabetic
insulin-antagonistic diseases and drugs, obesity, and pancreatitis. dogs is only 30% to 40%. Although destruction of beta cells sec-
Environmental factors may induce beta cell degeneration second- ondary to pancreatitis is an obvious explanation for the develop-
ary to chronic insulin resistance or may cause release of beta cell ment of hypoinsulinemic diabetes mellitus, other perhaps more
proteins, which induce immune-mediated destruction of the islets complex factors are involved in the development of diabetes mel-
(Nerup, 1994). litus in dogs without obvious exocrine pancreatic lesions.
Studies suggest an immune-mediated component in the devel-
opment of diabetes in some dogs. Immune-mediated insulitis
Type 2 Diabetes Mellitus
has been described and antibodies directed against islet cells,
insulin, proinsulin, intracellular glutamic acid decarboxylase 65 In humans, type 2 diabetes mellitus is an obesity-associated dis-
(GAD65), and insulinoma antigen 2 (IA-2) have been identified ease characterized by insulin resistance, loss of beta cell function
in diabetic dogs (Hoenig and Dawe, 1992; Alejandro etal, 1988; with or without loss of beta cell mass, impaired insulin secretion,
Davison etal, 2003a; 2008a; 2011; these are autoantibodies that and defects in insulin receptor function and insulin receptor-
are also identified in humans with type 1 diabetes. The presence signal transduction (Porte, 1990; Haataja etal, 2008; Poitout and
of circulating autoantibodies against insulin, proinsulin, GAD65, Robertson, 2008). Humans with type 2 diabetes are typically not
and IA-2 usually precede the development of hyperglycemia or dependent on insulin to control the disease. Control of the diabetic
clinical signs in humans with type 1 diabetes. A similar sequence state is usually possible through diet, exercise, and oral hypoglyce-
of events may also occur in dogs, although the onset of type 1 dia- mic drugshence the term non-insulin-dependent diabetes mellitus
betes mellitus occurs in young humans versus older dogs. Canine (NIDDM). However, insulin treatment may be necessary in some
|
CHAPTER 6 Canine Diabetes Mellitus 215
TABLE 6-2 B
REEDS WITH A SIGNIFICANTLY type 2 diabetics if insulin resistance, beta cell dysfunction, or both
(P < 0.05) DECREASED OR are severe. As such, humans with type 2 diabetes may be non-
INCREASED RISK OF DIABETES insulin dependent or insulin dependent depending on the severity
MELLITUS (VETERINARY MEDICAL of abnormalities affiliated with the disease. Obesity-associated dia-
DATA BASE, 1970-1999) betes also occurs in the cat and resembles type 2 diabetes mellitus
in humans (Appleton etal, 2001; see Chapter 7).
BREED CASES CONTROL ODDS RATIO Obesity-induced insulin resistance has been documented in
dogs, but progression to type 2 diabetes does not occur (Verkest
Australian Terrier 37 1 32.10
etal, 2012). Studies suggest that at least some of the etiopatho-
Standard Schnauzer 105 19 4.78 genic mechanisms responsible for development of obesity-
Samoyed 175 45 3.36 associated type 2 diabetes in humans and cats do not occur in
Miniature Schnauzer 624 172 3.13 dogs. For example, beta-cell sensitivity to changes in glucose
and the first-phase of the insulin secretory response by the beta
Fox Terrier 91 26 3.02 cell are lost in humans and cats but not in dogs despite years of
Keeshond 57 20 2.45 obesity-induced insulin resistance and compensatory hyperinsu-
Bichon Frise 50 18 2.40 linemia (Verkest etal, 2011a). In humans, loss of the first phase
of insulin secretion is an important early marker of beta-cell fail-
Finnish Spitz 35 13 2.32
ure (Gerich, 2002).
Cairn Terrier 67 28 2.07 Islet amyloid polypeptide (amylin) forms toxic intracellular
Miniature Poodle 737 356 1.79 oligomers in beta cells in humans and cats but not in dogs, and
Siberian Husky 80 45 1.53 amylin does not aggregate extracellularly as histologically vis-
ible amyloid in the pancreatic islets in dogs (Haataja etal, 2008;
Toy Poodle 208 139 1.29 Scheuner and Kaufman, 2008). Circulating concentrations of the
Mixed breed 1860 1609 1.00 (Reference) adipocyte-secreted hormone adiponectin are decreased in obese
Beagle 73 94 0.67 humans and low adiponectin concentrations predict progres-
English Setter 30 42 0.61
sion to type 2 diabetes in humans (Li etal, 2009). In contrast,
circulating adiponectin concentrations were not lower in chroni-
Labrador Retriever 246 364 0.58 cally obese dogs compared with lean dogs, and adiponectin was
Basset Hound 33 50 0.57 not associated with insulin sensitivity in obese dogs (Verkest etal,
Dalmatian 28 45 0.53 2011b). Although adiponectin does not appear to play a role in
the development of canine obesity-associated insulin resistance,
Doberman Pinscher 109 182 0.51
adiponectin receptors are present on pancreatic beta-cells, and adi-
Irish Setter 68 121 0.48 ponectin has been shown to protect beta-cells against fatty acid-
Boston Terrier 31 68 0.39 induced apoptosis (Kharroubi etal, 2003; Rakatzi etal, 2004).
Shih Tzu 31 69 0.38
Brittany 28 64 0.37 Other Specific Types and Diabetic Remission
Old English Sheepdog 14 35 0.35 The occurrence of diabetic remission after initiating insulin ther-
Norwegian Elkhound 10 26 0.33 apy is uncommon in the dog despite the presence of circulating
C-peptide in a small percentage of dogs at the time diabetes is
Golden Retriever 108 294 0.31
diagnosed (Montgomery et al, 1996; Fall et al, 2008a; German
English Pointer 11 36 0.26 etal, 2009; Pppl etal, 2013; Fig. 6-1). C-peptide is the connect-
Cocker Spaniel 90 307 0.25 ing peptide found in the proinsulin molecule, is secreted into the
Great Dane 15 54 0.24 circulation in equimolar concentrations as insulin, and is a marker
for functional beta cells. The presence of circulating C-peptide sug-
Bulldog 7 26 0.23 gests the presence of functional beta cells. Unfortunately, in our
Shetland Sheepdog 29 107 0.23 experience, these dogs have required insulin to control hypergly-
Collie 25 109 0.19 cemia, suggesting the increased C-peptide concentrations in these
Pekingese 14 66 0.18
dogs is most likely due to residual beta-cell function in dogs with
type 1 diabetes mellitus rather than a severe form of type 2 diabetes.
German Shepherd 70 365 0.16 A transient increase in endogenous insulin secretion and reduced
Airedale Terrier 8 45 0.15 insulin dosage requirements may occur during the initial weeks to
German Short-Hair Pointer 6 37 0.14 months after the diagnosis of type 1 diabetes mellitus in humans;
this is called the honeymoon period (Rossetti etal, 1990). A syndrome
Boxer 7 82 0.07
similar to the honeymoon period occurs in some newly diagnosed
The Veterinary Medical Data Base comprises medical records of 24 veterinary schools in diabetic dogs and is characterized by excellent glycemic control using
the United States and Canada. dosages of insulin considerably less than what would be expected
From Guptill L, etal.: Time trends and risk factors for diabetes mellitus in dogs: analysis (i.e., less than 0.2 U/kg per injection; Fig. 6-2). Presumably, the exis-
of veterinary medical data base records (1970-1999), Vet J 165:240, 2003. Breeds were tence of residual beta-cell function when diabetes is diagnosed (see
included in the analysis if there were at least 25 cases or 25 controls. Fig. 6-1) and possible correction of glucose toxicity (see Chapter 7)
after initiating insulin therapy accounts for the initial ease of treat-
ing the diabetic state. Continuing progressive destruction of residual
functioning beta cells results in worsening loss of endogenous insulin
secretory capacity and a greater need for exogenous insulin to control (Fall etal, 2010). Bitches that have undergone diabetic remission
the diabetes. As a result, glycemic control becomes more difficult to following diestrus have a high likelihood of developing permanent
maintain, and insulin dosages increase to more commonly required insulin dependent diabetes during the next estrus. For this reason,
amounts (0.5 to 1.0 U/kg per injection). This increase in insulin all female dogs that develop diabetes during diestrus should be
requirements usually occurs within the first 6 months of treatment. spayed as soon as possible after diabetes is diagnosed.
When diabetic remission occurs, it is usually in older female A similar sequence of events may occur with the administra-
dogs that are diagnosed with diabetes during diestrus or preg- tion of insulin antagonistic drugs, most notably glucocorticoids
nancy when serum progesterone and growth hormone concentra- and progestogens, and other insulin resistant disorders such as
tions are increased (Fall etal, 2008b; 2010; Mared etal, 2012). hyperadrenocorticism. Resolution of hyperglycemia is most likely
Diabetic remission may also occur in spayed females with ovarian to occur when the hyperglycemia is mild (less than 160 mg/dL; 9
remnant syndrome and in diestrual bitches with concurrent pyo- mmol/L) and has not yet resulted in glycosuria. Dogs that become
metra (Pppl etal, 2013). Documenting increased baseline serum euglycemic after correction of insulin resistance presumably do
insulin concentration supports the presence of functional beta cells not have a normal population of functional beta cells, should be
and concurrent insulin resistance. Documenting an increase in considered subclinical diabetics, and may or may not progress to
serum progesterone concentration (2 ng/mL or higher) confirms an insulin-requiring diabetic state in the future. Treatment with
the presence of functional corpora lutea and diestrus, regardless of insulin antagonistic drugs should be avoided, and disorders caus-
the presence or absence of owner observed signs of a recent heat ing insulin resistance should be treated quickly to prevent overt
cycle. These dogs presumably have an adequate mass of functional diabetes mellitus from developing.
beta cells to maintain carbohydrate tolerance when insulin resis-
tance is not present (e.g., during anestrus), but they are unable to PATHOPHYSIOLOGY
secrete an adequate amount of insulin to maintain euglycemia in
the presence of insulin antagonism (Fall etal, 2008a). Early rec- Diabetes mellitus results from a relative or absolute deciency of
ognition and correction of the insulin resistance (e.g., following insulin secretion by the beta cells. Insulin deciency, in turn, causes
ovariohysterectomy) while some beta-cell function is still present decreased tissue utilization of glucose, amino acids, and fatty acids,
may reestablish euglycemia without the long-term need for insu- accelerated hepatic glycogenolysis and gluconeogenesis, and accu-
lin therapy (Fig. 6-3). Failure to quickly correct insulin resistance mulation of glucose in the circulation, causing hyperglycemia. As
often results in progressive loss of beta cells and a greater likeli- the blood glucose concentration increases, the ability of the renal
hood for permanent insulin dependency to control hyperglycemia tubular cells to resorb glucose from the glomerular ultraltrate
C
2.4
Plasma C-peptide concentration (pM/mL)
S S A 2.0
S S *
S S
B
* *
C-Peptide
1.4
Insulin
S S A
S S 1.0

S S 0.8
B
0.6 * *
*
*
0.4

0.2
Pre 5 10 20 30
A B Time (minutes)
FIGURE 6-1 A, Schematic of the conversion of proinsulin (top) to insulin. Proteolytic cleavage of proinsulin forms
equimolar concentrations of connecting peptide (C-peptide) and insulin, which are stored in secretory granules of
beta cells. B, Mean plasma C-peptide concentration prior to and after intravenous (IV) administration of 1 mg glu-
cagon in 24 healthy dogs (broken lineopen circles), 35 dogs with diabetes mellitus and low baseline C-peptide
concentration (broken linetriangles), 7 dogs with diabetes mellitus and increased baseline C-peptide concen-
tration (broken lineXs), and 8 dogs with naturally acquired hyperadrenocorticism (solid linesolid circles).
(B, From Nelson RW: Diabetes mellitus. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine,
ed 4, Philadelphia, 1995, WB Saunders Co, p. 1511.) * = significantly (P < 0.05) different from baseline value;
+ = significantly (P < 0.05) different from corresponding time in healthy dogs.
|
500 is exceeded, resulting in glycosuria. In dogs, this typically occurs

whenever the blood glucose concentration exceeds 180 to 220 mg/
dL (10 to 12 mmol/L). The threshold for glucose resorption appears
more variable in cats, ranging from 200 to 280 mg/dL (11 to 16
mmol/L). Glycosuria creates an osmotic diuresis, causing polyuria.
400 Compensatory polydipsia prevents dehydration. The diminished
peripheral tissue utilization of ingested glucose results in weight
loss as the body attempts to compensate for perceived starvation.
Blood glucose concentration (mg/dL)
The interaction of the satiety center in the ventromedial

region of the hypothalamus with the feeding center in the lat-
300
eral region of the hypothalamus is responsible for controlling the
amount of food ingested (Barrett etal, 2012). The feeding center,
responsible for evoking eating behavior, is chronically functioning
but can be transiently inhibited by the satiety center after food
ingestion. The amount of glucose entering the cells in the satiety
center directly affects the feeling of hunger; the more glucose that
200
enters these cells, the less the feeling of hunger and vice versa (Bar-
rett et al, 2012). The ability of glucose to enter the cells in the
satiety center is mediated by insulin. In diabetics with a relative
or absolute lack of insulin, glucose does not enter satiety center
cells, resulting in failure to inhibit the feeding center. Thus these
100 individuals become polyphagic despite hyperglycemia.
The four classic signs of diabetes mellitus are polyuria, poly-
dipsia, polyphagia, and weight loss. The severity of these signs is
directly related to the severity of hyperglycemia. As these signs
become obvious to the owner, the pet is brought to the veterinar-
0 ian for care. Unfortunately, some dogs and cats are not identied
8 AM Noon 4 PM 8 PM by their owners as having signs of disease, and these untreated
animals may ultimately develop diabetic ketoacidosis (DKA),
FIGURE 6-2 Blood glucose curve in a 32 kg male dog receiving 0.3 U/kg sub-
systemic signs of illness, and potentially life-threatening derange-
cutaneously beef/pork source neutral protamine Hagedorn (NPH) insulin (solid
ments in fluid and acid/base balance. See Chapter 8 for a detailed
linesolid circles). The blood glucose curve was obtained shortly after initiat-
discussion of the pathophysiology of DKA.
ing insulin therapy. Five months later, glycemic control deteriorated and clinical
signs recurred despite increasing the insulin dosage to 0.6 U/kg (broken line SIGNALMENT
solid circles). The dog was referred for possible insulin resistance. Insulin under-
dosage was pursued initially, and glycemic control was reestablished at an insu-
Most dogs are 5 to 15 years old at the time diabetes mellitus is
lin dosage of 1.0 U/kg (solid lineopen circles). = insulin injection and food.
diagnosed (Table 6-3; Guptill etal, 2003). Juvenile-onset diabe-
tes occurs in dogs younger than 1 year of age and is uncommon.
One large epidemiologic study involving 6807 diabetic dogs and
6807 matched controls in the United States and Canada identi-
1.0 fied the following: female dogs were at increased risk for diabetes
compared with male dogs, neutered male dogs were at increased
risk compared with intact male dogs, mixed-breed dogs were at
0.8
increased risk compared with pure breeds, and dogs weighing less
C-peptide (nmol/L)
than 22.7 kg were at increased risk compared with larger dogs

0.6
(Guptill etal, 2003). A seasonal pattern in prevalence of diabe-
tes was not identified. Breeds with a significantly increased or
0.4 decreased risk for developing diabetes are listed in Table 6-2.
Breed popularity and regions of the world may also impact breed
0.2 predispositions. For example, breeds with the highest risk for dia-
betes in Italy include the Irish Setter, Poodle, Yorkshire Terrier,
0 and English Setter (Fracassi et al, 2004). In Sweden, high risk
Control dogs Diabetic dogs Recovered dogs breeds included Spitz type breeds (Samoyed, Swedish Elkhound,
and Swedish Lapphund) and Scandinavian hound dogs (Finnish
0 Minutes 10 Minutes 20 Minutes Hound, Hamilton Hound, and Drever) (Fall etal, 2007).
FIGURE 6-3 Box plots of the serum concentration of C-peptide before (0 min-
utes) and 10 and 20 minutes after the intravenous (IV) administration of a bolus
ANAMNESIS
dose of glucagon to 20 healthy dogs, 27 diabetic dogs, and 4 dogs that had
recovered from diabetes. The horizontal line represents the median, the box rep- The history in virtually all diabetic dogs includes the classic signs of
resents the interquartile range (i.e., 25% to 75%), the T-bars represent the main polydipsia, polyuria, polyphagia, and weight loss. Owners will often
body of data, and the circles represent outliers. (From Fall T, etal.: Glucagon bring their dog to the veterinarian because the dog can no longer
stimulation test for estimating endogenous insulin secretion in dogs, Vet Rec make it through the night without having to be let outside to urinate
163:266, 2008.) or it begins urinating in the home. Occasionally an owner brings in
a dog because of sudden blindness caused by cataract formation (Fig. PHYSICAL EXAMINATION
6-4). The classic signs of diabetes mellitus may have gone unnoticed
or been considered irrelevant by the owner. If the clinical signs asso- Performance of a thorough physical examination is imperative in
ciated with uncomplicated diabetes are not observed by the owner any dog suspected of having diabetes mellitus, in part, because of
and impaired vision caused by cataracts does not develop, a diabetic the high prevalence of concurrent disorders that can affect response
dog is at risk for the development of systemic signs of illness (i.e., to treatment. The physical examination findings in a dog with
lethargy, anorexia, vomiting, and weakness) as progressive ketone- newly-diagnosed diabetes depend on whether DKA is present and
mia and metabolic acidosis develop. The time sequence from the its severity, on the duration of diabetes prior to its diagnosis, and
onset of initial clinical signs to the development of DKA is unpre- on the nature of any other concurrent disorder. The nonketotic
dictable, ranging from days to weeks; an onset that is somewhat diabetic dog has no classic physical examination findings. Many
dependent on the type and severity of concurrent disease causing diabetic dogs are obese but are otherwise in good physical condi-
insulin resistance and accelerating the production of ketone bodies. tion. Dogs with prolonged untreated diabetes may have lost weight
A complete history is extremely important even in the obvious but are rarely emaciated unless concurrent disease (e.g., inflam-
diabetic dog to explore for concurrent disorders, which are almost matory bowel disease, pancreatic exocrine insufficiency) is pres-
always present at the time diabetes mellitus is diagnosed. The clini- ent. Lethargy may be evident. The hair coat in newly-diagnosed
cian should always ask, Why has the dog developed clinical signs or poorly-controlled diabetic dogs may be sparse; the hairs dry,
of diabetes now? In many dogs the insulin antagonism caused by brittle, and lusterless; and scales from hyperkeratosis may be pres-
concurrent disorders (e.g., pancreatitis, bacterial infections, recent ent. Diabetes-induced hepatic lipidosis may cause hepatomegaly.
estrus, chronic kidney disease [CKD], or hyperadrenocorticism) is Lenticular changes consistent with cataract formation are another
the final insult leading to overt diabetes. Identification and treat- common clinical finding in diabetic dogs. Anterior uveitis and
ment of concurrent disorders plays an integral role in the success- keratoconjunctivitis sicca may also be present. In contrast to dia-
ful management of the diabetic dog, and a thorough history is the betic cats, clinical signs suggestive of diabetic neuropathy (e.g., rear
first step toward identification of these disorders. limb weakness, ataxia) are uncommon in newly-diagnosed diabetic
dogs. Additional abnormalities may be identified in the ketoaci-
TABLE 6-3 A
GE AT TIME OF DIAGNOSIS OF
dotic diabetic.
DIABETES MELLITUS IN 6807
DOGS IDENTIFIED BETWEEN ESTABLISHING THE DIAGNOSIS OF DIABETES
JANUARY 1, 1970, AND MELLITUS
DECEMBER 31, 1999
A diagnosis of diabetes mellitus requires the presence of appropri-
ate clinical signs (i.e., polyuria, polydipsia, polyphagia, weight loss)
AGE (YEARS) NUMBER OF DOGS PERCENT OF DOGS
and documentation of persistent fasting hyperglycemia and glycos-
<1 154 2.2% uria. Measurement of the blood glucose concentration using a por-
1 to 2 46 0.7% table blood glucose monitoring (PBGM) device (see Serial Blood
3 to 4 195 2.8% Glucose Curve) and testing for the presence of glycosuria using
urine reagent test strips (e.g., KetoDiastix) allows the rapid con-
5 to 7 1058 15.4%
firmation of diabetes mellitus. The concurrent documentation of
8 to 10 2543 37.1% ketonuria establishes a diagnosis of diabetic ketosis or ketoacidosis.
11 to 15 2690 39.2% It is important to document both persistent hyperglycemia and
> 15 121 1.8%
glycosuria to establish a diagnosis of diabetes mellitus. Hypergly-
cemia without glycosuria does not cause polyuria and polydipsia
From Guptill L, etal.: Time trends and risk factors for diabetes mellitus in dogs: analysis and may occur with causes of hyperglycemia that do not typically
of veterinary medical data base records (1970-1999), Vet J 165:240, 2003. progress to a clinical diabetic state (Box 6-1). Glycosuria without
A B
FIGURE 6-4 A, Bilateral cataracts causing blindness in a diabetic dog. B, Mature cataract with suture lines in a
diabetic Collie.
|
hyperglycemia supports primary renal glycosuria or other renal CLINICAL PATHOLOGIC ABNORMALITIES
tubular disorders, not diabetes mellitus.
Documenting an increase in the serum fructosamine concentra- Overview of Patient Evaluation
tion supports the presence of sustained hyperglycemia; however, a
serum fructosamine concentration in the upper range of normal A thorough clinicopathologic evaluation is recommended once the
can occur in symptomatic diabetic dogs if the diabetes developed diagnosis of diabetes mellitus has been established. The clinician
shortly before presentation of the dog to the veterinarian. must be aware of any disease that may be causing or contributing to
Mild hyperglycemia (i.e., 130 to 180 mg/dL; 7.3 to 10 mmol/L) the carbohydrate intolerance (e.g., hyperadrenocorticism), that may
is clinically silent and is usually an unexpected and unsuspected result from the carbohydrate intolerance (e.g., bacterial cystitis), or
finding. If the dog with mild hyperglycemia is examined for poly- that may mandate a modification of therapy (e.g., pancreatitis) (Hess
uria and polydipsia, a disorder other than clinical diabetes melli- etal, 2000b; Peikes etal, 2001). The minimum laboratory evalu-
tus should be sought. Mild hyperglycemia can occur shortly after ation in any newly-diagnosed diabetic dog should include a com-
consuming large quantities of easily digestible carbohydrates; in plete blood count (CBC), serum biochemical panel, and urinalysis
stressed, hyperactive, aggressive, or extremely nervous dogs; in the with bacterial culture. Serum progesterone concentration should
early stages of development of diabetes mellitus (i.e., subclinical diabe determined if diabetes mellitus is diagnosed in an intact bitch,
betes); and with disorders and drugs causing insulin resistance, most regardless of her cycling history. If available, abdominal ultrasound is
notably hyperadrenocorticism, glucocorticoids, and during diestrus indicated to assess for pancreatitis, adrenomegaly, pyometritis in an
in older intact female dogs. A diagnostic evaluation for disorders intact bitch, and abnormalities affecting the liver and urinary tract
causing insulin resistance is indicated if mild hyperglycemia persists (e.g., changes consistent with pyelonephritis or cystitis). Because of
in the fasted, unstressed dog (see Concurrent Disorders Causing the relatively high prevalence of pancreatitis in diabetic dogs, mea-
Insulin Resistance). Insulin therapy is usually not indicated in these surement of pancreatic lipase immunoreactivity (cPLI) should be
animals, although some clinicians will initiate low-dose insulin considered, especially if abdominal ultrasound is not available. Addi-
therapy while searching for and treating the underlying cause of the tional tests may be warranted after obtaining the history, performing
insulin resistance in the hope that improving hyperglycemia will the physical examination, or identifying ketonuria. The laboratory
decrease the demand for insulin production and secretion by the evaluation of dogs with glycosuria and ketonuria is discussed in
beta cells and minimize further damage to the cells. detail in Chapter 8. Potential clinical pathologic abnormalities are
listed in Box 6-2.
BOX 6-1 E
tiologic Classification of Diabetes Mellitus
and Hyperglycemia
BOX 6-2 C
linicopathologic Abnormalities Commonly
1 . Type 1 diabetes mellitus Found in Dogs and Cats with Uncomplicated
2. Type 2 diabetes mellitus Diabetes Mellitus
3. Other specific types
A. Genetic defects Complete Blood Count
B. Disease of the exocrine pancreas Typically normal
Pancreatitis Neutrophilic leukocytosis, toxic neutrophils if pancreatitis or infection present
Exocrine pancreatic neoplasia Biochemistry Panel
C. Endocrinopathies Hyperglycemia
Hyperadrenocorticism Hypercholesterolemia
Acromegaly (cat) Hypertriglyceridemia (lipemia)
Pheochromocytoma (dog) Increased alanine aminotransferase activity (typically < 500 U/L)
Hyperthyroidism (cat) Increased alkaline phosphatase activity (typically < 500 U/L)
D. Drug or chemical induced
Urinalysis
Glucocorticoids
Urine specific gravity (typically > 1.025)
Progestagens
Glycosuria
Thyroid hormone
Variable ketonuria
Thiazide diuretics
Proteinuria
Beta adrenergic agonists
Bacteriuria
E. Infections
Pyometra Ancillary Tests
4. Gestational diabetes mellitus Hyperlipasemia (canine pancreatic-specific lipase [cPL]) if pancreatitis
A. Diestrus (bitch) present
B. Ovarian remnant syndrome Hyperamylasemia if pancreatitis present
5. Miscellaneous causes of hyperglycemia Serum trypsin-like immunoreactivity (TLI) usually normal
A. Head trauma Low with pancreatic exocrine insufficiency
B. Critical illness High with acute pancreatitis
C. Stress, aggression, fright (cat) Normal to high with chronic pancreatitis
D. Dextrose-containing fluids Variable serum baseline insulin concentration
E. Parenteral nutrition solutions Type 1 diabetes: Low, normal
F. Postprandial Type 2 diabetes: Low, normal, increased
Insulin resistance induced: Low, normal, increased
Modified from the American Diabetes Association etiologic classification for humans.
Complete Blood Count The presence and severity of glycosuria should be considered
when interpreting the urine specific gravity. Despite polyuria and
Results of a CBC are usually normal in the uncomplicated diabetic polydipsia, urine specific gravities typically range from 1.025 to
dog. A mild polycythemia may be present if the dog is dehydrated. 1.035 in untreated diabetic dogs, in part, because of the large
An elevation of the white blood cell count may be caused by either an amount of glucose in the urine. In general, 2% or 4+ glycosuria
infectious or inflammatory disorder, such as pancreatitis. The pres- as measured on urine reagent test strips will increase the urine
ence of toxic or degenerative neutrophils or a significant shift toward specific gravity 0.008 to 0.010 when urine specific gravity is mea-
immaturity of the cells supports the presence of an infectious process sured by refractometry. As such, identification of a urine specific
or severe necrotizing pancreatitis as the cause of the leukocytosis. gravity less than 1.020 in combination with 2% glycosuria sug-
gests a concurrent polyuric/polydipsic disorder, most notably
Serum Biochemical Panel hyperadrenocorticism or CKD.
Proteinuria may be the result of urinary tract infection or glo-
The prevalence and severity of abnormalities identified in the merular damage secondary to disruption of the basement mem-
serum biochemistry panel are dependent on the duration of brane (Struble et al, 1998). Identification of pyuria, hematuria,
untreated diabetes and the presence of concurrent disease, most and bacteriuria suggests the presence of a urinary tract infection.
notably pancreatitis (Hess etal, 2000b). The serum biochemical However, failure to identify pyuria and hematuria does not rule
panel is often unremarkable in healthy diabetic dogs without out urinary tract infection (McGuire etal, 2002). Because of the
significant concurrent disease, aside from hyperglycemia and relatively high prevalence of concurrent urinary tract infections
hypercholesterolemia. The most common abnormalities are an in diabetic dogs, urine obtained by antepubic cystocentesis using
increase in serum alanine aminotransferase and alkaline phospha- aseptic technique should be submitted for bacterial culture and
tase activities and hypercholesterolemia (see later). The increase antibiotic sensitivity testing in all dogs with newly-diagnosed dia-
in liver enzyme activities in healthy diabetic dogs is usually mild betes mellitus, regardless of the findings on urinalysis (Hess etal,
(less than 500 U/L) and presumed to be a result of hepatic lipi- 2000b).
dosis. Serum alkaline phosphatase activities in excess of 800 U/L
should raise suspicion for concurrent hyperadrenocorticism,
Serum Cholesterol and Triglyceride Concentrations
especially if other abnormalities consistent with hyperadre-
nocorticism are identified in the laboratory data (see Chapter Serum cholesterol and triglyceride concentrations are typically
10). Serum alanine aminotransferase activities in excess of 600 increased in newly-diagnosed diabetic dogs. Insulin is a powerful
U/L should raise suspicion for hepatopathy other than hepatic inhibitor of lipolysis and free fatty acid oxidation. During a state of
lipidosis, especially if additional abnormalities in endogenous insulin deficiency, lipoprotein lipase activity is reduced, hormone-
liver function tests (e.g., low urea nitrogen, hypoalbuminemia, sensitive lipase is activated, hepatic production of triglyceride-rich
or increased serum bile acids) are identified. An increase in the verylow-density lipoprotein (VLDL) particles is increased, and
serum total bilirubin concentration should raise suspicion for clearance of VLDL particles is decreased (Eckel, 1989; Massillon
extrahepatic biliary obstruction caused by concurrent pancre- et al, 1997; Semenkovich et al, 2011). Activation of hormone-
atitis. When appropriate, abdominal ultrasound and histologic sensitive lipase results in the release of large quantities of free fatty
evaluation of a liver biopsy specimen may be indicated to estab- acids from adipocytes into the blood. These free fatty acids are
lish concurrent liver disease. ultimately converted by the liver into triglycerides, packaged into
The blood urea nitrogen (BUN) and serum creatinine con- VLDL particles, and secreted back into the circulation. Increased
centrations are usually normal in the uncomplicated diabetic. intrahepatic cholesterol concentration down-regulates the hepato-
An elevation in these parameters may be due to either primary cyte low-density lipoprotein (LDL) receptor, consequently reduc-
renal failure or prerenal uremia secondary to dehydration. Primary ing the clearance of circulating cholesterol-containing LDL and
renal failure as a result of glomerulosclerosis, which is damage high-density lipoprotein (HDL) particles, which in turn causes
specifically related to chronic hyperglycemia, is a well-recognized hypercholesterolemia.
complication in humans but is uncommon in dogs (see Diabetic Chylomicrons and VLDLs are primarily involved in triglyceride
Nephropathy). Evaluation of urine specific gravity should help metabolism, whereas HDLs and LDLs are primarily involved in
differentiate primary renal failure from prerenal uremia. Remem- cholesterol metabolism. In diabetic humans, circulating concen-
ber to consider the impact of glycosuria on results of urine specific trations of LDLs and HDLs are increased and decreased, respec-
gravity determined by refractometry (see later). tively. The combination of high LDL and low HDL cholesterol
Alterations in serum electrolytes and acid-base parameters are concentrations may play a role in the accelerated development of
common in dogs with DKA and are discussed in Chapter 8. atherosclerotic vascular disease and coronary heart disease, which
is the major long-term complication of diabetes in humans (Garg
Urinalysis and Grundy, 1990). Similar vascular complications have been
infrequently documented in diabetic dogs (Hess etal, 2002), pre-
Abnormalities identified in the urinalysis that are consistent with sumably because HDLs predominate in dogs (as opposed to LDLs
diabetes mellitus include glycosuria, ketonuria, proteinuria, and in humans), and dogs have a shorter life span that may limit devel-
bacteriuria with or without associated pyuria and hematuria. The opment of atherosclerosis (Bauer, 2004). Fortunately, most lipid
dog with uncomplicated diabetes usually has glycosuria without derangements in diabetic dogs can be improved with insulin and
ketonuria. However, a relatively healthy diabetic may also have dietary therapy.
trace to small amounts of ketones in the urine. If large amounts
of ketones are present in the urineespecially in an animal with
Pancreatic Enzymes
systemic signs of illness (e.g., lethargy, vomiting, or dehydra-
tion), a diagnosis of DKA should be made and the animal treated Blood tests to assess for the presence of pancreatitis should always
appropriately. be considered in the newly-diagnosed diabetic dog, especially if
|
abdominal ultrasound is not available. Measurement of canine suspected at the time diabetes is diagnosed, we will evaluate serum
pancreatic-specific lipase (cPL) is currently the blood test of free T4 and TSH concentrations before initiating sodium levothy-
choice for identifying pancreatitis (Trivedi et al, 2011; McCord roxine treatment. See Chapter 3 for a more detailed discussion
et al, 2012). Sensitivity and specificity of cPL varies between of the effects of concurrent lipemia, illness, and drug therapy on
studies and is dependent on the severity of pancreatitis and the serum thyroid hormone concentrations and the tests used to diag-
cutoff value (200 versus 400 g/L) used to separate normal from nose hypothyroidism in dogs.
pancreatitis (McCord et al, 2012; Bostrom et al, 2013). Serum
cPL concentrations can be increased in dogs with a histologically Serum Insulin Concentration
confirmed normal pancreas and normal in dogs with histologi-
cally confirmed inflammation of the pancreas, especially when the Measurement of serum insulin concentration (either baseline
inflammatory process is chronic and mild (Forman et al, 2004; or after the administration of an insulin secretagogue) is not a
Trivedi et al, 2011). Interpretation of serum cPL results should routine part of our diagnostic evaluation of the newly-diagnosed
always be done in context with the history, physical examination diabetic dog. In theory, identifying increased endogenous serum
findings, and additional findings on the laboratory tests. In our insulin concentrations in a newly-diagnosed diabetic dog would
experience, abdominal ultrasound is the single best diagnostic test suggest the presence of functioning beta cells and the presence of
for identifying acute and chronic pancreatitis in the dog; how- an underlying insulin antagonistic disorder. However, because the
ever, results are equipment and operator dependent. Nevertheless, vast majority of dogs with newly-diagnosed diabetes have type 1
abdominal ultrasound should be considered if pancreatitis is sus- diabetes and serum insulin concentration is typically in the lower
pected after evaluation of the history, physical examination, and half of normal or undetectable, routine measurement of serum
laboratory test results. The concomitant presence of pancreatitis insulin concentration is not a cost-effective diagnostic procedure.
may necessitate the instigation of intensive fluid therapy and the The exceptions are older intact female dogs in diestrus and with
initiation of diets aimed at treating pancreatitis rather than dia- newly-diagnosed diabetes mellitus (see Other Specific Types and
betes. Identification of chronic pancreatitis also has important Diabetic Remission). It is imperative that the insulin assay has
prognostic implications regarding success of establishing and been validated in dogs; that the reference interval has been deter-
maintaining control of glycemia and long-term survival. mined using healthy, fasted dogs; and that the diabetic dog has not
Measurement of serum trypsin-like immunoreactivity (TLI) is been recently treated with exogenous insulin. Most insulin assays
no longer recommended for identifying pancreatitis but is cur- will measure exogenously administered insulin, resulting in an
rently the blood test of choice to diagnose exocrine pancreatic increased serum insulin concentration and a misinterpretation of
insufficiency; an uncommon complication of diabetes mellitus beta cell function in the diabetic dog. As a general rule, exogenous
that presumably develops as a sequela of chronic pancreatitis in insulin should be withheld for at least 24 hours before blood is
most diabetic dogs (Wiberg etal, 1999; Wiberg and Westermarck, obtained for endogenous serum insulin measurement.
2002). Exocrine pancreatic insufficiency should be suspected in
diabetic dogs that are difficult to regulate with insulin, are thin or
TREATMENT OF NONKETOTIC DIABETES
emaciated despite polyphagia, and defecate increased amounts of
MELLITUS
soft stoolsnot the voluminous, rancid stools considered classic
for exocrine pancreatic insufficiency (EPI). Mild diffuse thicken-
Goals of Therapy
ing of the small intestine may be evident during abdominal palpa-
tion. Serum TLI should be less than 2.5 g/L in diabetic dogs with There are two primary goals of therapy. The first goal is the elimi-
concurrent exocrine pancreatic insufficiency. nation of the owner-observed signs occurring secondary to hyper-
glycemia and glycosuria. A persistence of clinical signs and the
Serum Thyroxine Concentration development of chronic complications (Table 6-4) are directly cor-
related with the severity and duration of hyperglycemia. Limiting
The veterinarian may periodically have to interpret a serum thy- blood glucose concentration fluctuations and maintaining near-
roxine (T4) concentration in a diabetic dog, either because serum normal glycemia will help minimize the severity of clinical signs
T4 is a routine part of the serum biochemistry panel; because and prevent the complications of poorly controlled diabetes. In
hypothyroidism is suspected after a review of the history, clinical the diabetic dog, this can be accomplished through proper insulin
signs, and physical examination findings; or because severe hyper- therapy, diet, exercise, and the prevention or control of concurrent
lipidemia is identified or as part of the diagnostic evaluation for inflammatory, infectious, neoplastic, and hormonal disorders.
insulin resistance (Hofer-Inteeworn etal, 2012). Interpretation of Although it is worthwhile attempting to normalize the blood
serum T4 results must be done cautiously, especially in a dog with glucose concentration, the veterinarian must also guard against
newly-diagnosed diabetes mellitus and concurrent illness, such as the animal developing of hypoglycemia, which is a serious and
pancreatitis or infection. Healthy diabetic dogs without concur- potentially fatal complication of therapy. Hypoglycemia is most
rent illness usually have normal serum T4 concentrations. How- apt to occur as the result of overzealous insulin therapy. The
ever, the more poorly controlled the diabetic state and the more veterinarian must balance the benets of tight glucose control
severe the concurrent illness, the more likely serum T4 concen- obtainable with aggressive insulin therapy against the risk for
trations will be decreased into the hypothyroid range because of hypoglycemia.
the suppressive effect of concurrent illness on the pituitary-thyroid The second goal is to minimize the impact of therapy on the
axis rather than because of naturally-acquired hypothyroidism (see owners lifestyle. A recent study evaluated the psychological and
Chapter 3). As a general rule, in a newly-diagnosed diabetic dog social impact of diabetes and its treatment on the quality of life
with a concurrent low serum T4 concentration, we treat the dia- of 101 owners of diabetic dogs living in the United Kingdom,
betes and reevaluate serum T4 and thyroid-stimulating hormone United States, Canada, Australia, and Europe (Niessen et al,
(also known as thyrotropin; TSH) concentrations once control 2012). The top 10 negative impact items were associated mostly
of glycemia has been established. If hypothyroidism is strongly with the owners quality of life rather than the pets quality of
TABLE 6-4 C
OMPLICATIONS OF DIABETES TABLE 6-5 T
OP TEN NEGATIVE
MELLITUS IN DOGS AND CATS PSYCHOLOGICAL AND SOCIAL
IMPACTS OF DIABETES MELLITUS
COMMON UNCOMMON AND ITS TREATMENT ON THE
Iatrogenic hypoglycemia Peripheral neuropathy (dog) QUALITY OF LIFE OF OWNERS OF
A DIABETIC DOG
Persistent polyuria, polydipsia, Glomerulonephropathy,
weight loss glomerulosclerosis MEAN ITEM WEIGHTED
Cataracts (dog) Retinopathy ITEM IMPACT SCORE
Bacterial infections, Exocrine pancreatic insufficiency Worry about pets diabetes -5.92
especially in the urinary tract
Interferes with visiting family and friends -5.68
Pancreatitis Gastric paresis
Worry about the dog developing cataracts -5.58
Ketoacidosis Diabetic dermatopathy (dog)
Worry about boarding the dog -5.18
(i.e., superficial necrolytic
dermatitis) Worry about dog developing hypoglycemia -4.95
Hepatic lipidosis Having to fit the dogs needs into their social life -4.82
Peripheral neuropathy (cat) Cost of treating the diabetes -4.11
Worry about future ability to care for the dog -4.07
Having to fit the dogs needs into their work -3.88
life (Table 6-5). The only positive items identified by the owners schedule
were related to more interactions and development of a special Restricting the owners vacation and work activities -3.88
bond with their dog. Fortunately, 81% of diabetic dog owners
rated their dogs quality of life as good despite 84% reporting a Adapted from Niessen SJM, etal.: Evaluation of a quality-of-life tool for dogs with diabe-
negative impact of diabetes on their dogs quality of life. Aware- tes mellitus, J Vet Intern Med 26:953, 2012.
ness of the impact of the treatment regimen, home monitoring, The quality of life survey was completed by 101 owners originating from the United
Kingdom, United States, Canada, Australia, and Europe.
and frequency of evaluations by the veterinarian on the client
and simplifying the overall management of the diabetic dog as
much as possible without negatively impacting control of glyce- by the Food and Drug Administration (FDA) for treatment of
mia is important for the long-term success of treating diabetes. diabetes in dogs and cats, respectively and so are U40 insulin
preparations (i.e., 40 units of insulin per mL of solution). The
Insulin Therapy appropriate insulin syringe should be used for the insulin prepara-
tion being administered (i.e., U40 or U100 insulin syringe for a
Overview of Insulin Preparations U40 or U100 insulin preparation). Insulin pens are also available
Insulin preparations typically used for the home treatment of dia- for NPH insulin, porcine-source Lente insulin, insulin glargine,
betes in dogs and cats include intermediate-acting insulin prepara- and insulin detemir.
tions (neutral protamine Hagedorn [NPH], Lente) and long-acting Porcine-source Lente and recombinant human NPH insulin are
basal insulin preparations (protamine zinc insulin [PZI], insulin effective for the treatment of diabetes in dogs (Lorenzen, 1992;
glargine, insulin detemir; Table 6-6). NPH (Humulin N, Novolin Monroe etal, 2005). Problems with prolonged duration of insulin
N) is a recombinant human insulin, Lente (Vetsulin, Caninsulin) effect can occur with both insulin preparations but are not com-
is a purified pork-source insulin, PZI (Pro-Zinc) is a recombinant mon (Hess and Ward, 2000; Fleeman etal, 2009a). Problems with
human insulin, and insulin glargine (Lantus) and insulin detemir short duration of insulin effect despite twice a day administration
(Levemir) are insulin analogues. NPH and PZI insulin prepara- are more common than problems with prolonged duration of
tions contain the sh protein protamine and zinc to delay insulin insulin effect, especially with NPH insulin (see Complications
absorption and prolong the duration of insulin effect (Davidson of Insulin Therapy; Palm et al, 2009). For this reason, porcine-
et al, 1991). Lente insulin relies on alterations in zinc content source Lente insulin is considered the initial insulin of choice for
and the size of zinc-insulin crystals to alter the rate of insulin the home treatment of diabetes in dogs. For a period of time,
absorption from the subcutaneous site of deposition. The larger porcine-source Lente insulin was not available in the United States
the crystals are, the slower the rate of absorption and the longer and veterinarians were forced to use alternative insulin prepara-
the duration of effect. Lente insulin contains no foreign protein tions, most commonly NPH or insulin detemir. Fortunately
(i.e., protamine). Lente insulin is a mixture of three parts of short- porcine-source Lente insulin is once again available in the United
acting, amorphous zinc insulin and seven parts of long-acting, States.
crystalline zinc insulin. Lente insulin is considered an interme- Recombinant human PZI insulin is commonly used for the
diate-acting insulin, although plasma insulin concentrations may treatment of diabetes in cats but published experiences with PZI
remain increased for longer than 14 hours following subcutaneous in diabetic dogs is limited. In a recent study, PZI administered
administration in some dogs (Graham etal, 1997). The manufac- twice a day was effective in improving or maintaining control of
turer of porcine Lente insulin now recommends vigorous shak- glycemia in the majority of diabetic dogs enrolled in the study,
ing of the insulin vial until a homogeneous milky suspension is and more than 80% of owners were satisfied with the results of
obtained prior to withdrawal of the insulin into the syringe. treatment (Della-Maggiore et al, 2012). However, prolonged
NPH insulin, insulin glargine and insulin detemir are U100 duration of PZI effect was a common problem that resulted in
insulin preparations (i.e., 100 units of insulin per mL of solution). blood glucose nadirs often occurring at the beginning or end of
Porcine-source Lente and protamine zinc insulin are approved the blood glucose cure, inconsistency in blood glucose results in
|
TABLE 6-6 COMMONLY-USED INSULIN PREPARATIONS FOR TREATING DIABETES IN DOGS AND CATS
Administration Typical Duration of Effect (hour)

INSULIN ORIGIN INDICATIONS ROUTE FREQUENCY DOG CAT COMMON PROBLEMS
Regular Recombinant human Treat DKA IV Continuous infusion Rapid decrease in blood glucose con-
crystalline IM Hourly initially 4-6 4-6 centration; may cause hypokalemia
SC Every 6 to 8 hours 6-8 6-8
Treat diabetes at home SC Every 8 hours 6-8 6-8
Lispro Recombinant human Treat DKA IV Continuous infusion Rapid decrease in blood glucose con-
analog centration; may cause hypokalemia
NPH Recombinant human Treat diabetes at home SC Every 12 hours 6-12 6-10 Short duration of effect in dogs and cats
Lente 100% pork Treat diabetes at home; good SC Every 12 hours 8-14 6-12 Short duration of effect in cats
initial insulin for dogs
PZI Recombinant human Treat diabetes at home; good SC Every 12 hours 10-16 10-14 Duration of effect too long for every-
initial insulin for cats 12-hour therapy in some dogs;
unpredictable timing of glucose
nadir in some dogs
Glargine Recombinant human Treat diabetes at home; good SC Every 12 to 24 hours 8-16 8-16 Duration of effect too long for every-
analog initial insulin for cats 12-hour therapy in some cats
and dogs; weak glucose lowering
effect and unpredictable timing of
glucose nadir in some dogs
Detemir Recombinant human Treat diabetes at home SC Every 12 to 24 hours 8-16 8-16 Duration of effect too long for every-
analog 12-hour therapy in some cats and
dogs; insulin dosage requirements
considerably lower than with other
insulin preparations
From Nelson RW, Couto CG: Small animal internal medicine, ed 5, St Louis, 2014, Mosby Elsevier, p. 784.
DKA, Diabetic ketoacidosis; IM, intramuscular; IV, intravenous; NPH, neutral protamine Hagedorn; PZI, protamine zinc insulin; SC, subcutaneous.
individual dogs, and difficulty in achieving ideal control of hyper-

glycemia within the time period of the study (60 days) in some 500
dogs (Fig. 6-5). Problems with hypoglycemia and initiation of the

Somogyi response may occur when an insulin preparation with a 400 a
duration of effect longer than 12 hours is administered every 12
hours. Problems with prolonged duration of PZI effect precludes
300
routine use of PZI in newly-diagnosed diabetic dogs but supports
the potential use of PZI in diabetic dogs that are poorly controlled
because of short duration of effect of NPH or Lente insulin. 200
Insulin Analogues.Recently, recombinant DNA technology
has been applied for the production of insulin analogues that more
100
closely duplicate the basal and meal-time components of endog-
enous insulin secretion. Rapid-acting insulin analogues include
insulin lispro (Humalog), insulin aspart (Novolog) and insulin 0
glulisine (Apidra). The relatively slow absorption of regular insu- Day 1 Day 14 Day 30 Day 60
lin is attributed to hexamer formation of insulin molecules that FIGURE 6-5 Box plots of the 10-hour mean blood glucose concentrations in
occurs when zinc is added to the solution that makes up regular 17 dogs with diabetes mellitus treated by the administration of various doses
insulin (Hirsch, 2005). The hexamers of insulin molecules slowly of recombinant human protamine zinc insulin (PZI) twice daily for 60 days. The
dissociate before absorption into the circulation occurs. By replac- 10-hour mean blood glucose concentration is the mean of the six blood glucose
ing certain amino acids in the insulin molecule, the tendency to concentrations measured during a 10-hour period. The median time from insulin
self-associate can be reduced without affecting the insulin-receptor administration to the blood glucose nadir was 8 to 10 hours and occurred at the
kinetics. Insulin lispro is produced by inverting the natural amino start or end of the 10-hour blood sampling interval in 54% of 68 blood glucose
acid sequence of the B-chain at B28 (proline) and B29 (lysine), curves. The horizontal line represents the median, the box represents the inter-
insulin aspart is produced by substituting aspartic acid for proline quartile range (i.e., 25% to 75%), the T-bars represent the main body of data,
at position B28, and insulin glulisine is produced by substituting and the circles represent the outliers. (From Della-Maggiore A, etal.: Efficacy of
lysine for asparagine at position B3 and glutamic acid for lysine at protamine zinc recombinant human insulin for controlling hyperglycemia in dogs
position B29 (Lindholm etal, 2002; Home, 2012; Fig. 6-6). As with diabetes mellitus, J Vet Intern Med 26:109, 2012.) a, P = 0.0003, compared
a consequence of these alterations, insulin lispro, insulin aspart, with results on day 1.
LEU SER GLY ALA GLY PRO

PRO GLN GLY
LEU GLY
ALA GLY
LEU Connecting peptide LEU
GLU GLU
10
GLY VAL
SER GLN
C chain
LEU
Dipeptide GLY
linkage 31 GLN
VAL
LYS
GLN
ARG
LEU
1 GLY
C chain ASP
ILE
COOH GLU
VAL
NH2 ASN
A chain 21 ALA
GLU CYS
PHE S
S GLU
1 GLN TYR
VAL CYS ASN ARG
CYS A chain GLU
ASN THR ARG
LEU
B chain SER
GLN ILE CYS SER LEU TYR GLN S
S THR
HIS
10 B chain LYS 30
LEU S PRO
CYS Insulin S THR Dipeptide
GLY TYR linkage
SER PHE
HIS B chain PHE
LEU GLY
VAL ARG
GLU
10 GLU ALA
LEU TYR LEU VAL CYS GLY
20
FIGURE 6-6Amino acid structure of human proinsulin, connecting peptide (C-peptide) and insulin. The insulin
molecule consists of an A and B chain connected by two disulfide bridges. (From Masharani U, Karam JH: Pancre-
atic hormones and diabetes mellitus. In Gardner DA, Shoback D, editors: Greenspans basic & clinical endocrinol-
ogy, ed 9, New York, 2011, McGraw-Hill, with permission.)
and insulin glulisine exhibit monomeric behavior in solution and solution in the bottle of glargine is acidic, which keeps glargine
display a rapid absorption, faster pharmacodynamic action, and soluble and suspended in the solution (i.e., the solution is clear,
shorter duration of effect than short-acting regular crystalline insu- and the bottle does not need to be shaken prior to drawing up
lin (Howey etal, 1994; Home etal, 1999; Lindholm etal, 1999). the insulin into the syringe). Because of this dependency on pH,
Insulin lispro and insulin aspart are the current prandial insulins glargine should not be diluted or mixed with anything that may
(i.e., insulin administered before each meal) commonly used for change the pH of the solution. Glargine forms microprecipitates
control of postprandial blood glucose concentrations in human in the subcutaneous tissue at the site of injection from which small
diabetics and are typically administered three times a day before amounts of insulin glargine are slowly released and absorbed into
each of the three main meals (breakfast, lunch, and dinner). The the circulation. In humans, the slow sustained release of insulin
role, if any, of these insulins for the home treatment of diabetic glargine from these microprecipitates results in a relatively con-
dogs remains to be determined. Because of their extremely short stant concentration/time prole over a 24-hour period with no
duration of effect, insulin lispro and insulin aspart would have to pronounced peak in serum insulin. The glucose-lowering effect of
be used in conjunction with a longer-acting insulin preparation to insulin glargine is similar to that of human insulin, the onset of
maintain control of glycemia. A recent study documented similar action following subcutaneous administration is slower than NPH
effectiveness of insulin lispro and regular crystalline insulin for the insulin, and the duration of effect is prolonged compared with
treatment of DKA in dogs (Sears etal, 2012). NPH insulin (Owens et al, 2000). Insulin glargine is currently
Insulin glargine (Lantus) and insulin detemir (Levemir) are recommended as a basal insulin (i.e., sustained long-acting insulin
long acting (basal) insulin analogues that have a slow, sustained used to inhibit hepatic glucose production) administered once a
absorption from the subcutaneous site of insulin deposition, day at bedtime and used in conjunction with either rapid-acting
are designed to inhibit hepatic glucose production, are typically insulin analogs or oral hypoglycemic drugs in human diabetics
administered once a day at bedtime, and are used in conjunction (Rosenstock etal, 2000; 2001).
with rapid-acting (prandial) insulin analogues in diabetic humans. Insulin glargine is commonly used for the treatment of diabetes
Insulin glargine has been modified by replacing the amino acid in cats, but published experiences with insulin glargine in diabetic
asparagine with glycine at position A21 of the A chain, and two dogs are limited. Time-action profiles performed in three healthy
arginines have been added to the C-terminus of the B chain of dogs suggested the potential for prolonged duration of action of
insulin; these modifications shift the isoelectric point from a insulin glargine, a duration that could potentially cause problems if
pH of 5.4 toward a neutral pH (Pieber et al, 2000). This shift insulin glargine is administered twice a day (Mori etal, 2008; Fig.
makes insulin glargine more soluble at a slightly acidic pH and 6-7). In a recent study, insulin glargine administered twice a day
less soluble at a physiological pH than native human insulin. The was effective in improving or maintaining control of glycemia in
|
16
14
12
GIR (mg/kg/min)
10
FIGURE 6-7 Time-action profile comparison between neutral protamine 4

Hagedorn (NPH) insulin and insulin glargine for a 24-hour period. Results
are presented as mean standard error of the mean glucose infusion 2
rate (GIR) required to maintain euglycemia over time for three healthy
non-diabetic dogs after subcutaneous (SC) administration of either 0
0.5 U/kg NPH insulin or 0.5 U/kg insulin glargine at time 0. Higher val- 0 120 240 360 480 600 720 840 960 1080 1200 1320 1440
ues of GIR indicate stronger insulin action. (Adapted from Mori A, etal.: Time (min)
Comparison of time-action profiles of insulin glargine and NPH insulin in NPH duration effect Glargine duration effect
normal and diabetic dogs, Vet Res Commun 32:563, 2008).
40 diabetes in dogs, but we do consider using insulin glargine in dia-

betic dogs with problems of short duration of effect of NPH and
Blood glucose concentration (mmol/L)
Lente insulin and problems with prolonged duration of effect of

30
insulin detemir (see Complications of Insulin Therapy).
Insulin detemir is also a long-acting basal insulin analogue, in
which the amino acid threonine has been removed at B30 and a
14 carbon fatty acid (myristic acid) has been bound to the lysine
20 * amino acid at position B29 of the B chain of the insulin molecule.
*
* *
Prolonged action results from strong self-association of the insulin
*
molecules and binding of insulin detemir to albumin in the sub-
10 cutaneous tissues and the systemic circulation through the fatty
acid chain attached to lysine at B29. Binding to albumin resulted
in reduced free insulin detemir concentrations in the circula-
tion and slower distribution of insulin to peripheral target tissues
0 (Hamilton-Wessler etal, 1999). Insulin detemir is a clear, color-
0 1 2 4 8 12 24
less, aqueous neutral solution that does not need to be shaken
Week of study
prior to drawing up the insulin into the syringe. The manufacturer
FIGURE 6-8 Box plots of 12-hour mean blood glucose concentrations in the recommends that insulin detemir not be mixed or diluted with
blood glucose curves for 12 dogs with diabetes mellitus treated by various doses other insulin preparations. Insulin detemir can be diluted using
of insulin glargine administration twice daily for 24 weeks. Twelve-hour mean the Insulin Diluting Medium for NovoRapid (insulin aspart) and
blood glucose concentration is the mean of the seven blood glucose concentra- Levemir (detemir) supplied by Novo Nordisk.
tions measured during a 12-hour period. See Fig. 6-5 legend for interpretation of Published experiences with insulin detemir in diabetic dogs are
box plots. (From Fracassi F, etal.: Use of insulin glargine in dogs with diabetes limited. A recent study would suggest that insulin detemir is cur-
mellitus, Vet Rec 170:52, 2012.) * = P < 0.05. rently the longest acting insulin preparation for use in diabetic
dogs. Time-action profiles performed in three healthy dogs identi-
fied a prolonged duration of action of insulin detemir with peak
the majority of diabetic dogs enrolled in the study (Fracassi etal, insulin action at 8 to 12 hours after the subcutaneous adminis-
2012; Fig. 6-8). Fifty-eight (33%) of the dogs had attained good tration of insulin detemir and a duration of effect in excess of
or moderate glycemic control by week 24 of the study. Insulin dos- 16 hours (Sako etal, 2011; Fig. 6-10). In the same study, insu-
ages required to attain glycemic control were similar to insulin dos- lin detemir was more effective in attaining glycemic control in
ages reported with NPH, Lente, and PZI insulin (Table 6-7). The five diabetic dogs after 5 days of treatment than NPH or insulin
timing of the glucose nadir was variable, suggesting that short and glargine. Insulin dosages ranged from 0.41 to 0.63 U/kg, 0.34
especially prolonged duration of action of insulin glargine occurs in to 0.54 U/kg, and 0.07 to 0.23 U/kg for NPH, insulin glargine,
diabetic dogs (Fig. 6-9). The authors speculated that the published and insulin detemir, respectively. The lower dosage requirements
success rate of other types of insulins (i.e., NPH and Lente) was for insulin detemir are presumably related to the prolonged dura-
somewhat better than insulin glargine. Our experiences with insu- tion of insulin action combined with twice a day administration.
lin glargine in dogs have been mixed and somewhat disappoint- Sako, etal., (2011) speculated that insulin detemir carries a higher
ing. We have been unable to attain good glycemic control in the risk of inducing hypoglycemia as compared to either NPH insu-
majority of diabetic dogs treated with insulin glargine. We do not lin or insulin glargine. In an unpublished study, insulin detemir
consider insulin glargine a rst choice insulin for the treatment of was effective in improving control of glycemia in thirteen diabetic
TABLE 6-7 C
OMPARISON OF INSULIN PREPARATION DOSAGES REQUIRED TO ATTAIN CONTROL
OF GLYCEMIA IN DIABETIC DOGS
Insulin Dosage (U/kg/injection)

INSULIN PREPARATION NUMBER OF DOGS MEDIAN RANGE STUDY
NPH 54 0.8* 0.4-1.9 Lorenzen, 1992
0.4 0.3-0.8
Lente 35 0.8 0.3-1.4 Monroe etal, 2005
PZI 17 0.9 0.4-1.5 Della-Maggiore etal, 2012
Glargine 12 0.6 0.1-1.1 Fracassi etal, 2012
Detemir 13 0.2 NR Ford, 2010
Detemir 15 0.3 0.1-0.6 UCD, 2013
NPH, Neutral protamine Hagedorn; NR, not reported; PZI, protamine zinc insulin.
*Dogs weighing < 15 kg
Dogs weighing 15 kg
UCD, 2013: Insulin dosage required to attain glycemic control in 15 of 24 diabetic dogs treated with insulin detemir at UC Davis veterinary hospital; glycemic control could not be attained
using detemir in 9 of the 24 dogs.
30 30
25
Number of BGCs (%)
25
20
20
GIR (mg/kg/min)
15
10 15
5 10
0
0 2 4 6 8 10 12 5
Hours when nadir was observed
FIGURE 6-9 Histograms indicate the number of blood glucose curves (BGCs; 0
%) from 12 dogs with diabetes mellitus treated by the administration of various 0 2 4 6 8 10 12 14 16 18 20 22 24
doses of insulin glargine twice daily for 24 weeks where the glucose nadir was Time (hours)
observed before (0) or 2, 4, 6, 8, 10, or 12 hours after insulin injection, respec- Dog 1 Dog 2 Dog 3
tively. (From Fracassi F, etal.: Use of insulin glargine in dogs with diabetes A
mellitus, Vet Rec 170:52, 2012.) 30
dogs managed with home blood glucose monitoring during a 4 25

to 24 month (median, 10 month) period (Ford etal, 2010). Ten
of 13 dogs were previously treated with NPH or Lente insulin 20
GIR (mg/kg/min)
with poor results. The mean and median insulin dosage on the
last week of evaluation was 0.45 and 0.22 U/kg/injection. Bio- 15
chemical hypoglycemia (blood glucose less than 60 mg/dL; 3.4
mmol/L) was identified in approximately 2% of all blood glucose 10
measurements and occurred on average 7.5 times per dog dur-
ing the study. Our experiences with insulin detemir in dogs have
5
been mixed but better than our experiences with insulin glargine.
The absorption of insulin detemir from the subcutaneous site of
injection is variable. In some diabetic dogs, the absorption is slow 0
and sustained, resulting in relatively flat blood glucose curves (Fig. 0 2 4 6 8 10 12 14 16 18 20 22 24
6-11). In other dogs, the absorption is similar to that seen with B Time (hours)
intermediate-acting insulin preparations like Lente, resulting in FIGURE 6-10 Time-action profile of insulin detemir over a 24-hour period in
U-shaped blood glucose curves (see Fig. 6-24). The most common three individual healthy non-diabetic dogs (A) and mean standard deviation
problem with insulin detemir has been hypoglycemia and induc- (SD) results in the three dogs (B). Results are presented as glucose infusion rate
tion of glucose counterregulation (i.e., Somogyi response) when (GIR) required to maintain euglycemia after the subcutaneous (SC) administra-
insulin detemir is given twice a day (see Insulin Overdosing and tion of 0.5 U/kg insulin detemir at time 0. Higher values of GIR indicate stronger
Glucose Counterregulation [Somogyi Response]). We do not insulin action. (From Sako T, etal.: Time-action profiles of insulin detemir in
consider insulin detemir a rst choice insulin for the treatment of normal and diabetic dogs, Res Vet Sci 90:396, 2011.)
|
500 500

Insulin determir
400 400
Glucose (mg/dL)
300 300
200 200
100 100
0 0
0 2 4 6 8 10 12 8 AM Noon 4 PM 8 PM
Time (hours) A
Dog 1 Dog 2 Dog 3 500

Dog 4 Dog 5
FIGURE 6-11 Results of 12-hour serum glucose curves after subcutaneous (SC) 400
administration of various doses of insulin detemir twice a day for 5 days in five
insulin-dependent diabetic dogs. Insulin detemir dosages administered at time 300
0 on day 5 were as follows: Dog 1, 0.23 U/kg; Dog 2, 0.19 U/kg; Dog 3, 0.09 U/kg;
Dog 4, 0.18 U/kg; and Dog 5, 0.07 U/kg. (From Sako T, etal.: Time-action profiles
of insulin detemir in normal and diabetic dogs, Res Vet Sci 90:396, 2011.) 200
100
diabetes in dogs but consider it the insulin of choice in diabetic
dogs with problems of short duration of effect of NPH and Lente
insulin. Our starting dosage for insulin detemir is 0.1 U/kg twice 0
8 AM Noon 4 PM 8 PM
a day.
Insulin Mixtures. Mixtures of short- and long-acting insulin B
have been developed in an attempt to mimic the increase in portal FIGURE 6-12 A, Blood glucose curve in a miniature poodle receiving recombinant
insulin concentrations during and immediately following con- human Lente insulin, 6 U/kg body weight (solid line, triangles) and recombinant
sumption of a meal, thereby minimizing postprandial hypergly- human 70/30 neutral protamine Hagedorn (NPH)/regular insulin, 3 U/kg body
cemia. NPH insulin can be mixed with regular crystalline insulin, weight (solid line, circles) subcutaneous (SC). B, Blood glucose curve in an 8 kg
and if injected immediately, the regular insulin remains rapid- cat receiving 4 U recombinant human Ultralente insulin (solid line, circles) and
acting. Stable premixed 75% NPH/25% regular, 70% NPH/30% 4 U of recombinant human 70/30 NPH/regular insulin (broken line, triangles)
regular, and 50% NPH/50% regular preparations are available SC. (From Nelson RW: Diabetes mellitus. In Ettinger SJ, Feldman EC, editors:
(e.g., Humulin 70/30 and Mixtard 70/30). Similarly, mixtures Textbook of veterinary internal medicine, ed 4, Philadelphia, 1995, Saunders,
of lispro and lispro protamine suspension (e.g., Humalog Mix p. 1528.) = insulin injection and food.
75/25 and Humalog Mix 50/50) and aspart and aspart protamine
suspension (e.g., Novolog Mix 70/30) are available. In our expe-
rience, these premixed preparations are quite potent, causing a insulins. Although keeping the bottle of insulin at room tempera-
rapid decrease in blood glucose concentration within 60 to 90 ture does not inactivate insulin, we routinely instruct clients to
minutes of subcutaneous administration (Fig. 6-12). In addition, store the insulin bottle in the door of the refrigerator to maintain
the duration of effect has usually been short (less than 8 hours). a consistent environment. Some veterinarians advocate replacing
We generally use these insulin mixtures only as a last resort when insulin with a new bottle every 1 to 2 months to prevent problems
more conventional insulin preparations have been ineffective in caused by loss of activity or sterility. This practice can create finan-
establishing control of glycemia. Although regular insulin remains cial hardship for some clients and may not be necessary. The shelf
fast acting when added to NPH, when added to Lente insulin, life of a bottle of insulin that has been stored appropriately is longer
regular insulin binds to excess zinc in the vial of Lente, blunting than manufacturer recommendations. We have not appreciated a
regular insulins quick effect (Galloway, 1988). clinically significant loss of insulin action with time when insulin
preparations, including glargine and detemir, are maintained in a
Insulin Storage, Mixing, and Dilution constant environment (i.e., refrigerator) and handled appropriately.
Freezing and heating the insulin bottle will inactivate insulin in Routinely purchasing a new bottle of insulin every month may not
the bottle. Historically, shaking the bottle of NPH, Lente, or PZI be necessary, especially if the diabetic dog is doing well. However,
insulin was believed to inactivate the insulin, but recent studies development of cloudiness or discoloration suggest contamination,
performed by the pharmaceutical company have shown that shak- change in pH of the solution (glargine), and/or loss of insulin activ-
ing the bottle of Lente insulin does not impact insulin action, pro- ity. The bottle of insulin should be discarded and replaced with a
vides more uniform dispersal of insulin throughout the solution new bottle of insulin. Similarly, loss of insulin activity in the bottle
than rolling the bottle, and is currently recommended. Similar should always be considered whenever clinical signs recur, regard-
recommendations have not yet been reported for NPH and PZI less of the quantity of insulin remaining in the bottle.
Dilution of insulin is a common practice, especially in very glycemic control before sending the dog home. Rather, the objec-
small dogs and cats. Only diluting solutions provided by the tive is to begin to reverse the metabolic derangements induced by
respective company should be used. Although studies evaluating the disease, allow the dog to equilibrate to the insulin and change
the shelf-life of diluted insulin have not been published, I recom- in diet, teach the owner how to administer insulin, and give the
mend replacing diluted insulin preparations every 4 to 8 weeks. owner a few days to become accustomed to treating the diabetic
Even when these guidelines are observed, insufficient amounts of dog at home. Adjustments in insulin therapy are made on subse-
insulin are administered when diluted insulin is used in some dogs quent evaluations once the owner and pet have gotten used to the
and cats, despite appropriate dilution and insulin administration treatment regimen.
techniques. These inadequacies are corrected when full-strength Diabetic dogs are typically evaluated once weekly until an
insulin is used. It is important to remember that insulin glargine is effective insulin treatment protocol is identified. Glycemic con-
pH dependent and should not be diluted with solutions that may trol is attained when clinical signs of diabetes have resolved; the
change the pH of the solution. pet is healthy and interactive in the home; its body weight is
See Chapter 7 for additional information on insulin prepara- stable (unless the dog is undergoing weight loss to correct obe-
tions, insulin handling, and owner instructions. sity); the client is satisfied with the progress of therapy; and, if
possible, the blood glucose concentrations range between 100
Initial Insulin Treatment Recommendations and 250 mg/dL (5.6 to 14 mmol/L) throughout the day. The cli-
Once the diagnosis of diabetes is established, dogs should be con- ent is informed at the time insulin therapy is initiated that it will
sidered insulin dependent and treatment with insulin should be take approximately 1 month to establish a satisfactory insulin
initiated. Porcine source Lente insulin (Vetsulin, Caninsulin) is treatment protocol, assuming unidentified insulin-antagonistic
the initial insulin of choice for treating newly-diagnosed diabetic disease is not present. The goals of therapy are also explained
dogs (see Table 6-6). Recombinant human NPH insulin is also to the client. During this month, changes in insulin dose and
effective but problems with short duration of effect are common possibly insulin type are common and should be anticipated by
with NPH insulin. Studies to date suggest that the median dos- the client. At each evaluation the clients subjective opinion of
age of Lente and NPH insulin required to attain glucose control water intake, urine output, and overall health of the pet is dis-
in most diabetic dogs is approximately 0.5 U/kg/injection, with cussed; a complete physical examination is performed; change
a range of 0.2 to 1.0 U/kg (see Table 6-7). One important goal in body weight noted; and serial blood glucose measurements
in the initial regulation of the diabetic dog is avoidance of symp- obtained over a 10- to 12-hour period after insulin administra-
tomatic hypoglycemia, especially in the home environment. For tion are assessed. Adjustments in insulin therapy are based on
this reason, the starting insulin dosage should be on the low end this information, the pet is sent home, and an appointment is
of the range (i.e., approximately 0.25 U/kg). Dietary therapy is scheduled for the next week to reevaluate the response to any
initiated concurrently (see later). We routinely start with twice a change in therapy. If the dog remains poorly controlled, the dose
day insulin administration because the overwhelming majority of of insulin is gradually increased by 1 to 5 U/injection (depend-
diabetic dogs require Lente and NPH insulin twice a day (Hess ing on the size of the dog) each week until control is attained.
and Ward, 2000; Monroe etal, 2005). Establishing control of gly- This gradual increase in dose helps prevent hypoglycemia and
cemia is easier and problems with hypoglycemia and the Somogyi the Somogyi response. Control of glycemia can be established in
response (see Insulin Overdosing and Glucose Counterrergula- most dogs using insulin doses in the range of 1.0 U of insulin/
tion [Somogyi Response]) are less likely when twice daily insulin kg or less (median, 0.5 U/kg) administered twice each day. If the
therapy is initiated while the insulin dose is low (i.e., at the time insulin dose exceeds 1.0 U/kg/injection without adequate glyce-
insulin treatment is initiated). mic control, then further investigations to determine the reason
Although recombinant human PZI, insulin glargine, and insulin for treatment failure are indicated (see Complications of Insulin
detemir are effective in controlling glycemia in some diabetic dogs, Therapy). If hypoglycemia is noted either clinically or biochem-
problems with consistency of effect, variable and unpredictable tim- ically at any time, the insulin dosage should be decreased and
ing of the glucose nadir, prolonged duration of effect, and suspected further adjustments in the insulin dose performed as needed to
induction of the Somogyi response preclude recommending these attain glycemic control.
insulin preparations in the newly-diagnosed diabetic dog. However, Many factors affect the dogs glycemic control from day to day,
these insulin preparations should be considered when problems including variations in insulin administration and absorption,
caused by short duration of insulin effect develop with Lente or dietary indiscretions and caloric intake, amount of exercise, and
NPH insulin (see Complications of Insulin Therapy). variables that affect insulin responsiveness (e.g., stress, concurrent
inflammation, infection). As a consequence, the insulin dosage
Initial Adjustments in Insulin Therapy required to maintain glycemic control typically changes (increase
Diabetic dogs require several days to equilibrate to changes in or decrease) with time. Initially, a fixed dosage of insulin is admin-
insulin dosage or preparation. Newly-diagnosed diabetic dogs are istered at home during the first few months of therapy, and changes
typically hospitalized for no more than 24 to 48 hours to finish in insulin dosage are made only after the owner consults with the
the diagnostic evaluation and begin insulin therapy. During hos- veterinarian. As the insulin dose range required to maintain glyce-
pitalization, blood glucose concentrations are typically determined mic control becomes apparent and as confidence is gained in the
at the time insulin is administered and at 3, 6, and 9 hours later. clients ability to recognize signs of hypoglycemia and hypergly-
The intent is to identify hypoglycemia (blood glucose less than 80 cemia, the client is eventually allowed to make slight adjustments
mg/dL; 4.5 mmol/L) in those dogs that are unusually sensitive to in the insulin dose at home on the basis of clinical observations
the actions of insulin. If hypoglycemia occurs, the insulin dos- of the pets well-being. However, the client is instructed to stay
age is decreased prior to sending the dog home. A minor adjust- within the agreed-upon insulin dose range. If the insulin dose is at
ment in the insulin dosage may be done in those dogs that remain the upper or lower end of the established range and the pet is still
hyperglycemic during these first few days of insulin therapy; how- symptomatic, the client is instructed to call the veterinarian before
ever, the objective during this first visit is not to establish perfect making further adjustments in the insulin dose.
|
of glycemia. Most diabetic diets contain a blend of soluble and

Dietary Therapy
insoluble fiber sources, including moderately fermentable fibers
Diet plays an important role in the management of the diabetic (e.g., rice bran, soy fiber, beet pulp) that have both soluble and
dog (Box 6-3). What diet is ultimately fed is dictated, in part, by insoluble fiber characteristics.
the weight of the dog, concurrent disease, and owner and dog Complications of feeding diabetic diets containing high fiber
preferences. Correction of obesity is the most beneficial step that content include excessive frequency of defecation, constipation,
can be taken to improve control of glycemia. Obesity-induced obstipation, soft stools, excessive flatulence, and refusal to eat the
insulin resistance has been documented in dogs and is an impor- diet (Box 6-4). Most of these problems will resolve by changing
tant factor accounting for variations in response to insulin therapy the type or quantity of fiber consumed (i.e., a change in the diet).
in diabetic dogs (Gayet etal, 2004; Yamka etal, 2006). Weight Problems with palatability are usually a result of too rapid of a
loss improves insulin resistance in obese diabetic dogs. Weight switch from the dogs usual diet to the diabetic diet or a result of
loss usually requires a combination of restricting caloric intake, boredom after consuming the diabetic diet for months. If palat-
feeding low calorie-dense diets, and increasing caloric expendi- ability is a problem initially, the dog can be gradually switched
ture through exercise. Diets specifically designed for weight loss from its regular diet to a diabetic diet over a 2- to 4-week period.
should be considered for obese diabetic dogs to promote weight Periodic changes in the types of diabetic diets and mixtures of dia-
loss. Weight loss diets contain higher quantities of insoluble fiber betic diets have been helpful in alleviating the problem of boredom
than diabetic diets and lower fat content to decrease the caloric with a diet. Palatability issues affiliated with feeding diets contain-
density of the food. High-fiber, low calorie-dense diets should not ing an increased amount of fiber should always be considered in
be fed to thin or emaciated diabetic dogs until control of glycemia the list of differential diagnoses for inappetence in a diabetic dog.
is established and a normal body weight is attained using a higher- Type and quantity of carbohydrate in the diet may also affect
calorie-dense, lower-fiber diet designed for maintenance. post-prandial blood glucose concentrations. For example, sor-
Most premium pet food companies offer diets designed for dia- ghum and barley have a lower glycemic index (i.e., lower impact
betic dogs (see Box 6-3). The composition of these diets varies on postprandial blood glucose and insulin concentrations) than
but most contain fiber. Increasing the fiber content of the diet is rice. Some diabetic diets for dogs use low glycemic index carbo-
beneficial for treating obesity and improving control of glycemia hydrates in an effort to minimize post-prandial hyperglycemia.
in diabetic dogs (Nelson etal, 1991; 1998; Graham etal, 1994; Digestible carbohydrate content of the diet (i.e., percentage of
Fig. 6-13). The ability of the food fiber to form a viscous gel and metabolizable energy derived from carbohydrates) also affects
thus impair convective transfer of glucose and water to the absorp- post-prandial blood glucose concentrations (Nguyen etal, 1998).
tive surface of the intestine appears to be of greatest importance In a recent study, consumption of a lower carbohydrate-contain-
in slowing intestinal glucose absorption. The more rapidly fering diet resulted in lower post-prandial blood glucose concentra-
mentable viscous soluble fibers (e.g., gums, citrus pectin) slow tions in healthy dogs, compared with a maintenance diet and a
glucose diffusion to a greater degree than the slowly fermentable diabetic diet containing increased carbohydrate content (Elliott
less viscous insoluble fibers (e.g., cellulose, hemicellulose) and, as etal, 2012). Although diets with moderate versus high carbohy-
such, are believed to be of greater benefit in improving control drate content may be preferred for diabetic dogs, a correspond-
ing increase in the percent metabolizable energy derived from fat
should be minimized to avoid an increase in blood lipid param-
eters, including cholesterol, triglycerides, free glycerol, and free
BOX 6-3 R
ecommendations for Dietary Treatment
fatty acids (Fleeman etal, 2009b). Derangements in fat metabo-
of Diabetes Mellitus in Dogs
lism are common in diabetic dogs and include increased serum
concentrations of cholesterol, triglycerides, lipoproteins, chylomi-
Correct obesity and maintain body weight in an acceptable range.
crons, and free fatty acids, hepatic lipidosis, atherosclerosis, and a
Control daily caloric intake.
predisposition for development of pancreatitis (Hess etal, 2002).
Increase daily exercise.
Dietary fat may also cause insulin resistance, promote hepatic glu-
Avoid excessive amounts of insulin.
cose production, and in healthy dogs, suppress beta-cell function
Maintain consistency in the timing and caloric content of the meals.
(Massillon etal, 1997; Kaiyala etal, 1999). Low fat highly digest-
Feed within the time frame of insulin action.
ible diets (e.g., Royal Canin Gastrointestinal Low Fat Diet) are
Feed one half the daily caloric intake at the time of each insulin injection
an alternative to fiber-containing diabetic diets, especially if acute
with every 12-hour insulin therapy or at the time of the insulin injection
or chronic pancreatitis or persistent hyperlipidemia are concur-
and 6 to 10 hours later with every 24-hour insulin therapy.
rent problems or palatability is a problem with diabetic diets. A
Minimize the impact of food on postprandial blood glucose concentrations.
higher fat content may be needed for weight gain in thin or emaci-
Avoid monosaccharides and disaccharides, propylene glycol, and corn
ated diabetic dogs. Feeding lower-fat diets may help minimize the
syrup.
risk of pancreatitis, control some aspects of hyperlipidemia, and
Let nibbler dogs nibble throughout the day and night; ensure that other
reduce overall caloric intake to favor weight loss or maintenance
pets do not have access to the food; provide one-half of total daily calo-
(Remillard, 1999).
ries at time of each insulin injection.
Increase the fiber content of the diet. Feeding Schedule
Examples of Veterinary Diets Designed for Diabetic Dogs The feeding schedule should be designed to enhance the actions
Hills Prescription Diet w/d of insulin and minimize postprandial hyperglycemia. The devel-
Hills Prescription Diet r/d (obese diabetic dog) opment of postprandial hyperglycemia depends, in part, on the
Purina DCO amount of food consumed per meal, the rate at which glucose
Purina OM (obese diabetic dog) and other nutrients are absorbed from the intestine, and the effec-
Royal Canin Diabetic tiveness of exogenous insulin during the postprandial period. The
daily caloric intake should be ingested when insulin is still present
Serum glucose concentration (mg/dL) 400
300
*
200 * * * * * FIGURE 6-13Mean ( standard error of
* *
* the mean) serum concentrations of glucose
in eleven dogs with naturally occurring
100 diabetes mellitus fed high-insoluble fiber
(i.e., cellulose; solid line) and low-fiber (broken
line) diet. (From Nelson RW, etal.: Effect of
dietary insoluble fiber on glycemic control in
dogs with naturally-occurring diabetes mel-
8 AM Noon 4 PM 8 PM Midnight 4 AM 8 AM litus, J Am Vet Med Assoc 212:380, 1998.)
Time = Insulin administration and consumption
of half of daily caloric intake; * = p < 0.05,
compared with low fiber diet.
600 60

BOX 6-4 C
ommon Complications Associated
Serum insulin concentration (U/mL)

with Feeding Diets Containing Increased 50
500
Quantities of Fiber
400 40
Inappetence caused by poor palatability or boredom with food
Increased frequency of defecation 30
300
Constipation and obstipation (insoluble fiber)
Soft stools and diarrhea (soluble fiber)
200 20
Increased flatulence (soluble fiber)
Weight loss
100 10
Hypoglycemia
8 AM Noon 8 PM Mid 8 AM
in the circulation and is capable of disposing of glucose absorbed
from the meal. If the meals are consumed while exogenous insulin * *
is still metabolically active, the postprandial increase in blood glu-
FIGURE 6-14 Mean blood glucose (solid line) and serum insulin (broken line)
cose concentration is minimal or absent. In contrast, feeding the
concentrations in eight dogs with diabetes mellitus treated with beef/pork source
diabetic dog after insulin action has waned results in increasing
neutral protamine Hagedorn (NPH) insulin subcutaneously once daily. The duration
blood glucose concentration beginning 1 to 2 hours postprandi-
of NPH effect is too short, resulting in prolonged periods of hyperglycemia begin-
ally (Fig. 6-14). If this occurs, either the type of insulin, frequency
ning shortly after feeding the evening meal. (From Nelson RW: Diabetes mellitus.
of insulin administration, or timing of the meals in relationship to
In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine,
the insulin injection should be adjusted.
ed 4, Philadelphia, 1995, Saunders, p. 1525.) = Insulin injection; * = equal-
Typically, dogs receiving exogenous insulin twice a day are fed
sized meals consumed.
equal-sized meals at the time of each insulin injection. If the dog
is receiving exogenous insulin once a day, one half of the daily
caloric intake is fed at the time of the insulin injection and the be allowed to continue their pattern of eating. For these dogs, half
remaining half approximately 8 hours later. Unfortunately, the of the total daily food intake should be available beginning at the
eating behavior of dogs varies considerably, from finicky eaters time of each insulin injection and the dog allowed to choose when
that nibble on food periodically throughout the day to gluttonous and how much to eat. The dog should have access to the food
dogs that quickly consume everything placed in their food dish. throughout the day and night, and other dogs in the household
Gluttonous dogs are fed as discussed earlier. Finicky dogs gener- cannot have access to the food.
ally resist attempts by owners to convert them to a gluttonous
type of eating behavior, which can be frustrating to the owner Modifications in Dietary Therapy
instructed to have their pet eat all of its food at the time of the Concurrent disease in which diet is an important aspect of ther-
insulin injection. However, if one adheres to the principle that apy also dictates the type of diet to be fed. For example, diabetic
feeding multiple small meals rather than one large meal within dogs with concurrent chronic pancreatitis or exocrine pancreatic
the time frame of insulin action helps minimize the hyperglycemic insufficiency (pancreatic acinar atrophy) should be fed a low fat,
effect of each meal, then allowing a finicky eater to eat whenever it low fiber, highly digestible diet. Diabetic dogs with CKD should
wants should help control fluctuations in blood glucose. For this be fed a lower protein diet designed for kidney failure. Diabetic
reason, dogs that are finicky and nibble throughout the day should dogs with concurrent inflammatory bowel disease may need a
|
Blood glucose (mg/dL) 500 must be aware of the signs of hypoglycemia and have a source of
400
glucose (e.g., candy, food, sugar solution) readily available to give
their dog should any of these signs develop.
300
200 Oral Hypoglycemic Drugs

100 Oral hypoglycemic drugs work by stimulating pancreatic insulin
0
secretion (e.g., sulfonylureas, meglitinides, glucagon-like pep-
6 AM 9 AM Noon 3 PM 6 PM 9 PM Mid tide-1 [GLP-1] receptor agonists, dipeptidyl peptidase-4 [DPP-4]
inhibitors), inhibiting glucagon secretion (e.g., DPP-4 inhibitors
Insulin 2 mile walk Fed or gliptins), enhancing tissue sensitivity to insulin (e.g., met-
Fed formin, thiazolidinediones), or slowing postprandial intestinal
FIGURE 6-15 Serial blood glucose curve obtained by the owner at home after the glucose absorption (-glucosidase inhibitors). Although contro-
administration of 1 U/kg porcine Lente insulin to a 35 kg male-castrate diabetic versial, chromium and vanadium are trace minerals that may also
Labrador Retriever. The treatment regimen adopted by the owner included the function as insulin sensitizers. Oral hypoglycemic drugs are pri-
administration of porcine Lente insulin once a day at 6 AM, equal-sized meals fed marily used for the treatment of type 2 diabetes; a form of diabetes
at 6 AM and 5 PM, and a 2-mile walk beginning at 9 AM. The owner was obtaining that is not recognized in dogs. Oral sulfonylurea drugs (e.g., glipi-
blood glucose curves almost every day and adjusting the insulin dose based on zide, glyburide) directly stimulate insulin secretion by beta cells
the results. The blood glucose concentration typically decreased 70 to 140 mg/dL and are the most commonly used oral hypoglycemic drugs for the
after the walk as illustrated in this glucose curve, compared with days when the treatment of diabetes mellitus in humans and cats but are ineffec-
dog was not walked. The owner sought help because of persistence of polyuria tive in diabetic dogs, presumably because dogs have an inadequate
and polydipsia, especially at night, despite increasing the insulin dose. Polyuria mass of functional beta cells at the time diabetes is diagnosed.
and polydipsia improved with initiation of twice a day administration of porcine
Lente insulin and feeding the dog at the time of each insulin injection. Acarbose
Acarbose is a complex oligosaccharide of microbial origin that com-
petitively inhibits pancreatic alpha-amylase and alpha-glucosidases
hypoallergenic diet to help control inflammation and clinical (glucoamylase, sucrase, maltase, and isomaltase) in the brush border
signs. Whenever possible, dietary therapy for all disorders should of the small intestinal mucosa, which delays digestion of complex
be blended; however, if this is not possible, dietary therapy carbohydrates, delays absorption of glucose from the intestinal tract,
for the most serious disorder should take priority. For example, and decreases postprandial blood glucose concentrations. Placebo-
dietary therapy for chronic renal failure, heart failure, or recurring controlled clinical studies completed in healthy and diabetic dogs
pancreatitis is a higher priority than dietary therapy for diabetes documented a decrease in postprandial total glucose absorption and
mellitus. Dietary therapy for diabetes mellitus should be consid- total insulin secretion when healthy dogs were treated with acarbose
ered adjunctive; glycemic control can be maintained with insulin, (compared with placebo) and a decrease in daily insulin dose, mean
regardless of the diet fed. blood glucose concentration during an 8 hour blood sampling
period, and blood glycated protein concentrations in diabetic
dogs treated with acarbose (compared with placebo) (Robertson
Exercise
etal, 1999; Nelson etal, 2000; Fig. 6-16). Although acarbose may
Exercise plays an important role in maintaining glycemic control be beneficial in improving control of glycemia in some dogs with
in the diabetic dog by helping promote weight loss and by elimi- insulin-requiring diabetes, the high prevalence of adverse effects
nating the insulin resistance induced by obesity. Exercise also has (diarrhea and weight loss) resulting from carbohydrate malassimila-
a glucose-lowering effect by increasing the mobilization of insulin tion and the expense of the drug limit its usefulness.
from its injection site, presumably resulting from increased blood
and lymph flow, by increasing blood flow (and therefore insu- Chromium
lin delivery) to exercising muscles, by stimulating translocation Chromium is a ubiquitous trace element that exerts insulin-like
(i.e., upregulation) of glucose transporters (primarily GLUT-4) in effects invitro. The exact mechanism of action is not known, but
muscle cells, and by increasing glucose effectiveness (i.e., ability of the overall effect of chromium is to increase insulin sensitivity, pre-
hyperglycemia to promote glucose disposal at basal insulin con- sumably through a post-receptor mechanism of action (Anderson,
centrations) (Fernqvist etal, 1986; Galante etal, 1995; Phillips 1992; Striffler etal, 1995; Anderson et al, 1997). Chromium does
etal, 1996; Nishida etal, 2001; Fig. 6-15). The daily routine for not increase serum insulin concentrations. Chromium is an essen-
diabetic dogs should include exercise, preferably at the same time tial cofactor for insulin function, and chromium deficiency results
each day and not around the time of peak insulin effect. Strenuous in insulin resistance. In one study, dietary chromium picolinate
and sporadic exercise can cause severe hypoglycemia and should supplementation improved results of an intravenous (IV) glucose
be avoided. If unavoidable, the insulin dose should be decreased tolerance test in healthy dogs, compared with healthy dogs not
in dogs subjected to sporadic strenuous exercise on those days treated with chromium (Spears etal, 1998). Other studies failed to
of anticipated increased exercise. The reduction in insulin dose identify an effect of dietary chromium picolinate supplementation
required to prevent hypoglycemia is variable and determined by on glucose tolerance in obese dogs during weight reduction (Gross
trial and error. Reducing the insulin dose by 50% initially is rec- etal, 2000) nor did it improve control of glycemia in the diabetic
ommended, and further adjustments should be based on mea- dogs treated with 200 to 400 g of chromium picolinate by mouth
surement of blood glucose concentration with a portable blood twice daily (Schachter et al, 2001; Fig. 6-17). Chromium pico-
glucose monitor during exercise, the occurrence of symptomatic linate is considered a nutraceutical in the United States and can
hypoglycemia, and the severity of polyuria and polydipsia that be purchased in health food and drug stores. It is inexpensive, and
develops during the ensuing 24 to 48 hours. In addition, owners there are no known toxic effects associated with its ingestion.
Total AUI6h (U/mL/6 hr SD)

3000
2000
*
*
1000
0
0 25 50 100 200
A Acarbose dose (mg/dog)
FBG MBG8h Gly Hgb

(mg/dL) (mg/dL) (%)
400 400 8 FIGURE 6-16 A, Mean total insulin secretion for five healthy dogs
during the first 6 hours after consumption of a meal and a placebo
300 300 6 * or 25, 50, 100, or 200 mg of acarbose. T-bars represent standard er-
ror of the mean. B, Fasting blood glucose (FBG), mean blood glucose
over an 8-hour time period (MGB8h), and blood total glycosylated
200 200 4
hemoglobin (Gly Hgb) in five dogs with insulin-dependent diabetes
*
mellitus treated with insulin and placebo (black bars) and insulin
100 100 2 and acarbose (gray bars) for 2 months each in a randomly assigned
treatment sequence. T-bars represent standard deviation. (A, From
0 0 0 Robertson J, etal.: Effects of the alpha-glucosidase inhibitor acar-
bose on postprandial serum glucose and insulin concentrations in
Placebo Acarbose healthy dogs, Am J Vet Res 60:541, 1999.) A, B, * = p < 0.05, com-
B pared with value obtained after treatment with placebo.
500 long-term complications of diabetes (e.g., coronary artery disease,

Blood glucose (mg/dL)
retinopathy); and improving the overall well-being of the patient

400
(Roszler, 2001; Box 6-5). Proposed beneficial effects vary with the
300 herb, supplement, or vitamin utilized and include delaying nutri-
ent absorption from the gastrointestinal tract, stimulating insulin
200 secretion, improving insulin sensitivity, altering lipid metabolism,
100 improving circulation, and benefits attributed to antioxidant
properties. Some herbs, supplements, and vitamins (e.g., ginseng,
0 chromium, fish oils, and psyllium) have been critically evaluated
0 2 hrs 4 hrs 6 hrs 8 hrs 10 hrs
for efficacy, whereas others are recommended based primarily
on folklore and testimonials (Pastors et al, 1991; Striffler et al,
FIGURE 6-17Mean ( standard deviation) blood glucose concentrations 1995; Vuksan et al, 2001). Critical studies assessing the effects
obtained from 13 dogs with insulin-dependent diabetes mellitus before insulin of herbs, supplements, and vitamins on diabetic control and
and feeding (8 AM = Time 0) and for 10 hours after insulin administration only complications are needed before these alternative therapies can
(broken line) or after insulin and chromium tripicolinate administration (solid be recommended in diabetic dogs. Intuitively, it seems doubtful
line). Dogs were treated for 3 months with insulin and then 3 months with insulin that the herbs, supplements, and vitamins listed in Box 6-5 will
and chromium tripicolinate. Mean blood glucose concentrations are the mean have much of an impact in diabetic dogsin part because these
of all corresponding blood glucose values obtained during the 10-hour blood therapies are primarily used for treating type 2 diabetes, which
sample collection period for each dog at 1, 2, and 3 months of each treatment is not recognized in diabetic dogs, and delaying chronic diabetic
period. (From Schachter S, etal.: Oral chromium picolinate and control of glyce- complications, which are uncommon in dogs.
mia in insulin-treated diabetic dogs, J Vet Intern Med 15:379, 2001.) = time of
insulin or insulin and chromium picolinate administration.
Identification and Control of Concurrent Problems
Concurrent disease and administration of insulin-antagonistic
Herbs, Supplements, and Vitamins drugs are commonly identified in the dog with newly-diagnosed
Alternative therapies that include herbs, supplements, and vita- diabetes mellitus (Hess et al, 2000b; Peikes et al, 2001). Con-
mins in conjunction with or in lieu of the more conventional current disease and insulin-antagonistic drugs can interfere with
treatment options have been used by some individuals with type tissue responsiveness to insulin, resulting in insulin resistance
2 diabetes. The goals for using herbs, supplements, and vitamins and poor control of the diabetes. Concurrent disease and insu-
are primarily centered around decreasing blood glucose, tri- lin-antagonistic drugs typically cause insulin resistance by alter-
glyceride, and cholesterol concentrations; delaying the onset of ing insulin metabolism (prereceptor problem), by decreasing the
|
BOX 6-5 Herbs, Supplements, and Vitamins that have been Used to Treat Diabetes Mellitus in Humans
Improve Hyperglycemia Capsaicin (cayenne pepper) (topical ointment)

Alpha-lipoic acid Evening primrose oil
Vitamin C
Improve Hyperlipidemia
Vitamin E
Vitamin E
Chromium
Evening primrose oil
Vanadium
Fish oils (e.g., omega-3 fatty acids)
Fenugreek seeds
Selenium
American and Asian ginseng
Gymnema sylvestre Prevent Cataracts
Psyllium seeds Alpha-lipoic acid
Cinnamon Vitamin C
Prevent Coronary Artery Disease Prevent Retinopathy
Vitamin C Vitamin E
Vitamin E Pycnogenol (pine bark extract)
Quercetin Antioxidant
Improve Circulation Alpha-lipoic acid
Gingko biloba Vitamin A
Pycnogenol Vitamin C
Vitamin E
Prevent/Control Pain from Neuropathy
Pycnogenol
Alpha-lipoic acid
Quercetin
Vitamin B6
Selenium
From Roszler J: Herbs, supplements and vitamins: what to try, what to buy, Diabetes Interviews August: 45, 2001.
concentration or binding affinity of insulin receptors on the cell

membrane (receptor problem), by interfering with the insulin BOX 6-6 Complications of Diabetes Mellitus
receptor signaling cascade (postreceptor problem), or by a com-
bination of these. Depending on the etiology, insulin resistance
may be mild and easily overcome by increasing the dose of insu- Common
lin (e.g., obesity); may be severe, causing sustained and marked Iatrogenic hypoglycemia
hyperglycemia regardless of the type and dose of insulin admin- Persistent or recurring polyuria, polydipsia, weight loss
istered (e.g., hyperadrenocorticism); or may fluctuate in severity Cataracts
over time (e.g., chronic pancreatitis). Some causes of insulin resis- Lens-induced uveitis
tance are readily apparent at the time diabetes is diagnosed, such Bacterial infections, especially involving the urinary tract
as obesity and the administration of insulin-antagonistic drugs Chronic pancreatitis
(e.g., glucocorticoids). Other causes of insulin resistance are not Recurring ketosis, ketoacidosis
readily apparent and require an extensive diagnostic evaluation to Hepatic lipidosis
be identified. In general, any concurrent inflammatory, infectious, Peripheral neuropathy
hormonal, or neoplastic disorder can cause insulin resistance and Systemic hypertension
interfere with the effectiveness of insulin therapy. Identification Uncommon
and treatment of concurrent disease plays an integral role in the Diabetic nephropathy
successful management of the diabetic dog. A thorough his- Significant proteinuria
tory, physical examination, and complete diagnostic evaluation Glomerulosclerosis
are imperative in the newly-diagnosed diabetic dog (see Clinical Retinopathy
Pathologic Abnormalities). Exocrine pancreatic insufficiency
Gastric paresis
TECHNIQUES FOR MONITORING DIABETIC Intestinal hypomotility and diarrhea
CONTROL Diabetic dermatopathy (i.e., superficial necrolytic dermatitis)
The basic objective of insulin therapy is to eliminate the clini-

cal signs of diabetes mellitus while avoiding or delaying the onset
of common complications associated with the disease (Box 6-6). recurring ketosis, and recurrence of polyuria and polydipsia. The
Blindness caused by cataract formation is inevitable for most dia- devastating chronic complications of human diabetes (e.g., dia-
betic dogs but can be delayed if good glycemic control can be betic nephropathy, atherosclerosis) require years to develop and
established and wide fluctuations in the blood glucose concentra- become clinically relevant, and are uncommon in diabetic dogs,
tion avoided (see Cataracts). Complications to avoid include poor in part, because diabetes is diagnosed in older dogs. As such, the
hair coat and unthrifty appearance, weight loss, hypoglycemia, need to establish nearly normal blood glucose concentrations is
not necessary in diabetic dogs. Most clients are happy, and most TABLE 6-8 S
AMPLE HANDLING, METHODOL-
dogs are healthy and relatively asymptomatic if most blood glu- OGY, AND NORMAL VALUES FOR
cose concentrations are kept between 100 mg/dL and 250 mg/dL SERUM FRUCTOSAMINE
(5.6 to 14 mmol/L). CONCENTRATIONS MEASURED
IN OUR LABORATORY IN DOGS
History and Physical Examination
Blood sample 1 to 2 mL serum
The most important initial parameters for assessing control of gly-
cemia are the owners subjective opinion of severity of clinical signs Sample handling Freeze until assayed
and overall health of their pet, findings on physical examination, Methodology Automated colorimetric assay using
and stability of body weight. If the owner is happy with results nitroblue tetrazolium chloride
of treatment, the physical examination is supportive of good gly- Factors affecting results Hypoalbuminemia (decrease), hypothy-
cemic control, and the body weight is stable, the diabetic dog is roidism (increase), hyperlipidemia
usually adequately controlled (Briggs etal, 2000). Measurement (mild decrease), azotemia (mild
of serum fructosamine concentration can add further objective decrease), prolonged storage at
evidence for status of glycemic control (see Serum Fructosamine room temperature (decrease), hemo-
Concentration). Poor control of glycemia should be suspected lysis (decrease)
and additional diagnostics (i.e., serial blood glucose curve, serum Normal range 225 to 365 mol/L
fructosamine concentration, tests for concurrent disorders) or a
change in insulin therapy considered if the client reports clinical Interpretation in diabetic dogs:
signs suggestive of hyperglycemia or hypoglycemia (i.e., polyuria, Excellent control 350 to 400 mol/L
polydipsia, lethargy, weakness, ataxia), the physical examination Good control 400 to 450 mol/L
identifies problems consistent with poor control of glycemia (e.g.,
Fair control 450 to 500 mol/L
thin appearance, poor hair coat), or the dog is losing weight.
Poor control > 500 mol/L
Single Blood Glucose Determination Prolonged hypoglycemia < 300 mol/L

Diabetic remission < 300 mol/L
Measuring a single blood glucose concentration is helpful only if
hypoglycemia is identified. Documenting hypoglycemia supports
insulin overdosage and the need to decrease the insulin dose, espe-
cially if glycemic control is poor. In contrast, documenting an glucose concentration, as occurs with stress or excitement-
increased blood glucose concentration does not, by itself, confirm induced hyperglycemia (Crenshaw et al, 1996). Serum fruc-
poor control of glycemia. Stress or excitement can cause marked tosamine concentrations can be measured during the routine
hyperglycemia, which does not reflect the dogs responsiveness evaluation of the diabetic dog; to clarify the effect of stress or
to insulin and can lead to the erroneous belief that the diabetic excitement on blood glucose concentrations; to clarify discrepan-
dog is poorly controlled. If a discrepancy exists between the his- cies between the history, physical examination findings, and serial
tory, physical examination findings, and blood glucose concen- blood glucose concentrations; and to assess the effectiveness of
tration or if the dog is fractious, aggressive, excited, or scared changes in insulin therapy.
and the blood glucose concentration is known to be unreliable, Serum for fructosamine determination should be frozen and
measurement of serum fructosamine concentration should be shipped on cold packs overnight to the laboratory. Although
done to further evaluate status of glycemic control. In addition, freezing does not cause a significant change in results, prolonged
a single blood glucose concentration is not reliable for evaluating storage of serum at room temperature can decrease serum fruc-
the effect of a given insulin type and dose in a poorly-controlled tosamine results; storage of serum in the refrigerator can also
diabetic dog. decrease the serum fructosamine result (Jensen, 1992). An auto-
mated colorimetric assay using nitroblue tetrazolium chloride is
Serum Fructosamine Concentration used for measurement of fructosamine concentrations in serum.
A linear relationship between serum total protein, albumin, and
Serum fructosamines are glycated proteins found in blood that fructosamine concentration has been identified, and hypopro-
are used to monitor control of glycemia in diabetic dogs and cats teinemia and hypoalbuminemia can decrease the serum fructos-
(Reusch etal, 1993; Crenshaw etal, 1996; Elliott etal, 1999). amine concentration below the reference range in healthy dogs
Fructosamines result from an irreversible, non-enzymatic, insu- and presumably diabetic dogs as well (Loste and Marca, 1999;
lin-independent binding of glucose to serum proteins. Serum Reusch and Haberer, 2001; Table 6-8). A decrease in serum fruc-
fructosamine concentrations are a marker of the average blood tosamine results has also been identified with hyperlipidemia,
glucose concentration during the circulating lifespan of the pro- azotemia, hyperthyroidism (cats), and interfering substances such
tein, which varies from 1 to 3 weeks depending on the protein as hemolysis (Reusch and Haberer, 2001; Reusch and Tomsa,
(Kawamoto et al, 1992). The extent of glycosylation of serum 1999). An increase in serum fructosamine concentration above
proteins is directly related to the blood glucose concentration; the reference range has been identified in two dogs with hyper-
the higher the average blood glucose concentration during the globulinemia caused by multiple myeloma and in dogs with nat-
preceding 2 to 3 weeks, the higher the serum fructosamine con- urally-acquired hypothyroidism; an increase that decreased after
centration, and vice versa. Serum fructosamine concentrations initiation of sodium levothyroxine treatment (Zeugswetter etal,
increase when glycemic control of the diabetic dog worsens and 2010; Reusch et al, 2002). A significant change in serum fruc-
decrease when glycemic control improves. Serum fructosamine tosamine results was not detected in healthy dogs with hyperpro-
concentration is not affected by acute increases in the blood teinemia or hyperbilirubinemia or in healthy dogs treated with
|
600 600 12
500 500 10
400 400 8
300 300 6
200 200 4
100 100 2
0 0 0
MBG8h Fructosamine Gly Hgb
(mg/dL SD) (mol/L SD) (% SD)
FIGURE 6-18 Mean blood glucose concentration determined over an 8-hour period (MBG8h), serum fructosamine
concentration, and blood total glycosylated hemoglobin (Gly Hgb) in 10 diabetic dogs with poor control of glycemia
caused by the Somogyi phenomenon (gray bars) and 12 diabetic dogs with poor control of glycemia caused by
hyperadrenocorticism-induced insulin resistance (black bars). Note the similar glycated protein results in both
groups of dogs. Although the average blood glucose concentration is lower on the day hypoglycemia is identified in
dogs with the Somogyi phenomenon, high blood glucose concentrations on subsequent days result in high glycated
protein concentrations.
glucosamine-chondroitin sulfate (Lenox etal, 2010). Each labo- assess glycemic control conflicts, reliance on the history, physical
ratory should furnish its own reference range for serum fructos- examination, and body weight is recommended when deciding if
amine. In our laboratory, the normal reference range for serum a change in insulin therapy is indicated.
fructosamine in dogs is 225 to 365 mol/L, which is a range deter-
mined in healthy dogs with persistently normal blood glucose
Blood Glycated Hemoglobin Concentration
concentrations (Briggs etal, 2000). Serum fructosamine concen-
tration in newly diagnosed diabetic dogs ranged from 320 to 850 Glycated hemoglobin (Gly Hb) is a glycated protein that results
mol/L. The normal serum fructosamine concentration in a few from an irreversible, nonenzymatic, insulin-independent bind-
diabetic dogs suggests hyperglycemia severe enough to cause clini- ing of glucose to hemoglobin in red blood cells. Blood Gly Hb
cal signs had only been present for a short time prior to diagnosis. is a marker of the average blood glucose concentration during the
Interpretation of serum fructosamine in a diabetic dog must circulating lifespan of the red blood cell, which is approximately
take into consideration the fact that hyperglycemia is common, 110 days in the dog (Jain, 1993). The extent of glycosylation of
even in well-controlled diabetic dogs (see Table 6-8). Most own- hemoglobin is directly related to the blood glucose concentration;
ers are happy with their pets response to insulin treatment if the higher the average blood glucose concentration during the
serum fructosamine concentrations can be kept between 350 and preceding 3 to 4 months, the higher the blood Gly Hb, and vice
450 mol/L. Values greater than 500 mol/L suggest inadequate versa. Gly Hb is used to monitor long-term effectiveness of treat-
control of the diabetic state, and values greater than 600 mol/L ment in human diabetics, in part, because diabetic humans self-
indicate serious lack of glycemic control. Serum fructosamine monitor their blood glucose and adjust their insulin dose daily,
concentrations in the lower half of the reference range (i.e., < 300 and Gly Hb assesses a longer treatment interval than fructosamine
mol/L) or below the reference range should raise concern for sig- (i.e., 3 to 4 months versus 2 to 3 weeks, respectively). In con-
nificant periods of hypoglycemia in the diabetic dog or concurrent trast, measurement of serum fructosamine is used to assess control
problems that decrease the serum fructosamine concentration (see of glycemia in diabetic dogs, in part, because the assay is readily
Table 6-8). Increased serum fructosamine concentrations (i.e., available commercially and is better for assessing the impact of
> 500 mol/L) suggest poor control of glycemia but do not iden- changes in insulin therapy on control of glycemia in fractious dogs
tify the underlying problem (Fig. 6-18). Obtaining a serial blood because concentrations of fructosamine change more quickly than
glucose curve is usually the next diagnostic step to identify the Gly Hb.
problem (see Serial Blood Glucose Curve). In dogs and cats, there are three fractions of Gly Hbone
Serum fructosamine concentrations should not be used as the major fraction (Gly HbA1c) that binds glucose and two minor
sole indicator of status of glycemic control but rather should be fractions (Gly HbA1a and Gly HbA1b) that do not (Hasegawa
interpreted in conjunction with the history, findings on physical etal, 1991; 1992). Measurement of Gly HbA1c is typically used
examination, and stability of body weight. A disconnect between to evaluate status of glycemic control in human diabetics, whereas
interpretation of the serum fructosamine concentration and the studies in diabetic dogs have used assays that measure all three
clinical picture or, more commonly, results of blood glucose con- fractionsi.e., total Gly Hg (Elliott et al, 1997) or Gly HbA1c
centrations may occur in some diabetic dogs. When a low serum (Marca etal, 2000; Marca and Loste, 2001). Most techniques that
fructosamine concentration is identified in a dog with suspected measure total Gly Hg have been shown to be clinically valid for
poor control of the diabetic state, reasons for a low fructosamine assessing degree of diabetic control (Elliott etal, 1997; Mahaffey
test result (see Table 6-8) or an increase in serum glucose concen- and Cornelius, 1982).
trations should be considered, and vice versa when a high serum Gly Hb is measured in whole blood collected in ethylenediami-
fructosamine concentration is identified in a dog with suspected netetraacetic acid (EDTA). Blood samples can be refrigerated up
good control of the diabetic state. Whenever information used to to a week without significant change in the Gly Hb concentration.
TABLE 6-9 SAMPLE HANDLING, cats because, in our experience, blood Gly Hb did not have any
METHODOLOGY, AND NORMAL diagnostic advantage over serum fructosamine determinations for
VALUES FOR BLOOD TOTAL assessing control of glycemia.
GLYCOSYLATED HEMOGLOBIN
CONCENTRATIONS MEASURED Urine Glucose Monitoring
IN OUR LABORATORY IN DOGS
Occasional monitoring of urine for glycosuria and ketonuria is
Blood sample 1 to 2 mL whole blood in EDTA helpful in diabetic dogs that have problems with recurring ketosis
or hypoglycemia to identify ketonuria or persistent negative gly-
Sample handling Refrigerate until assayed
cosuria, respectively. The client is instructed not to adjust daily
Methodology Affinity chromatography and hemoly- insulin doses on the basis of morning urine glucose measure-
sates derived from canine red blood ments, except to decrease the insulin dose in dogs with recurring
cells hypoglycemia and persistent negative glycosuria. Many diabetic
Factors affecting results Storage at room temperature (decrease); dogs develop complications because clients are misled by morning
storage at 4o C for longer than 7 days urine glucose concentrations and increase the insulin dose, which
(decrease); anemia (Hct < 35%) eventually results in the Somogyi response (see Insulin Overdos-
(decrease) ing and Glucose Counterregulation [Somogyi Response]). Persis-
Normal range 1.7% to 4.9% tent glycosuria throughout the day and night suggests inadequate
control of the diabetic state and the need for a more complete
Interpretation in diabetic dogs: evaluation of diabetic control using other techniques discussed in
Excellent control 4% to 5% this section.
Good control 5% to 6%
Fair control 6% to 7% Serial Blood Glucose Curve
Poor control > 7% If an adjustment in insulin therapy is deemed necessary after
Prolonged hypoglycemia < 4% reviewing the history, physical examination, changes in body
weight, and serum fructosamine concentration, then a serial blood
EDTA, Ethylenediaminetetraacetic acid; Hct, hematocrit. glucose curve should be generated to provide guidance in making
the adjustment unless blood glucose measurements are unreliable
because of stress, aggression, or excitement. The serial blood glu-
In dogs, blood Gly Hb has been measured by affinity chromatog- cose curve provides guidelines for making rational adjustments in
raphy (Wood and Smith, 1982; Elliott et al, 1997), colorimet- insulin therapy. Evaluation of a serial blood glucose curve is man-
ric analysis (Mahaffey and Cornelius, 1981), ion-exchange high datory during the initial regulation of the diabetic dog and is nec-
performance liquid chromatography (Hasegawa etal, 1991), and essary in the dog in which clinical manifestations of hyperglycemia
immunoturbidimetric assay (Marca and Loste, 2001). Assays for or hypoglycemia have developed. Reliance on history, physical
measuring Gly Hb are designed for use in humans. As such, it is examination, body weight, and serum fructosamine concentra-
important that the Gly Hb assay be validated for use in the dog tion to determine when a serial blood glucose curve is needed help
and that a normal reference range is established for the dog. In our reduce the frequency of performing serial blood glucose curves,
experience, several Gly Hb assays, especially in-house automated thereby minimizing the dogs aversion (and stress) to these evalu-
analyzers for rapid measurement of Gly HbA1c in human diabet- ations and improving the chances of obtaining meaningful blood
ics, have not provided valid results in dogs or cats. Any condition glucose results when a serial blood glucose curve is needed.
that affects red cell life span may affect Gly Hb concentration.
Anemia and polycythemia can falsely decrease and increase Gly Protocol for Generating the Serial Blood Glucose
Hb concentrations, respectively (Elliott etal, 1997). The hemato- Curve in the Hospital
crit should be taken into consideration when interpreting Gly Hb When a blood glucose curve is being generated, the insulin and
concentrations. feeding schedule used by the client should be maintained and the
In our laboratory, the normal reference range for total Gly Hb as dog dropped off at the hospital early in the morning. Owners of
measured by affinity chromatography in dogs was 1.7% to 4.9%, diabetic dogs who are finicky eaters should feed their pet at their
which is a range determined in healthy dogs with persistently nor- home, not at the hospital. Inappetence can profoundly alter the
mal blood glucose concentrations (Elliott etal, 1997). Blood total results of a serial blood glucose curve (Fig. 6-19). The first blood
Gly Hb in newly diagnosed diabetic dogs ranged from 6.0% to sample for blood glucose measurement is obtained when the dog
15.5%. Interpretation of blood Gly Hb in a diabetic dog must enters the hospital and subsequent blood samples are typically
take into consideration the fact that hyperglycemia is common, obtained every 2 hours throughout the day for glucose determi-
even in well-controlled diabetic dogs (Table 6-9). Most owners nation. Glucose measurements should be done more frequently
were happy with their pets response to insulin treatment if blood than every 2 hours if the blood glucose is dropping quickly or
total Gly Hb was kept between 4% and 6%. Values greater than hypoglycemia is identified. If there are concerns regarding the cli-
7% suggest inadequate control of the diabetic state, and values ents technique for administering insulin, the client can administer
greater than 8% indicate serious lack of glycemic control. Blood insulin (using his or her own insulin and syringe) in the hospital
total Gly Hb less than 4% should raise concern for significant after the initial blood glucose is obtained or can demonstrate his or
periods of hypoglycemia in the diabetic dog, assuming anemia is her technique using sterile saline after arriving to pick up the pet
not present. Increased total Gly Hb (i.e., > 7%) suggests poor at the end of the day. The veterinarian or a veterinary technician
control of glycemia but does not identify the underlying problem should closely evaluate the entire insulin administration proce-
(see Fig. 6-18). We no longer measure Gly Hg in diabetic dogs or dure. By measuring blood glucose concentration every 2 hours
|
400 500
Serum glucose (mg/dL)
300 400

300
200
200
100
100
0
8 AM 12 PM 4 PM 8 PM Mid 4 AM 8 AM
0
8 AM Noon 4 PM 8 PM
FIGURE 6-19 Mean blood glucose concentrations in eight diabetic dogs after
administration of neutral protamine Hagedorn (NPH) insulin () and feeding
equal-sized meals at 8 am and 6 pm (solid line) or feeding nothing (broken line) FIGURE 6-20 Blood glucose concentration curve in a Dachshund receiving 0.8 U
during the 24 hours of blood sampling. (From Nelson RW, Couto CG: Essentials of recombinant human Lente insulin per kilogram body weight twice a day (solid
of small animal internal medicine, St Louis, 1992, Mosby-Year Book, p. 572.) line), a Miniature Poodle receiving 0.6 U of recombinant human Lente insulin per
kilogram body weight twice a day (broken line), and a Terrier-mix receiving 1.1 U
of recombinant human Lente insulin per kilogram body weight twice a day (dot-
throughout the day, the clinician will be able to determine if the ted line). Insulin and food were given at 8 am for each dog. Interpretation of the
insulin is effective and identify the glucose nadir, time of peak blood glucose curves suggest short duration of insulin effect in the Dachshund,
insulin effect, approximate duration of insulin effect, and range insulin underdosage in the Miniature Poodle, and the Somogyi effect in the Ter-
of blood glucose concentrations in that particular dog. Identify- rier-mix. Notice that the blood glucose concentrations were similar in all dogs at
ing the glucose nadir and the time of the glucose nadir in relation 2 pm and 4 pm, and the glucose results at these times do not establish the diagnosis
to the time of insulin administration is critical for assessing the in any of the dogs. (From Nelson RW, Couto CG: Small animal internal medicine,
duration of insulin effect. If the glucose nadir has not been identied 3, St Louis, 2003, Mosby, p. 741.)
fied by the time of the next insulin injection, the glucose curve
should be continued, the scheduled insulin injection aborted, and
the dog fed its evening meal (see Prolonged Duration of Insulin signs despite apparently acceptable blood glucose results. One
Effect). Obtaining only one or two blood glucose concentrations exception is the AlphaTRAK by Abbott Laboratories, which is a
during the day has not been reliable for evaluating the effect of PBGM device designed for use in diabetic dogs and cats. Accu-
a given insulin dose (Fig. 6-20). Persistent poor control of the racy of this PBGM device is very good, but glucose values may
diabetic state often stems from misinterpretation of the effects of be higher or lower than glucose values measured by reference
insulin that is based on assessment of only one or two blood glu- methodologies on the same blood sample, forcing the veterinarian
cose concentrations. to accept the blood glucose concentration at face value (Cohen
Changes in blood glucose concentrations are typically assumed to et al, 2009). Hematocrit may also affect the results of PBGMs.
be comparable following the morning and evening administration of In one study, results of the AlphaTRAK were less accurate com-
insulin, so most dogs receive the same dose of insulin morning and pared with a laboratory reference method in blood samples with
evening (Mori etal, 2013). This assumption is fine as long as the dog a lower hematocrit (< 30%) but not an increased hematocrit (>
is doing well. However, different blood glucose results during the day 50%), whereas results from a PBGM for use in humans was less
versus the night should be suspected if polyuria and polydipsia persist accurate with increased hematocrit but not a decreased hematocrit
despite blood glucose concentrations that are close to acceptable dur- (Paul etal, 2011).
ing the day, especially if polyuria and polydipsia are worse at night. Insulin therapy should be adjusted according to interpretation of
For these cases, obtaining a 24-hour blood glucose curve or use of a a single serial blood glucose curve and the impact of the change ini-
continuous glucose monitoring (CGM) device should be considered. tially assessed by client perceptions of clinical response and change
Blood glucose concentrations are typically determined by either in serum fructosamine concentration. If problems persist, the
a point-of-care glucose analyzer or hand-held portable blood glu- blood glucose curve can be repeated. If possible, performing blood
cose meter (PBGM) device. The accuracy of commercially avail- glucose curves on multiple, consecutive days should be avoided,
able PBGM devices designed for use in human diabetics varies because it promotes stress-induced hyperglycemia and it takes time
considerably when used in diabetic dogs, compared with results (several days) for derangements in hepatic glucose production and
using standard reference methods (i.e., glucose oxidase and hexo- secretion to reset. Information gained from a prior serial blood
kinase methods) (Cohn et al, 2000; Wess and Reusch, 2000a; glucose curve should never be assumed to be reproducible on sub-
Cohen etal, 2009; Table 6-10). Blood glucose values determined sequent curves, especially if several weeks to months have passed or
by most PBGM devices designed for use in human diabetics are the dog has developed recurrence of clinical signs. The reproduc-
typically lower than actual glucose values determined by reference ibility of serial blood glucose curves varies from dog to dog. In
methods, and the difference between the actual glucose value and some dogs, results of serial blood glucose curves may vary dramati-
value obtained from the PBGM increases as hyperglycemia wors- cally from day to day or month to month. Lack of consistency in
ens (Fig. 6-21). This bias may result in an incorrect diagnosis of the results of serial blood glucose curves is a source of frustration
hypoglycemia or the misperception that glycemic control is better for many veterinarians. This lack of consistency is a direct reflec-
than it actually is. Failure to consider this error could result in tion of all the variables that affect the blood glucose concentration
insulin underdosage and the potential for persistence of clinical in diabetics. Daily self-monitoring of blood glucose concentrations
TABLE 6-10 B
IAS ASSOCIATED WITH BLOOD GLUCOSE CONCENTRATIONS OBTAINED WITH FIVE PORTABLE
BLOOD GLUCOSE METERS DESIGNED FOR HUMAN DIABETICS AND ONE METER DESIGNED FOR
DIABETIC DOGS VERSUS A REFERENCE ANALYZER
Glucose concentration obtained with the reference analyzer (mg/dL)

<100 100-199 200-299 300-400 > 400
METER N = 29 N = 31 N = 36 N = 36 N = 26
AlphaTRAK 8 (0-28) 12 (1-44) 18 (0-99) 32 (3-110) 58 (2-179)
PBGM 1 22 (2-37) 30 (6-53) 52 (4-112) 85 (24-152) 134 (48-234)
PBGM 2 20 (12-32) 34 (18-50) 46 (0-97) 64 (1-144) 82 (30-155)
PBGM 3 30 (22-52) 54 (38-76) 81 (7-141) 95 (5-182) 102 (5-197)
PBGM 4 21 (10-52) 34 (20-54) 47 (9-104) 72 (1-136) 121 (44-196)
PBGM 5 13 (2-29) 22 (4-43) 17 (0-80) 31 (1-113) 45 (2-118)
From Cohen TA, etal.: Evaluation of six portable blood glucose meters for measuring blood glucose concentration in dogs, J Am Vet Med Assoc 235:276, 2009.
N, Number of blood samples; PBGM, portable blood glucose meter.
Data are given as median bias (range) and represent results from 158 blood samples from 49 dogs. Bias was defined as the absolute value of the difference between blood glucose
results obtained with the meter and the corresponding glucose value obtained with the reference analyzer (Roche/Hitachi 917 Chemistry Analyzer).
8 8
7 7
6 6
5 5
4 4
3 3
Difference (mmol/L)
Difference (mmol/L)
2 2
1 1
0 0
1 1
2 2
3 3
4 4
5 5
6 6
7 7
8 8
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
A Reference (mmol/L) B Reference (mmol/L)
8 8
7 7
6 6
5 5
4 4
3 3
Difference (mmol/L)
Difference (mmol/L)
2 2
1 1
0 0
1 1
2 2
3 3
4 4
5 5
6 6
7 7
8 8
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
C Reference (mmol/L) D Reference (mmol/L)
FIGURE 6-21 A to D, Scatterplots of the difference between blood glucose concentration obtained with four por-
table blood glucose meters and concentration obtained with a reference method versus concentration obtained with
the reference method for blood samples from 170 dogs. (From Wess G, Reusch C: Evaluation of five portable blood
glucose meters for use in dogs, J Am Vet Med Assoc 216:203, 2000.)
|
400 CGM systems measure interstitial fluid glucose concentrations

rather than blood glucose concentrations. The correlation between
Serum glucose (mg/dL)
interstitial and blood glucose concentrations is good in diabetic dogs

300 and cats (Davison etal, 2003b; Moretti etal, 2010). A commonly
used CGM system (Guardian REAL-time) measures interstitial glu-
200
cose with a small, flexible sensor inserted through the skin into the
subcutaneous space and secured to the skin (Fig. 6-23). Interstitial
glucose is detected via the glucose oxidase reaction, and detection
100 occurs entirely at the electrode within the sensor component. Glu-
cose results are transmitted by a wireless transmitter to a pager-sized
monitor. The interstitial fluid glucose concentration is recorded and
0
8 AM 12 PM 4 PM 8 PM Mid 4 AM 8 AM
stored every 5 minutes, and the data can be downloaded to a com-
puter for analysis (Fig. 6-24). Calibration of the CGM system is
required at initiation of and periodically during glucose monitoring.
FIGURE 6-22 Blood glucose concentration curves in a fractious Terrier-mix. The The working glucose range for the CGM system is 40 to 400 mg/dL
same dose of neutral protamine Hagedorn (NPH) insulin was given for each curve. (2.2 to 22 mmol/L). Studies to date suggest that the primary advan-
One glucose curve (solid line) was obtained with the dog in an agitated state tage of continuous glucose monitoring is detection of hypoglycemic
requiring physical restraint each time a blood specimen was obtained; blood for periods that are not detected with serial blood glucose curves and
the other glucose curve (dotted line) was obtained through a jugular catheter a PBGM device (Dietiker-Moretti etal, 2011). See Chapter 7 for
with minimal-to-no restraint and the dog in a quiet state. = Insulin administra- more information on continuous glucose monitoring.
tion and food.
Interpreting the Serial Blood Glucose Curve
Results of the blood glucose curve allow the veterinarian to assess
and adjustments in insulin dose are used in human diabetics to the effectiveness of the administered insulin to lower the blood
minimize the effect of these variables on control of glycemia. A glucose concentration and determine the glucose nadir and the
similar approach for diabetic dogs is becoming more common, as approximate duration of insulin effect (Fig. 6-25). Ideally, all blood
home blood glucose monitoring techniques are refined. For now, glucose concentrations should range between 100 and 250 mg/dL
initial assessment of control of glycemia is primarily based on the (5.6 to 14 mmol/L) during the time period between insulin injec-
clients perception of the diabetic pets health combined with peri- tions, although many diabetic dogs do well despite blood glucose
odic examinations by the veterinarian. Serial blood glucose mea- concentrations consistently in the high 100s to low 300s. The goal
surements are indicated if poor control of glycemia is suspected. of insulin therapy is to have the highest blood glucose concentra-
The purpose of serial blood glucose measurements is to obtain a tion less than 300 mg/dL (17 mmol/L), the glucose nadir between
glimpse of the actions of insulin in that diabetic dog and identify a 80 and 130 mg/dL (4.5 and 7.3 mmol/L), and the mean of all the
possible reason that the diabetic dog is poorly controlled. blood glucose values measured that day to be less than 250 mg/
dL (14 mmol/L). Typically, the highest blood glucose concentra-
Protocol for Generating the Serial Blood Glucose Curve at Home tions occur at the time of each insulin injection, but this does not
Hyperglycemia induced by stress, aggression, or excitement is the always occur. If the blood glucose nadir is greater than 130 mg/
single biggest problem affecting accuracy of the serial blood glu- dL, the insulin dose may need to be increased, and if the nadir is
cose curves (Fig. 6-22). The biggest factors causing stress-induced less than 80 mg/dL, the insulin dose should be decreased.
hyperglycemia are frequent hospitalizations and multiple venipunc- Duration of insulin effect can be assessed if the glucose nadir
tures. An alternative to hospital-generated blood glucose curves is is greater than 80 mg/dL (4.5 mmol/L) and there has not been
to have the client generate the blood glucose curve at home using a rapid decrease in the blood glucose concentration after insulin
the ear or metacarpal, metatarsal or foot pad prick technique and a administration. Assessment of duration of insulin effect may not
PBGM device that allows the client to touch the drop of blood on be valid when the blood glucose decreases to less than 80 mg/
the ear or foot pad with the end of the glucose test strip (Wess and dL or decreases rapidly because of the potential induction of the
Reusch, 2000b). There are several excellent websites on the Inter- Somogyi response, which can falsely decrease the apparent dura-
net that demonstrate home blood glucose monitoring techniques tion of insulin effect (see Insulin Overdosing and Glucose Coun-
for the owner of a diabetic dog, most notably the Abbott Labora- terregulation [Somogyi Response]). A rough approximation of
tories website for the AlphaTRAK. This technique should be con- the duration of effect of insulin can be gained by examining the
sidered for diabetic dogs in which the reliability of blood glucose time of the glucose nadir. For most well-controlled diabetic dogs,
results generated in the veterinary hospital is questionable and is the initial blood glucose concentration near the time of insulin
also becoming a routine monitoring technique used by clients. The administration is less than 300 mg/dL (17 mmol/L) and the glu-
biggest problem has been overzealous owners who monitor blood cose nadir occurs approximately 8 hours after injection of insulin.
glucose concentrations too frequently and begin to interpret results An initial blood glucose concentration greater than 300 mg/dL
and adjust the insulin dose without consulting their veterinarian, a (17 mmol/L), combined with a glucose nadir occurring 6 hours
practice that ultimately leads to insulin overdosage and the Somo- or less after insulin administration and subsequent blood glucose
gyi response (see Fig. 6-27). See Chapter 7 for more information concentrations increasing to greater than 300 mg/dL is support-
on home blood glucose monitoring. ive of short duration of insulin effect. A glucose nadir occurring
12 hours or longer after insulin administration is supportive of
Continuous Glucose Monitoring Systems prolonged duration of insulin effect. Dogs may develop hypogly-
CGM systems are frequently used to monitor glucose concentra- cemia or the Somogyi response if the duration of insulin effect is
tions in diabetic humans and are beginning to be used in diabetic 14 hours or longer and the insulin is being administered twice a
dogs and cats (Wiedmeyer et al, 2008; Affenzeller et al, 2011). day (Fig. 6-26).
Transmitter
Glucose Sensor
Monitor
FIGURE 6-23 Guardian REAL-time continuous glucose monitor includes a small, flexible sensor that is inserted
into the subcutaneous (SC) space, and interstitial glucose is measured by the glucose oxidase reaction within
the sensor component. Glucose results are transmitted by a wireless transmitter to a pager-sized monitor. The
interstitial fluid glucose concentration is recorded and stored every 5 minutes and the data can be downloaded to a
computer for analysis. A, Glucose sensor and transmitter. B, Monitor attached to the dogs collar. The monitor can
be kept in a basket next to the cage for cats.
Guardian BG Meter BG Sensor Sensor alarm Target range Hypo
300
Glucose (mg/dL)
200
140
100
70
60
0
Fri 12:00AM 2:00AM 4:00AM 6:00AM 8:00AM 10:00AM 12:00PM 2:00PM 4:00PM 6:00PM 8:00PM 10:00PM Sat 12:00AM
5:30AM 12:00PM 5:00AM
261 (ICU) 200 (AT) 274 (ICU)
1.5 Detemir SC 1.5 Detemir SC

FIGURE 6-24 Example of results of continuous glucose monitoring using the Guardian REAL-time monitor in a
6 kg female-spayed diabetic Miniature Schnauzer with persistent polyuria, polydipsia, and weight loss despite
various doses of insulin detemir twice daily. Hypoglycemia and possible glucose counterregulation was suspected,
but blood glucose concentrations obtained by venipuncture were always increased. Stress-induced hyperglycemia
was believed to be interfering with glucose results. Results of continuous glucose monitoring with minimal blood
sampling documented efficacy of insulin detemir and the occurrence of hypoglycemia in the dog.
|
Guidelines for interpreting serial

blood glucose curve
1. Was insulin effective in lowering blood glucose?
Yes No
2. What is the lowest blood glucose? 2. Measure serum fructosamine
<80 mg/dL 80-150 mg/dL >150 mg/dL >500 mol/L <450 mol/L
Insulin dosage Insulin dosage Consider stress

and reevaluate in and reevaluate in hyperglycemia or
7-10 days 7-10 days Somogyi
3. What is the duration of insulin effect? 3. What is the insulin dosage?
<10 hours 10-14 hours >14 hours <1.0 U/kg >1.0 U/kg
Change to longer- Measure serum Change to shorter- Insulin dosage Consider insulin
acting insulin q12h fructosamine acting insulin q12h; and reevaluate underdosage, Somogyi,
administer current in 7 to 10 days and causes of insulin
insulin SID ineffectiveness
(see Table 6-11)
Reevaluate <450 mol/L >500 mol/L Reevaluate in If no improvement,

in 7 to 10 days 7 to 10 days consider Somogyi and
causes of insulin
ineffectiveness (see
No change Consider Table 6-11)
Somogyi or
insulin
underdosage
FIGURE 6-25 Algorithm for interpreting results of a serial blood glucose concentration curve. (From Nelson RW,
Couto CG: Small animal internal medicine, ed 5, St Louis, 2014, Mosby, p. 792.)
Problems with loss of insulin activity in the bottle, insulin of stress on blood glucose results may lead to the erroneous per-
administration technique, insulin underdosage, and insulin resis- ception that the diabetic dog is poorly-controlled; insulin therapy
tance should be considered if the insulin is not effective in lowering is invariably adjusted, often by increasing the insulin dosage; and
the blood glucose concentration. In general, insulin underdosage repetition of this cycle eventually culminates in induction of the
should be considered if the insulin dosage is less than 1.0 U/kg Somogyi response, clinically-apparent hypoglycemia, or referral
per injection in the diabetic dog, and insulin resistance should be for evaluation of insulin resistance. Stress hyperglycemia should be
considered if the insulin dosage exceeds 1.0 U/kg per injection. suspected if the dog is visibly upset, excessively nervous or hyper-
The veterinarian should always be wary of the Somogyi response, active, aggressive, or difficult to restrain during the venipuncture
especially in toy and miniature breeds, and the effect of stress on process. Stress hyperglycemia should also be suspected when there
blood glucose results. is disparity between assessment of glycemic control based on
results of the history, physical examination and stability of body
Stress Hyperglycemia weight, and assessment of glycemic control based on results of
Transient hyperglycemia is a well-recognized problem in fractious, blood glucose measurements.
scared, or otherwise stressed cats and can also occur, albeit less
frequently, in diabetic dogs. Hyperglycemia presumably develops Role of Serum Fructosamine in Aggressive, Excitable,
as a result of increased catecholamine and glucocorticoid secretion or Stressed Dogs
and increased hepatic glucose production. Stress hyperglycemia
can significantly increase blood glucose concentrations in diabetic Hyperglycemia induced by stress, aggression, or excitement is
dogs despite the administration of insulinan effect that has seri- the single biggest problem affecting accuracy of the serial blood
ous consequences on the clinicians ability to accurately judge the glucose curve. Stress can override the glucose-lowering effect of
effectiveness of the insulin injection. Failure to recognize the effect the insulin injection, causing high blood glucose concentrations
500 insulin therapy and the lack of food intake during the periop-
erative period. The stress of anesthesia and surgery also cause the
release of diabetogenic hormones, which in turn promotes keto-
400
genesis. Insulin should be administered during the perioperative
period to prevent severe hyperglycemia and minimize production

300 of ketones. To compensate for the lack of food intake and to pre-
vent hypoglycemia, the amount of insulin administered during
the perioperative period is decreased and IV dextrose is adminis-
200 tered, when needed. To correct marked hyperglycemia (i.e., blood
glucose concentration greater than 300 mg/dL; 17 mmol/L),
100 regular crystalline insulin is administered intramuscularly or by
continuous IV infusion (see Chapter 8). Frequent blood glucose
monitoring and appropriate adjustments in therapy are the key
0 to avoiding hypoglycemia and severe hyperglycemia during the
8 AM Noon 4 PM 8 PM perioperative period.
We use the following protocol during the perioperative period
in dogs undergoing surgery. The day before surgery, the dog is
FIGURE 6-26 Blood glucose concentration curves obtained from three diabetic
given its normal dose of insulin and fed as usual. Food is with-
dogs treated with recombinant human Lente insulin twice a day, illustrating
held after 10 PM. On the morning of the procedure, the blood
a difference between dogs in the duration of insulin effect. The insulin is effective
glucose concentration is measured before the animal is given
in lowering the blood glucose concentration in all dogs, and the blood glucose
insulin. If the blood glucose concentration is less than 100 mg/
nadir is between 100 and 175 mg/dL for the dogs. However, the duration of
dL (5.6 mmol/L), insulin is not given, and an IV infusion of
insulin effect is approximately 12 hours (solid line) in one dog with good control of
2.5% to 5% dextrose is initiated. If the blood glucose concentra-
glycemia (ideal duration of effect), approximately 8 hours (dotted line) in one dog
tion is between 100 and 200 mg/dL (11 mmol/L), one-quarter
with persistently poor control of glycemia (short duration of effect), and greater
of the animals usual morning dose of insulin is given, and an IV
than 12 hours (dashed line) in one dog with a history of good days and bad days
infusion of dextrose is initiated. If the blood glucose concentra-
of glycemic control (prolonged duration of effect)a history suggestive of the
tion is more than 200 mg/dL, one-half of the usual morning dose
Somogyi response (see Fig. 6-28). = Insulin injection and food.
of insulin is given, but the IV dextrose infusion is withheld until
the blood glucose concentration is less than 150 mg/dL (8.4
mmol/L). In all three situations, the blood glucose concentra-
despite the presence of adequate amounts of insulin in the circulation is measured every 30 to 60 minutes during the surgical pro-
tion and leading to a spiraling path of insulin overdosage, hypo- cedure. The goal is to maintain the blood glucose concentration
glycemia, the Somogyi response, and poor control of glycemia. between 150 and 250 mg/dL (8.4 and 14 mmol/L) during the
An alternative to hospital-generated blood glucose curves in dogs perioperative period. A 2.5% to 5% dextrose infusion is admin-
where the accuracy of blood glucose results is in question is to istered intravenously as needed to correct or prevent hypoglyce-
have the owner measure blood glucose concentrations at home as mia. When the blood glucose concentration exceeds 300 mg/dL
discussed previously. Alternatively, serum fructosamine concentra- (17 mmol/L), the dextrose infusion should be discontinued and
tions can be used to assess control of glycemia and effectiveness of the blood glucose concentration evaluated 30 and 60 minutes
adjustments in insulin therapy. If a change in insulin therapy is later. If the blood glucose concentration remains greater than
deemed necessary, the clinician must make an educated guess as 300 mg/dL, regular crystalline insulin is administered intramus-
to where the problem lies (e.g., low insulin dose, short duration of cularly at approximately 20% of the dose of the long-acting insu-
insulin effect), make an adjustment in therapy, and rely on owner lin being used at home. Subsequent doses of regular crystalline
perception of response and the change in subsequent serum fruc- insulin should be given no more frequently than every 4 hours (6
tosamine concentration to assess the benefit of the change in treat- hours if administered subcutaneously), and the dosage should be
ment. Serum fructosamine concentrations should be measured adjusted based on the effect of the first insulin injection on the
prior to and 2 to 3 weeks after changing insulin therapy. If the blood glucose concentration.
change in insulin therapy improves control of glycemia, improve- On the day after surgery, the diabetic dog can usually be returned
ment in clinical signs and a decrease in serum fructosamine con- to the routine schedule of insulin administration and feeding. A
centration of at least 50 mol/L should occur. If the severity of dog that is not eating can be maintained with IV dextrose infu-
clinical signs and the serum fructosamine concentration are the sions and regular crystalline insulin injections given subcutane-
same or have worsened, the change was ineffective in improving ously every 6 to 8 hours. Once the animal is eating regularly, it can
glycemic control, another change in therapy should be done and be returned to its normal insulin and feeding schedule.
the serum fructosamine measured again 2 to 3 weeks later.
COMPLICATIONS OF INSULIN THERAPY
INSULIN THERAPY DURING SURGERY
Hypoglycemia
Generally, elective surgery should be delayed in diabetic dogs until
the animals clinical condition is stable and the diabetic state is Hypoglycemia is a common complication of insulin therapy.
controlled with insulin. The exception is those situations in which Signs of hypoglycemia are most apt to occur after sudden large
surgery is required to eliminate insulin resistance (e.g., ovariohys- increases in the insulin dose, with excessive overlap of insulin
terectomy in a diestrus bitch) or to save the dogs life. The sur- action in dogs receiving insulin twice a day, after prolonged
gery itself does not pose a greater risk in a stable diabetic dog inappetence, during unusually strenuous exercise, and follow-
than in a non-diabetic dog. The concern is the interplay between ing sudden improvement in concurrent insulin resistance. In
|
these situations severe hypoglycemia may occur before glucose glucose begins to decline. If the inappetence persists or if other
counterregulation (i.e., secretion of glucagon, epinephrine, signs of gastrointestinal dysfunction develop (e.g., vomiting),
cortisol, and growth hormone) is able to compensate for and insulin therapy should be modified or discontinued until the vet-
reverse hypoglycemia. Signs of hypoglycemia include lethargy, erinarian has examined the dog. Common causes of inappetence
weakness, head tilting, ataxia, seizures, and coma. The occurin diabetic dogs include pancreatitis, ketoacidosis, hepatopathy,
rence and severity of clinical signs is dependent on the rate of inflammatory bowel disease, bacterial infection, finicky eaters,
blood glucose decline and the severity of hypoglycemia. Symp- and boredom with high fiber diets. Appropriate diagnostic and
tomatic hypoglycemia is treated with glucose administered as therapeutic steps should be initiated, depending on results of the
food, sugar water, or dextrose IV (see Chapter 9). Whenever physical examination.
signs of hypoglycemia occur, the owner should be instructed to
stop insulin therapy until hyperglycemia and glycosuria recur.
Recurrence or Persistence of Clinical Signs
Urine glucose testing by the owner with the dog in its home
environment is useful for identifying when glycosuria recurs. Recurrence or persistence of clinical signs (i.e., polyuria, poly-
The adjustment in the subsequent insulin dosage is somewhat dipsia, polyphagia, weight loss) is perhaps the most common
arbitrary; as a general rule of thumb, the insulin dosage initially complication of insulin therapy in diabetic dogs. Recurrence or
should be decreased 25% to 50%, and subsequent adjustments persistence of clinical signs is usually caused by problems with
in the dosage should be based on clinical response and results biologic activity of the insulin or with owner technique in admin-
of blood glucose measurements. Failure of glycosuria to recur istering insulin; problems with the insulin treatment regimen; or
following a hypoglycemic episode is very uncommon in diabetic problems with responsiveness to insulin caused by concurrent
dogs and suggests diabetic remission (see Other Specific Types inflammatory, infectious, neoplastic, or hormonal disorders (i.e.,
and Diabetic Remission) or impaired glucose counterregulation insulin resistance). The most common problems with the insulin
(see later). treatment regimen in the dog include insulin underdosage, induc-
In many diabetic dogs, signs of hypoglycemia are not apparent tion of the Somogyi response, short duration of effect of Lente or
to clients, and hypoglycemia is identified during evaluation of a NPH insulin, and once a day insulin administration. Discrepan-
serial blood glucose curve or suspected when a low serum fructos- cies in the parameters used to assess glycemic control, resulting
amine concentration is identified. Failure to identify hypoglycemia in an erroneous belief that the diabetic dog is poorly controlled,
during a blood glucose curve or low-normal serum fructosamine should also be considered. This is usually caused by erroneously
concentration does not rule out asymptomatic hypoglycemia, in high blood glucose concentrations induced by stress that suggest
part, because of hypoglycemia-induced glucose counterregulation insulin ineffectiveness or presence of a concurrent unrecognized
(Somogyi response). Clinical signs of hyperglycemia, transient disorder that also causes polyuria and polydipsia, such as early
asymptomatic hypoglycemia, and high serum fructosamine con- renal insufficiency. When evaluating a diabetic dog for suspected
centrations dominate the clinical picture in diabetic dogs with the insulin ineffectiveness, it is important that all parameters used
Somogyi response. to assess glycemic control be critically analyzed, most notably
Treatment of asymptomatic hypoglycemia involves decreasing the owners perceptions of how their dog is doing in the home
the dose of insulin (typically 10% to 20%) and assessing the clini- environment, findings on physical examination, and changes
cal response, change in serum fructosamine concentration, and in body weight. If the history, physical examination, change in
blood glucose concentrations. If hypoglycemia remains a reoc- body weight, and serum fructosamine concentration suggest poor
curring problem despite reductions in the insulin dose, problems control of the diabetic state, a diagnostic evaluation to identify
with prolonged duration of insulin effect should be considered. the cause is warranted, beginning with evaluation of the owners
insulin administration technique and the biologic activity of the
Impaired Glucose Counterregulation insulin preparation.
Secretion of the diabetogenic hormones, most notably epineph-
rine and glucagon, stimulates hepatic glucose secretion and Problems with Owner Administration and Activity
helps counter severe hypoglycemia. A deficient counterregu- of the Insulin Preparation
latory response to hypoglycemia has been identified as early as Failure to administer an appropriate dose of biologically active
1year after diagnosis of type 1 diabetes in humans (White etal, insulin results in recurrence or persistence of clinical signs. Com-
1983). As a consequence, when the blood glucose concentration mon reasons include administration of biologically inactive
approaches 60 mg/dL (3.4 mmol/L), there is no compensatory insulin (e.g., outdated, previously heated or frozen; see Insulin
response by the body to increase the blood sugar, and prolonged Storage, Mixing, and Dilution), administration of diluted insu-
hypoglycemia ensues. An impaired counterregulatory response to lin, use of inappropriate insulin syringes for the concentration of
hypoglycemia has also been documented in diabetic dogs (Dues- insulin (e.g., U100 syringe with U40 insulin), or problems with
berg etal, 1995). Dogs with impaired counterregulation had more insulin administration technique (e.g., failure to correctly read the
problems with hypoglycemia than diabetic dogs without impaired insulin syringe, inappropriate injection technique). These prob-
counterregulation. Impaired counterregulation should be consid- lems are identified by evaluating the clients insulin administration
ered in a diabetic dog exquisitely sensitive to small doses of insulin technique and by administering new, undiluted insulin and mea-
or with problems of prolonged hypoglycemia after administration suring several blood glucose concentrations throughout the day.
of an acceptable dose of insulin. In addition, the skin and subcutaneous tissues should be assessed
in the area where insulin injections are given. Some diabetic dogs
Inappetence develop low-grade inflammation, edema, and thickening of the
A healthy, well-regulated diabetic dog should maintain an excel- dermis and subcutaneous tissues in areas of chronic insulin admin-
lent appetite. Occasional inappetence at mealtime is not, by istration and these changes can interfere with insulin absorption
itself, an indication to stop insulin therapy. Most diabetic dogs following subcutaneous administration (see Allergic Reactions to
eat within a couple of hours of the insulin injection, as the blood Insulin).
Problems with the Insulin Treatment Regimen 800

The most common problems causing poor control of glycemia
in this category include insulin underdosage, the Somogyi phe- 600
nomenon, short duration of effect of Lente and NPH insulin, and

once a day insulin administration. The insulin treatment regimen 400
should be critically evaluated for possible problems in these areas,
and appropriate changes should be made to try to improve insulin
200
effectiveness, especially if the history and physical examination do
not suggest a concurrent disorder causing insulin resistance.
100
Insulin Underdosage
100
Control of glycemia can be established in most dogs using 1.0
U or less of insulin/kg of body weight administered twice each
day (see Table 6-7). An inadequate dose of insulin in conjunction 8 AM 12 4 8 PM 12 4 8 PM
with once a day insulin therapy is a common cause for persistence Time (hr)
of clinical signs. In general, insulin underdosing should be con-
sidered if the insulin dosage is less than 1.0 U/kg and the dog is FIGURE 6-27 Blood glucose concentrations in a 6.1 kg Cairn terrier after receiv-
receiving insulin twice a day. If insulin underdosing is suspected, ing beef/pork source neutral protamine Hagedorn (NPH) insulin at 8 am. The dog
the dose of insulin should be gradually increased by 1 to 5 U/ was fed at 8 am and 6 pm. Solid line, 20 units; broken line, 4 units; (From Feldman
injection (depending on the size of the dog) per week. The effec- EC, Nelson RW: Insulin-induced hyperglycemia in diabetic dogs, J Am Vet Med As-
tiveness of the change in therapy should be evaluated by client soc 180:1432, 1982.) = insulin injection.
perception of clinical response and measurement of serum fruc-
tosamine or serial blood glucose concentrations. Although some
dogs require insulin dosages as high as 1.5 U/kg to attain control dampen the severity of the post-hypoglycemic hyperglycemia his-
of glycemia, other causes for insulin ineffectiveness, most notably torically affiliated with the Somogyi response, presumably because
the Somogyi response and concurrent insulin resistance, should insulin derived from the injected insulin is still present in the cir-
be considered once the insulin dose exceeds 1.0 U/kg/injection, culation. The diabetogenic hormonal response to hypoglycemia is
the insulin is being administered every 12 hours, and control of still intact, and persistently increased concentrations of these hor-
glycemia remains poor. mones will still negatively impact control of glycemia, especially
if hypoglycemia and the diabetogenic hormonal response reoccur
Insulin Overdosing and Glucose Counterregulation frequently.
(Somogyi Response) Clinical signs of hypoglycemia are typically mild or not recog-
nized by the client; clinical signs caused by hyperglycemia tend
The Somogyi response results from a normal physiologic response to dominate the clinical picture. The insulin dose that induces
to impending hypoglycemia induced by excessive insulin. When the Somogyi response is variable and unpredictable. The Somogyi
the blood glucose concentration declines to less than 65 mg/dL response should be suspected in poorly-controlled diabetic dogs in
(3.6 mmol/L) or when the blood glucose concentration decreases which insulin dosage exceeds 1.0 U/kg body weight/injection but
rapidly regardless of the glucose nadir, direct hypoglycemia- can also occur at insulin dosages less than 0.5 U/kg/injection (see
induced stimulation of hepatic glycogenolysis and secretion of Table 6-7). Toy and miniature breeds of dogs are especially suscep-
diabetogenic hormones (most notably epinephrine and glucagon) tible to development of the Somogyi response with lower-than-
increase the blood glucose concentration, minimize signs of hypo- expected doses of insulin. The Somogyi response should always be
glycemia, and cause marked hyperglycemia within 12 hours of suspected in any poorly-controlled diabetic dog, regardless of the
glucose counterregulation. The marked hyperglycemia that occurs amount of insulin being administered. Induction of the Somogyi
after hypoglycemia is due, in part, to an inability of the diabetic response typically leads to high insulin doses as the veterinarian
dog to secrete sufficient endogenous insulin to dampen the ris- reacts to the persistence of clinical signs, absence of clinical hypo-
ing blood glucose concentration in conjunction with insufficient glycemia, and high blood glucose and serum fructosamine con-
concentrations of circulating insulin derived from the injected centrations by increasing the insulin dose and perpetuating the
insulin (Fig. 6-27; see Hypoglycemia and the Counterregulatory problem.
Response in Chapter 9; Cryer and Polonsky, 1998; Karam, 2001). The diagnosis of the Somogyi response requires demonstra-
By the next morning, the blood glucose concentration can be tion of hypoglycemia (less than 65 mg/dL; 3.6 mmol/L) followed
extremely elevated (greater than 400 mg/dL; 22 mmol/L), and the by hyperglycemia (greater than 300 mg/dL; 17 mmol/L) after
morning urine glucose concentration is consistently 1 to 2 gm/dL insulin administration (Feldman and Nelson, 1982; Fig. 6-28).
as measured with urine glucose test strips. The Somogyi response should also be suspected when the blood
Unrecognized short duration of insulin effect combined with glucose concentration decreases rapidly regardless of the glucose
insulin dose adjustments based on morning urine glucose con- nadir (e.g., a drop from 400 to 100 mg/dL [22 to 5.6 mmol/L]
centrations is historically the most common cause for the Somo- in 2 to 3 hours). If the duration of insulin effect is greater than
gyi response in dogs. Currently, the most common cause for the 12 hours, hypoglycemia often occurs at night after the evening
Somogyi response are clients who monitor their pets blood glucose dose of insulin, and the serum glucose concentration is typically
concentration at home and adjust the insulin dose (i.e., increase greater than 300 mg/dL the next morning. Unfortunately, the
the dose) without consulting their veterinarian. The increasing use diagnosis of the Somogyi response can be elusive, in part because
of longer-acting insulin preparations (i.e., insulin glargine, insulin of the effects of the diabetogenic hormones on blood glucose
detemir) that have the potential to last longer than 12 hours may concentrations after an episode of glucose counterregulation.
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500 600 60

400 500 50
300 400 40
200 300 30
100 200 20
0 100 10
8 AM Noon 4 PM 8 PM
FIGURE 6-28 Blood glucose concentration curves obtained from three poorly- 8 AM Noon 8 PM Mid 8 AM
controlled diabetic dogs treated with recombinant human Lente insulin twice
a day, illustrating the typical blood glucose curves suggestive of the Somogyi
response. In one dog (solid line) the glucose nadir is less than 80 mg/dL and * *
is followed by a rapid increase in the blood glucose concentration. In one dog FIGURE 6-29 Mean blood glucose (solid line) and serum insulin (dotted line)
(dashed line) a rapid decrease in the blood glucose concentration occurs within concentrations in eight dogs with diabetes mellitus treated with a beef/pork
2 hours of insulin administration and is followed by a rapid increase in the blood source neutral protamine Hagedorn (NPH) insulin subcutaneously once daily. The
glucose concentration; the rapid decrease in blood glucose stimulates glucose duration of NPH effect is too short, resulting in prolonged periods of hyperglyce-
counterregulation, despite maintaining the blood glucose nadir above 80 mg/dL. mia beginning shortly after the evening meal. (From Nelson RW, Couto CG: Small
In one dog (dotted line) the blood glucose curve is not suggestive of the Somogyi animal internal medicine, ed 5. St Louis, 2014, Mosby, p. 795.) = Insulin injec-
response, per se. However, the insulin injection causes the blood glucose to tion; * = equal-sized meals consumed.
decrease by approximately 300 mg/dL during the day, and the blood glucose
concentration at the time of the evening insulin injection is considerably lower
than the 8 am blood glucose concentration. If a similar decrease in the blood
However, if the client reports no change or improvement in poly-
glucose occurs with the evening insulin injection, hypoglycemia and the Somogyi
uria and polydipsia, continued gradual reduction of the insulin
response would occur at night and would explain the high blood glucose concen-
dose should be pursued until polyuria and polydipsia worsen
tration in the morning and the poor control of the diabetic state. (From Nelson
again, which identifies an inadequate dose of insulin for the dog.
RW, Couto CG: Small animal internal medicine, ed 5, St Louis, 2014, Mosby,
Alternatively, glycemic regulation of the diabetic dog could be
p. 794.) = Insulin injection and food.
started over using an insulin dose of 0.25 U/kg given twice daily.
Short Duration of Insulin Effect

Secretion of diabetogenic hormones during the Somogyi response
may induce insulin resistance, which can last 24 to 72 hours For most dogs, the duration of effect of recombinant human
after the hypoglycemic episode. If a serial blood glucose curve is Lente and NPH insulin is 10 to 14 hours, and twice a day insulin
obtained on the day glucose counterregulation occurs, hypoglyce- administration is effective in controlling blood glucose concentra-
mia will be identified and the diagnosis established. However, if tions. However, in some diabetic dogs, the duration of effect of
the serial blood glucose curve is obtained on a day when insulin Lente and NPH insulin is less than 10 hours; a duration that is
resistance predominates, hypoglycemia will not be identified and too short to prevent periods of hyperglycemia and persistence of
the insulin dose may be incorrectly increased in response to the clinical signs (Fig. 6-29; see Fig. 6-14). Diabetic dogs with the
high blood glucose values. A cyclic history of 1 or 2 days of good problem of short duration of insulin effect have persistent morn-
glycemic control followed by several days of poor control should ing glycosuria (> 1 g/dL on urine glucose test strips) regardless of
raise suspicion for insulin resistance caused by glucose counter- the insulin dose being administered. Owners of these pets usually
regulation. Serum fructosamine concentrations are unpredictable mention continuing problems with evening polyuria and polydip-
but are usually increased >500 mol/L, results that confirm poor sia, or weight loss. If owners are adjusting the daily insulin dosage
glycemic control but do not identify the underlying cause (see based on the morning urine glucose concentration, they usually
Fig. 6-18). induce the Somogyi response as the insulin dosage is gradually
Establishing the diagnosis may require several days of hospi- increased in response to persistent morning glycosuria. Serum
talization and serial blood glucose curves, an approach that even- fructosamine concentrations are variable but typically greater
tually leads to problems with stress-induced hyperglycemia. An than 500 mol/L. A diagnosis of short duration of insulin effect
alternative, preferable approach is to arbitrarily gradually reduce is made by demonstrating an initial blood glucose concentration
the insulin dose 1 to 5 units (depending on the size of the dog greater than 300 mg/dL combined with a glucose nadir above 80
and dose of insulin) and have the client evaluate the dogs clinical mg/dL (4.5 mmol/L) that occurs less than 8 hours after insulin
response over the ensuing 2 to 5 days, specifically as it relates to administration and recurrence of hyperglycemia (greater than 300
changes in polyuria and polydipsia. If the severity of polyuria and mg/dL; 17 mmol/L) within 12 hours of the insulin injection (see
polydipsia worsens after an initial reduction in the insulin dose, Fig. 6-26). Diabetic dogs that have a short duration of insulin
another cause for the insulin ineffectiveness should be pursued. effect can be diagnosed only by determining serial blood glucose
effective treatment depends, in part, on the duration of effect of

Less potent Insulin detemir Longest duration the insulin. An extended blood glucose curve should be generated
of effect after administration of insulin once in the morning and feeding
Insulin glargine
the dog at the normal times of the day. This allows the clini-
Protamine Zinc cian to evaluate the effect of the evening meal on postprandial
Lente blood glucose concentrations and estimate whether insulin from
the morning injection is still present in the blood and capable of
NPH preventing a postprandial increase in the blood glucose. If the
70% NPH postprandial blood glucose increases (typically 75 mg/dL [4.2
30% regular crystalline mmol/L] or more) within 2 hours of feeding, the duration of
effect is close to 12 hours and manipulation of the insulin dose,
50% NPH the timing of the meals in relation to the timing of the insulin
50% regular crystalline injections, or both, should be tried before switching to a longer
acting insulin. Failure of the blood glucose to increase 2 hours or
Regular crystalline
longer after eating the evening meal suggests a prolonged dura-
More potent Insulin lyipro, aspart Shortest duration tion of effect (i.e., longer than 14 hours). Switching to a longer
of effect acting insulin (e.g., insulin detemir) administered once a day can
be tried initially (see Fig. 6-30).
FIGURE 6-30 Types of commercial insulin based on their potency and duration
of effect. An inverse relationship exists between the potency and duration of Inadequate Insulin Absorption
effect. (From Nelson RW, Couto CG: Small animal internal medicine, ed 5, St
Slow or inadequate absorption of insulin from the subcutaneous
Louis, 2014, Mosby, p. 793.)
site is uncommon in diabetic dogs treated with NPH or Lente
insulin. Impaired absorption of insulin may occur as a result of
concentrations. One or two afternoon blood glucose determina- thickening of the skin and inflammation of the subcutaneous tis-
tions consistently fail to identify the problem. They may identify sues caused by chronic injection of insulin in the same area of the
normal glucose concentrations or mild hyperglycemia, findings body (see Allergic Reactions to Insulin). Rotation of the injection
that are not consistent with the worries of the owner and do not site helps prevent this problem, and avoidance of regions that have
identify the underlying problem. Alternatively, one or two after- become thickened should improve insulin absorption.
noon blood glucose determinations may reveal severe hyperglyce-
mia, findings that do not differentiate short duration of insulin
Circulating Insulin-Binding Antibodies
effect from the Somogyi response or insulin resistance. Treatment
involves changing to a longer-acting insulin (Fig. 6-30). Although Insulin antibodies result from repeated injections of a foreign pro-
PZI, insulin glargine, and insulin detemir all have the potential to tein (i.e., insulin). The structure and amino acid sequence of the
be effective in diabetic dogs, my preference is to switch to insu- injected insulin relative to the native endogenous insulin influence
lin detemir when Lente and NPH are ineffective because of short the development of insulin antibodies. The presence of substances
duration of insulin effect. Insulin detemir is a potent insulin with in the insulin preparation designed to prolong insulin effect (e.g.,
the potential for prolonged duration of effect (greater than 14 protamine) may also play a role in inducing antibody formation
hours), which can create issues with hypoglycemia and the Somo- (Kurtz etal, 1983). Conformational insulin epitopes are believed to
gyi response when insulin detemir is given twice a day. Regardless, be more important in the development of insulin antibodies than
most diabetic dogs require insulin detemir twice a day to attain differences in the linear subunits of the insulin molecule, per se
diabetic control, recognizing that the insulin dosage can be quite (Thomas etal, 1985; 1988; Nell and Thomas, 1989; Davison etal,
small to compensate for the potency and prolonged duration of 2008b). The more divergent the insulin molecule being adminis-
effect of the insulin. The recommended starting dosage for insulin tered from the species being treated is, the greater the likelihood that
detemir is 0.1 U/kg administered every 12 hours. significant amounts of insulin antibodies will be formed. Canine,
porcine, and recombinant human insulin are similar, and develop-
Prolonged Duration of Insulin Effect ment of a clinically relevant amount of insulin antibodies is uncom-
mon in dogs treated with porcine or recombinant human insulin.
In some diabetic dogs, the duration of effect of Lente and NPH In contrast, canine and beef insulin differ and serum insulin anti-
insulin is greater than 12 hours, and twice a day insulin admin- bodies have been identified in 40% to 65% of dogs treated with
istration creates problems with hypoglycemia and the Somogyi beef/pork or beef insulin (Haines, 1986; Davison etal, 2008b).
response. In these dogs, the glucose nadir following the morning Insulin-binding antibodies can enhance and prolong the phar-
administration of insulin typically occurs near or after the time macodynamic action of insulin by serving as a carrier, or they can
of the evening insulin administration, and the morning blood reduce insulin action by excessive binding and reduction of cir-
glucose concentration is usually greater than 300 mg/dL (17 culating unbound free insulin (Bolli etal, 1984; Marshall etal,
mmol/L) (see Fig. 6-26). Gradually decreasing blood glucose con- 1988; Lahtela etal, 1997). Antibodies may also have no appar-
centrations measured at the time of sequential insulin injections ent clinical effect on insulin dosage or status of glycemic control
is another indication of prolonged duration of insulin effect. The (Lindholm et al, 2002). In our experience, the presence of sig-
effectiveness of insulin in lowering the blood glucose concentra- nificant amounts of insulin-binding antibodies is associated with
tion is variable from day to day, presumably because of varying erratic and often poor control of glycemia, an inability to main-
concentrations of diabetogenic hormones whose secretion was tain control of glycemia for extended periods of time, frequent
induced by prior hypoglycemia. Serum fructosamine concen- adjustments in insulin dose, and occasional development of severe
trations are variable but typically greater than 500 mol/L. An insulin resistance (Fig. 6-31). Insulin-binding antibodies can also
|
500 1000
400 800

FIGURE 6-31Blood glucose and serum in-

sulin concentrations in a 7.6 kg, spayed dog
300 600 receiving 1.1 U/kg beef/pork source Lente in-
sulin (solid line) subcutaneously. The dog had
severe polyuria, polydipsia, and weight loss.
A baseline serum insulin concentration was
greater than 1000 U/mL 48 hours after dis-
continuing insulin therapy. Interference from
200 400 anti-insulin antibodies was suspected, and
the source of insulin was changed to recom-
binant human insulin. Clinical signs improved
within 2 weeks, and a blood glucose curve was
obtained 4 weeks later with the dog receiving
0.9 U/kg recombinant human Lente insulin
100 200 (broken line), showed excellent glycemic con-
trol. Presumably, loss of anti-insulin antibody
interference with the insulin radioimmunoas-
say (RIA) allowed a more accurate assessment
of changes in the serum insulin concentration
after recombinant human insulin administra-
0 0
8 AM Noon 4 PM 8 PM 8 AM Noon 4 PM 8 PM tion. (From Nelson RW, Couto CG: Small animal
internal medicine, ed 5. St Louis, 2014, Mosby,
p. 795.) = Insulin injection and food.
cause erratic fluctuations in the blood glucose concentration with insulin values when a single-phase separation system utilizing
no correlation between the timing of insulin administration and antibody-coated tubes is used to measure serum insulin concen-
changes in blood glucose concentration (Fig. 6-32). Presumably, tration. This interference can be used to raise the clinicians index
fluctuations in blood glucose concentration result from erratic of suspicion for insulin-binding antibodies as a cause for insulin
and unpredictable changes in the circulating free (i.e., nonanti- resistance. The serum insulin concentration is typically less than
body-bound) insulin concentration (Bolli etal, 1984). This phe- 50 U/mL (360 pmol/L) 24 hours after insulin administration
nomenon causes inappropriate and potentially life-threatening in diabetic dogs without antibodies causing interference with
hypoglycemia at unexpected times in human diabetics. We have the RIA. In contrast, serum insulin concentrations are typically
observed a similar syndrome in diabetic dogs treated with beef/ greater than 400 U/mL (2800 pmol/L) 24 hours after insulin
pork insulin preparations. Problems with glycemic control typi- administration when insulin-binding antibodies interfere with
cally improve or resolve with the initiation of porcine-source or the RIA resultsan interaction that causes spurious results (see
recombinant human insulin preparations. Although uncommon, Fig. 6-31).
insulin antibodies can develop in dogs treated with recombinant A switch to porcine-source or recombinant human insulin
human insulin and should be suspected as the cause of poor glyce- preparation, a switch to an insulin preparation that does not con-
mic control when another cause cannot be identified. tain protamine, or both should be considered if insulin-binding
Documentation of serum insulin-binding antibodies should antibodies are identified in a poorly-controlled diabetic dog. Stud-
make use of assays that have been validated in diabetic dogs. A ies evaluating the antigenicity of insulin analogues (i.e., glargine,
radioimmunoassay (RIA) for identifying insulin antibodies in detemir) in diabetic dogs have not yet been reported. In our
dogs is currently available at the Diagnostic Center for Popula- experience, insulin antibody results greater than 15% using the
tion and Animal Health, Michigan State University, East Lansing, Michigan State University insulin antibody assay are uncommon
Mich. Although the finite range of possible results with this assay in diabetic dogs treated with insulin analogues.
is 0% to 100%, normal results are typically 15% or less and sig-
nificant positive results are greater than 40% to 50%. Allergic Reactions to Insulin
Circulating insulin-binding antibodies may interfere with
some RIA techniques used to measure serum insulin concen- Significant reactions to insulin occur in as many as 5% of human
tration in a manner similar to the effects of thyroid hormone diabetics treated with insulin and include erythema, pruritus,
antibodies on RIA techniques for serum triiodothyronine (T3) induration, and lipoatrophy at the injection site. Allergic reactions
and T4 concentrations (see Chapter 3). The presence of insulin- to insulin have been poorly documented in diabetic dogs. Pain on
binding antibodies in the serum sample causes spuriously high injection of insulin is usually caused by inappropriate injection
400 500
400
300

300
200
200
100 100
0
8 AM Noon 4 PM 8 PM
0
8 AM Noon 4 PM 8 PM Mid 4 AM 8 AM
FIGURE 6-33 Blood glucose curve in a 12 kg male diabetic dog with untreated
hypothyroidism receiving 2.2 U/kg recombinant human Lente insulin (solid line).
FIGURE 6-32 Blood glucose curve in a 50 kg male dog receiving 0.7 U/kg beef/ The large amount of insulin required to lower the blood glucose concentration
pork source Lente insulin (solid line) subcutaneously. Note the erratic fluctua- suggests insulin resistance. Glycemic control was improved, and the insulin dos-
tions in the blood glucose concentration. The dog had polyuria, polydipsia, and age was decreased to 0.9 U/kg after sodium levothyroxine therapy was initiated
weight loss and was blind from cataract formation. A baseline serum insulin con- (broken line). = Subcutaneous (SC) insulin injection and food.
centration was 825 U/mL 24 hours after discontinuing insulin therapy. Interfer-
ence from anti-insulin antibodies was suspected, and the source of insulin was
changed to recombinant human insulin. Clinical signs improved within 1 month, result from problems occurring prior to the interaction of insulin
and a blood glucose curve was obtained 8 weeks later with the dog receiving 0.5 with its receptor (e.g., circulating insulin-binding antibodies), at
U/kg recombinant human Lente insulin (broken line), showing excellent glycemic the receptor (e.g., altered insulin receptor binding affinity or con-
control and loss of erratic fluctuations in the blood glucose concentration. centration), or at steps distal to the interaction of insulin and its
receptor (e.g., block in insulin signal transduction). Prereceptor
problems reduce free metabolically active insulin concentration
technique, inappropriate site of injection, a reaction to the cold and include increased insulin degradation and insulin-binding
temperature of insulin stored in the refrigerator, the acidic pH of antibodies. Receptor problems include alterations in insulin-recep-
insulin glargine, or issues with behavior and not an adverse reac- tor binding affinity and concentration and insulin-receptor anti-
tion to insulin, per se. Chronic injection of insulin in the same bodies. Postreceptor problems are difficult to differentiate clinically
area of the body may cause inflammation and thickening of the from receptor problems, and both often coexist. In dogs, receptor
skin and subcutaneous tissues and may be caused by an immune and postreceptor abnormalities are usually attributable to obesity,
reaction to insulin or some other protein (e.g., protamine) in circulating acute phase proteins, and inflammatory cytokines (e.g.,
the insulin bottle. Inflammation and thickening of the skin and tumor necrosis factor alpha [TNF], interleukin-1, interleukin-6)
subcutaneous tissues may impair insulin absorption, resulting that interfere with insulin signal transduction or a disorder causing
in recurrence of clinical signs of diabetes. Rarely, diabetic dogs excessive or deficient secretion of an insulin-antagonistic hormone,
develop acute focal subcutaneous edema and swelling at the site of such as cortisol, growth hormone, progesterone, or thyroid hor-
an insulin injection. Insulin allergy is suspected in these animals. mone (Tilg and Moschen, 2006; Vick etal, 2008).
Treatment includes switching to a less antigenic insulin and to a No insulin dose clearly defines insulin resistance. For most dia-
more purified insulin preparation. Systemic allergic reactions to betic dogs, control of glycemia can usually be attained using 1.0 U
insulin in dogs have yet to be identified. or less of Lente or NPH insulin per kilogram of body weight given
twice daily (see Table 6-7). Insulin resistance should be suspected
Concurrent Disorders Causing Insulin Resistance if control of glycemia is poor despite an insulin dosage in excess of
1.5 U/kg, when excessive amounts of insulin (i.e., insulin dosage
Insulin resistance is a condition in which a normal amount of insu- >1.5 U/kg) are necessary to maintain the blood glucose concentra-
lin produces a subnormal biologic response. Insulin resistance may tion below 300 mg/dL (Fig. 6-33), and when control of glycemia
|
TABLE 6-11 R
ECOGNIZED CAUSES OF INSULIN INEFFECTIVENESS OR INSULIN RESISTANCE
IN DIABETIC DOGS
DISORDERS TYPICALLY CAUSING SEVERE INSULIN DISORDERS TYPICALLY CAUSING MILD OR

CAUSED BY INSULIN THERAPY RESISTANCE FLUCTUATING INSULIN RESISTANCE
Inactive insulin Hyperadrenocorticism Obesity
Diluted insulin Diestrus in intact female Infection
Improper administration technique Progesterone secreting adrenocortical tumor Chronic inflammation
Inadequate dose Diabetogenic drugs Chronic pancreatitis
Somogyi response Glucocorticoids Chronic inflammatory bowel disease
Inadequate frequency of insulin administration Progestagens Disease of the oral cavity
Impaired insulin absorption Chronic kidney disease (CKD)
Insulin-binding antibodies Hepatobiliary disease
Cardiac disease
Hypothyroidism
Hyperthyroidism
Pancreatic exocrine Insufficiency
Hyperlipidemia
Neoplasia
Glucagonoma
Pheochromocytoma
is erratic and insulin requirements are constantly changing in an examination is the most important initial step in identifying these
attempt to maintain control of glycemia. Failure of the blood glu- concurrent disorders. If the history and physical examination are
cose concentration to decrease below 300 mg/dL (17 mmol/L) unremarkable, a CBC, serum biochemical analysis, serum cPL,
during a serial blood glucose curve is suggestive of, but not defini- serum progesterone concentration (intact female dog), abdominal
tive for, the presence of insulin resistance. An insulin resistance ultrasound, and urinalysis with bacterial culture should be obtained
type blood glucose curve can also result from stress-induced to further screen for concurrent illness. Additional tests will be
hyperglycemia, the Somogyi response, and other problems with dependent on results of the initial screening tests (Box 6-7).
insulin therapy (Table 6-11), and a decrease in the blood glucose Treatment and reversibility of insulin resistance is dependent
concentration below 300 mg/dL can occur with disorders caus- on the etiology. Insulin resistance is reversible with treatable
ing relatively mild insulin resistance (e.g., obesity, inflammation). disordersfor example, sodium levothyroxine treatment in a
Serum fructosamine concentrations are typically greater than 500 diabetic dog with concurrent hypothyroidism (Ford etal, 1993)
mol/L in dogs with insulin resistance and can exceed 700 mol/L or ovariohysterectomy in an intact female diabetic dog in dies-
if resistance is severe. Unfortunately, an increased serum fructos- trus (see Other Specific Types and Diabetic Remission; Fall etal,
amine concentration is merely indicative of poor glycemic control 2008b). In contrast, insulin resistance often persists with disorders
not insulin resistance, per se. that are difficult to treat, such as chronic recurring pancreatitis. In
The severity of insulin resistance is dependent, in part, on the some situations, measures can be taken to prevent insulin resis-
underlying etiology. Insulin resistance may be mild and easily over- tance, such as avoidance of glucocorticoids in diabetic dogs and
come by increasing the dosage of insulin or may be severe, causing an ovariohysterectomy at the time diabetes mellitus is diagnosed
marked hyperglycemia regardless of the type and dosage of insulin in an intact female dog.
administered. Some causes of insulin resistance are readily apparent
at the time diabetes is diagnosed, such as obesity and the adminis- Insulin Dosage Adjustments
tration of insulin-antagonistic drugs (e.g., glucocorticoids, proges- Adjustments in the insulin dosage should always be considered
togens). Other causes of insulin resistance are not readily apparent at the time treatment of the insulin-resistant disorder is initiated.
and require an extensive diagnostic evaluation to be identified. In How much to decrease the insulin dosage is variable and depen-
general, any concurrent inflammatory, infectious, hormonal, neo- dent, in part, on the severity of insulin resistance, the amount of
plastic, or organ system disorder can cause insulin resistance and insulin being administered, and the expected rapidity of improve-
interfere with the effectiveness of insulin therapy (see Table 6-11). ment in insulin resistance after treatment of the disorder. For
In our experience, the most common concurrent disorders interfer- example, poorly-controlled diabetic dogs with newly diagnosed
ing with insulin effectiveness in diabetic dogs include diabetogenic hypothyroidism will have a rapid improvement in insulin resis-
drugs (glucocorticoids), severe obesity, hyperadrenocorticism, tance after initiating thyroid hormone treatment (see Fig. 6-33;
diestrus, chronic pancreatitis, CKD, inflammatory bowel disease, Ford et al, 1993). Failure to decrease the insulin dosage may
oral cavity disease, infections of the urinary tract, hyperlipidemia, result in symptomatic hypoglycemia within days of starting thy-
and insulin-binding antibodies in dogs receiving beef insulin. roid hormone treatment. In contrast, correction of obesity and
Obtaining a complete history and performing a thorough physical subsequent improvement in insulin resistance is a relatively slow
Naturally occurring hyperadrenocorticism and diabetes mellitus

BOX 6-7 D
iagnostic Tests to Consider for the Evaluation are common concurrent diseases in dogs. For most dogs, glycemic
of Insulin Resistance in Diabetic Dogs control remains poor despite insulin therapy and good glycemic
control is generally not possible until the hyperadrenocorticism is
CBC, serum biochemistry panel, urinalysis controlled. The initial focus should be on treating the hyperadrenal
Bacterial culture of the urine state in a poorly-controlled diabetic dog diagnosed with hyperad-
Serum cPL (pancreatitis) renocorticism. Insulin treatment is indicated; however, aggressive
Serum TLI (exocrine pancreatic insufficiency) efforts to control hyperglycemia should not be attempted. Rather, a
Adrenocortical function tests conservative dose (approximately 0.5 U/kg) of intermediate-acting
Urine cortisol-to-creatinine ratio (spontaneous hyperadrenocorticism) insulin (i.e., Lente or NPH) should be administered twice a day to
Low-dose dexamethasone suppression test (spontaneous prevent ketoacidosis and severe hyperglycemia. Monitoring water
hyperadrenocorticism) consumption and frequency of urination is not reliable because
ACTH stimulation test (iatrogenic hyperadrenocorticism) both diseases cause polyuria and polydipsia; polyuria and polydipsia
Thyroid function tests may persist if poor control of hyperglycemia persists despite attain-
Baseline serum total and free T4 (hypothyroidism or hyperthyroidism) ing control of hyperadrenocorticism. As control of hyperadrenocor-
Endogenous serum TSH (hypothyroidism) ticism is achieved, insulin resistance resolves and tissue sensitivity
TSH stimulation test (hypothyroidism) to insulin improves. Home blood glucose monitoring and testing
Serum progesterone concentration (diestrus in intact female dog) urine for the presence of glucose can be done by the owner to help
Plasma growth hormone or serum IGF-1 concentration (acromegaly) prevent hypoglycemia and identify when insulin resistance is resolv-
Serum insulin antibody test (see Circulating Insulin-Binding Antibodies) ing. Any blood glucose concentration less than 150 mg/dL (8.4
Fasting serum triglyceride concentration (hyperlipidemia) mmol/L) or urine sample found to be negative for glucose should
Abdominal ultrasonography (adrenomegaly, adrenal mass, pancreatitis, be followed by a 20% to 25% reduction in the insulin dose and
pancreatic mass) evaluation of control of the hyperadrenocorticism. Critical assess-
Thoracic radiography (cardiomegaly, neoplasia) ment of glycemic control and adjustments in insulin therapy should
CT or MRI (pituitary mass) be initiated once hyperadrenocorticism is controlled. The ability to
ACTH, Adrenocorticotropic hormone; CBC, complete blood count; cPL, canine establish consistent glycemic control seems more problematic for
pancreatic-specific lipase; CT, computed tomography; IGF-1, insulin-like growth dogs treated with trilostane versus mitotane (lysodren), presumably
factor-1; MRI, magnetic resonance imaging; T4, thyroxine; TLI, trypsin-like immuno- because of differences in their mechanism of action and ability to
reactivity; TSH, thyroid-stimulating hormone (also known as thyrotropin). maintain decreased cortisol concentrations (see Chapter 10).
Chronic Pancreatitis
process affiliated with a gradual reduction in the insulin dosage Chronic pancreatitis is the most significant concurrent inflamma-
over a period of time as obesity improves. Avoiding hypoglycemia tory disorder in diabetic dogs. Chronic pancreatitis is identified at
is the primary goal when adjusting the insulin dosage. Always err necropsy in approximately 35% of diabetic dogs (Alejandro etal,
on the side of decreasing the insulin dose too much rather than 1988). Most of these animals have a similar history, characterized
too little, recognizing that hyperglycemia is not life-threatening by poorly controlled diabetes, fluctuating insulin requirements,
but severe hypoglycemia can be. Monitoring urine for ketonuria blood glucose concentrations often greater than 300 mg/dL (17
identifies those dogs in which the reduction in insulin combined mmol/L), intermittent lethargy and inappetence, and owner con-
with insulin resistance resulted in ketone formation and the need cerns that their pet is just not doing well. An inability to cor-
for more insulin (see Chapter 8). When in doubt, I decrease the rect these problems ultimately leads to euthanasia for many dogs.
insulin dose to approximately 0.5 U/kg per injection for diabetic Establishing a diagnosis relies on a combination of clinical signs,
dogs and rely on owner observations regarding the overall health physical examination findings, serum cPL, ultrasound evaluation
of their pet and the presence of clinical signs suggestive of hypo- of the pancreas, and clinical suspicion for the disorder (see Pan-
glycemia. Home blood glucose monitoring and monitoring ran- creatic Enzymes). Feeding a low-fat highly digestible diet is the
dom urine samples for negative glycosuria may also be considered. cornerstone of treatment.
Glucocorticoids and Hyperadrenocorticism Chronic Kidney Disease
Diabetic dogs are often treated with glucocorticoids for treatment CKD and diabetes mellitus are common geriatric diseases and
of concurrent disease (e.g., allergic skin disease). Glucocorticoids often occur concurrently. Abnormal kidney function may result
have the potential to cause severe insulin resistance, creating a from the deleterious effects of the diabetic state (i.e., diabetic
tendency for large amounts of insulin to be administered in an nephropathy) or may be an independent problem that has devel-
attempt to control hyperglycemia (Tiley et al, 2008). If gluco- oped in conjunction with diabetes in the geriatric dog. As kidney
corticoids are required for treatment of a concurrent disease, the function declines, human diabetics with concurrent nephropathy
glucocorticoid dose should be kept as low as possible and adminis- are at increased risk for severe hypoglycemia as a result of decreased
tered as infrequently as possible to minimize the severity of insulin renal clearance of insulin and decreased renal glucose production
resistance. Insulin dosage requirements will be higher in the pres- by gluconeogenesis (Stumvoll etal, 1997; Rave etal, 2001). Tissue
ence of insulin resistance to maintain some semblance of glycemic responsiveness to insulin (i.e., insulin sensitivity) is also attenu-
control. It is important to remember the interplay between dosage ated, resulting in poorer metabolic control of the diabetic state
adjustments of glucocorticoids and the impact of the adjustment (Eidemak etal, 1995). Prolonged duration of insulin effect, insu-
on severity of insulin resistance and insulin dosage requirements. lin resistance, and less commonly hypoglycemia are recognized
Appropriate adjustments in the insulin dose should be done when- problems in diabetic dogs with concurrent CKD. The interplay
ever the glucocorticoid dose is increased or decreased to minimize between progression and severity of CKD, severity of insulin resis-
hyper- and hypoglycemia, respectively. tance, and impairment of insulin clearance creates unpredictable
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fluctuations in control of glycemia and insulin requirements and

frustration for the owner and veterinarian. In addition, reliance on BOX 6-8 Causes of Hyperlipidemia in Dogs and Cats
an important indicator of diabetic control (i.e., severity of poly-
uria and polydipsia) is no longer reliable because of the concurrent Postprandial hyperlipidemia
CKD. Indicators for possible mild (i.e., non-azotemic) concurrent Primary hyperlipidemia
CKD include persistent polyuria and polydipsia despite good gly- Idiopathic hyperlipoproteinemia (Miniature Schnauzers)
cemic control of the diabetic state and urine specific gravities less Idiopathic hyperchylomicronemia (cats)
than 1.020 despite 1% to 2% glycosuria. In most cases, treatment Lipoprotein lipase deficiency (cats)
for CKD and failure takes priority and insulin therapy is modi- Idiopathic hypercholesterolemia
fied, as needed, to attain the best possible control of the diabetic Secondary hyperlipidemia
state while trying to avoid hypoglycemia, recognizing that attain- Hypothyroidism
ment of good control may be difficult and polyuria and polydipsia Diabetes mellitus
will persist regardless of the status of glycemic control. Hyperadrenocorticism
Pancreatitis
Hypertriglyceridemia Cholestasis
Increased serum concentrations of cholesterol and triglycerides Hepatic insufficiency
are common in newly diagnosed diabetic dogs and usually resolve Nephrotic syndrome
after initiation of insulin treatment (see Serum Cholesterol and Drug-induced hyperlipidemia
Triglyceride Concentrations). Persistent hypertriglyceridemia may Glucocorticoids
impair insulin receptor-binding affinity, promote downregulation Progestagens (cats)
of insulin receptors, and cause a postreceptor defect in insulin
action (Berlinger etal, 1984; Bieger etal, 1984) Hypertriglyceri-
demia may be secondary to other disorders or may be a primary Chronic hyperglycemia is the central initiating factor for all
hyperlipidemic disorder (Box 6-8). The insulin resistance caused types of microvascular complications in diabetic humans. The
by hypertriglyceridemia is most commonly appreciated in dia- duration and severity of hyperglycemia is strongly correlated
betic dogs that develop hypothyroidism and in diabetic Miniature with the extent and progression of diabetic microvascular disease.
Schnauzers with idiopathic hyperlipidemia but should be consid- Although all cells are exposed to hyperglycemia, hyperglycemic
ered in any poorly-controlled diabetic dog with persistent lipe- damage is limited to those cell types (e.g., endothelial cells in
mia (Xenoulis etal, 2011). Unfortunately, hypertriglyceridemia is the retina, glomerulus, and nerve vasa nervosum) that develop
common in poorly-regulated diabetic dogs, and the differentiation intracellular hyperglycemia (Brownlee et al, 2011). The com-
between hypertriglyceridemia caused by poorly controlled diabe- mon pathophysiologic feature of diabetic microvascular disease is
tes versus hypertriglyceridemia that has developed independent of progressive narrowing and eventual occlusion of vascular lumina,
the diabetic state can be difficult. As a general rule, serum triglyc- which results in inadequate perfusion and function of affected tis-
eride concentrations in poorly-controlled diabetics are usually less sues and microvascular cell loss.
than 500 mg/dL. Serum triglyceride concentrations in excess of Four major hypotheses for how hyperglycemia causes diabetic
500 mg/dL, especially 800 mg/dL, should raise suspicion for a complications have been extensively studied and are listed here: (1)
concurrent disorder causing the hypertriglyceridemia, most nota- increased polyol pathway flux involving aldose reductase and sorbi-
bly pancreatitis, hypothyroidism, and primary hyperlipidemic dis- tol, (2) increased intracellular formation of advanced glycation end
orders. Restriction of dietary fat is the cornerstone of therapy for products, (3) activation of protein kinase C, and (4) increased hex-
hypertriglyceridemia. osamine pathway flux with increased shunting of glucose into the
hexosamine pathway (Brownlee etal, 2011). All four of these differ-
CHRONIC COMPLICATIONS OF DIABETES ent pathogenic mechanisms reflect a single hyperglycemia-induced
MELLITUS process: overproduction of superoxide by the mitochondrial elec-
tron transport chain. Hyperglycemia increases the production of
Complications resulting from diabetes, its treatment, or affiliated reactive oxygen species, which inhibits the activity of a key glycolytic
disorders are common in diabetic dogs and include blindness and enzyme (glyceraldehyde-3-phosphate dehydrogenase). Inhibition
anterior uveitis resulting from cataract formation, diabetic reti- of this enzyme results in the upstream accumulation of glycolytic
nopathy (retinal hemorrhage, microaneurysms), hypoglycemia, intermediates which, in turn, activate each of the four proposed
chronic pancreatitis, recurring infections, poor glycemic control, mechanisms. The pathophysiologic mechanisms for chronic com-
and ketoacidosis (see Table 6-4). Many owners are hesitant to plications in diabetic dogs have been poorly characterized but are
treat their newly diagnosed diabetic dog because of knowledge assumed to be comparable to those in diabetic humans.
regarding chronic complications experienced in human diabetics
and concern that a similar fate awaits their pet. However, clients
Cataracts
should be assured that the devastating chronic complications of
human diabetes (e.g., nephropathy, neuropathy, vasculopathy) Cataract formation is the most common long-term complication
require years to develop and become clinical and therefore are of diabetes mellitus in the dog (see Fig. 6-4). A retrospective-
uncommon in diabetic dogs. Diabetes mellitus is a disease of older cohort study on the development of cataracts in 132 diabetic dogs
dogs and most do not live beyond 5 years from the time of diagno- referred to a university referral hospital found cataract formation
sis (Fall etal, 2007). In our experience, owners are usually willing in 14% of dogs at the time diabetes was diagnosed and a time
to tackle the care of their diabetic dog once the fears related to interval for 25%, 50%, 75%, and 80% of the study population
chronic complications seen in human diabetics are alleviated and to develop cataracts at 60, 170, 370, and 470 days, respectively
assurances are made that administering insulin is easy and dogs are (Beam etal, 1999). The pathogenesis of diabetic cataract forma-
very tolerant of insulin injections. tion is thought to be related to altered osmotic relationships in
the lens induced by the accumulation of sorbitol and galactitol, dogs (Good etal, 2003). Corneal nerves are critical for eliciting
which are sugar alcohols that are produced following reduction of and regulating corneal protection via their role in the mediation of
glucose and galactose by the enzyme aldose reductase in the lens. tear production and eyelid closure and regulation of corneal col-
Sorbitol and galactitol are potent hydrophilic agents and cause an lagen expression and epithelial cell function and integrity (Baker
influx of water into the lens, leading to swelling and rupture of the etal, 1993; Marfurt, 2000). Corneal sensory deficits are thought
lens fibers and the development of cataracts (Richter etal, 2002). to be a component of the diffuse neuropathy affecting the periph-
Cataract formation is an irreversible process once it begins, and it eral sensorimotor nervous system of diabetic humans and animals
can occur quite rapidly. Diabetic dogs that are poorly controlled and may have important implications regarding corneal healing
and have problems with wide fluctuations in the blood glucose and the development of recurrent or nonhealing corneal ulcers in
concentration seem especially at risk for rapid development of diabetic dogs.
cataracts. Good glycemic control and minimal fluctuation in the
blood glucose concentration prolongs the onset of cataract forma-
Diabetic Retinopathy
tion. Once blindness occurs as a result of cataract formation, the
need for stringent blood glucose control is reduced. Diabetic retinopathy in the dog is characterized histologically by
Blindness may be eliminated by removing the abnormal lens. damage to the retinal vasculature and retinal neurons, specifically
Vision is restored in approximately 80% of diabetic dogs that degeneration of retinal ganglion cells (Howell etal, 2013). Oph-
undergo cataract removal (Appel et al, 2006; Sigle and Nasisse, thalmoscopically identifiable retinal hemorrhages and microaneu-
2006). Factors that affect the success of surgery include the degree rysms are considered the maker for diabetic retinopathy in dogs.
of glycemic control preceding surgery, presence of retinal disease, Additional ophthalmoscopic findings include dilatation and tor-
and presence of lens-induced uveitis. Acquired retinal degenera- tuosity of retinal venules, hyper-reflectivity of the tapetal portion
tion affecting vision is more of a concern in older diabetic dogs of the retina, and chorioretinal exudates. In one study, 11 of 52
than is diabetic retinopathy. Fortunately, acquired retinal degener- (21%) diabetic dogs developed ophthalmoscopic signs of retinal
ation is unlikely in an older diabetic dog with vision immediately hemorrhages or microaneurysms, compared with 1 of 17 (0.6%)
before cataract formation. If available, electroretinography should non-diabetic dogs (Landry etal, 2004). Median time from diagno-
be performed before surgery to evaluate retinal function. sis of diabetes to diagnosis of retinopathy was 1.4 years (range, 0.5
In a study by Kador, etal., (2010), the topical administration to 3.2 years). Histologic changes include an increased thickness
of the aldose reductase inhibitor Kinostat significantly delayed the of the capillary basement membrane, loss of pericytes, capillary
onset and/or progression of cataracts in dogs with diabetes melli- shunts, and microaneurysms. The cause of diabetic retinopathy
tus during a 12-month period. If Kinostat becomes available com- is probably multifactorial and may involve biochemical changes
mercially, it may offer a medical option for preventing or slowing secondary to hyperglycemia and increased aldose reductase activ-
the formation of cataracts in diabetic dogs. ity, advanced glycation end products, hemodynamic alterations,
and vascular endothelial and pericyte loss (Merimee, 1990; Stitt,
Lens-Induced Uveitis 2003). Risk factors for development of diabetic retinopathy have
been poorly characterized in diabetic dogs, although status of
During embryogenesis, the lens is formed within its own capsule glycemic control may be associated with progression of diabetic
and its structural proteins are not exposed to the immune sys- retinopathy (Engerman and Kern, 1987). Retinal ganglion cell
tem. Therefore, immune tolerance to the crystalline proteins does degeneration is significantly inhibited by good to moderate glyce-
not develop (van der Woerdt etal, 1992). During cataract forma- mic control in diabetic dogs (Howell etal, 2013). Loss of vision is
tion and reabsorption, lens proteins are exposed to local ocular uncommon in dogs with diabetic retinopathy.
immune system, resulting in inflammation and uveitis. Uveitis Unfortunately, the rapid development of cataracts often inhibits
that occurs in association with a reabsorbing, hypermature cata- the ability to evaluate the retina in the dog with diabetes mellitus.
ract may decrease the success of cataract surgery and must be con- Because of the high incidence of cataract formation, the retinas
trolled before surgery (Bagley and Lavach, 1994). The treatment should always be evaluated in the newly-diagnosed diabetic pet to
of lens-induced uveitis focuses on decreasing the inflammation ensure normal function and lack of grossly visible disease should
and preventing further intraocular damage. Topical ophthalmic cataract formation and subsequent lens removal become necessary
glucocorticoids (e.g., prednisone acetate) are the most commonly in the future. Lens removal would be unwarranted in a diabetic
used drugs for the control of ocular inflammation. However, sys- dog with retinal changes sufficiently severe to result in blindness
temic absorption of topically applied glucocorticoids may cause itself. An electroretinogram can also be used to evaluate the func-
insulin resistance and interfere with glycemic control of the diation of the retina prior to cataract surgery.
betic state, especially in toy and miniature breeds. An alternative
is the topical administration of nonsteroidal anti-inflammatory Diabetic Neuropathy
agents, such as diclofenac (Voltaren) or flurbiprofen ophthalmic
(Ocufen). Although not as potent an anti-inflammatory agent as Although a common complication in diabetic cats, diabetic neu-
glucocorticoids, nonsteroidal anti-inflammatory drugs should not ropathy is infrequently recognized in the diabetic dog (Braund and
interfere with glycemic control. Steiss, 1982; Johnson etal, 1983; Katherman and Braund, 1983;
Morgan etal, 2008). Diabetic neuropathy in the dog is primarily
a distal polyneuropathy, characterized by segmental demyelination
Corneal Ulceration
and remyelination and axonal degeneration. Subclinical neuropa-
Diabetes mellitus has been associated with pathologic changes in thy is more common than severe neuropathy resulting in clinical
the corneas of dogs, which are directly related to the degree of dia- signs. Clinical signs consistent with diabetic neuropathy are most
betic control (Yee etal, 1985), and a significant reduction in cor- commonly recognized in dogs that have been diabetic for a long
neal sensitivity in all regions of the cornea has been documented period of time (i.e., 5 years or longer), although dogs have been
in diabetic dogs, compared with non-diabetic normoglycemic diagnosed with diabetic neuropathy shortly after the diagnosis of
|
diabetes is established (Morgan et al, 2008). Clinical signs and developed microalbuminuria. There is no specific treatment for
physical examination findings suggestive of diabetic neuropathy diabetic nephropathy apart from meticulous metabolic control
include pelvic limb paresis, abnormal gait, decreased muscle tone, of the diabetic state, conservative medical management of the
muscle atrophy, depressed limb reflexes, and deficits in postural kidney disease, administration of angiotensin converting enzyme
reaction testing. Electrodiagnostic abnormalities include spontane- (ACE) inhibitors to minimize proteinuria, and control of systemic
ous sharp waves and fibrillation potentials and decreased M-wave hypertension.
amplitude on electromyogram, suggestive of axonal disease, and
decreased motor and sensory nerve conduction velocities, sugges- Systemic Hypertension
tive of demyelinating disease (Steiss etal, 1981; Boulton etal, 2005;
Morgan et al, 2008). There is no specific treatment for diabetic Diabetes mellitus and hypertension commonly coexist in dogs.
neuropathy besides meticulous metabolic control of the diabetic Struble etal. (1998) found the prevalence of hypertension to be
state. See Chapter 7 for more information on diabetic neuropathy. 46% in 50 insulin-treated diabetic dogs, in which hypertension
was defined as systolic, diastolic, or mean blood pressure greater
than 160, 100, and 120 mm Hg, respectively. Median (range)
Diabetic Nephropathy
systolic, diastolic, and mean blood pressure in the hypertensive
Diabetic nephropathy has occasionally been reported in the dog. diabetic dogs were 175 (160 to 205) mmHg, 112 (101 to 150)
Diabetic nephropathy is a microvascular disease involving the mmHg, and 132 (120 to 186) mmHg, respectively. The develop-
capillary and precapillary arterioles and is manifested mainly by ment of hypertension was associated with the duration of diabetes
thickening of the capillary basement membrane. Histopathologic and an increased albumin-to-creatinine ratio in the urine. Dia-
findings include membranous glomerulonephropathy, glomeru- stolic and mean blood pressure were higher in dogs with longer
lar and tubular basement membrane thickening, an increase in duration of disease. A correlation between control of glycemia
the mesangial matrix material, the presence of subendothelial and blood pressure was not identified. Systemic hypertension may
deposits, glomerular fibrosis, and glomerulosclerosis (Steffes etal, result from existing subclinical kidney disease or develop second-
1982; Jeraj etal, 1984). Glucose plays a central role in the devel- ary to the effects of diabetes on vascular compliance, glomerular
opment of microvascular damage. Clinical signs depend on the function, or some other mechanism (Dukes, 1992). Treatment for
severity of glomerulosclerosis and the functional ability of the hypertension should be initiated if the systolic blood pressure is
kidney to excrete metabolic wastes. Initially, diabetic nephropathy consistently greater than 160 mm Hg.
is manifested as proteinuria, primarily albuminuria. As glomeru-
lar changes progress, glomerular filtration becomes progressively PROGNOSIS
impaired, resulting in the development of azotemia and eventually
uremia. With severe fibrosis of the glomeruli, oliguric and anuric The prognosis for dogs diagnosed with diabetes mellitus depends,
kidney failure develop. in part, on owner commitment to treating the disorder, ease of
Monitoring urine for the presence of microalbuminuria is used glycemic regulation, presence and reversibility of concurrent dis-
as an early marker for development of diabetic nephropathy in orders, avoidance of chronic complications associated with the
diabetic humans. Microalbuminuria occurs in diabetic dogs and diabetic state, and minimization of the impact of treatment on
increased urine albumin-to-creatine ratios precede increased urine the quality of life of the owner (see Table 6-5). In a large study
protein-to-creatinine ratios. In one study, 11 (55%) of 20 diabetic involving insured dogs in Sweden, the median survival time after
dogs had an increase in the urine albumin-to-creatinine ratio and the first diabetes mellitus claim (686 dogs) was 57 days and for
only 6 of these 11 dogs also had an increase in urine protein- dogs surviving at least 1 day (463 dogs) was 2.0 years (Fall etal,
to-creatinine ratio, suggesting that monitoring urine albumin- 2007). For dogs surviving at least 30 days after the first diabetes
to-creatinine ratio may be of value as an early marker for kidney mellitus claim (347 dogs), the proportion of dogs surviving 1, 2,
disease in diabetic dogs (Mazzi etal, 2008). However, the predic- and 3 years was 40%, 36%, and 33%, respectively. However, sur-
tive value of microalbuminuria for diabetic nephropathy and the vival times vary between countries and between socioeconomic
clinical relevance of microalbuminuria in diabetic dogs remains to regions within a country, and survival time is somewhat skewed
be clarified. Diabetic nephropathy is a significant chronic compli- because dogs are often 8 to 12 years old at the time of diagnosis;
cation in diabetic humans that takes years to progress to chronic a relatively high mortality rate exists during the first 6 months
end-stage kidney disease; a time line that may explain why clini- because of concurrent life-threatening or uncontrollable disease
cally relevant diabetic nephropathy is uncommon in diabetic dogs. (e.g., ketoacidosis, acute pancreatitis, kidney failure). In our expe-
Presumably in most dogs, diabetes mellitus and CKD develop as rience, diabetic dogs that survive the first 6 months can easily
independent events in aged dogs. maintain a good quality of life for longer than 5 years with proper
Regardless, proteinuria, kidney function, and systemic care by the owners, timely evaluations by the veterinarian, and
blood pressure should be monitored in diabetic dogs that have good client-veterinarian communication.
REFERENCES
Affenzeller N, etal.: Home-based subcutane- Braund KG, Steiss JE: Distal neuropathy in Dietiker-Moretti S, etal.: Comparison of a con-
ous continuous glucose monitoring in 10 spontaneous diabetes mellitus in the tinuous glucose monitoring system with a
diabetic dogs, Vet Rec 169:206, 2011. dog, Acta Neuropathol (Berl) 57:263, portable blood glucose meter to determine
Alejandro R, etal.: Advances in canine diabe- 1982. insulin dose in cats with diabetes mellitus,
tes mellitus research: etiopathology and Briggs C, etal.: Reliability of history and J Vet Intern Med 25:1084, 2011.
results of islet transplantation, J Am Vet physical examination findings for assessing Duesberg C, etal.: Impaired counterregulatory
Med Assoc 193:1050, 1988. control of glycemia in dogs with diabetes response to insulin-induced hypoglycemia
Andersen MK, etal.: Latent autoimmune mellitus: 53 cases (1995-1998), J Am Vet in diabetic dogs (abstract), J Vet Intern
diabetes in adults differs genetically Med Assoc 217:48, 2000. Med 9:181, 1995.
from classical type 1 diabetes diagnosed Brownlee M, etal.: Complications of diabetes Dukes J: Hypertension: a review of the mecha-
after the age of 35 years, Diabetes Care mellitus. In Melmed S, Polonsky KS, Lars- nisms, manifestations and management,
33:3062, 2010. en PR, Kronenberg HM, editors: Williams J Small Anim Pract 33:119, 1992.
Anderson RA: Chromium, glucose tolerance, textbook of endocrinology, ed 12, St Louis, Eckel RH: Lipoprotein lipase: a multifunc-
and diabetes, Biol Trace Element Res 2011, Elsevier Saunders, p 1462. tional enzyme relevant to common meta-
32:19, 1992. Catchpole B, etal.: Genetics of canine diabe- bolic diseases, N Engl J Med 320:1060,
Anderson RA, etal.: Elevated intakes of sup- tes mellitus: are the diabetes susceptibility 1989.
plemental chromium improve glucose and genes identified in humans involved in Eidemak I, etal.: Insulin resistance and
insulin variables in individuals with type 2 breed susceptibility to diabetes mellitus in hyperinsulinaemia in mild to moderate
diabetes, Diabetes 46:1786, 1997. dogs? Vet J 195:129, 2013. progressive chronic renal failure and its
Appel SL, etal.: Evaluation of client percep- Cohen TA, etal.: Evaluation of six portable association with aerobic work capacity,
tions concerning outcome of cataract blood glucose meters for measuring blood Diabetologia 38:565, 1995.
surgery in dogs, J Am Vet Med Assoc glucose concentrations in dogs, J Am Vet Elliott DA, etal.: Glycosylated hemoglobin
228:870, 2006. Med Assoc 235:276, 2009. concentrations in the blood of healthy dogs
Appleton DJ, etal.: Insulin sensitivity de- Cohn LA, etal.: Assessment of five portable and dogs with naturally developing diabe-
creases with obesity, and lean cats with blood glucose meters, a point-of-care ana- tes mellitus, pancreatic beta-cell neoplasia
low insulin sensitivity are at greatest risk lyzer, and color test strips for measuring hyperadrenocorticism, and anemia, J Am
of glucose intolerance with weight gain, blood glucose concentration in dogs, J Am Vet Med Assoc 211:723, 1997.
J Feline Med Surg 3:211, 2001. Vet Med Assoc 216:198, 2000. Elliott DA, etal.: Comparison of serum fructos-
Bagley LH, Lavach JD: Comparison of postop- Crenshaw KL, etal.: Serum fructosamine con- amine and blood glycosylated hemoglobin
erative phacoemulsification results in dogs centration as an index of glycemia in cats concentrations for assessment of glycemic
with and without diabetes mellitus: 153 with diabetes mellitus and stress hypergly- control in cats with diabetes mellitus,
cases (1991-1992), J Am Vet Med Assoc cemia, J Vet Intern Med 10:360, 1996. J Am Vet Med Assoc 214:1794, 1999.
205:1165, 1994. Cryer PE, Polonsky KS: Glucose homeostasis Elliott KF, etal.: A diet lower in digestible
Baker KS, etal.: Trigeminal ganglion neu- and hypoglycemia. In Wilson JD, Foster carbohydrate results in lower postprandial
rons affect corneal epithelial phenotype: DW, Kronenberg HM, Larsen PR, editors: glucose concentrations compared with a
influence of type VII collagen expression Williams textbook of endocrinology, ed 9, traditional canine diabetes diet and an
invitro, Invest Ophthalmol Vis Sci 34:137, Philadelphia, 1998, WB Saunders, p 939. adult maintenance diet in healthy dogs,
1993. Davidson JK, etal.: Insulin therapy. In David- Res Vet Sci 93:288, 2012.
Barrett KE, etal.: Ganongs review of medi- son JK, editor: Clinical diabetes mellitus: Engerman RL, Kern TS: Progression of incipi-
cal physiology, ed 24, New York, 2012, a problem oriented approach, New York, ent diabetic retinopathy during good glyce-
McGraw-Hill Lange. 1991, Thieme Medical Publishers, p 266. mic control, Diabetes 36:808, 1987.
Bauer JE: Lipoprotein-mediated transport of Davison LJ, etal.: Anti-insulin antibodies in Fall T, etal.: Diabetes mellitus in a population
dietary and synthesized lipids and lipid dogs with naturally occurring diabetes of 180,000 insured dogs: incidence, sur-
abnormalities of dogs and cats, J Am Vet mellitus, Vet Immunol Immunopath 91:53, vival, and breed distribution, J Vet Intern
Med Assoc 224:668, 2004. 2003a. Med 21:1209, 2007.
Beam S, etal.: A retrospective-cohort study on Davison LJ, etal.: Evaluation of a continuous Fall T, etal.: Glucagon stimulation test for
the development of cataracts in dogs with glucose monitoring system in diabetic estimating endogenous insulin secretion in
diabetes mellitus: 200 cases, Vet Ophthal- dogs, J Small Anim Pract 44:435, 2003b. dogs, Vet Rec 163:266, 2008a.
mology 2:169, 1999. Davison LJ, etal.: Study of 253 dogs in the Fall T, etal.: Gestational diabetes mellitus
Berlinger JA, etal.: Lipoprotein-induced insulin United Kingdom with diabetes mellitus, in 13 dogs, J Vet Intern Med 22:1296,
resistance in aortic endothelium, Diabetes Vet Rec 156:467, 2005. 2008b.
33:1039, 1984. Davison LJ, etal.: autoantibodies to GAD65 Fall T, etal.: Diabetes mellitus in Elkhounds is
Bieger WP, etal.: Diminished insulin receptors and IA-2 in canine diabetes mellitus, Vet associated with diestrus and pregnancy,
on monocytes and erythrocytes in hypertri- Immunol Immunopath 126:83, 2008a. J Vet Intern Med 24:1322, 2010.
glyceridemia, Metabolism 33:982, 1984. Davison LJ, etal.: Anti-insulin antibodies in Feldman EC, Nelson RW: Insulin-induced
Bolli GB, etal.: Abnormal glucose counter- diabetic dogs before and after treatment hyperglycemia in diabetic dogs, J Am Vet
regulation after subcutaneous insulin in with different insulin preparations, J Vet Med Assoc 180:1432, 1982.
insulin-dependent diabetes mellitus, N Intern Med 22:1317, 2008b. Fernqvist E, etal.: Effects of physical exercise
Engl J Med 310:1706, 1984. Davison LJ, etal.: Autoantibodies to recombi- on insulin absorption in insulin-dependent
Bostrom BM, etal.: Chronic pancreatitis in nant canine proinsulin in canine diabetic diabetics: a comparison between human
dogs: a retrospective study of clinical, patients, Res Vet Sci 91:58, 2011. and porcine insulin, Clin Physiol 6:489,
clinicopathological, and histopathological Della-Maggiore A, etal.: Efficacy of protamine 1986.
findings in 61 cases, Vet J 195:73, 2013. zinc recombinant human insulin for Fleeman LM, etal.: Pharmacokinetics and
Boulton AJM, etal.: Diabetic neuropathies: a controlling hyperglycemia in dogs with dia- pharmacodynamics of porcine insulin zinc
statement by the American Diabetes As- betes mellitus, J Vet Intern Med 26:109, suspension in eight diabetic dogs, Vet Rec
sociation, Diabetes Care 28:956, 2005. 2012. 164:232, 2009a.
|
Fleeman LM, etal.: Lack of advantage of high- Haines DM: A re-examination of islet cell cy- Kador PF, etal.: Topical KINOSTAT amelio-
fibre, moderate-carbohydrate diets in dogs toplasmic antibodies in diabetic dogs, Vet rates the clinical development and progres-
with stabilised diabetes, J Small Anim Immunol Immunopathol 11:225, 1986. sion of cataracts in dogs with diabetes
Pract 50:604, 2009b. Hamilton-Wessler M, etal.: Mechanism of mellitus, Vet Ophthalmol 13:363, 2010.
Ford SL, etal.: Insulin resistance in three dogs protracted metabolic effects of fatty acid Kaiyala KJ, etal.: Reduced beta-cell function
with hypothyroidism and diabetes mellitus, acylated insulin, NN304, in dogs: reten- contributes to impaired glucose tolerance
J Am Vet Med Assoc 202:1478, 1993. tion of NN304 by albumin, Diabetologia in dogs made obese by high-fat feeding,
Ford SL, etal.: Evaluation of detemir insulin in 42:1254, 1999. Am J Physiol 277:E659E667, 1999.
diabetic dogs managed with home blood Hasegawa S, etal.: Glycated hemoglobin Karam JH: Hypoglycemic disorders. In Greens-
glucose monitoring, Proceedings, ACVIM fractions in normal and diabetic dogs pan FS, Gardner DG, editors: Basic and
Forum, Anaheim, CA, 2010, p 442. measured by high performance liquid chro- clinical endocrinology, ed 6, New York,
Forman MA, etal.: Evaluation of serum pan- matography, J Vet Med Sci 53:65, 1991. 2001, Lange Medical Books/McGraw-Hill,
creatic lipase immunoreactivity and helical Hasegawa S, etal.: Glycated hemoglobin frac- p 699.
computed tomography versus conventional tions in normal and diabetic cats measured Katherman AE, Braund KG: Polyneuropathy
testing for the diagnosis of feline pancre- by high performance liquid chromatogra- associated with diabetes mellitus in a dog,
atitis, J Vet Intern Med 18:807, 2004. phy, J Vet Med Sci 54:789, 1992. J Am Vet Med Assoc 182:522, 1983.
Fracassi F, etal.: Breed distribution of canine Hess RS, Ward CR: Effect of insulin dosage on Kawamoto M, etal.: Relation of fructosamine
diabetes mellitus in Italy, Vet Res Commun glycemic response in dogs with diabetes to serum protein, albumin, and glucose
28:339, 2004. mellitus: 221 cases (1993-1998), J Am concentrations in healthy and diabetic
Fracassi F, etal.: Use of insulin glargine in Vet Med Assoc 216:217, 2000. dogs, Am J Vet Res 53:851, 1992.
dogs with diabetes mellitus, Vet Rec Hess RS, etal.: Breed distribution of dogs Kennedy LJ, etal.: Identification of suscepti-
170:52, 2012. with diabetes mellitus admitted to a bility and protective major histocompatibil-
Galante P, etal.: Acute hyperglycemia provides tertiary care facility, J Am Vet Med Assoc ity complex haplotypes in canine diabetes
an insulin-independent inducer for GLUT4 216:1414, 2000a. mellitus, Tissue Antigens 68:467, 2006.
translocation in C2C12 myotubes and rat Hess RS, etal.: Concurrent disorders in dogs Kharroubi I, etal.: Expression of adiponectin
skeletal muscle, Diabetes 44:646, 1995. with diabetes mellitus: 221 cases (1993- receptors in pancreatic beta cells, Biochem
Galloway JA: Chemistry and clinical use of 1998), J Am Vet Med Assoc 217:1166, Biophys Res Commun 312:1118, 2003.
insulin. In Galloway JA, etal., editors: 2000b. Kurtz AB, etal.: Circulating IgG antibody
Diabetes mellitus, Indianapolis, 1988, Hess RS, etal.: Association between hypothy- to protamine in patients treated with
Eli Lilly, p 105. roidism, diabetes mellitus, and hyperadre- protamine insulins, Diabetologia 25:322,
Garg A, Grundy SM: Management of dyslipid- nocorticism and development of athero- 1983.
emia in NIDDM, Diabetes Care 13:153, sclerosis in dogs (abstract), J Vet Intern Lahtela JT, etal.: Severe antibody-mediated
1990. Med 16:360, 2002. human insulin resistance: successful
Gayet C, etal.: Insulin resistance and changes Hirsch IB: Insulin analogues, N Engl J Med treatment with the insulin analog lispro,
in plasma concentration of TNF, IGF-1, 352:174, 2005. Diabetes Care 20:71, 1997.
and NEFA in dogs during weight gain Hoenig M, Dawe DL: A qualitative assay for Landry MP, etal.: Funduscopic findings fol-
and obesity, J Anim Physiolo Anim Nutr beta cell antibodies: preliminary results in lowing cataract extraction by means of
88:157, 2004. dogs with diabetes mellitus, Vet Immunol phacoemulsification in diabetic dogs: 52
Gerich JE: Is reduced first-phase insulin Immunopathol 32:195, 1992. cases (1993-2003), J Am Vet Med Assoc
release the earliest detectable abnormality Hofer-Inteeworn N, etal.: Effect of hypothyroid- 225:709, 2004.
in individuals destined to develop type 2 ism on insulin sensitivity and glucose toler- Lenox CE, etal.: Effects of glucosamine-
diabetes? Diabetes 51(suppl):S117, 2002. ance in dogs, Am J Vet Res 73:529, 2012. chondroitin sulfate supplementation
German AJ, etal.: Improvement in insu- Home PD: The pharmacokinetics and phar- on serum fructosamine concentration
lin resistance and reduction in plasma macodynamics of rapid-acting insulin in healthy dogs, J Am Vet Med Assoc
inflammatory adipokines after weight loss analogues and their clinical consequences, 236:183, 2010.
in obese dogs, Domest Anim Endocrinol Diabetes Obes Metab 14:780, 2012. Li S, etal.: Adiponectin levels and risk of type 2
37:214, 2009. Howell SJ, etal.: Degeneration of retinal diabetes: a systematic review and meta-anal-
Good KL, etal.: Corneal sensitivity in dogs ganglion cells in diabetic dogs and mice: ysis, J Am Vet Med Assoc 302:179, 2009.
with diabetes mellitus, Am J Vet Res 64:7, relationship to glycemic control and Lindholm A, etal.: Improved postprandial
2003. retinal capillary degeneration, Mol Vision glycemic control with insulin aspart: a
Graham PA, etal.: Canned high fiber diet and 19:1413, 2013. randomized double-blind cross-over trial
postprandial glycemia in dogs with natu- Howey DC, etal.: [Lys(B28), Pro(B29)]-human in type 1 diabetes, Diabetes Care 22:801,
rally occurring diabetes mellitus, J Nutri insulin: a rapidly absorbed analog of hu- 1999.
124:2712S, 1994. man insulin, Diabetes 43:396, 1994. Lindholm A, etal.: Immune responses to
Graham PA, etal.: Pharmacokinetics of a Jain NC: Erythrocyte physiology and changes in insulin aspart and biphasic insulin aspart
porcine insulin zinc suspension in diabetic disease. In Jain NC, editor: Essentials of in people with type 1 and type 2 diabetes,
dogs, J Small Anim Pract 38:434, 1997. veterinary hematology, Philadelphia, 1993, Diabetes Care 25:876, 2002.
Gross KL, etal.: Dietary chromium and Saunders. Lorenzen FH: The use of isophane insulin for
carnitine supplementation does not affect Jensen AL: Serum fructosamine in canine the control of diabetes mellitus in dogs,
glucose tolerance in obese dogs (abstr), diabetes mellitus: an initial study, Vet Res Acta Vet Scand 33:219, 1992.
J Vet Intern Med 14:345, 2000. Commun 16:1, 1992. Loste A, Marca MC: Study of the effect of total
Guptill L, etal: Time trends and risk factors Jeraj K, etal.: Immunofluorescence studies serum protein and albumin concentrations
for diabetes mellitus in dogs: analysis of renal basement membranes in dogs on canine fructosamine concentration, Can
of veterinary medical data base records with spontaneous diabetes, Am J Vet Res J Vet Res 63:138, 1999.
(1970-1999), Vet J 165:240, 2003. 45:1162, 1984. Mahaffey EA, Cornelius LM: Evaluation of a
Haataja L, etal.: Islet amyloid in type 2 dia- Johnson CA, etal.: Peripheral neuropathy and commercial kit for measurement of glyco-
betes, and the toxic oligomer hypothesis, hypotension in a diabetic dog, J Am Vet sylated hemoglobin in canine blood, Vet
Endocr Rev 29:303, 2008. Med Assoc 183:1007, 1983. Clin Path 10:21, 1981.
Mahaffey EA, Cornelius LM: Glycosylated he- Nell LJ, Thomas JW: Human insulin autoan- Rakatzi I, etal.: Adiponectin counteracts
moglobin in diabetic and nondiabetic dogs, tibody fine specificity and H and L chain cytokine- and fatty acid-induced apoptosis
J Am Vet Med Assoc 180:635, 1982. use, J Immunol 142:3063, 1989. in the pancreatic beta-cell line INS-1,
Marca MC, Loste A: Glycosylated haemoglobin Nelson RW, etal.: Effects of dietary fiber Diabetologia 47:249, 2004.
in dogs: study of critical difference value, supplementation on glycemic control in Rave K, etal.: Impact of diabetic nephropathy
Res Vet Sci 71:115, 2001. dogs with alloxan-induced diabetes mel- on pharmacodynamic and pharmacokinetic
Marca MC, etal.: Blood glycated hemoglobin litus, Am J Vet Res 52:2060, 1991. properties of insulin in type 1 diabetic
evaluation in sick dogs, Can J Vet Res Nelson RW, etal.: Effect of dietary insoluble patients, Diabetes Care 24:886, 2001.
64:141, 2000. fiber on control of glycemia in dogs with Remillard RL: Nutritional management of
Mared M, etal.: Evaluation of circulating naturally acquired diabetes mellitus, J Am diabetic dogs, Compend Contin Educ Pract
concentrations of glucose homeostasis Vet Med Assoc 212:380, 1998. Vet 21:699, 1999.
biomarkers, progesterone, and growth Nelson RW, etal.: Effect of the alpha- Reusch CE, Haberer B: Evaluation of fruc-
hormone in healthy Elkhounds during an- glucosidase inhibitor acarbose on control tosamine in dogs and cats with hypo- or
estrus and diestrus, Am J Vet Res 73:242, of glycemia in dogs with naturally acquired hyperproteinaemia, azotaemia, hyperlipi-
2012. diabetes mellitus, J Am Vet Med Assoc daemia and hyperbilirubinaemia, Vet Rec
Marfurt C: Nervous control of the cornea. In 216:1265, 2000. 148:370, 2001.
Burnstock G, Sillito AM, editors: Nervous Nerup J: On the pathogenesis of IDDM, Diabe- Reusch CE, Tomsa K: Serum fructosamine
control of the eye, Amsterdam, 2000, tologia 37(suppl 2):S82, 1994. concentration in cats with overt hyperthy-
Harwood Academic Publishers, p 41. Nguyen P, etal.: Glycemic and insulinemic roidism, J Am Vet Med Assoc 215:1297,
Marshall MO, etal.: Development of insulin responses after ingestion of commercial 1999.
antibodies, metabolic control and B-cell foods in healthy dogs: influence of food Reusch CE, etal.: Fructosamine: a new param-
function in newly diagnosed insulin composition, J Nutr 128:2654S, 1998. eter for diagnosis and metabolic control
dependent diabetic children treated with Niessen SJM, etal.: Evaluation of a quality-of- in diabetic dogs and cats, J Vet Int Med
monocomponent human insulin or mono- life tool for dogs with diabetes mellitus, 7:177, 1993.
component porcine insulin, Diabetes Res J Vet Intern Med 26:953, 2012. Reusch CE, etal.: Serum fructosamine concen-
9:169, 1988. Nishida Y, etal.: Effect of mild exercise trations in dogs with hypothyroidism, Vet
Massillon D, etal.: Induction of hepatic training on glucose effectiveness in Res Comm 26:531, 2002.
glucose-6-phosphatase gene expression by healthy men, Diabetes Care 24:1008, Richter M, etal.: Aldose reductase activity
lipid infusion, Diabetes 46:153, 1997. 2001. and glucose-related opacities in incubated
Mazzi A, etal.: Ratio of urinary protein to cre- Owens DR, etal.: Pharmacokinetics of 125I- lenses from dogs and cats, Am J Vet Res
atinine and albumin to creatinine in dogs labeled insulin glargine (HOE901) in 63:1591, 2002.
with diabetes mellitus and hyperadrenocor- healthy men-comparison with NPH insulin Robertson J, etal.: Effects of the alpha-
ticism, Vet Res Commun 32:S299, 2008. and the influence of different subcutane- glucosidase inhibitor acarbose on
McCord K, etal.: A multi-institutional study ous injection sites, Diabetes Care 23:813, postprandial serum glucose and insulin
evaluating the diagnostic utility of the spec 2000. concentrations in healthy dogs, Am J Vet
cPL and SNAP cPL in clinical acute Palm CA, etal.: An investigation of the action Res 60:541, 1999.
pancreatitis in 84 dogs, J Vet Intern Med of neutral protamine Hagedorn human Rosenstock J, etal.: Basal insulin glargine
26:888, 2012. analogue insulin in dogs with naturally oc- (HOE901) versus NPH insulin in patients
McGuire NC, etal.: Detection of occult urinary curring diabetes mellitus, J Vet Intern Med with type 1 diabetes on multiple daily
tract infections in dogs with diabetes 23:50, 2009. insulin regimens, Diabetes Care 23:1137,
mellitus, J Am Anim Hosp Assoc 38:541, Pastors JG, etal.: Psyllium fiber reduces rise 2000.
2002. in postprandial glucose and insulin Rosenstock J, etal.: Basal insulin therapy in
Merimee TJ: Diabetic retinopathy: a synthesis concentrations in patients with non-insulin- type 2 diabetes: 28-week comparison of
of perspectives, N Engl J Med 322:978, dependent diabetes, Am J Clin Nutr insulin glargine (HOE901) and NPH insu-
1990. 53:1431, 1991. lin, Diabetes Care 24:631, 2001.
Monroe WE, etal.: Efficacy and safety of a Paul AEH, etal.: Effect of hematocrit on ac- Rossetti L, etal.: Glucose toxicity, Diabetes
purified porcine insulin zinc suspension for curacy of two point-of-care glucometers Care 13:610, 1990.
managing diabetes mellitus in dogs, J Vet for use in dogs, Am J Vet Res 72:1204, Roszler J: Herbs, supplements and vitamins:
Intern Med 19:675, 2005. 2011. what to try, what to buy, Diabetes views,
Montgomery TM, etal.: Basal and glucagon- Peikes H, etal.: Dermatologic disorders in dogs August:45, 2001.
stimulated plasma C-peptide concentra- with diabetes mellitus: 45 cases (1986- Sako T, etal.: Time-action profiles of insulin
tions in healthy dogs, dogs with diabetes 2000), J Am Vet Med Assoc 219:203, detemir in normal and diabetic dogs, Res
mellitus, and dogs with hyperadrenocorti- 2001. Vet Sci 90:396, 2011.
cism, J Vet Intern Med 10:116, 1996. Phillips SM, etal.: GLUT-1 and GLUT-4 after Schachter S, etal.: Oral chromium picolinate
Moretti S, etal.: Evaluation of a novel real-time endurance training in humans, Am J and control of glycemia in insulin-treated
continuous glucose-monitoring system for Physiol 270:E456, 1996. diabetic dogs, J Vet Intern Med 15:379,
use in cats, J Vet Intern Med 24:120, 2010. Pieber TR, etal.: Efficacy and safety of HOE 2001.
Morgan MJ, etal.: Clinical peripheral neuropa- 901 versus NPH insulin in patients with Scheuner D, Kaufman RJ: The unfolded pro-
thy associated with diabetes mellitus in 3 type 1 diabetes, Diabetes Care 23:157, tein response: a pathway that links insulin
dogs, Can Vet J 49:583, 2008. 2000. demand with -cell failure and diabetes,
Mori A, etal.: Comparison of time-action Poitout V, Robertson RP: Glucolipotoxicity: fuel Endocr Rev 29:317, 2008.
profiles of insulin glargine and NPH insulin excess and -cell dysfunction, Endocr Rev Sears KW, etal.: Use of lispro insulin for treat-
in normal and diabetic dogs, Vet Res Com- 29:351, 2008. ment of diabetic ketoacidosis, J Vet Emerg
mun 32:563, 2008. Pppl AG, etal.: Diabetes mellitus remis- Critic Care 22:211, 2012.
Mori A, etal.: Comparison of glucose fluc- sion after resolution of inflammatory and Semenkovich CF, etal.: Disorders of lipid me-
tuations between day- and night-time progesterone-related conditions in bitches, tabolism. In Melmed S, Polonsky KS, Larsen
measured using a continuous glucose Res Vet Sci 94:471, 2013. PR, Kronenberg HM, editors: Williams
monitoring system in diabetic dogs, J Vet Porte D: Beta-cells in type II diabetes mellitus, textbook of endocrinology, ed 12, St Louis,
Med Sci 75:113, 2013. Diabetes 40:166, 1991. 2011, Elsevier Saunders, p 1633.
|
Sigle SJ, Nasisse MP: Long-term complica- Tilg H, Moschen AR: Adipocytokines: mediators Wess G, Reusch C: Capillary blood sampling
tions after phacoemulsification for cataract linking adipose tissue, inflammation and from the ear of dogs and cats and use
removal in dogs: 172 cases (1995-2002), immunity, Nat Rev Immunol 6:772, 2006. of portable meters to measure glucose
J Am Vet Med Assoc 228:74, 2006. Trivedi S, etal.: Sensitivity and specificity of concentration, J Small Anim Pract 41:60,
Spears JW, etal.: Influence of chromium on canine pancreas-specific lipase (cPL) and 2000b.
glucose metabolism and insulin sensitivity. other markers for pancreatitis in 70 dogs White NH, etal.: Identification of type I
In Reinhart GA, Carey DP, editors: Recent with and without histopathologic evidence diabetic patients at increased risk for
advances in canine and feline nutrition, of pancreatitis, J Vet Intern Med 25:1241, hypoglycemia during intensive therapy,
Vol II. Wilmington, Ohio, 1998, Orange 2011. N Engl J Med 308:485, 1983.
Frazer Press, p 97. van der Woerdt A, etal.: Lens-induced uveitis Wiberg ME, Westermarck E: Subclinical exo-
Steffes MW, etal.: Diabetic nephropathy in in dogs: 151 cases (1985-1990), J Am crine pancreatic insufficiency in dogs,
the uninephrectomized dog: microscopic Vet Med Assoc 201:921, 1992. J Am Vet Med Assoc 220:1183, 2002.
lesions after one year, Kidney Int 21:721, Verkest KR, etal.: Evaluation of beta-cell sen- Wiberg ME, etal.: Serum trypsinlike immuno-
1982. sitivity to glucose and first-phase insulin reactivity measurement for the diagnosis of
Steiss JE, etal.: Electrodiagnostic analysis of secretion in obese dogs, Am J Vet Med subclinical exocrine pancreatic insufficien-
peripheral neuropathy in dogs with diabetes 72:357, 2011a. cy, J Vet Intern Med 13:426, 1999.
mellitus, Am J Vet Res 42:2061, 1981. Verkest KR, etal.: Distinct adiponectin profiles Wiedmeyer CE, etal.: Continuous glucose
Stitt AW: The role of advanced glycation in the might contribute to differences in sus- monitoring in dogs and cats, J Vet Intern
pathogenesis of diabetic retinopathy, Exp ceptibility to type 2 diabetes in dogs and Med 22:2, 2008.
Mol Pathol 75:95, 2003. humans, Domest Anim Endocrinol 41:67, Wood AW, Smith JE: Elevation rate of glycosyl-
Striffler JS, etal.: Chromium improves insulin 2011b. ated hemoglobins in dogs after induction
response to glucose in rats, Metabolism Verkest KR, etal.: Spontaneously obese dogs of experimental diabetes mellitus, Metab
44:1314, 1995. exhibit greater postprandial glucose, 31:906, 1982.
Struble AL, etal.: Systemic hypertension and triglyceride, and insulin concentrations Yamka RM, etal.: Identification of canine
proteinuria in dogs with naturally occurring than lean dogs, Domest Anim Endocrinol markers related to obesity and the effects
diabetes mellitus, J Am Vet Med Assoc 42:103, 2012. of weight loss on the markers of interest,
213:822, 1998. Vick MM, etal.: Effects of systemic inflamma- Int J Apl Res Vet Med 4:282, 2006.
Stumvoll M, etal.: Renal glucose production tion on insulin sensitivity in horses and in- Xenoulis PG, etal: Association of hypertriglyc-
and utilization: new aspects in humans, flammatory cytokine expression in adipose eridemia with insulin resistance in healthy
Diabetologia 40:749, 1997. tissue, Am J Vet Res 69:130, 2008. Miniature Schnauzers, J Am Vet Med
Thomas JW, etal.: Heterogeneity and specific- Vuksan V, etal.: American ginseng (Panax Assoc 238:1011, 2011.
ity of human anti-insulin antibodies deter- quinquefolius L.) attenuates postprandial Yee RW, etal.: Corneal endothelial changes in
mined by isoelectric focusing, J Immunol glycemia in a time-dependent but not diabetic dogs, Curr Eye Res 4:759, 1985.
134:1048, 1985. dose-dependent manner in healthy indi- Zeugswetter F, etal.: Elevated fructosamine
Thomas JW, etal.: Spectrotypic analysis of viduals, Am J Clin Nutr 73:753, 2001. concentrations caused by IgA paraprotein-
antibodies to insulin A and B chains, Mol Watson PJ, etal.: Observational study of 14 emia in two dogs, J Vet Sci 11:359, 2010.
Immunol 25:173, 1988. cases of chronic pancreatitis in dogs, Vet
Tiley HA, etal.: Effects of dexamethasone Rec 167:968, 2010.
administration on insulin resistance and Wess G, Reusch C: Evaluation of five portable
components of insulin signaling and blood glucose meters for use in dogs, J Am
glucose metabolism in equine skeletal Vet Med Assoc 216:203, 2000a.
muscle, Am J Vet Res 69:51, 2008.
CHAPTER 7 Feline Diabetes Mellitus
Claudia E. Reusch
CHAPTER CONTENTS Techniques for Monitoring Diabetic Control, 289

Prevalence and Risk Factors in Humans and Cats, 259 History and Physical Examination, 290
Classification of Diabetes Mellitus, 259 Serum Fructosamine Concentration, 290
Types of Diabetes in Humans, 260 Glycated Hemoglobin Concentration, 291
Types of Diabetes in Cats, 262 Urine Glucose Monitoring, 291
Remission of Diabetes in Cats, 266 Single Blood Glucose Determination, 292
Insulin, Metabolic Effects, and Pathophysiology, 269 Blood Glucose Curve, 292
Insulin Synthesis, Structure, and Regulation, 269 Generation of Blood Glucose Curves in the Hospital, 292
Metabolic Effects of Insulin, 270 Home Monitoring of Blood Glucose, 293
Pathophysiology, 271 Continuous Glucose Monitoring, 299
Signalment, 271 Insulin Therapy During Surgery, 300
Anamnesis, 272 Complications of Insulin Therapy, 300
Physical Examination, 272 Stress Hyperglycemia, 300
Establishing a Diagnosis of Diabetes Mellitus, 273 Hypoglycemia, 302
Clinical Pathology, 275 Insulin Overdose and Glucose Counterregulation (Somogyi Effect), 303
Complete Blood Count, Serum Biochemical Panel, Urinalysis, and Urine Technical Problems, 303
Culture, 275 Insulin Underdose, 303
Pancreatic Enzymes, 276 Short Duration of Insulin Effect, 304
Serum Thyroxine Concentration, 276 Prolonged Duration of Insulin Effect, 304
Serum Insulin Concentration, 277 Impaired Absorption of Insulin, 304
Diagnostic Imaging, 277 Binding of Insulin by Insulin Antibodies, 304
Treatment of Nonketotic Diabetes Mellitus, 278 Allergic Reaction to Insulin, 305
Goals of Therapy, 278 Concurrent Disorders Causing Insulin Resistance
Initial Insulin Therapy, 279 and Drug-Induced Diabetes 305
Insulin Choice and Initial Dose, 281 Fluctuating Insulin Requirements (Glycemic Instability), 306
Insulin Handling and Owner Instruction, 282 Chronic Complications of Diabetes Mellitus, 307
Reevaluations and Adjustment of Insulin Dose, 282 Systemic Hypertension, 307
Oral Hypoglycemic Agents and Non-Insulin Injectables, 283 Diabetic Cataracts, 307
Dietary Management, 287 Diabetic Nephropathy, 307
Exercise, 289 Diabetic Neuropathy, 308
Concurrent Problems, 289 Prognosis, 308
Diabetes mellitus in dogs and cats differs in a number of ways, hyperadrenocorticism and variable in the case of hypersomatot-
which are important to consider for work-up and therapy. The ropism. Cats are prone to stress hyperglycemia, which may cause
majority of cats suffer a type of diabetes similar to type 2 in difficulties in diagnosis and monitoring of the disease, whereas
humans; in dogs, this type is extremely rare or may not exist in dogs, stress associated increase in blood glucose is of minor
at all. Unlike dogs, obesity is an important risk factor for the importance. The so-called renal threshold for glucose absorption
development of diabetes in cats; the difference is most likely is higher in cats than in dogs, rendering measurement of urine
associated with the different types of diabetes in the two species, glucose for monitoring purposes in diabetic cats even more prob-
because obesity and type 2 diabetes are closely related. A substan- lematic than in the dog. Diabetes-associated complications differ
tial percentage of cats with type 2 diabetes experience diabetic between the two species: diabetic cataract is rare in cats and com-
remission, and achievement of remission is nowadays one of the mon in dogs, whereas gait abnormalities due to diabetic neuropa-
major treatment goals in diabetic cats. In dogs, however, remis- thy are common in cats and rare in dogs. Of note, both cataract
sion is a very rare event, it usually only occurs after castration and diabetic neuropathy also exist in the respective counterpart,
of a bitch with diestrus-associated diabetes. In cats, other endo- however, usually at a subclinical level. Cats, but not dogs are obli-
crine disorders (e.g., hypersomatotropism and hyperadrenocorti- gate carnivores and therefore, dietary management is different.
cism) are associated with the development of diabetes in most Last but not least, duration of effect of exogenous insulin in cats
cases, whereas concurrent diabetes is relatively rare in dogs with is often shorter than in dogs.
258
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CHAPTER 7 Feline Diabetes Mellitus 259
PREVALENCE AND RISK FACTORS IN HUMANS female cats and that cats with reduced insulin sensitivity have a
AND CATS higher risk of becoming glucose intolerant after weight gain. Male
cats tend to gain more weight when fed ad libitum than female
In humans, diabetes mellitus is one of the most common chronic cats (Appleton etal, 2001). It is not clear if neutering is an inde-
diseases in nearly all countries (Whiting et al, 2011). Type 2 pendent risk factor, as one study found neutering (in both sexes)
diabetes is the predominant form, which accounts for approxi- to be associated with an increased risk of diabetes, whereas another
mately 90% of cases worldwide. Type 2 has long been the dis- study did not find this association (McCann et al, 2007; Prahl
ease of elderly people; however, this has changed substantially and etal, 2007). Neutered cats are at greater risk of gaining weight,
nowadays more and more children and young adults are affected. and it is probably the increased risk of obesity that contributes to
Due to the dramatic increases in prevalence during the last few the development of diabetes (McCann etal, 2007). In the United
decades, diabetes has also been called a new epidemic (Kaufman, States, no particular breed of cats appears to be associated with
2002). The International Diabetes Federation routinely publishes an increased risk for diabetes; in Australia, New Zealand, and the
estimates of diabetes prevalence every 3 years starting in the year United Kingdom, however, the Burmese breed is known to be at
2000. In 2011, there were 366 million people with diabetes, and increased risk (Panciera etal, 1990; Crenshaw and Peterson, 1996;
the number is expected to rise to 552 million by 2030. Although Rand etal, 1997; Wade etal, 1999; McCann etal, 2007; Lederer
the number differs between countries, every region of the world et al, 2009). In a study using a large insured cat population in
will have an increase well in excess of adult population growth the United Kingdom, Burmese cats were approximately four times
(Whiting etal, 2011). Excessive caloric intake leading to obesity more likely to develop diabetes than non-pedigree cats. Data from
and sedentary lifestyle are known to be the major risk factors in New Zealand point to a genetic predisposition; the differences
humans; an increase in the incidence of obesity has always been between the countries are most likely the result of different breed-
paralleled by an increase in diabetes incidence. Aging, female sex, ing programs and different lines within the Burmese breed (Wade
and belonging to certain racial and ethnic groups are additional etal, 1999; McCann, etal, 2007). Treatment with glucocorticoids
critical factors. There is no doubt that diabetes has become one or progestagens also increases the likelihood of the development of
of the most important global health problems (Kaufman, 2002; diabetes (Slingerland etal, 2009). In summary, many of the risk
Buse etal, 2011; Whiting etal, 2011). factors for development of diabetes are similar in humans and cats,
As in humans, diabetes is a common disorder in cats. Different including obesity, physical inactivity, and increasing age. Interest-
from human medicine, however, there are only limited data on ingly, however, the predominance in the male gender is unique
the prevalence of the disease. Some recent publications provide a to the cat. Although data are scarce, it is the impression of most
general overview of the current situation, although the methods endocrinologists that the incidence of diabetes in cats is increas-
of data collection differ. Most numbers reflect the proportion of ing, which is most likely associated with the increased incidence of
diabetic cats in a particular practice or a hospital (hospital preva- obesity, physical inactivity, and longevity.
lence) and not the situation in the field. A study from the United
States reported an increase in hospital prevalence over 30 years
CLASSIFICATION OF DIABETES MELLITUS
from 0.08% in 1970 to 1.2% in 1999. At the same time, case fatal-
ity at the first visit decreased from 40% to 10% suggesting either Traditionally, the classification of diabetes mellitus in cats has more
improvement in treatment regimens or an increased willingness of or less followed the scheme used in human medicine. Although
owners to undertake long-term management (Prahl etal, 2007). the etiopathogenic mechanisms may not be completely identical,
Studies from Australia showed overall hospital prevalence (i.e., all the human model provides a guide for identification and dif-
cat breeds) of 0.55% and 0.74%; prevalence in the Burmese cats ferentiation of the various forms of the disease.
was much higher with 1.8% and 2.2%, respectively (Baral etal, The first real attempt to classify human diabetes in a uniform
2003; Lederer et al, 2009). Recently, a non-hospital prevalence way was done in 1965 by the World Health Organization (WHO)
was evaluated in a large population of insured cats in the United Expert Committee, recognizing that without a clear classification,
Kingdom and was found to be 0.43%. Prevalence of diabetes in it is difficult to take a systematic epidemiological approach to
the Burmese cats was again higher with 1.8%, which compared clinical research and develop evidence-based guidelines for ther-
well with the studies from Australia (McCann etal, 2007). As in apy and prevention (George etal, 2011). At that time, little was
humans, obesity is a major risk factor for diabetes in cats, and known about the etiology of diabetes and the classification scheme
overweight cats are several times more likely to develop diabetes contained somewhat confusing categories. The second report of
than optimal weight cats (Scarlet and Donoghue, 1998). Physical the WHO Expert Committee in 1980 offered a classification that
inactivity and indoor confinement, which is most likely associated was widely accepted. Two main classes were introduced: insulin-
with obesity (sedentary lifestyle) as well as advancing age, have dependent diabetes mellitus (IDDM) and non-insulin-depen-
also been identified as important risk factors in cats. The over- dent diabetes mellitus (NIDDM). Additional classes were other
representation of male cats within the feline diabetic population types and gestational diabetes mellitus. During the following
has been known for a long time and has been confirmed by vari- years, understanding of the complex facets of the diabetic disease
ous studies (Panciera etal, 1990; Crenshaw and Peterson, 1996; improved, leading to a new classification scheme that included
McCann etal, 2007; Prahl etal, 2007; Slingerland etal, 2009). both etiology and clinical stages. The categories were named type 1,
The exception is the Burmese cat, for which a gender predisposi- type 2, other specific types, and gestational diabetes. It was sug-
tion is less clear. A study performed in the United Kingdom did not gested that the terms insulin-dependent and non-insulin-dependent
identify male gender as a risk factor in the Burmese breed, whereas diabetes mellitus (IDDM, NIDDM) should be abandoned, because
in the study from Australia, male Burmese cats were twice as likely they were considered confusing and frequently resulted in patients
to develop diabetes as were female Burmese cats (McCann etal, being classified on the basis of treatment rather than on etiopatho-
2007; Lederer etal, 2009). The reason for the male predominance genesis (World Health Organization, 1999). Up until now, a few
in most breeds has not yet been clarified. What is known is that updates were made; however, there are no fundamental changes
insulin sensitivity is generally lower in normal male than in normal compared with the report in 1999 (George etal, 2011; American
Diabetes Association, 2013). Although the scheme is helpful, it is Similarly, a woman with gestational diabetes may continue to be
recognized that assigning a type of diabetes to an individual often diabetic after delivery and may in fact suffer from type 2 diabetes
depends on the circumstances present at the time of diagnosis, (American Diabetes Association, 2013). Box 7-1 lists the classi-
and individuals may not easily fit into one class. For instance, a fication scheme according to etiology currently used in human
person who becomes diabetic after receiving exogenous steroids medicine. Fig. 7-1 displays the clinical stages and their dynamics
may regain normoglycemia after the discontinuation of the drug, within the four types of diabetes.
but may again develop diabetes after episodes of pancreatitis.
Types of Diabetes in Humans
The discussion of the various types of diabetes is done separately
BOX 7-1 E
tiological Classification of Diabetes Mellitus
for humans and cats; this will enable a better overview over the
in Humans
current state of knowledge in the two species. Many of the find-
ings in humans may also be of importance for feline diabetes, and
I. Type 1 diabetes
it is recommended to read the sections on humans prior to reading
(-cell destruction, usually leading to absolute insulin deficiency)
the feline sections.
a. Immune-mediated
b. Idiopathic Type 1 Diabetes Mellitus
II. Type 2 diabetes
Type 1 diabetes mellitus accounts for 5% to 10% of human cases
(ranging from predominantly insulin resistance with relative insulin
and was previously known as IDDM or juvenile-onset diabetes.
deficiency to predominantly an insulin secretory defect with
Although it is commonly seen in childhood and adolescence, it
insulin resistance)
can occur at any age, even in the 8th or 9th decade of life. It
III. Other specific types of diabetes
most commonly (> 90%) results from cellular-mediated autoim-
a. Genetic defects of -cell function
mune destruction of the -cells leading to failure of insulin syn-
b. Genetic defects in insulin action
thesis (American Diabetes Association, 2013). The characteristic
c. Diseases of the exocrine pancreas
pathological lesion in the pancreas is the presence of mononuclear
(e.g., pancreatitis, neoplasia, trauma, pancreatectomy)
immune cells around and within the islets. This infiltration, also
d. Endocrinopathies
called insulitis, is dominated by T lymphocytes, in particular
(e.g., hypersomatotropism, hyperadrenocorticism, pheochromocytoma,
cytotoxic (cluster of differentiation 8 [CD8]) T lymphocytes;
hyperthyroidism, hyperaldosteronism)
others are helper (cluster of differentiation 4 [CD4]) T lympho-
e. Drug- or chemical-induced
cytes and macrophages. The destructive process is limited to the
f. Infection
-cells, all other endocrine cells of the islets are spared (Peakman,
g. Uncommon forms of immune-mediated diabetes
2011). The rate of -cell destruction is variable; rapid destruction
h. Other genetic syndromes sometimes associated with diabetes
is often seen in children, whereas the destructive process often
IV. Gestational diabetes mellitus
is prolonged in adults (American Diabetes Association, 2013).
Modified from American Diabetes Association: Diagnosis and classification of Interestingly, the pattern of -cell destruction is markedly heter-
diabetes mellitus, Diabetes Care 36 (suppl 1):67, 2013. ogenous, and an intact pancreatic islet can be located next to an
Stages Normoglycemia Hyperglycemia
Impaired glucose Diabetes mellitus

Normal glucose
tolerance Not insulin Insulin requiring Insulin requiring
Types tolerance
(Prediabetes) requiring for control for survival
Type 1
Type 2
Other specific
types
Gestational
diabetes
FIGURE 7-1 Clinical stages and etiological types of diabetes in humans. Arrows indicate that an individual may
move between the clinical stages; broken arrows illustrate that individuals in one category who would by definition
not require insulin for survival may develop the need for insulin under certain circumstances (e.g., disease progres-
sion, development of diabetic ketoacidosis [DKA]). (Modified from George K, et al.: Classification and diagnosis of
diabetes mellitus. In Wass JAH, Stewart PM, Amiel SA, Davies MC, editors: Oxford textbook of endocrinology and
diabetes, ed 2, Oxford, 2011, Oxford University Press; and American Diabetes Association: Diagnosis and classifica-
tion of diabetes mellitus, Diabetes Care 36[suppl 1]:67, 2013.)
|
islet with completely destroyed -cells (Klinke, 2008). Recently, that individuals cannot develop type 2 diabetes without having
the widely-held belief that the disease only becomes clini- dysfunctional -cells. Therefore, at the time of diagnosis, both
cally apparent when 80% to 90% of the individuals -cells are insulin resistance and -cells abnormalities are present (Robertson,
destroyed has been challenged. It was suggested, that the extent 2009; Masharani and German, 2011). The term insulin resistance
of -cell destruction at which hyperglycemia develops is age- describes the inability of insulin to exert its normal biological
dependent. In younger humans (at age 20) a reduction of 40% effects at concentrations that are effective in normal individuals.
of -cell mass was sufficient to precipitate clinical signs (Klinke, The main sites of insulin resistance are liver, muscle, and adipose
2008). A major marker of autoimmune type 1 diabetes is the tissue. The defects seem to involve the insulin receptor binding only
presence of circulating autoantibodies against glutamic acid to a minor extent; most abnormalities are at post-receptor levels in
decarboxylase 65 (GAD65), islet antigen-2 (IA-2), insulin, and the insulin-signaling cascade. Insulin resistance leads to impaired
zinc transporter 8 (ZnT8). One or more of these islet-related suppression of hepatic gluconeogenesis (under basal conditions
autoantibodies can be detected months to years before the clinical as well as after meals) and impaired glucose uptake of peripheral
onset of the disease in most human patients. Their measurement tissues (Yki-Jrvinen, 2010). A large number of genes associated
is useful to differentiate type 1 diabetes from other types in newly with the disease have been identified, the majority of which are
diagnosed individuals and to follow individuals at risk to predict associated with reduction in -cell function; only a few are related
the development of the disease. Although their predictive value is to insulin sensitivity (De Silva and Frayling, 2010; Schfer etal,
very high, not all subjects with autoantibodies will develop diabe- 2011; Kahn et al, 2012). Besides genetics, insulin sensitivity is
tes, most likely because of protective genes. With time, autoanti- negatively influenced by various factors, including obesity, physical
bodies tend to decline (Delli etal, 2010; Masharani and German, inactivity, some drugs, and high glucose levels. Obesity is recog-
2011). What exactly triggers the autoimmune process has not nized as the major critical factor worldwide. With an increase in
yet been unraveled. It has been known for quite some time that obesity, there has been a parallel global increase in the incidence
genetic factors increase the predisposition for the disease and that of type 2 diabetes mellitus. Approximately 80% of humans with
genetic susceptibility is most closely associated with allelic variants type 2 diabetes are obese, and the risk of diabetes increases with
within the human leukocyte antigen (HLA) region that lie on the body fat mass. The pattern of obesity is important, as central (intra-
short arm of chromosome 6. High and lower risk haplotypes as abdominal) fat carries a much higher risk than fat deposition at
well as protective haplotypes have been identified. Genes outside other sites. Individuals with type 2 diabetes with a body mass index
of the HLA region also contribute to the risk of type 1 diabetes, not meeting the definition for obesity may still have an excessive
however, to a much smaller extent (Erlich etal, 2008; Concan-
non etal, 2009). Although genetics play an important role, stud-
ies in monozygotic twins revealed that the concordance rate is
Environment
only approximately 50%, indicating that other causes are at least Obesity
as important. Environmental factors, assumed to be associated Inactivity
with increased risk of type 1 diabetes, are virus infections (e.g., Drugs
mumps virus, rubella virus, and the Cocksackie B virus), dietary Genes Gluco-, lipotoxicity
factors (short breast-feeding/bovine milk), and toxic substances.
The incidence of type 1 diabetes increases steadily, in particular
in Western societies. It has been suggested that the sharp rise is Insulin resistance
due to a change in environmental factors operating early in life. (muscle, fat, liver)
According to the hygiene hypothesis, the lack of exposure to
common pathogens (in particular parasites) in a clean, more ster-
ile environment may result in an exaggerated immune response Glucose
(Bilous and Donelly, 2010; Masharani and German, 2011).
Genes
Type 2 Diabetes Mellitus
Type 2 diabetes mellitus was previously referred to as NIDDM - cell
Environment
or adult-onset diabetes and accounts for up to 90% of human Gluco-, lipotoxicity
cases (American Diabetes Association, 2013). Type 2 diabetes is a Amyloid
complex and heterogeneous disease resulting from a large number Drugs
of genetic and environmental insults. The genetic association is
stronger than for type 1 diabetes, and the concordance rate in Insulin Insulin
monozygotic twins is much higher. Depending on the popula-
tion studied, the latter may be as high as 90%; however, it has Normoglycemia IGT Diabetes mellitus
been assumed that part of the high rate may also be due to simi- FIGURE 7-2 Simplified model of etiopathogenesis of type 2 diabetes mellitus.
lar environmental factors (Bilous and Donnelly, 2010; Masharani Although this graph is taken from human medicine, it is currently assumed that
and German, 2011). the principal factors are similar in cats. At the time of diagnosis of type 2 diabe-
Type 2 diabetes is characterized by two defects, namely insulin tes the two defects, insulin resistance and -cell dysfunction, are present. Ini-
resistance and relative insulin deficiency due to -cell dysfunction tially, -cells are able to compensate for insulin resistance by increasing insulin
(as opposed to absolute deficiency in type 1 diabetes) (American synthesis and normoglycemia is maintained. With time, however, dysfunctional
Diabetes Association, 2013) (Fig. 7-2). It has long been assumed -cells are not able to meet the increased demand, leading to impaired glucose
that insulin resistance was the primary and most important defect. tolerance and thereafter, to overt diabetes. In individuals without -cell defect,
However, most humans with insulin resistance do not develop dia- diabetes mellitus will not develop because -cells are able to compensate.
betes, because their -cells are able to compensate by augment- (Modified from Bilous R, Donnelly R: Handbook of diabetes, ed 4, 2010, Wiley-
ing insulin production and secretion. It is now generally agreed Blackwell.) IGT, Impaired glucose tolerance.
intra-abdominal fat accumulation (Bilous and Donnelly, 2010). leads to -cell death; similarly free fatty acids increase during the
The discovery that adipose tissue (in particular the central visceral course of diabetes and in turn may cause -cell damage. Amyloid
stores) is an active endocrine organ, and part of the innate immune derives from islet amyloid polypeptide (IAPP), which is co-secreted
system has sparked intense research on obesity. Factors secreted by from the -cell with insulin. Either the mature insoluble amyloid
adipose tissue play a major role in the regulation of metabolism. fibrils lying outside the -cell or, more likely, small oligomers within
These factors include non-esterified fatty acids (NEFAs) and pro- the cell may contribute to the progressive -cell damage (Alsahli and
teins, called adipocytokines, which act in an autocrine, paracrine, Gerich, 2010).
or endocrine fashion. Adipose tissue in lean subjects secretes rela-
tively high levels of the adipocytokine adiponectin, which has anti- Other Specific Types of Diabetes and Gestational Diabetes
inflammatory actions and is associated with an increase in insulin The category other specific types refers to diabetes that develops
sensitivity and therefore with a favorable metabolic status. With in association with diseases or factors other than those described
obesity, adiponectin secretion decreases considerably and instead, under type 1 or type 2 diabetes mellitus. A large number of
large amounts of NEFA, leptin, and pro-inflammatory cytokines, genetic syndromes, which have not been described in animals, are
such as tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), listed in this category. One example is the maturity-onset of dia-
monocyte chemotactic protein-1 (MCP-1) and others, are secreted betes of the young (MODY), which is inherited in an autosomal
by adipocytes and/or activated macrophages within the adipose tis- dominant pattern. Diabetes may occur secondary to disorders of
sue. These factors impair insulin signaling and therefore induce or the exocrine pancreas, and any process that diffusely injures the
worsen insulin resistance. Additionally, inflammatory factors are pancreas can cause diabetes (e.g., pancreatitis, trauma, infection,
released into the systemic circulation and may promote inflamma- or pancreatic carcinoma). Several endocrinopathies (e.g., hyperso-
tion in other tissues, including the islets (Rasouli and Kern, 2008; matotropism, hyperadrenocorticism, hyperthyroidism, pheochro-
Donath and Shoelson, 2011). mocytoma, hyperaldosteronism, and glucagonoma) are associated
Dysfunction of -cells is crucial in the development of type 2 with excessive secretion of hormones that antagonize the insulin
diabetes mellitus. Initially, the -cells are able to increase insulin effect. Similarly, the administration of diabetogenic drugs may
synthesis and release to meet the increased demand caused by the result in glucose intolerance or overt disease. Diabetes mellitus
insulin resistance. With time, however, -cells start to fail, first usually only occurs in humans with pre-existing -cell defect. A
leading to glucose intolerance, which is usually followed by overt fourth category in the human model is gestational diabetes, which
diabetes mellitus. It is currently assumed that the primary defect is is defined as carbohydrate intolerance with onset or first recogni-
a genetic predisposition and that additional acquired or environ- tion during pregnancy (American Diabetes Association, 2013).
mental factors amplify the genetic damage, ultimately worsening
the hyperglycemia (Robertson, 2009). By the time of diagnosis, Types of Diabetes in Cats
-cell function is reduced by approximately 50% and continues
to decline. Beta-cell mass will also decrease during type 2 diabetes, Type 1 Diabetes Mellitus
however, not to an extent that would fully explain the extent of Type 1-like diabetes is generally considered to be rare in cats. Lym-
dysfunction. Therefore, besides morphological defects (reduction phocytic infiltration into the islets (insulitis) as a marker of immune-
in number of -cells), important functional defects contribute to mediated disease has only been described in a few cases (Minkus
the disease. The latter may be, at least in part, reversible and are etal, 1991; Hall etal, 1997). In a recent study, when examining islet
therefore an interesting topic for new drug therapies (Robertson, lesions in a larger group of diabetic cats against a control population
2009). Characteristic reflections of -cell defects include dis- (matched in age, sex, and body weight), a tendency of lymphocytes
ruption of the normal basal oscillatory pattern of insulin release, to be more frequent in diabetic cats was found (in 20% of diabetic
reduced or absent first phase insulin secretion in response to intra- cats and in 5% of control cats). The infiltration was usually mild and
venous (IV) glucose (and with time reduced second phase release), may reflect an inflammatory situation also known to be present in
reduced insulin response to a mixed-meal, and insufficient conver- type 2 diabetes. Only one of the 27 diabetic cats had severe lympho-
sion of proinsulin to insulin. The other cells of the islets remain cytic infiltration, which was similar in severity to those described
intact (Alsahli and Gerich, 2010). Type 2 is a polygenic disease, in the two studies mentioned earlier (Zini etal, 2012; Fig. 7-3, A).
and many genetic variants contribute to the susceptibility of the Beta cell and insulin antibodies have so far not been demonstrated
disease. As already mentioned, most of the risk genes affect -cell in newly diagnosed diabetic cats (Hoenig etal, 2000a).
function, in particular glucose-stimulated insulin secretion,
incretin-stimulated insulin secretion, and proinsulin-to-insulin Type 2 Diabetes Mellitus
conversion. So far, the most important type 2 risk gene is the gene It is currently assumed that approximately 80% of diabetic cats
encoding transcription factor 7-like 2 (TCF7L2); mutations are suffer from a type 2-like diabetes mellitus, although there are no
mainly associated with an impairment of the incretin effect (Schfer thorough studies to support this assumption. Nevertheless, most
etal, 2011) (incretins are discussed in Oral Hypoglycemic Agents endocrinologists would agree that type 2-like diabetes is the most
and Non-Insulin Injectables). Acquired or environmental factors frequent form in cats. Similar to human type 2 diabetes mellitus,
that worsen the damage of the -cells in genetically predisposed feline type 2 diabetes is a heterogeneous disease attributable to a
individuals include glucotoxicity, lipotoxicity, oxidative stress, pro- combination of impaired insulin action in liver, muscle, and adi-
inflammatory cytokines derived from adipose tissues, and increased pose tissue (insulin resistance), and -cell failure. Environmental
deposition of amyloid. They may induce an inflammatory reaction as well as genetic factors are thought to play a role in the develop-
within the islets, as suggested by the presence of infiltrating macro- ment of both defects (see Fig. 7-2).
phages and increased IL-1 (Donath and Shoelson, 2011). Gluco- Genetic Factors. Genetic factors have just started to be inves-
and lipotoxicity are covered in the Remission of Diabetes in Cats tigated (Forcada et al, 2010). However, most likely similar to
section, and amyloid deposition is covered in the Types of Diabetes humans, diabetes in the cat is a polygenic disease, and many
in Cats section. In brief, glucotoxicity describes the phenomenon genes will be associated with an increased risk for the disease. The
that hyperglycemia per se impairs insulin secretion and possibly most convincing evidence of a genetic basis comes from studies
|
A B
C D
FIGURE 7-3 Pancreatic histology. A, Severe infiltration with T lymphocytes within a pancreatic islet in an
18-year-old Domestic Short-Hair (DSH) cat with diabetes mellitus. This is a rare finding, because usually only
few or no lymphocytes are found in islets of diabetic cats. Immunohistochemistry for cluster of differentiation
3 (CD3), hematoxylin and eosin (H&E) counterstain ( 40). B, Islet amyloidosis in a 16-year-old, spayed female,
DSH cat with diabetes mellitus (H&E, 40). C, Vacuolar degeneration of an islet in a 9-year-old, castrated
male, DSH with diabetes (H&E, 40). D, Fibrosis in exocrine pancreas in an 8-year-old Siamese cat with dia-
betes mellitus (H&E, 40). (From Zini E, etal.: Histological investigation of endocrine and exocrine pancreas
in cats with diabetes mellitus, J Vet Intern Med 26 (abstract):1519, 2012.)
in the Burmese cat. In breeding lines from Australia, New Zea- 30% loss in insulin sensitivity (Hoenig et al, 2007). Insulin
land, and the United Kingdom, the frequency of diabetes mellitus sensitivity differs considerably between individuals, and it was
was shown to be about four times higher in Burmese cats than in suggested that cats with intrinsically low insulin sensitivity are
domestic cats. In some families of Burmese cats, more than 10% at increased risk of developing glucose intolerance with weight
of the offspring were affected by diabetes (Rand etal, 1997; Wade gain. Male cats tended to have lower insulin sensitivity prior to
etal, 1999; McCann etal, 2007; Lederer etal, 2009). the feeding trial and gained more weight than female cats, which
Obesity, Gender, and Other Risk Factors. One of the major might explain in part why male cats are at increased risk of devel-
risk factors for the development of diabetes in cats is obesity. oping diabetes mellitus (Appleton etal, 2001). The mechanisms
Others are male gender, physical inactivity and indoor confine- of insulin resistance on a cellular level and the interrelations of
ment, increasing age, and the administration of glucocorticoids the different findings are not yet understood in cats. Most of the
and progestagens (Panciera etal, 1990; Crenshaw and Peterson, research to date has focused on glucose transporters (GLUTs),
1996; Scarlet and Donoghue, 1998; McCann etal, 2007; Prahl insulin signaling genes in insulin-sensitive tissues, and secretion
et al, 2007; Slingerland et al, 2009). It has been shown that of adipocytokines from adipose tissue. In cats that became obese,
obese cats are 3.9 times more likely to develop diabetes mellitus the expression of the insulin-sensitive GLUT-4 in muscle and fat
than were cats with an optimal weight (Scarlett and Donoghue, was significantly lower than in lean cats, whereas the expression
1998). Experimental studies in healthy cats showed that an aver- of GLUT-1, which is not insulin-sensitive, remained unchanged
age weight gain of 1.9 kg during a feeding trial was associated (Brennan et al, 2004). Expression of several insulin signaling
with a decrease in insulin sensitivity of more than 50% (Apple- genes in liver and skeletal muscles were significantly lower in
ton et al, 2001). Similar results were reported in another trial obese cats than in lean cats, which is similar in humans with
in which each kilogram increase in weight led to approximately insulin resistance (Mori etal, 2009a).
340 Baseline + Weight gain Fasting

b+ Recovery
300 ab b
+ b
260 a
a b b
Glucose (mg/dL)
+
a c
220 b b
a a b
+
180
b b
a
140 a +
a a
100 a + a
+ +
a a a
60
0 20 40 60 80 100 120
Glucose Time (min)

A injection
45 Baseline + Weight gain Fasting Recovery

b b
40 c
b
c
b
35 b
+ b
30 c +
Insulin (U/mL)
b b bc
FIGURE 7-4Mean glucose (A) and insulin (B) concentrations 25
( standard error of the mean [SEM]) in 12 cats after intravenous +
(IV) administration of 0.5 g of glucose per kilogram of body weight 20 b
b a
at entry into the study (baseline), after 9 2 months of weight gain, b
15 +
after a voluntary fast of 5 to 6 weeks (weight loss), and 5 weeks ab ab
after the end of fasting (recovery). a to c, Points with a different a
10 b a ab
letter are significantly different (p < 0.05) among periods. Note the a a a a
b a a
development of impaired glucose tolerance despite increased insulin 5 a a
a
secretion with weight gain and improvement in glucose tolerance
and the exaggerated insulin secretory response with weight loss. 0
0 20 40 60 80 100 120
(From Biourge V, etal.: Effect of weight gain and subsequent weight
loss on glucose tolerance and insulin response in healthy cats, J Vet Glucose Time (min)
B injection
Intern Med 11:86, 1997).
Adipokines and Proinflammatory Cytokines. Also similar to negative influence on insulin signaling. Today, various additional
humans, it is now recognized in cats that adipose tissue is an active cytokines and chemokines (e.g., IL-6, MCP-1) are known also to
and complex endocrine organ. It was shown that adiponectin, which be involved in the inflammatory process in humans (Kanaya and
is almost exclusively produced in adipose tissue, decreases with obe- Vaisse, 2011). Adipose tissue in cats may behave in a similar man-
sity and diabetes mellitus in cats (Brmel etal, 2004; Hoenig etal, ner, because the level of TNF (in fat) was significantly higher in
2007). Adiponectin belongs to the large group of molecules syn- obese than in lean cats (Hoenig et al, 2006). Further studies, in
thesized in adipose tissue and collectively termed adipokines. Adi- particular in naturally acquired diabetes, are needed to substantiate
ponectin enhances insulin sensitivity and has anti-inflammatory those findings. The interested reader is referred to the reviews of
properties; a decrease, therefore, contributes to insulin resistance Radin, etal., (2009) and German, etal., (2010) for more details on
and inflammation. Leptin, the prototypic adipokine, is involved obesity, adipokines, and inflammation. For everyday practice, it is
in appetite suppression and energy expenditure and plays a role in important to know that insulin resistance evolving during weight
modulation of insulin sensitivity (Radin et al, 2009). Obese cats gain is reversible after weight loss. When healthy cats were fed ad
have been found to be leptin-resistant (i.e., they have much higher libitum, weight gain was associated with a significant increase in
leptin levels than lean cats without causing an appropriate physi- glucose, and insulin concentrations during an intravenous glu-
ological response) (Hoenig, 2012). As described earlier, it is known cose tolerance test (IVGTT) compared to baseline and the total
in humans that adipose tissue secretes a number of proinflamma- amount of insulin secretion was significantly higher. Several weeks
tory cytokines, and obesity is now considered a state of low-grade after weight loss was achieved by low caloric intake, the results of
chronic inflammation. TNF was the first adipose-derived factor the IVGTT were similar to those at baseline (Biourge etal, 1997;
suggested to represent a link between obesity and the insulin resis- Fig. 7-4). The study underscores the importance of weight manage-
tance seen in human type 2 diabetes; this cytokine exerts a strong ment throughout life and in particular in cats with diabetes.
|
Beta-Cell Dysfunction, Amyloid, and Glucotoxicity.It is is little doubt that glucotoxicity is a secondary event, because hyper-
important to note that although obesity induces insulin resistance, glycemia becomes apparent only after -cells start to fail. However,
not all obese cats develop diabetes mellitus. Healthy -cells adapt improving glycemic control by insulin therapy will reverse some of
to obesity and insulin resistance by increasing insulin secretion to the negative effects, and reversal of glucotoxicity is an important
maintain normal glucose tolerance (see also Fig. 7-2). Additionally, mechanism to explain diabetic remission. Lipotoxicity is the term
cats also seem to be able to lower their glucose output from the liver used for the damaging effect of high levels of free fatty acids; in
in case of peripheral insulin resistance (Hoenig, 2012). For diabetes cats, however, lipotoxicity may not be as important as glucotoxicity
to develop, there must be -cell dysfunction leading to impaired glu- (Zini etal, 2009a). Details are discussed in the section on remission
cose tolerance and eventually type 2 diabetes. Unfortunately, there of diabetes. In humans with type 2 diabetes, inflammatory changes
are nearly no data on -cell function and insulin secretion in cats within the islets have been reported, potentially contributing to
during the natural development of diabetes. Most studies were done -cell apoptosis (Robertson, 2009; Donath and Shoelson, 2011).
in healthy cats in which obesity was induced within a short period As mentioned in the beginning of this section, more lymphocytes
of time by ad libitum feeding. In one study, cats were made diabetic were found in the islets of diabetic cats than in a matched con-
by pancreatectomy and administration of insulin antagonistic drugs trol population. It was speculated that they may have contributed
(Hoenig etal, 2000b). From this study one can conclude that in to the loss of -cells (Zini etal, 2012). Clearly, more studies are
the early stage of diabetes the first phase of insulin release becomes needed to define the role of islet inflammation.
delayed and smaller, whereas insulin secretion during the second
phase is more pronounced; during this stage, baseline glucose is still Other Specific Types of Diabetes (Secondary Diabetes Mellitus)
normal. With time, the first phase of insulin secretion disappears Diabetes in cats may develop as a consequence of another disease or
almost completely, insulin secretion becomes erratic, and the total the administration of diabetogenic drugs, such as glucocorticoids
amount of insulin during the 2-hour IVGGT decreases substan- and progestins. In humans, this category encompasses various dis-
tially. At this time, baseline glucose concentration is increased (i.e., orders (in particular genetic disorders), which are so far unknown
overt diabetes is present). As a reminder: Healthy lean cats have in cats. Some of the subcategories, such as diabetes associated with
a biphasic insulin secretion pattern when stimulated with glucose pancreatic diseases or other endocrinopathies, are known to occur
during an IVGGT (Hoenig etal, 2000b; Hoenig, 2012). also in cats. These diseases may account for approximately up to
The big question, What exactly leads to -cell failure under 20% of diabetic cases in cats. Diabetes induced by glucocorticoids
natural conditions? is unanswered until today. One long-known or progestins is relatively common (see also Concurrent Disorders
hypothesis concerns -cell destruction by amyloid deposition. Causing Insulin Resistance and Drug-Induced Diabetes). The inter-
Islet amyloid derives from a hormone named IAPP also known as relationships of the endocrine and exocrine parts of the pancreas are
amylin. IAPP is a normal product of the -cells, which is stored complex. For instance, acinar tissue is in close contact with the islets
together with insulin in secretory vesicles and is co-secreted with without surrounding capsule or basement membrane, and an islet-
insulin into the circulation. IAPP levels are elevated in condi- acinar portal system communicates between both parts (Chen etal,
tions associated with insulin resistance (e.g., in cats with obesity) 2011). It is, therefore, easy to understand that a disease in one part
(Henson et al, 2011). Only cats, humans, and nonhuman pri- will also affect the other one. Pancreatitis has gained a lot of attention
mates have an amyloidogenic amino acid structure of IAPP with during the past years, and it is now known that it is a relatively com-
the potential to form amyloid depositions within the islets of the mon disease in cats. The cause and effect of pancreatitis and diabetes
pancreas (OBrien, 2002; Hull etal, 2004). Amyloid depositions in cats, however, is difficult to define and is largely unknown. In pre-
have been found in many cats with diabetes; it is, however, also vious studies, histological abnormalities consistent with pancreatitis
a frequent finding in non-diabetic cats. In a recent study, 56% of were found in 22% and 51% of diabetic cats. Findings included
diabetic cats and 42% of control cats matched for age, sex, and neutrophilic infiltration and necrosis considered consistent with
body weight had amyloid depositions, the amount of which was acute pancreatitis and diffuse lymphocytic and lymphoplasmacytic
also comparable (Zini etal, 2012; see Fig. 7-3, B). The situation is infiltration considered consistent with chronic pancreatitis (Kraus
similar in humans, because many of the type 2 diabetics, but also a etal, 1997; Goossens etal, 1998). However, recent histological stud-
substantial percentage of non-diabetics, have amyloid depositions ies also revealed a high prevalence of pancreatitis in cats without dia-
in the pancreatic islets (Alshali and Gerich, 2010). betes. De Cock, etal., (2007) performed histological examinations
The open questions are: Why arent all individuals with an amy- of the pancreas of 115 cats that had been euthanized for various
loidogenic structure of amylin forming amyloid depositions? and reasons; 41 of them had been clinically healthy. The overall preva-
Is amyloid a cause or consequence of the disease? It has been lence of pancreatitis was 67%, evidence for chronic pancreatitis was
shown that disturbed protein folding and/or trafficking of amylin found in 50.4%, for acute pancreatitis in 6.1% of cases, and approx-
within the -cells lead to the formation of so-called toxic oligomers. imately 10% of cases had both acute and chronic pancreatitis. We
These intracellular molecules induce cytotoxicity and may lead to recently studied pancreatic tissue of 37 diabetic cats in comparison
a decline in -cell function and to -cell apoptosis. The extracel- to tissue from 20 matched control cats using the same histological
lular amyloid deposits seem to be less toxic and represent the end criteria as De Cock, etal. The findings in control cats were similar
point of misfolding (Costes et al, 2013). Loss of -cell function to their study, and interestingly, the prevalence of pancreatic lesions
may therefore be present before amyloid depositions are visible. in diabetic cats was as high as in the non-diabetic control cats. The
Opinions on the importance of IAPP/amyloid in the pathogen- overall prevalence of pancreatitis in diabetic cats was 57% and in
esis of -cell failure differ between research groups (in particular control cats 60%. Diabetic cats had a trend for more severe lesions
in human medicine). It is likely that the misfolding is a reflection and higher prevalence of acute pancreatitis; however, the difference
of another defect within the -cells and not the primary cause of was not significant (Zini et al, 2012). As suggested by De Cock,
-cell dysfunction. When present, however, these abnormalities etal., (2007), the pancreas generally seems to be very sensitive to
may accelerate further damage. An additional factor, which has a drugs, stress, metabolic derangements, or ischemia associated with
negative impact on -cell function and survival, is high blood glu- a wide variety of diseases. According to the currently available data
cose concentrationsa phenomenon known as glucotoxicity. There and the impression of the author, pancreatitis is not a frequent cause
of diabetes mellitus. Although in principle, severe pancreatitis with infiltration may be found (see Fig. 7-3, A to D). Necrosis and
extensive tissue destruction may result in damage of the pancreatic fibrosis as well as neutrophilic or lymphocytic infiltration may
islets and -cell loss, but this seems to be a rare event. Pancreatitis, be present in the exocrine pancreas reflecting acute or chronic
however, seems to be a frequent comorbidity, and it is very likely pancreatitis.
that pancreatitis emerges during the course of the diabetic disease. In
a substantial percentage of cats, it seems to be a clinical insignificant REMISSION OF DIABETES IN CATS
bystander; in others, it causes clinical signs and may render diabetic
regulation at times very difficult. Pancreatitis may also play a role Remission of diabetes is defined as a situation in which clinical
in the development of diabetic ketoacidosis (DKA) (Goossens etal, signs disappear, blood glucose concentration normalizes, and
1998; Armstrong and Williams, 2012). Diabetes mellitus may also insulin treatment (or other antidiabetic drugs) can be discon-
be seen with pancreatic adenocarcinoma; in humans, there is debate tinued. In human medicine, the duration of normoglycemia
as to which diabetes is due to direct effects of the tumor or induced has to be at least 1 year to be labelled remission, and prolonged
by diabetogenic substances produced by the cancer cells (Chen etal, remission is a period of normoglycemia of at least 5 years (Buse
2011). Among the endocrinopathies listed under Other specific etal, 2009). In cats, a cut-off of 4 weeks of normoglycemia has
types of diabetes in Box 7-1, hypersomatotropism (acromegaly) been used (i.e., the disease-free interval should last for at least 4
and hyperadrenocorticism are the most relevant in cats. Nearly all weeks before the diabetes is considered to be in remission; Sieber-
cats with hypersomatotropism and approximately 80% of cats with Ruckstuhl et al, 2008; Zini et al, 2010; Tschuor et al, 2011).
hyperadrenocorticism will develop diabetes, which oftentimes is dif- Prolonged remission may be in duration of at least 1 year. The
ficult to regulate due to severe insulin resistance. Whereas hyperad- first publication on 10 cats that had experienced diabetic remis-
renocorticism is a rare disorder, hypersomatotropism may be present sion appeared about 15 years ago; at that time the phenomenon
in 10% to 15% of diabetic cats. See Chapters 2 and 11 for more was termed transient diabetes (Nelson etal, 1999). Interestingly, at
details. In cats, hyperthyroidism and hyperaldosteronism are rarely the time of diagnosis of the diabetes, baseline insulin concentra-
associated with overt diabetes and pheochromocytoma is extremely tions were undetectably low or within the reference range and did
uncommon. not increase after IV glucagon administration, mimicking type 1
In summary, diabetes mellitus in cats is a heterogeneous disease diabetes. The cats were treated with insulin or glipizide for 4 to
caused by a large number of different factors; the exact etiopatho- 16 weeks, after which treatment could be discontinued. A second
genic mechanisms are unknown at the moment. The main histo- glucagon test, performed after remission had occurred, showed
logical findings within the islets are reduced numbers of -cells, an immediate and significant increase in insulin concentration,
whereas the other endocrine cells are unaffected; amyloid deposi- insulin peak response, and total insulin secretion compared with
tion and vacuolar degeneration, in some of the cats lymphocytic initial values; the results of the glucagon test after remission were
70 Healthy
Transient clinical diabetes
Clinical diabetes resolved
60
Permanent insulin-requiring diabetes
50 a,d
a,c,d
a,c,d
40
c,d
30 a,d a,d
c,d
c,d
20
d
c,d
d
10 b
b b b
b b
b b b b
0
0 5 10 20 30 60
Time (min)
FIGURE 7-5 Mean ( standard deviation [SD]) serum insulin concentrations before and after intravenous (IV) ad-
ministration of 0.5 mg of glucagon per cat in ten healthy cats10 cats with transient clinical diabetes at the time
clinical diabetes was diagnosed and after clinical diabetes resolved, and six cats with permanent insulin-requiring
diabetes at the time diabetes was diagnosed. a, Significantly (p < 0.05) different compared with baseline value.
b, Significantly (p < 0.05) different compared with corresponding time in healthy cats. c, Significantly (p < 0.05) different
compared with corresponding time when clinical diabetes was diagnosed. d, Significantly (p < 0.05) different compared
with corresponding time in cats with permanent insulin-requiring diabetes. Arrow indicates glucagon administration.
(From Nelson RW, etal.: Transient clinical diabetes mellitus in cats: 10 cases (19891991), J Vet Intern Med 13:28, 1999).
|
similar to test results in healthy cats (Fig. 7-5). Histological evalu- Cats are newly diagnosed with diabetes and have no severe con-
ation of the pancreas was possible in some of the cats and revealed current diseases.
decreased numbers of islets, islet amyloidosis, and vacuolar degen- They are treated according to a standardized treatment proto-
eration of islet cells. This study demonstrates that initial insulin col, which includes administration of insulin glargine b.i.d. and
secretion is severely impaired even in cats with the potential of feeding a low-carbohydratehigh-protein diet.
remission and that the glucagon test performed at the time of diag- Frequent reevaluations are done during the first 4 months of
nosis does not allow differentiation between cats with reversible therapy.
and cats with irreversible -cell function. Treatment can lead to Home monitoring of blood glucose has been shown to be
improvement of -cell function, most likely due to abolishment advantageous because it allows close supervision and more
of the damaging effects of high blood glucose on -cell function frequent dose amendments. Remission rates are influenced
(glucotoxicity). The study also showed that cats experiencing dia- substantially by which cats are evaluated. In cats with severe
betic remission are not cured, because they have islet cell pathol- concurrent disease or in cats with long duration of diabetes,
ogy, potentially predisposing them to a relapse of clinical diabetes remission rate will be lower. In cats with previous steroid treat-
(Nelson etal, 1999). Since this first report, remission is increas- ment, remission rates will usually be relatively high. A recent
ingly recognized, and it is now well accepted that good glycemic survey among primary practitioners in the United States
control improves -cell function and that diabetic remission can be revealed an approximate remission rate of 26% (Smith et al,
achieved in a substantial percentage of cats. Those cats most likely 2012). This seems to be a realistic number under an everyday
have a type 2-like diabetes resulting from insulin resistance and condition, in which cats are not preselected and treatment as
-cell dysfunction and some degree of -cell loss. Their remaining well as monitoring is more difficult to standardize than in an
-cells, however, have the capacity to recover, at least in part, dur- university environment.
ing treatment. Cats that do not experience diabetic remission may Recently, the question if the capacity of -cells can be assessed
be in a more advanced stage of their disease with more pronounced by the time of diagnosis was investigated with the rationale if
-cell loss and/or a more pronounced functional defect. Diabetic remission of diabetes can be predicted before initiating therapy.
remission most often occurs during the first 3 to 4 months of ther- As shown some time ago by Nelson, et al., (1999), no differ-
apy; however, remission 1 year and longer after start of therapy ence in insulin response during glucagon test was seen in cats
may occasionally be seen. The currently available studies, which with and without remission. Studies in humans have demon-
have included information on remission, are difficult to compare, strated that the first defect in the early phase of diabetes is a
because they differ with regard to definition of remission, inclusion loss response to IV glucose, followed by a loss of response to
criteria of cats, blood glucose targets, and monitoring protocols, IV glucagon, whereas response to arginine persists the longest.
as well as type of insulin and type of diet. Published remission It was therefore hypothesized that cats that experience remis-
rates vary between 13% and 100% (Nelson etal, 1999; Bennett sion at some time after starting treatment have less severe -cell
etal, 2006; Martin and Rand, 2007; Boari etal, 2008; Michiels defects than cats with permanent disease and would therefore
etal, 2008; Marshall etal, 2009; Roomp and Rand, 2009; 2012; show normal or at least some degree of insulin response after
Hall et al, 2009; Zini et al, 2010; Hafner et al, 2011; Tschuor IV arginine. However, the expectations were not met. In both
etal, 2011). It has been suggested that remission rates are higher groups of cats (remission and no remission) insulin concentra-
in cats when treated with newer types of insulin (e.g., insulin tions increased mildly after IV arginine, but there was no sig-
analogues such as glargine or detemir) than with other/older types nificant difference between the two groups, similar to what has
of insulin (e.g., Lente type) (Marshall etal, 2009; Roomp and Rand, been shown with the glucagon test (Tschuor et al, 2011; Fig.
2009; 2012). Although type of insulin and improved time-action 7-6). Therefore, none of the tests used so far allows discrimina-
profiles of newer insulins may have an important effect on glycemic tion between cats with and without the chance of remission. A
control and remission rates, other factors such as glucose targets few other studies have evaluated clinical parameters that may
and intensity of monitoring certainly contribute to the high remis- be associated with the likelihood of diabetic remission. Interest-
sion rates in some of the studies. For instance, in two recent studies ingly, in a study including 90 cats with newly-diagnosed diabe-
using insulin glargine and detemir respectively, overall remission tes, remission rate was shown to increase with increasing age at
rates of 64% and 67% were achieved (Roomp and Rand, 2009; diagnosis (Fig. 7-7). This finding was unexpected, because it is
2012). Those studies, however, used an extremely intensive treat- known that generally -cell mass decreases with age in healthy
ment and monitoring protocol: Glucose targets were set very low individuals. It is possible that in case of diabetes, -cell destruc-
(50 to 200 mg/dL and 50 to 100 mg/dL respectively; 2.8 to 11.1 tion is slower in elderly cats, which is similar to what is known
mmol/L, 2.8 to 5.5. mmol/L); the owners had to measure blood from human diabetics (Zini etal, 2010). Other factors shown to
glucose at home at least three times daily and adapt the insulin dos- be associated with higher likelihood of remission are early treat-
age accordingly. Those treatment protocols can only be used under ment of diabetes and prior steroid therapy (Roomp and Rand,
very close supervision, because there is an increasing risk of hypo- 2009). Some factors such as presence of peripheral neuropathy
glycemia the lower the glucose targets are set. Low-carbohydrate and increased cholesterol have been identified to be associated
diets may also contribute to good glycemic control and possible with reduced likelihood of remission (Roomp and Rand, 2009;
diabetic remission, although data are slim. One study found that Zini et al, 2010). Both may reflect a more advanced state of
remission rate was higher in cats fed a low-carbohydrate diet com- the disease with more pronounced -cell loss; hypercholester-
pared to a moderate carbohydrate diet, whereas in another study, olemia may also be a contributing factor to -cell dysfunction
remission rates were similar (Bennet etal, 2006; Hall etal, 2009). (lipotoxicity). Of note, DKA has not been identified as a nega-
However, as mentioned earlier, the studies are difficult to com- tive predictive factor and remission may also occur in cats pre-
pare because diet composition, type of insulin, and treatment pro- sented with DKA (Sieber-Ruckstuhl etal, 2008). In many cats,
tocols differed. In our own institution, remission rate has varied remission lasts for months to years and may even be life-long.
between 40% and 50% over the years under the following Roughly 30% of cats with remission will have a relapse with
conditions: recurrence of clinical signs and hyperglycemia and will again
70
15
60
12
50
Insulin (U/mL)
Insulin (U/mL)
40 9
30
6
20
3
10
0 0
0 2 4 7 9 15 25 30 0 2 4 7 9 15 25 30
A Minutes B Minutes
FIGURE 7-6 A, Insulin concentration after intravenous (IV) arginine administration in 7 healthy cats (open circles)
and 17 cats with newly-diagnosed diabetes (closed circles). Insulin concentrations in healthy cats were signifi-
cantly higher 2, 4, 7, 9, and 15 minutes after arginine administrations, where no difference was found between
the groups at baseline and after 25 and 30 minutes. B, The insulin concentrations of the 17 newly-diagnosed
cats shown in A were divided into two groups. Open circles, 7 cats that experienced diabetic remission during
subsequent therapy; closed circles, 10 cats with permanent diabetes. The insulin concentrations did not differ at
any time point. (Data from Tschuor F, etal.: Remission of diabetes mellitus cannot be predicted by the arginine
stimulation test, Am J Vet Res 25:83, 2011).
100 when Link and Rand (1996) performed a similar experiment.

Percentage of cats with remission
90 They showed that insulin levels in healthy cats decreased within

days when high blood glucose levels were maintained by glucose
80
infusion. Several cats even became ketonuric and required 1 to 2
70 weeks of insulin therapy after cessation of the glucose infusion
60 (Link and Rand, 1996; Link etal, 2013). The cellular mechanisms
50 by which chronic hyperglycemia affects insulin secretion and insu-
40
lin sensitivity are poorly understood. In humans, it has been pro-
posed that oxidative stress and inflammatory cytokines play an
30 important role (Robertson, 2009; Donath and Shoelson, 2011).
20 In a recent study, glucose-induced lesions in -cells were
10 investigated in cats. After 10 days of IV glucose infusion, healthy
0 cats had 50% fewer -cells per islet area than control cats. Islet
6 7-9 10-12 12 cells showed apoptotic features and were caspase-3 (a marker
for apoptosis) positive (Fig. 7-8). Interestingly, hyperglycemia
Age at diagnosis (years) induced a systemic inflammatory response, characterized by an
FIGURE 7-7 Percentage of diabetic remission in cats of different ages. It is obvi- increased plasma concentration of 1-acid glycoprotein. Sys-
ous that remission rates increases with age at the time of diagnosis. Remission temic inflammation has also been described in human type 2
rate was approximately 30% when the cats were 6 years at the time of diabetes diabetes. Another potential acquired cause of beta-cell dysfunc-
diagnosis and remission rate was approximately 70% in cats that were 12 years tion is lipotoxicity (i.e., the deleterious effects of fatty acids on
and older. (Data from Zini E, etal.: Predictors of clinical remission in cats with -cells). However, in contrast to the 10-day glucose infusion,
diabetes mellitus, J Vet Int Med 24:1314, 2010). lipid infusion over the same time period did not affect plasma
insulin or glucose levels or result in -cell apoptosis. In human
medicine, it has been proposed that glucotoxicity occurs inde-
pendently of lipotoxicity, whereas lipotoxicity requires increased
require insulin therapy. In some of them, a second remission blood glucose levels to fully manifest. This may also apply to cats
is possible. More often, however, permanent insulin therapy is (Zini etal, 2009a).
required. The latter situation most likely reflects deterioration The concept of glucotoxicity (and possibly lipotoxicity) is very
of -cell function and reduction of -cell mass. important to understand because immediate treatment of diabetes
The damaging effects of chronic hyperglycemia have been may reverse the negative effects of glucose on -cells and increase
known for a long time; nowadays those effects are usually sum- the chance of remission. Of note, islet cell pathology is present in
marized under the umbrella term of glucotoxicity. In 1948, Dohan cats in diabetic remission and remission should not be confused
and Lukens administered large doses of glucose to normal cats with cure of the disease. Recurrence of clinical overt diabetes is
and induced permanent hyperglycemia, hydropic degenera- always possible and may be triggered by stressors (increase in body
tion of the islets of Langerhans, and ketonuria. It took nearly weight, concurrent disease, diabetogenic drugs) or without any
50 years for those findings to be recognized in veterinary medicine obvious event.
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Saline Glucose Lipids

FIGURE 7-8 Pancreatic islets of healthy cats after receiving 0.9% NaCl, intravenous (IV) glucose infusion and IV
lipids for 10 days. No lesions were seen in the control cat and in the cat that received lipids. In the glucose-infused
cat, a large area of the islet appeared devoid of nuclei and included several vacuoles, which is suggestive of hy-
dropic degeneration. Hydropic degeneration of islet cells indicates accumulation of glycogen. The remaining islet
nuclei appear larger than in the control cat. (H&E, 40) (From Zini E, etal.: Hyperglycemia but not hyperlipidemia
causes beta-cell dysfunction and loss in the domestic cat, Diabetologia 52:336, 2009a [with permission].)
INSULIN, METABOLIC EFFECTS, AND TABLE 7-1 D

IFFERENCES IN AMINO ACID
PATHOPHYSIOLOGY* SEQUENCE OF THE INSULIN
MOLECULE BETWEEN SPECIES
Insulin Synthesis, Structure, and Regulation
A8 A10 A18 B30
Glucose homeostasis is maintained by a complex system of regu-
lating and modulating hormones and factors, the most impor- Human Thr Ile Asn Thr
tant of which is insulin. Insulin is the only hormone capable of Pig/dog Thr Ile Asn Ala
decreasing blood glucose levels. Cattle Ala Val Asn Ala
Insulin synthesis begins in the rough endoplasmic reticulum
with the formation of preproinsulin, which is then converted to Cat Ala Val His Ala
proinsulin by removal of a small peptide fragment. Proinsulin is
further processed to insulin in the Golgi apparatus by removing
another peptide, called connecting peptide (C-peptide). Insulin and
C-peptide are packed and stored in secretory granules and released one amino acid; it differs from canine and human insulin at three
in equimolar amounts by the process of exocytosis. Within the and four positions, respectively (Table 7-1).
granules, insulin co-precipitates with zinc ions to form hexam- Insulin circulates almost entirely unbound in the blood, has a
ers and microcrystals, whereas in the circulation, insulin exists as half-life of about 5 to 8 minutes, and is mainly metabolized by
monomer. the liver and the kidneys (Sjaastad etal, 2010). Continuous avail-
Normally, proinsulin conversion is largely completed before ability of insulin and moment-to-moment adjustments are crucial
secretion and is therefore not encountered in the circulation in for normal carbohydrate, protein, and lipid metabolism. The body
appreciable quantities. In human diabetics, increased proinsulin exhibits complex mechanisms to ensure adequate basal insulin
concentrations may be found in plasma, which is considered to secretion between meals as well as increased insulin secretion after
be an indicator of -cell dysfunction (Breuer etal, 2010; Wang a meal. The most important regulator is the glucose concentration
and Osei, 2011). Knowledge in cats is limited to obese individu- in the blood, and there is a positive feedback mechanism between
als, which revealed abnormal proinsulin to insulin ratios during blood glucose concentration and insulin secretion rate.
IVGTTs (Kley etal, 2008). Glucose is transported into -cells via the glucose transporter
Insulin consists of two polypeptide chains: an A chain with 21 protein GLUT-2, which allows rapid equilibration of extra- and
amino acids and a B chain with 30, which are connected by two intracellular glucose concentrations. Glucose is metabolized
disulfide bridges. The insulin molecule has been highly conserved (phosphorylation by glucokinase and production of pyruvate)
during evolution, and the differences between species are small. within the -cells to produce adenosine triphosphate (ATP).
Feline insulin is most similar to bovine insulin, differing by only The increase in the ATP/adenosine diphosphate (ADP) ratio is
followed by the closure of ATP-sensitive potassium channels in
the -cell membrane, preventing potassium ions from leaving the
*The section on insulin, metabolic effects and pathophysiology has been
-cell. This in turn causes membrane depolarization and open-
published in a similar form in two other book chapters: Reusch CE,
et al.: Endocrine pancreas. In Rijnberk A, Kooistra HG, editors: Clini- ing of voltage-dependent calcium channels in the membrane. The
cal endocrinology of dogs and cats, ed 2, Hannover, Germany, 2010, Schlu- increase in cytosolic calcium then triggers insulin release.
etersche, pp. 155-185; Reusch CE: Feline diabetes mellitus. In Ettinger Oral glucose induces a more pronounced insulin secretion
SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, than glucose given intravenously. This phenomenon is due to
St Louis, 2010, Saunders/Elsevier, pp. 1796-1816. the actions of so-called incretin hormonesthe most important
being glucagon-like peptide-1 (GLP-1) and glucose-dependent potassium, and phosphate into cells. After a few minutes, interme-
insulinotropic polypeptide, previously called gastric inhibitory diate actions occur, mainly effecting protein and glucose metabo-
polypeptide (GIP). Incretins are secreted by endocrine cells in the lism, followed several hours later by delayed actions, which mainly
gastrointestinal tract in response to nutrients. They are then car- include effects on lipid metabolism.
ried in the bloodstream to the pancreatic islets where they interact Glucose is a polar molecule and cannot diffuse across cell
with specific -cell receptors to amplify insulin secretion. GLP-1 membranes. Transport of glucose is facilitated by a fam-

has additional effects, which include reduction of glucagon secre- ily of GLUT proteins or by active transport with sodium in
tion, stimulation of beta-cell differentiation and proliferation, the intestine and kidney. Currently, 14 different GLUTs are
delayed gastric emptying, and induction of satiety (Reusch and known for humans, which are named in order of discovery
Padrutt, 2013). GLUT 1 to 14. GLUT-4 is the major insulin-responsive trans-
In addition to glucose and other sugars, amino acids and fatty porter and is found almost exclusively in muscle and adipose
acids are also stimulators of insulin secretion; stimulation may be tissue. Insulin stimulates glucose transport in those two tis-
direct or potentiated by incretins. The autonomous nervous sys- sues by causing the translocation of GLUT-4 from the cyto-
tem modulates islet hormone release; secretion of insulin is stim- sol to the cell membrane with which they fuse. There, they
ulated by vagal nerve fibers and inhibited by sympathetic nerve function as pores enabling glucose entry. When insulin levels
fibers. Several other pancreatic and extra-pancreatic hormones, decrease, GLUT-4 is removed from the cell membrane (see
such as IAPP, glucagon, somatostatin, cortisol, and growth hor- Fig. 7-9). In various other tissues (e.g., brain, liver, kidney,
mone (GH), affect insulin secretion directly or indirectly (Flatt, and intestinal tract), glucose uptake is insulin- independent
2003; Persaud and Howell, 2003; Utzschneider etal, 2004). and occurs by other GLUT proteins (Garvey, 2004; Thorens and
Mueckler, 2010; Barrett etal, 2012).
Insulin is the most important anabolic hormone in the body
Metabolic Effects of Insulin
and prevents catabolism of nutrient stores. Its main function is
Insulin regulates numerous metabolic processes through binding to ensure storage of glucose as glycogen, amino acids as protein
to high-affinity cell surface receptors. Like the receptors for other and fatty acids as fat. The primary target tissues for insulin are
protein hormones, the receptor for insulin is embedded in the liver, muscle, and fat. Insulin facilitates the oxidation of glucose
plasma membrane. It is a tetrameric protein, composed of two to pyruvate and lactate through the induction of enzymes, such as
- and two -subunits linked by disulfide bonds. The -subunits glucokinase, some hexokinases, phosphofructokinase, and pyru-
are extracellular and house insulin binding domains, whereas vate kinase. Insulin promotes glycogen synthesis in liver, adipose
the -subunits penetrate through the cell membrane (Fig. 7-9). tissue, and muscle by increasing glycogen synthase activity. Glu-
The insulin receptor belongs to the large group of tyrosine kinase coneogenesis is decreased by insulin because of the promotion of
receptors. protein synthesis in peripheral tissues, thus decreasing the amount
Binding of insulin to the -subunits triggers the tyrosine kinase of amino acids available for gluconeogenesis. Additionally, insulin
activity of the -subunits leading to autophosphorylation, thus decreases the activity of hepatic enzymes that are involved in the
activating the catalytic activity of the receptor. The substrate conversion of amino acids to glucose.
proteins, which are phosphorylated by the insulin receptor, are In adipose tissue, insulin promotes the synthesis of lipids and
called insulin-receptor substrate (IRS) molecules. They are key medi- inhibits their degradation. Insulin activates the enzymes pyruvate
ators in the insulin signaling pathway and act as docking proteins dehydrogenase and acetyl coenzyme A (acetyl-CoA) carboxylase,
between the insulin receptor and a complex network of intracel- which promote the synthesis of fatty acids from acetyl-CoA. Insu-
lular molecules. Dysregulation within the signaling cascade may lin also increases the activity of lipoprotein lipase, an enzyme that
lead to insulin resistance, and in this context, IRS molecules seem is located in the endothelium of capillaries of extrahepatic tissues
to play a major role. and promotes the entry of fatty acids into adipose tissue. Inhibi-
Within seconds after insulin binds to its receptor, the so-called tion of lipolysis is mediated through the inhibition of the enzyme
rapid insulin actions lead to the uptake of glucose, amino acids, hormone-sensitive lipase.
Insulin
Glucose
Insulin receptor
GLUT-4 Cell membrane
IRS
GLUT-4 vesicles
Glucose uptake Glycogen Protein Lipid Cell growth and differentiation

synthesis synthesis synthesis Gene expression
FIGURE 7-9 Simplified scheme of insulin signaling pathways. GLUT-4, Glucose transporter 4; IRS, insulin receptor substrate.
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Insulin stimulates protein synthesis and inhibits protein deg- SIGNALMENT

radation, therefore promoting a positive nitrogen balance. Glu-
cagon is the main antagonist of insulin. It acts predominantly on Most cats with diabetes mellitus are older than 4 years of age at
the liver where it increases gluconeogenesis and glycogenolysis the time of diagnosis, although the disease may occur at any age.
and decreases glycogen synthesis. It is also a ketogenic hormone, Juvenile onset of diabetes (i.e., diabetes during the first year of age)
because of its ability to enhance lipolysis. Insulin and gluca- is a rare event. In a recent study involving 2576 cats with diabetes
gon act in concert after ingestion of protein. Both hormones mellitus in the United States, only 1.3% of cats were 1 year old or
are released when the concentration of amino acids increases in younger, another 1.3% were between 1 and 2 years old, whereas
the plasma. Insulin leads to a decrease in blood glucose concen- nearly 50% of the cats were between 10 and 15 years old (Prahl
tration in concert with a decrease in amino acid levels. Gluca- etal, 2007; Table 7-2). There is a male predominance; in two large
gon counterbalances the decrease in glucose concentration by studies from the United States and the United Kingdom, 63% and
stimulation of hepatic gluconeogenesis. This interaction allows 65% of diabetic cats were male. It is not yet clear if neutering (in
growth and survival with diets containing almost exclusively both sexes) is associated with an increased risk of diabetes; in the
protein and fat. study performed in the United Kingdom, neutered cats were more
likely to be diabetic than intact ones, whereas this was not the case
in the study performed in the United States (McCann etal, 2007;
Pathophysiology
Prahl etal, 2007). The vast majority of diabetic cats are mixed-breed
Hyperglycemia develops when insulin secretion is absent or inad- cats (i.e., Domestic Short-Hair and Domestic Long-Hair). In some
equate for the degree of insulin resistance. Absolute or relative lack countries (e.g., Australia, New Zealand, and the United Kingdom),
of insulin has profound effects on carbohydrate, fat, and protein the Burmese breed has been shown to be at increased risk (Wade
metabolism. Hyperglycemia results in part from reduced glucose etal, 1999; McCann etal, 2007; Lederer etal, 2009), whereas this
entry into muscle, adipose tissue, and liver. Intestinal absorption risk seems not to be present in breeding lines of other countries. In
of glucose and glucose entry into brain, kidney, and erythrocytes our own population of diabetic cats, approximately 50% to 60% are
are not affected. The second and perhaps most important cause overweight, 30% to 40% are normal weight, and 5% to 10% are
of hyperglycemia is unopposed glucose production in the liver underweight (Reusch, 2010). For more details on prevalence and
(by gluconeogenesis and glycogenolysis). Glucagon contributes to risk factors, see Prevalence and Risk Factors in Humans and Cats at
increased production of glucose, as do other (stress) hormones. the beginning of the chapter.
When the renal capacity for glucose reabsorption is exceeded, glu-
cose is lost in the urine. The resulting osmotic diuresis is com-
pensated by increased water intake, which may lead to severe TABLE 7-2 A
GE OF 2576 CATS WITH
polydipsia. Diabetic polyphagia is regulated by central mecha- DIABETES MELLITUS FROM
nisms, in which ghrelin-signaling and other pathways are impor- THE VETERINARY MEDICAL DATA
tant. Derangement of lipid metabolism plays a major role in the BASE JANUARY 1, 1970,
development of diabetes mellitus and its complications. Intracel- THROUGH DECEMBER 31, 1999
lular deficits of glucose and lack of insulin lead to acceleration of
lipid catabolism. Increased levels of NEFA are transported to the
AGE (YEARS) NUMBER OF CATS PERCENT
liver, where they undergo -oxidation to produce acetyl-CoA, the
amount of which may exceed the capacity for further oxidation. 1 32 1.3
This results in a shift to ketone body production and may lead to 1 to 2 34 1.3
the development of ketoacidosis. An increased hepatic concentra- 2 to 4 83 3.3
tion of fatty acids also results in enhanced hepatic synthesis of
4 to 7 288 11.3
triglycerides and verylow-density lipoproteins (VLDLs). The
consequences are hepatic steatosis and hyperlipidemia. 7 to 10 570 22.5
Protein metabolism shifts towards decreased protein synthe- 10 to 15 1220 48.1
sis and increased proteolysis. The increased availability of amino > 15 311 12.2
acids further accelerates hepatic gluconeogenesis. Consequences
are negative nitrogen balance, loss of muscle mass, and possibly From Prahl A, etal.: Time trends and risk factors for diabetes mellitus in cats presented
cachexia (Fig. 7-10). to veterinary teaching hospitals, J Feline Med Surg 9:351, 2007.
Insulin
deficiency
Glucose uptake Protein catabolism Lipid catabolism

Gluconeogenesis
Hyperglycemia Excess amino acids used Increased NEFAs

Glucosuria for gluconeogenesis Production of ketones
Electrolyte loss due to Weight loss, weakness Hepatic lipidosis
osmotic diuresis Poor wound healing Weight loss
Polyphagia
FIGURE 7-10 Effects of insulin deficiency (simplified overview). NEFAs, Non-esterified fatty acids.
ANAMNESIS inflammatory bowel disease, or hyperthyroidism) is present. It is

helpful to characterize the cats according to one of the currently
The typical history includes the classic signs of polydipsia, poly- available body scoring systems (e.g., a 5- or 9-point scale) at
uria, polyphagia, and weight loss. A common complaint of cat initial evaluation and during all rechecks (Fig. 7-11). The same
owners is the need to frequently change the litter and an increase system should be consistently used by all doctors and staff of
in the size of the litter clumps, indicating polyuria. Oftentimes, the hospital. It should be noted that the commonly-used body
additional clinical signs are present, such as lethargy, decreased condition scoring (BCS) focuses mainly on the determination
interaction with family members, lack of regular grooming, of body fat through evaluation of body silhouette and palpa-
and the development of a dry, lusterless, and unkempt hair tion of adipose tissue (Laflamme, 1997; Michel et al, 2011).
coat. Generally, severity of clinical signs ranges between mild/ Loss of muscle mass may be missed or underestimated or only
moderate to severe depending on the duration and extent of detected in seriously underweight cats. Assessing muscle condi-
the diabetic disease. Approximately 10% of diabetic cats have tion, however, is important, because loss of muscle adversely
overt signs of diabetic neuropathy, which include hind limb affects strength and immune function and has been shown to
weakness, decreased ability to jump, and a plantigrade posture be independently associated with mortality in humans (Bald-
while standing or walking. Usually, those signs are restricted win et al, 2010). Evaluation of muscle mass should be done
to the hind limbs; on rare occasion, additional weakness and additionally to the determination of the BCS. It includes visual
plantigrade stance may be seen in the front legs. Some owners inspection and palpation over the temporal bones, scapulae,
may overlook the more typical signs of diabetes and the cat is lumbar vertebrae, and pelvic bones. Currently, a 4-point scale is
presented because of lameness or difficulty to walk and jump. used to assess muscle mass, ranging from normal muscle mass,
Different to dogs, cats with diabetes are almost never presented to mild, moderate, and marked muscles wasting (Baldwin etal,
because of sudden blindness caused by diabetic cataract. Inter- 2010; Michel etal, 2011). See the AAHA Nutritional Assess-
estingly, however, the vast majority of diabetic cats reveal some ment Guidelines for Dogs and Cats for further details (Baldwin
degree of cataract when a specific ophthalmic examination is etal, 2010). Diabetic cats may be lethargic, although this may
performed (for details see Chronic Complications of Diabetes not be obvious immediately if the cat is severely stressed in the
Mellitus; Williams and Heath, 2006). In diabetic cats with con- examination room. Cats with newly diagnosed or poorly con-
current disease, additional or other than the classical signs may trolled diabetes often stop grooming and develop a dry, luster-
be reported by the owner. For instance, cats with concurrent less, and unkempt hair coat. The vast majority of diabetic cats
pancreatitis may show reduced appetite or complete lack of food show nerve lesions similar to those seen in humans with diabetic
intake, some show vomiting, whereas diarrhea is rare. If the clin- neuropathy when histological examinations of peripheral nerves
ical signs of uncomplicated diabetes go unnoticed by the owner, are performed. Obvious clinical signs, however, are present only
a diabetic cat may be at risk to develop DKA. In such a case, the in approximately 10% of cases. Abnormalities include weakness
classical clinical signs of diabetes usually are no longer present in the hind limbs, inability to jump, ataxia, muscle atrophy, and
at the time of presentation. Cats with DKA have similar signs a plantigrade posture when standing and walking (Fig. 7-12).
as cats with pancreatitis (both problems often occur in concert), A palmigrade posture may also be seen in rare cases. Cats may
such as lethargy, anorexia, and vomiting; water intake may also be object to touching and palpation limbs or feet, presumably
be reduced. The time sequence from the onset of diabetes to the because of pain associated with the neuropathy. Findings dur-
development of DKA is unpredictable, ranging from weeks to ing neurological examination include postural reaction defi-
months and depends in part on the type and severity of any con- cits and decreased tendon reflexes of different severity. Subtle
current disease. A complete history is of utmost importance, and neurological changes may go unnoticed if the cats gait is not
the clinician should always consider the possibility of concurrent evaluated carefully and no thorough neurological examination is
disorders. Any disorder may reduce insulin sensitivity and may performed. See Box 7-2 and Chronic Complications of Diabetes
potentially lead to overt diabetes in predisposed animals. Simi- Mellitus for further details.
larly, a detailed medical history should be taken as glucocorti- Abdominal palpation may reveal hepatomegaly due to diabe-
coids (systemic and topical) and progestagens have diabetogenic tes-induced hepatic lipidosis. In cats with concurrent pancreati-
effects (see Fig. 7-2). Identification and treatment of concurrent tis, a mass in the cranial abdomen, consisting of pancreas and
disorders and cessation of diabetogenic drugs play major roles in inflamed peripancreatic fat, can sometimes be palpated. This
the successful management of the diabetic cats. Dietary history mass can easily be misdiagnosed as another intraabdominal struc-
and feeding management (meal or continuous feeding) should ture (e.g., neoplasia within the intestinal tract, enlarged mesen-
also be taken. teric lymph node). Palpation may or may not elicit a response
of pain. Severe acute or acute on chronic pancreatitis may be
PHYSICAL EXAMINATION associated with dehydration, tachycardia, tachypnea, and icterus;
cats may be hypothermic; fever is also possible but less common
The findings during the physical examination depend on the (Armstrong and Williams, 2012; Caney, 2013). For more details
duration and severity of the diabetic disease as well as the pres- on pancreatitis, see Types of Diabetes in Cats and the discussion
ence or absence of DKA and the nature of any concurrent dis- on pancreatic enzymes in Clinical Pathology. Similarly, in cats
eases. Cats with recent onset of diabetes or in which severity with DKA, severe lethargy, dehydration, abdominal pain, and
of diabetes is mild may appear clinically normal and physical icterus may be present. Pancreatitis and DKA oftentimes occur
examination may be more or less unremarkable. In contrast, cats in concert.
with long-duration of untreated diabetes may appear seriously Lens opacities associated with diabetic cataract are usually
ill, in particular if DKA is present. Many newly diagnosed dia- mild and only visible by ophthalmoscopy in most cases. More
betic cats are overweight, although they usually have lost weight. severe cataracts may be present in diabetic kittens compared
They are rarely emaciated unless a serious concurrent disease with adult cats with diabetes (Thoresen etal, 2002; Williams and
(e.g., exocrine pancreatic insufficiency, pancreatic neoplasia, Heath, 2006).
|
A B
C
FIGURE 7-11Three cats with newly-diagnosed diabetes mellitus and different body condition scores using a
9-point scale. A, An example of a relatively normal looking diabetic cat. B, A severely overweight cat. C, An un-
derweight cat. A, Domestic Short-Hair (DSH), spayed female, 13 years old with a body weight of 4.2 kg and a
body condition score (BCS) of 5/9. The cat suffered from polyuria/polydipsia, polyphagia, and some weight loss
for approximately 4 weeks before presentation. The cat was clinically well, initial blood glucose concentration
was 468 mg/dL (26 mmol/L), and fructosamine concentration was 636 mol/L. B, British Shorthair cat, castrated
male, 12 years old with a body weight of 8 kg and a BCS of 9/9. The presenting complaint was polydipsia. The
cat was slightly lethargic, initial blood glucose was 223 mg/dL (12.4 mmol/L), and fructosamine was 615 mol/L.
C, Norwegian Forest cat, castrated male, 14 years old with a body weight of 4.8 kg and a BCS of 3/9. The cat had lost
2 kg of body weight during the previous 2 months, and more recently, the owner had noticed polyuria and polydipsia
and reduced appetite. He was dehydrated and had a poor hair coat, initial blood glucose concentration was
509 mg/dL (28.3 mmol/L), and fructosamine concentration was 706 mol/L. Lipase activity and feline pancreas-
specific lipase (Spec fPL) were slightly increased, and ultrasonographic findings were consistent with chronic pancre-
atitis of moderate severity. After initiating insulin therapy the clinical condition improved and body weight increased.
ESTABLISHING A DIAGNOSIS OF DIABETES

MELLITUS
A diagnosis of diabetes mellitus is based on the presence of appro-
priate clinical signs (i.e., polyuria, polydipsia, polyphagia, weight
loss) and documentation of persistent fasting hyperglycemia and
glycosuria. In contrast to human medicine, no precise diagnostic
criteria for feline diabetes have so far been established. Therefore,
the cut-off value for blood glucose concentration, above which the
animal is considered diabetic, is somewhat vague. The vast majority
of cats are not presented until blood glucose concentrations exceed
the renal capacity for glucose reabsorption (approximately 270 mg/
dL, 15 mmol/L). It is usually only at this stage of the disease that
clinical signs become apparent. Glycosuria alone is insufficient to
FIGURE 7-12 Plantigrade stance due to diabetic neuropathy in a 15-year-old, diagnose diabetes, because it may also occur with primary renal
castrated male, Domestic Short-Hair (DSH) with diabetes mellitus. The gait defects and some of the commercially available urine reagent test
improved slightly during insulin therapy. strips and tablets may show false positive results associated with
BOX 7-2 C
riteria for Neurological Assessment of Severity
of Signs and Determination of Severity Rank of
Nondiabetic and Diabetic Cats 900
Severity of
N eurological Signs Criteria 720
Blood glucose mg/dL

Very mild Walks with base-narrow gait
Difficulty in jumping
No evidence of plantigrade stance 540
Normal postural reactions and reflexes
Mild Irritable when touching and manipulating feet
Partially plantigrade, partially crouched limb 360
position
Mild postural reaction deficits
Normal tendon reflexes 180
Mild/moderate Irritable when touching and manipulating feet

Base-narrow gait
0
Partially plantigrade when walking and
Diabetes mellitus Stress hyperglycemia
standing
Moderately decreased postural reactions and FIGURE 7-13 Blood glucose concentrations in cats with diabetes mellitus and
reflexes in cats with stress hyperglycemia. Diabetic cats had significantly higher glucose
Normal tendon reflexes concentrations; however, substantial overlap was seen, and in 20% of the cats
with stress hyperglycemia, blood glucose concentrations were increased above
Moderate Irritable when touching and manipulating feet the renal threshold. To convert mg/dL to mmol/L multiply by 0.056. (Data from
Plantigrade when walking and standing Laluha P, etal.: Stress hyperglycemia in sick cats: a retrospective study over
Mild generalized muscle atrophy 4 years, Schweiz Arch Tierheilkd 146:375, 2004.)
Decreased postural reactions
Mildly to moderately decreased tendon reflexes
Fig. 7-13). In cats with mild to moderate stress hyperglycemia, gly-
Moderate/severe Irritable when touching and manipulating feet cosuria usually does not occur. However, if stress induces an increase
Obvious ataxia and paresis, especially in of blood glucose above the renal threshold for some time (hours),
pelvic limbs glycosuria may be present as in cats with diabetes. Stress hyperglyce-
Palmigrade and plantigrade when standing mia may be diagnosed by repeated blood glucose measurements and
Plantigrade when walking the demonstration of normalized glucose levels. Some cats, however,
Generalized muscle atrophy are stressed throughout the period of hospitalization, and glucose
Severe postural reaction deficits levels remain high. In those cases, the measurement of serum fruc-
Hyporeflexia to areflexia tosamine may be helpful (see Serum Fructosamine Concentration).
Severe Irritable when touching and manipulating feet Recently, the term prediabetes has started to be used in veterinary
Obvious generalized ataxia and paresis medicine. In humans, the term describes individuals whose glucose
Palmigrade and plantigrade when standing levels do not meet the criteria for diabetes, yet they are higher than
Fully palmigrade and plantigrade when walking those considered normal (American Diabetes Association, 2013;
Generalized muscle atrophy Table 7-3). So far, there is no officially recognized definition in
Severe postural reaction deficits dogs and cats and the term is somewhat arbitrarily used for any
Hyporeflexia to areflexia degree of mild hyperglycemia. Cats that have blood glucose con-
centrations below the renal threshold usually do not have clinical
Modified from Mizisin AP, etal.: Neurological complications associated with signs of diabetes, and therefore, glucose concentrations between
spontaneously occurring feline diabetes mellitus, J Neuropathol Exp Neurol approximately 120 and 270 mg/dL (6.7 to 15 mmol/L) may be
61:872, 2002.
considered to represent mild hyperglycemia. Differential diag-
nosis includes blood glucose increase after a carbohydrate-rich
the administration of drugs (e.g., some antimicrobials) (Rees and meal, stress hyperglycemia, and mild/beginning diabetes mel-
Boothe, 2004). Cats are prone to stress-induced hyperglycemia, litus. Postprandial hyperglycemia may be ruled out by repeating
which may be difficult to differentiate from hyperglycemia due the measurement in a fasted state. Stress hyperglycemia and mild/
to diabetes. Increases in blood glucose caused by stress are often beginning diabetes mellitus, however, are difficult to differentiate,
only mild to moderate. However, in some cats, blood glucose may because fructosamine may be normal in both instances. Normal-
increase to levels higher than 270 mg/dL (15 mmol/L) (Rand ization of blood glucose concentrations over time is indicative for
et al, 2002; Laluha et al, 2004). In a recent study, blood glucose stress hyperglycemia. Mild/beginning diabetes may have various
levels in 106 cats with stress hyperglycemia ranged from 146 to causes; one of them is the previous or current administration of
592 mg/dL with a median of 192 (8.1 to 32.9 mmol/L, median glucocorticoids or progestagens. In principle, any disease may lead
10.7), 21 of the 106 cats (20%) had glucose levels higher than to some degree of insulin resistance and some cats may not be able
270 mg/dL (15 mmol/L). Although blood glucose concentrations in to compensate by increasing their insulin production (see Fig. 7-2).
cats with stress hyperglycemia were significantly lower than in cats Cats with mild hyperglycemia should undergo a thorough evalu-
with diabetes, substantial overlap was seen (Laluha et al, 2004; ation and repetitive blood glucose measurements in a fasted state.
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TABLE 7-3 CRITERIA FOR THE DIAGNOSIS OF PREDIABETES AND DIABETES IN HUMANS
CRITERIA FOR DIAGNOSIS OF PREDIABETES CRITERIA FOR DIAGNOSIS OF DIABETES

IN HUMANS IN HUMANS
Fasting blood glucose 100 to 125 mg/dL (5.6 to 6.9 mmol/L) 126 mg/dL (7.0 mmol/L)
2-hour glucose in the 75-g oral glucose tolerance test 140 to 199 mg/dL (7.8 to 11.0 mmol/L) 200 mg/dL (11.1 mmol/L)
From American Diabetes Association: Diagnosis and classification of diabetes mellitus, Diabetes Care 36 (suppl 1):67, 2013.
If no treatable cause is identified, regular reevaluations should be increased liver enzyme activities. The vast majority of newly diag-
performed to determine if overt diabetes develops. In the stage of nosed diabetic cats have blood glucose concentrations above 300
prediabetes, weight reduction and feeding a low-carbohydrate mg/dL (17 mmol/L); on rare occasions, blood glucose may be as
high-protein diet should be recommended, and insulin treatment high as 900 mg/dL (50 mmol/L) or even higher. Extremely ele-
should be initiated if blood glucose concentrations begin to rise. vated blood glucose concentrations in diabetic cats are often asso-
In cats with DKA or severe concurrent disease (e.g., acute pan- ciated with concurrent chronic renal failure. Between 40% and
creatitis), the typical clinical signs of diabetes may not be present 50% of diabetic cats have increased serum alanine aminotrans-
at the time of diagnosis, and instead signs of systemic illness will ferase (ALT) and/or alkaline phosphatase (ALP) activities, which
dominate the clinical picture. In those cases, confirmation of dia- is presumably due to diabetes-associated hepatic lipidosis. The
betes relies on the documentation of hyperglycemia, glycosuria, increases are typically up to five times the upper limit of normal
and increased fructosamine concentration. Immediate further in cases of ALT and up to three times the upper limit of normal
work-up is required, because the animal may be in a life-threatening in cases of ALP. More pronounced increases should raise suspi-
condition. The finding of ketone bodies in urine by use of urine cion for hepatic lipidosis being more severe than what is consistent
test strips or increased -hydroxybutyrate concentration in blood with uncomplicated diabetes, other liver diseases, or pancreatitis.
by a handheld meter (Precision Xtra or Precision Xceed, Abbott) Increased cholesterol and triglyceride concentrations are present
is indicative for DKA. Please see Chapter 8 for further details. in roughly one-third of diabetic cats, which is usually up to three
Diagnosis of pancreatitis is discussed later in this chapter. times the upper limit of normal.
A mild increase in total bilirubin concentration (up to two times
CLINICAL PATHOLOGY the upper limit of normal) is quite common and most likely caused
by the typical diabetes-associated hepatic lipidosis. If moderate to
After establishing the diagnosis of diabetes, it is important to severe hyperbilirubinemia is present, severe hepatic lipidosis, other
evaluate the cat for the presence of concurrent diseases. Any dis- liver diseases, or extrahepatic biliary obstruction by pancreatitis
ease can worsen insulin resistance and has the potential to ren- should be considered as the most likely causes. Some diabetic cats
der insulin therapy difficult. In some cases, it is only because a reveal hypocalcemia, potentially associated with the presence of
concurrent problem occurred that the diabetic disease progressed pancreatitis. Blood urea nitrogen (BUN) and serum creatinine are
from a subclinical to a clinically overt state. Reducing insulin resis- usually normal in cats with uncomplicated diabetes. An elevation
tance by treating the concurrent problem(s) is an important part in these parameters may either be due to a prerenal cause (most
of diabetic management. The minimum laboratory evaluation in likely dehydration) or renal disease. In humans, nephropathy is
a newly diagnosed diabetic cat should include a complete blood a common complication of diabetes mellitus, whereas in cats,
count (CBC), a serum biochemical panel, and an urinalysis with diabetes-associated kidney lesions seem to be rare (see Chronic
bacterial culture. If available, abdominal ultrasonography should Complications of Diabetes Mellitus). Chronic renal failure in dia-
also be performed as part of the routine work-up (see later). betic cats should therefore be considered a coincidence, because
both diseases are relatively frequent in the elderly cat population.
Complete Blood Count, Serum Biochemical Panel, The most typical finding in the urinalysis is moderate to marked
Urinalysis, and Urine Culture glycosuria. Cats with uncomplicated diabetes usually do not have
ketonuria; however, trace to small amounts of ketone bodies may
Cats and dogs with diabetes mellitus have similar clinical patho- occasionally be found. Moderate to large amounts of ketones are
logical abnormalities. See Chapter 6 for more details. indicative of DKA, in particular in cats with signs of systemic ill-
In cats with uncomplicated diabetes, a CBC usually does not ness. In the majority of cats, urine specific gravity is more than
reveal major abnormalities. Mild normochromic, normocytic ane- 1.020; approximately 50% to 70% of cases have proteinuria, which
mia (packed cell volume [PCV] 25% to 30%) is a relatively fre- is usually mild to moderate with a urine protein-to-creatinine
quent finding, most likely reflecting chronic disease. In dehydrated ratio less than 2.0. Hematuria, pyuria, and bacteriuria in the urine
cats, mild polycythemia may be present, which is frequently asso- sediment have been shown to correlate strongly with a positive
ciated with an increase in total protein concentrations. Cats with urine culture. However, in some cats with bacterial urinary tract
uncomplicated diabetes oftentimes have a normal white blood cell infection, the urine sediment is unremarkable. Therefore, urine
count or a so-called stress leukogram (mature neutrophilia, lym- culture should be performed in all cats with diabetes, irrespective
phopenia, eosinopenia). Pronounced neutrophilia, in particular of urine specific gravity, presence or absence of proteinuria, and
when associated with an increase in immature neutrophils as well abnormal sediment findings. In two recent studies, urinary tract
as the finding of toxic neutrophils (with or without neutrophilia), infection was identified in 12% and 13.2% of diabetic cats, with
points to an inflammatory or infectious process. In the latter situ- Escherichia coli being the most common isolate (Bailiff etal, 2006;
ation, the clinician should consider acute pancreatitis as one of Mayer-Roenne etal, 2007). Urinary tract infections with Candida
the major differential diagnosis. The most common biochemical spp. have been reported sporadically in diabetic cats (Pressler etal,
abnormalities include hyperglycemia, hypercholesterolemia, and 2003; Jin and Lin, 2005).
Pancreatic Enzymes see later), additional laboratory findings, and abdominal ultraso-
nography. In some cats, however, pancreatitis remains a diagnosis
Pancreatitis has been recognized as a common concurrent disease by exclusion.
in cats with diabetes mellitus. Feline pancreatitis is classified into Very recently, the belief that the normal serum lipase activity
acute and chronic forms, the latter being more common. Some is of no diagnostic utility has been challenged. It was shown in a
cats suffer from both acute and chronic pancreatitis, and recurrent large number of cats that a particular lipase assay (DGGR assay)
bouts of acute phases may occur. The cause and effect relation- agrees substantially with the Spec fPL. The DGGR assay can be
ship between pancreatitis and diabetes is largely unknown and performed by routine autoanalysis and therefore be incorporated
very difficult to explore due to the lack of longitudinal studies, into a serum biochemical panel rendering lipase measurement
which would include histopathology of the pancreas. Severe pan- more readily available and less expensive (Oppliger etal, 2013b).
creatitis may result in damage not only of the exocrine but also Increase in serum fTLI is only very short lived in cats after the
of the endocrine part of the pancreas, which then would lead to onset of pancreatitis and its sensitivity is therefore low. Its mea-
diabetes. Most likely, however, this is a relatively rare event. In surement is mainly recommended for the diagnosis of exocrine
the opinion of the author, it is more common for pancreatitis to pancreatic insufficiency in the cat, which may develop as a sequela
develop during the course of the diabetic disease. The clinical pre- of chronic pancreatitis. Exocrine pancreatic insufficiency should
sentation of pancreatitis varies widely. In some cats, pancreatitis is be considered as differential diagnosis in cats with weight loss,
clinically insignificant with no obvious clinical signs. Other cats polyphagia, and loose stools; a low fPLI would support the diag-
suffer from recurrent bouts of pancreatitis ranging from mild leth- nosis (Steiner, 2012).
argy and reduced appetite of a few days duration to severe illness
with complete lack of food intake, vomiting, and dehydration and Serum Thyroxine Concentration
again others may be constantly unwell. Another subset of diabetic
cats suffers from a single episode of severe pancreatitis, which may Hyperthyroidism is a common endocrine disorder and its preva-
be severe and life-threatening. Pancreatitis (and/or DKA) should lence has increased continuously over the last decades. A recent
be considered in any diabetic cat presented with lethargy, reduced study performed in more than 200 diabetic cats treated with
appetite or anorexia, vomiting, and dehydration. Pancreatitis is insulin for at least 1 month revealed that 4.5% of them had
also an important differential diagnosis in a difficult to regulate increased serum thyroxine (T4) concentrations. This number was
diabetic cat, in particular if the course of the disease is waxing considered to approximate the prevalence of hyperthyroidism in
and waning (i.e., times of good glycemic control or hypoglycemia the general elderly cat population (Schaefer etal, 2013). Natural
alter with times of poor control). Diagnosis of pancreatitis, how- occurring and experimentally induced hyperthyroidism has been
ever, is challenging, because all available tests have major limita- shown to cause insulin resistance. (Hoenig and Ferguson, 1989;
tions. Serum amylase activity is often low or normal in cats with Hoenig et al, 1992). Insulin resistance and possibly impaired
pancreatitis and therefore considered to be of no diagnostic value insulin secretion is also a well-known phenomenon in humans
(Kitchell etal, 1986; Parent etal, 1995; Zoran, 2006). Similarly, with hyperthyroidism (Hanley, 2010). The presence of concurrent
traditional assays of lipase activity are widely described to be unre- hyperthyroidism is therefore important to recognize, and the thy-
liable due to poor sensitivity and specificity. During the recent roid status should be evaluated in every diabetic cat. When inter-
years, assays that specifically measure the pancreatic lipase activity preting the laboratory results, the veterinarian should remember
(known as fPLI or Spec fPL) became available and are currently that poor glycemic control and any other concurrent diseases may
considered to be the most accurate blood tests for diagnosing pan- lower the T4 concentration (euthyroid sick syndrome) and the
creatitis in cats (Steiner etal, 2004; Forman etal, 2009; Armstrong diagnosis may be missed. Similarly, in newly diagnosed diabetic
and Williams, 2012). One study reported an overall sensitivity cats, T4 concentrations often are quite low and increase during
of fPLI for pancreatitis of 67% (100% for moderate to severe insulin therapy. This is true for diabetic cats with and without
pancreatitis and 54% for mild pancreatitis). Overall specificity concurrent hyperthyroidism. The latter may therefore be over-
was 91% (100% in healthy cats and 67% in symptomatic cats looked if T4 measurements are not repeated after insulin therapy
with normal pancreatic histology) (Forman etal, 2004). Another has been performed for some weeks (Fig. 7-14).
study evaluated the Spec fPL and also found 100% sensitivity for In our hospital, we routinely measure T4 concentrations in
severe chronic pancreatitis; specificity, however, was only 54% newly-diagnosed diabetic cats. Increased T4 levels support hyper-
(Oppliger et al, 2013a). These numbers nicely demonstrate the thyroidism and appropriate therapy is initiated additionally to the
problems associated with the measurement of the fPLI/Spec fPL treatment of diabetes. If the T4 concentration is normal or low,
test: In cats with severe pancreatitis, the test will usually be positive, initial measures are restricted to diabetic management. T4 mea-
whereas it may be negative in mild disease. A positive test result, surements are repeated after a few weeks, in particular in cats in
however, does not mean that the cat has pancreatitis, as specificity which we do not successfully regulate the diabetic disease. We have
is low (67% and 54%). A few studies evaluated fPLI/Spec fPL in seen quite a number of diabetic cats in which T4 measurement
cats with diabetes mellitus so far. Prevalence of increased fPLI or had to be repeated several times before hyperthyroidism could be
Spec fPL was 30%, 43%, and 83% (Forcada etal, 2008; Zini etal, demonstrated. T4 is also routinely evaluated in all diabetic cats
2011; Schfer etal, 2013). Interestingly, none of the more than with poor glycemic control, including cats in which glycemic con-
200 cats showed any clinical signs suggestive of pancreatitis. It is trol suddenly deteriorates during therapy. As mentioned earlier,
possible that those cats had pancreatic lesions that were not severe hyperthyroidism lowers serum fructosamine concentrations due
enough to cause clinical signs; histopathology, however, was not to accelerated protein metabolism. Therefore, a low or normal
performed. We do not recommend measuring Spec fPL in cats fructosamine concentration or a sudden decrease in fructosamine
with uncomplicated diabetes, because any increased value will be concentration in a cat with poor glycemic control should alert
difficult to interpret. In diabetic cats with clinical signs suggestive the veterinarian to the possibility of concurrent hyperthyroidism.
of pancreatitis, diagnosis should be based on the careful assess- Chapter 4 presents a detailed discussion on diagnosis of hyperthy-
ment of history, physical examination, Spec fPL (or DGGR lipase, roidism. It also includes information on diagnostic tests that may
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5.0 weighed carefully against any potential benefit. See Remission of

*
Diabetes in Cats earlier and Figs. 7-5 and 7-6 for more details.
*
4.0 DIAGNOSTIC IMAGING
Serum T4 concentration (g/dL)
Thoracic and abdominal radiographs play a limited role in the

3.0
work-up of cats with newly diagnosed diabetes. In uncomplicated
cases, hepatomegaly usually is the only relevant finding. Loss of
detail or a mass-like effect would raise suspicion for pancreatitis
or pancreatic neoplasia. We perform survey radiographs cats in
2.0 which we suspect the presence of concurrent disease (e.g., car-
diorespiratory, skeletal, urolithiasis); this includes cats that are
difficult to regulate and cats presented with DKA. In contrast,
1.0 abdominal ultrasonography is part of our routine work-up in any
cat presented with diabetes. Ultrasonography is helpful to inves-
tigate size and parenchyma of abdominal organs and abdominal
lymph nodes, the bile duct for obstruction, the renal pelvis for
0 6-8 24 dilatation (e.g., in case of pyelonephritis), and the wall thickness
Weeks and layering of the intestinal tract. In diabetic cats, the pancreas
is of particular interest, and ultrasonography is one of the major
FIGURE 7-14Serum thyroxine (T4) concentrations in 30 cats with newly- tools to diagnose pancreatitis. However, visualization of the pan-
diagnosed uncomplicated diabetes mellitus. At the time of diagnosis of diabe- creas is quite difficult and therefore dependent on the experience
tes, nine of the cats (30%) had T4 concentrations below the reference range, of the operator and the ultrasonographic equipment. The nor-
which normalized after 6 to 8 weeks of insulin therapy. After 24 weeks of insulin mal sonographic appearance of the pancreas in cats is isoechoic to
therapy, two cats revealed increased T4 concentrations; those cats were consid- slightly hyperechoic to the adjacent liver and nearly isoechoic to
ered hyperthyroid and medical treatment was started. Their initial T4 concentra- the surrounding mesenteric fat. Pancreatitis has various ultraso-
tions were 2.2 and 2.5 g/dL, respectively. Reference range: 1.0 to 3.5 g/dL. To nographic appearances, depending on the severity, duration of the
convert g/dL to nmol/L multiply by 12.87. (Unpublished data from Hafner M, disease, and extent of pancreatic and peripancreatic inflammation
University of Zurich, Switzerland.) * = Significant difference. (Penninck, 2008; Fig. 7-15).
Findings associated with acute pancreatitis include enlargement
be performed in questionable cases (i.e., cats suspected of hyper- of the pancreas, irregular pancreatic margins, hypoechoic irregular
thyroidism but have normal T4 concentrations). parenchyma, pancreas surrounded by hyperechoic mesentery and/
or hyperechoic fat as a result of fat saponification, dilation of the
Serum Insulin Concentration biliary duct, peripancreatic fluid accumulation, and thickening of
gastric and duodenal wall, and altered wall layering. Some cats
Measurement of the serum insulin concentration is not part of the show signs of pain associated with the pressure of the ultrasound
routine work-up in our hospital. In newly-diagnosed diabetic cats, probe. Hyperechoic or mixed echogenicity, nodular echotexture,
baseline insulin and insulin concentrations after the administra- and acoustic shadowing due to mineralization and scarring may
tion of a secretagogue (e.g., glucagon, arginine) are usually low be found in cases with chronic pancreatitis. Pancreatic pseudocysts
or low-normal and do not differ between cats in which diabetic and abscesses may be seen as a sequela to pancreatitis, appearing
remission occurs during subsequent therapy and cats with perma- as round to irregularly marginated fluid-filled mass lesions (Hecht
nent diabetes (Nelson etal, 1999; Tschuor etal, 2011). Insulin and Henry, 2007). Findings of acute and chronic pancreatitis may
measurements therefore are not helpful to differentiate between an overlap, because cats may have acute or chronic disease. The most
irreversible -failure and -cells that have the potential to recover useful criteria appear to be thickening of the pancreas, severely
after the negative effects of high blood glucose concentrations irregular pancreatic margins, and hyperechoic peripancreatic fat
(glucotoxicity) have been reversed by insulin treatment. In theory, (Williams etal, 2013). It is important to note, however, that the
a high insulin concentration in a newly diagnosed diabetic cat sug- pancreas may also look unremarkable in cats with pancreatitis and
gests the presence of functioning -cells and the presence of an that ultrasonographic findings may not correlate with clinical dis-
insulin-antagonistic disorder. However, as insulin concentrations ease. Additionally, the appearance of different pancreatic diseases
are low or low-normal in the vast majority of cats at the time overlap (e.g., a mass may represent an inflammatory lesion, nodu-
of diagnosis, this is not a cost-effective diagnostic procedure. In lar hyperplasia, or neoplasia). Therefore, ultrasonographic find-
cases in which insulin measurements are performed, it is of utmost ings need to be interpreted in the light of the clinical situation and
importance that the insulin assay is validated for the cat and that laboratory abnormalities.
species-specific reference ranges are available. Most commercially Reported sensitivity of ultrasonography differs widely between
available assays are designed to measure human insulin and do not studies; in part this is certainly due to differences in technical
work in the cat due to amino acid differences between human and equipment and study design. In a study with histological confir-
feline insulin. Recently, an enzyme-linked immunosorbent assay mation of pancreatitis, overall sensitivity of abdominal ultrasound
(ELISA) designed to measure feline insulin was validated (Strage was 67% (80% for moderate to severe pancreatitis, 62% for mild
etal, 2012). Most assays will cross-react with exogenously admin- pancreatitis) and overall specificity was 73% (88% in healthy cats
istered insulin; therefore, treatment should be withheld for at least and 33% in symptomatic cats without pancreatic histology) (Forman
24 hours in cats already undergoing insulin therapy. Insulin with- et al, 2004). Ultrasonography is also used to guide fine-needle
drawal may, however, put the cat at risk for DKA, in particular in aspiration (FNA), particularly in cats with pancreatic masses. FNA
a stressful environment (i.e., in the hospital). The risk should be cytology awaits studies to investigate its diagnostic accuracy for
A B 3.5
Pancreas right
C
FIGURE 7-15 Ultrasonographic images of the pancreas in three cats with diabetes mellitus at initial presentation.
A, Siamese cat, castrated male, 7 years old. The pancreas was of normal size, echogenicity was homogenous with
smooth margins, and the pancreatic duct was of homogenous width. The pancreas was considered unremarkable.
White arrows indicate the right branch of the pancreas; white arrow heads indicates the papilla duodeni. B, Norwe-
gian Forest cat, castrated male, 14 years old (same cat as in Fig. 7-11, C). The pancreas was slightly enlarged, echo-
genicity was heterogenous and slightly hypoechoic, and the pancreatic duct was of homogenous width. Organ mar-
gins were slightly irregular. The findings were considered consistent with chronic pancreatitis of moderate intensity.
White arrows indicate the pancreas; white arrow heads indicates the pancreatic duct. C, Domestic Short-Hair (DSH),
castrated male, 16 years old. Severe diffuse enlargement of the pancreas with mixed echogenicity and irregular
margins surrounded by hyperechoic fat was present. The diameter of the pancreatic duct was variable and appeared
mildly dilated. The findings were consistent with pancreatitis, which was most likely an overlap between acute
and chronic disease. White arrows indicate pancreas; white arrow heads indicates pancreatic duct. (Courtesy of
Dr. Matthias Dennler and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty Zurich, Switzerland.)
the diagnosis of pancreatitis. Knowledge on the value of computed prevent complications (e.g., hypoglycemia, DKA) and thereby
tomography (CT) in the diagnosis of pancreatitis is still scarce. enable a good quality of life. Early treatment and good glycemic
According to currently available studies, its sensitivity seems to be control is important to increase the chance of diabetic remission.
very low (Gerhardt etal, 2001; Forman etal, 2004). We routinely However, this issue requires special attention and one should
evaluate the adrenal glands in diabetic cats during abdominal remember that aggressive insulin therapy and aiming for normal
ultrasound. Symmetrical enlargement may suggest acromegaly or or near normal blood glucose concentrations increases the risk
pituitary-dependent hyperadrenocorticism. An unilateral nodule of hypoglycemia. We routinely discuss the possibility of diabetic
or a mass may have various causes (see Table 13-5). remission with owners of newly diagnosed diabetic cats. However,
we do not stress remission as the major treatment goal for two
reasons: to avoid treatment that is too aggressive (i.e., autonomous
TREATMENT OF NONKETOTIC DIABETES
increase of insulin dose by the owner) and to avoid frustration of
MELLITUS
the owner if remission does not occur.
Successful treatment requires that the owner is highly motivated,
Goals of Therapy
able, and willing to adapt his or her daily routine to the cats treat-
The primary goal in treating nonketotic diabetes mellitus is to ment plan and to work in close collaboration with the veterinarian.
eliminate the clinical signs of diabetes, such as polyuria, poly- It may be difficult for some of the owners to understand the nature
dipsia, polyphagia, and weight loss by good glycemic control, to of the diabetic disease and the various treatment and monitoring
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options. Therefore, treatment should follow a precise and compre- insulin can be confusing because insulin availability (particularly if
hensive protocol, and the owner should receive written information animal-derived) differs between countries as do the names for the
on all relevant aspects of the disease and the insulin injection. Short same kind of insulin (e.g., Vetsulin is called Caninsulin outside
videos demonstrating handling and injection of insulin are also of the United States). Insulin preparations available today may be
helpful (provided on websites of insulin manufacturers or diabetes withdrawn from the market tomorrow. The Internet is helpful to
forums). Another goal is to minimize the potential negative impact determine the status of a particular insulin (e.g., announcement of
of the cats disease on the owner and thereby avoid cessation of withdrawal of Vetsulin starting in 2009 and announcement of its
therapy or euthanasia. Recently, a study evaluated the psychologi- re-approval in April 2013 in the United States).
cal and social impact of diabetes and its daily treatment regimen Insulin preparations are classified as short-acting, intermediate
on quality of life of both owner and diabetic cat. 221 cat owners -acting, long-acting, and so-called premixed or biphasic insulins.
from the United States, Canada, Australia, and various countries in In principle, more potent insulin preparations have a shorter dura-
Europe completed the survey. The factors with the most negative tion of action than less potent ones (see Fig. 6-30). Short-acting
impact on quality of life were boarding difficulties, owners want- insulin (regular insulin, short-acting analogues such as aspartate,
ing more control on diabetes, difficulties leaving cat with friends or lispro, glulisine) is typically used in cats with DKA, hypergly-
family, general worry about the cats diabetes, worried about hypo- cemic hyperosmolar state, or with extremely unstable glycemic
glycemia, adapting social life, diabetes-related costs, and adapting control. Intermediate and long-acting preparations are used for
work life (Niessen etal, 2010). The results of this study may help long-term control of cats with uncomplicated diabetes. The longer
the veterinarian to address those issues and to make amendments duration of action is achieved by slowing the rate of absorption
to the treatment and monitoring protocol according to the needs of from the subcutaneous tissue. Delayed absorption is due either
the individual owner (e.g., simplification of treatment if social life, to the addition of substances that are virtually inert and do not
work life, or costs are the major problems, access to home monitor- have therapeutic properties themselves (e.g., protamine and zinc)
ing of blood glucose if owner wants more control, and avoidance of or to a modification of the insulin molecule (as in insulin glargine
tight glucose regulation if owner is worried about hypoglycemia). and insulin detemir). Insulin detemir has some additional pro-
Treatment of a diabetic cat consists of medical therapy (usually tracting effect because it binds to albumin not only in the subcu-
insulin therapy), dietary management (including weight reduc- taneous and extracellular compartment but also in the systemic
tion if the cat is overweight), cessation of diabetogenic drugs, and circulation (Havelund etal, 2004; Owens, 2011). A number of
prevention or control of any concurrent disease. premixed or biphasic insulin formulations are available to facili-
tate treatment regimens in humans. They are designed to provide
Initial Insulin Therapy a more convenient approach to cover both basal and prandial
insulin requirements and consist of a mixture of a short-acting
The administration of insulin is the most important part of the and an intermediate/long-acting component. Ratios of the two
treatment regimen in diabetic cats and should be initiated as soon components vary (e.g., 75:25, 70:30, and 50:50 intermediate-/
as possible after the diagnosis is established. In humans with type long-acting-to-short-acting), premixed preparations are available
2 diabetes, initial treatment usually consists of lifestyle modifi- as insulin analogues or as mixtures of conventional insulin prepa-
cation and oral hypoglycemic drugs. Because many of the cat rations (Bilous and Donnelly, 2010). The use of premixed insulins
owners are either diabetic themselves or have diabetic relatives or has so far not been studied in cats. It is likely, however, that they
friends, they tend to ask for those treatment modalities. We then will not be beneficial because cats do not have the same type of
explain our reason for using insulin as first line choice, which is postprandial hyperglycemia as humans. See the section on insulin
mainly that insulin therapy is superior to the currently available therapy in Chapter 6 for more details on insulin preparations.
oral hypoglycemic drugs to reverse the negative effects of glucose
toxicity and to increase the chance of diabetic remission. In overt Neutral Protamine Hagedorn Insulin
diabetes mellitus, dietary management alone is insufficient and Neutral protamine Hagedorn (NPH) insulin preparations are
may lead to deterioration of the disease and potentially to DKA. potent insulins with a marked peak. Unfortunately, duration of
Diet, however, is an important part of the treatment. action is considerably less than 12 hours in most cats, often result-
In the last two decades, the manufacture and development ing in hyperglycemia for several hours during the day. Addition-
of insulin for human use has undergone revolutionary changes, ally, the strong peak action increases the risk of hypoglycemia a
which have had important implications in veterinary medicine. few hours after administration. The use of NPH insulin is there-
First, insulins derived from animal sources are being more and fore not recommended.
more replaced by recombinant human preparations and will even-
tually disappear from the market. Although there are differences Lente Insulin
in the amino acid sequences (see Table 7-1) human insulins (and A porcine-derived Lente-type insulin (Vetsulin/Caninsulin, Merck/
their analogues) are fortunately biologically active in cats. Second, MSD Animal Health) is licensed for use in cats in many countries.
insulin preparations for human use containing 40-IU/mL have It is identical to canine insulin and differs from feline insulin by
largely been replaced by 100-IU/mL insulins. It is important that three amino acids (see Table 7-1). Vetsulin/Caninsulin is avail-
owners understand the difference, because two insulin prepara- able at a concentration of 40 IU/mL, and should be administered
tions for veterinary use (Vetsulin/Caninsulin and ProZinc) are twice a day (b.i.d.). Recently, a pen specifically designed to be
supplied as 40-IU/mL, and using the wrong syringe size would used with this insulin has been marketed under the name of Vet-
lead to substantial dosing errors. Third, new classes of insulins Pen. The pen comes in two sizes (0.5 to 8 IU and 1 to 16 IU);
called insulin analogues have been developed. They were designed the smaller of the two allows insulin dosing in steps of 0.5
to improve the pharmacodynamic properties of insulin and render units. The pen is used with cartridges containing 2.7 mL
insulin absorption or insulin delivery to tissues more predictable. (= 108 units) of insulin. Several studies have shown that Vetsulin/
The currently available insulin analogues are certainly just the Caninsulin is effective and safe for the treatment of diabetes in cats.
start of a whole new area of insulin preparations. The market for They are, however, difficult to compare due to the different study
designs. As a rough summary, one may state that approximately 70% of effect compared with several other insulin preparations. Initial
to 80% of cats were adequately controlled or diabetic remission was studies confirmed that its duration of action is clearly longer than
achieved and remission rates varied between 15% and 43%. Clini- that of Lente insulin and comparable to PZI (Marshall etal, 2008a;
cal hypoglycemia was seen in up to 25% of cats, and biochemical 2008b). Recently, the pharmacodynamics of insulin glargine was
hypoglycemia was seen in more than 40% of cats. The time until the compared to insulin detemir (Levemir, Novo Nordisk), which is
glucose nadir was reached varied substantially and ranged between another long-acting insulin analogue. The study was performed
2 and 12 hours, and mean/median nadir was reached between using an isoglycemic clamp method, which is considered to be the
4 and 6 hours (Martin and Rand, 2001; 2007; Weaver etal, 2006; gold standard method in humans. Performance of the two insulin
Michiels etal, 2008; Marshall etal, 2009). Vetsulin/Caninsulin is a analogues was similar, the only significant difference was a faster
mixture of 30% to 35% short-acting amorphous and 65% to 70% onset of action of insulin glargine (mean of 1.3 hours versus mean of
long-acting crystalline insulin; in theory, this combination should 1.8 hours). Mean time to peak action was 5.3 hours in glargine and
result in a relatively fast onset of action and duration of action of 6.9 hours in detemir, and end of action was reached after a mean of
approximately 12 hours. However, in a substantial percentage of 11.3 hours in glargine and 13.5 hours in detemir (Table 7-4). Inter-
cats, the duration of action is considerably shorter, and adequate estingly, there were considerable variations in the shape of glucose
control cannot be achieved. The recently published American curves; some cats had a flat curve whereas others revealed a pro-
Animal Hospital Association (AAHA) guidelines therefore do not nounced peak (Gilor etal, 2010a). The results from this study com-
recommend Vetsulin/Caninsulin as the initial insulin option for pare quite well with our clinical experience made over the past years.
diabetic cats (Rucinsky etal, 2010). Of note, the manufacturer has Although duration of insulin glargine is quite long, b.i.d. adminis-
recently changed the label and now recommends vigorous shaking tration is usually required to achieve adequate control or diabetic
the vial prior to first use until a homogenous, uniformly milky sus- remission; shape of the glucose curves differ considerably between
pension is obtained. This should ensure adequate homogenization cats and also within the same cat. So far, insulin glargine has not
of the two parts of the insulin, which obviously was a problem with been evaluated systematically in large clinical trials. A few pilot stud-
the former recommendation of gently rolling the vial. ies showed that it is safe and effective in diabetic cats and adequate
glycemic control can be achieved in many cases. Insulin glargine
Protamine Zinc Insulin used over a 4-month period resulted in diabetic remission in 8 of 8
Protamine zinc insulin (PZI) is insulin combined with protamine cats (100%), whereas only 3 of 8 cats (38%) treated with PZI and
and zinc. It contains more protamine than NPH and therefore has 2 of 8 cats (25%) treated with Lente insulin achieved remission
a longer duration of action. Duration of action is also longer than (Marshall et al, 2009). Other studies using insulin glargine were
in Lente insulin (Marshall etal, 2008a). The previous PZI prod- not able to repeat the high treatment success: remission rates ranged
uct often used for diabetic cats, which was made from bovine and between 17% and 47% (Boari etal, 2008; Hall etal, 2009; Hafner
porcine insulin (PZI-Vet, IDEXX Laboratories), was discontinued etal, 2011). In an Internet-based study using 55 diabetic cats from
some years ago. PZI-Vet was considered a good treatment option; a German diabetes forum, a remission rate of 64% was achieved
a study reported that 90% of cats had good glycemic control (Roomp and Rand, 2009). However, owners were required to
after 45 days of therapy based on owner assessment (Nelson etal, measure blood glucose at least three times per day, and insulin dos-
2001). The gap was filled by the release of ProZinc (Boehringer age was constantly adjusted, which is a regimen suitable for only
Ingelheim), which is a recombinant human insulin, formulated as a selected group of owners. The occurrence of hypoglycemia in
protamine zinc insulin. The level of glycemic control was shown glargine treated cats has also not yet been evaluated systematically.
to be similar between the animal-derived and the recombinant In the study by Roomp and Rand (2009), clinical hypoglycemia was
product. Good glycemic control was achieved in 85% of cases by reported in only 1 of 55 cats (1.8%), whereas 93% of cats revealed
the end of the study (day 45). The final median insulin dose was biochemical hypoglycemia at various levels of severity. The latter is
0.59 IU/kg b.i.d. (range 0.1 to 1.4). The glucose nadir occurred certainly mostly associated with the intensive treatment protocol
between 1 and 9 hours (mean 4.6); of note in 24% of cats, the used in the particular study and not with the type of insulin.
lowest blood glucose concentration was at the last blood sampling, There is so far little experience with insulin detemir in diabetic
and the nadir presumably was later than 9 hours after the insulin cats. Roomp and Rand (2012) performed a similar study with
administration. A long duration of effect may result in a substantial insulin glargine, again using the intensive treatment protocol and
overlap and potentially hypoglycemia. Clinical hypoglycemia was an online German diabetes forum for owners of diabetic cats. The
rare and seen in only 1.5% of cases; biochemical hypoglycemia, results were similar, remission rate was 67% with insulin detemir;
however, was a frequent event and seen in 64% of cats at some time
during the study period (Nelson etal, 2009). So far, knowledge on
TABLE 7-4 PHARMACODYNAMIC PARAMETERS
remission rates with PZI is scarce. One study reported a remission
OF INSULIN GLARGINE AND
rate of 38% (Marshall etal, 2009). The AAHA Diabetes Manage-
INSULIN DETEMIR
ment Guidelines lists ProZinc and Lantus (Insulin glargine, Sanofi)
as the two insulin preparations of choice to initiate insulin therapy
INSULIN GLARGINE INSULIN DETEMIR
in cats (Rucinsky et al, 2010). ProZinc contains 40 IU insulin/
(Lantus) (Levemir)
mL. Contrary to the recommendation for Vetsulin/Caninsulin, the
n = 10 n = 10 p-value
manufacturer of ProZinc recommends mixing by gently rolling the
vial. It should be used b.i.d.; in some cats with very long duration Onset of action (h) 1.3 (0.9 to 1.6) 1.8 (1.1 to 2.3) 0.03
of effect, once a day (s.i.d.) administration may be also be effective. Time to peak 2.5 to 8.0 (5.3) 4.7 to 9.2 (6.9) 0.31
action (h)
Long-Acting Insulin Analogues
End of action (h) 8.0 to 14.5 (11.3) 11.0 to 16.0 (13.5) 0.18
Lantus (insulin glargine, Sanofi) has been the focus of attention in
veterinary medicine for several years because of its theoretical ben- Modified from Gilor C, etal.: Pharmacodynamics of insulin detemir and insulin glargine
efits, namely a more constant rate of absorption and longer duration assessed by an isoglycemic clamp method in healthy cats, J Vet Intern Med 24:870, 2010a.
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clinical hypoglycemia was seen in 1 of the 18 cats (6%), whereas recommended by the AAHA Diabetes Management Guidelines
biochemical hypoglycemia was common. The starting dose of (Rucinsky etal, 2010). In previous years, we achieved good glyce-
insulin detemir was similar to the starting dose of insulin glargine mic control in many diabetic cats using Lente insulin (Vetsulin/
in the two studies (0.25 IU/kg of ideal body weight); however, Caninsulin), and therefore it may in principle also be used. As
maximal dose of detemir was lower than the maximal dose of mentioned earlier, however, duration of action is often shorter
insulin glargine (0.5 to 4.0 IU, median 1.75 versus 1.0 to 9.0 than 12 hours (i.e., shorter than the duration of action of insulin
IU, median 2.5). Another difference was the relatively frequent glargine and PZI). If a diabetic cat is well regulated with Vetsulin/
development of chronic renal failure in cats treated with insulin Caninsulin, there is no reason to switch it to one of the other insu-
detemir. It is unknown so far if this is related to the insulin itself lins preparations. Nearly all cats require insulin twice daily, there-
or to the fact that the cats in the detemir study were slightly older fore we always start with b.i.d. administration. The initial dose in
than the cats in the glargine study. cats weighing 4 kg is 1 IU/cat b.i.d., and in cats weighing > 4 kg
it is usually 1.5 IU/cat (2.0 IU/cat) b.i.d. In cats with a blood
glucose concentration < 350 mg/dL (20 mmol/L) at the time of
Insulin Choice and Initial Dose
diagnosis, no more than 1 IU/cat b.i.d. is given, independent of
The initial insulin of choice depends on personal preference and the body weight. The starting dose should not exceed 2.0 IU/cat
availability. Cats are unpredictable in their response to insulin and b.i.d., even in a very large cat. It is better to start conservatively
none of the insulin preparations described above are routinely (e.g., maximum dose of 1.5 IU/cat b.i.d.), than to risk hypoglyce-
effective to control the disease. We nowadays start treatment in mia during the first few days, which may lead to owner frustration
diabetic cats with insulin glargine (Lantus). PZI (ProZinc) would and potentially cessation of therapy. Very small cats ( 2 kg) are
also be a good first choice. Both, insulin glargine and PZI are started on no more than 0.5 IU/cat b.i.d. (Box 7-3).
BOX 7-3 Protocol for the Management of Non-Ketotic Diabetic Cats
Initial Presentation Reevaluation 2 to 3 Weeks after Diagnosis

Diagnosis of diabetes mellitus (clinical signs, hyperglycemia, glucosuria, Repeat all procedures as during first reevaluation
increased fructosamine) Introduction to home monitoring, and instruction on all relevant technical
Routine laboratory evaluation (CBC, serum biochemistry panel* urine aspects (requires at least hour)
analysis, urine culture) Frequency of home monitoring
Abdominal ultrasonography During initial phases of therapy approximately one BGC per week
Cessation of diabetogenic drugs (glucocorticoids, progestagens) After stabilization (i.e., when adequate glycemic control is achieved),
Start with intermediate-/long-acting insulin approximately one BGC every 3 to 4 weeks
First-line: Lantus, ProZinc; second-line: Vetsulin/Caninsulin BGC results should be sent to hospital and dose changes discussed
Initial dose with the veterinarian
Depends on severity of clinical signs and degree of hyperglycemia;
Reevaluation 6 to 8 Weeks after Diagnosis
initial dose should not exceed 1.5 to 2.0 IU/cat b.i.d., even in very
All procedures as during first reevaluation; BGC may not be required if
large cats
pet appears clinically well, blood glucose measured close to the time
0.5 IU/cat b.i.d. if body weight is 2 kg
of insulin administration is 10 to 15 mmol/L (180 to 270 mg/dL) and
1.0 IU/cat b.i.d. if body weight is 2.5 to 4 kg
fructosamine is 350 to 450 mol/L
1.5 IU/cat ( 2.0 IU/cat) b.i.d. if body weight is > 4 kg
Home monitoring results should be assessed and owner technique
Treatment of concurrent problems (e.g., urinary tract infection, stomatitis/
evaluated
gingivitis)
If glycemic control is inadequate and insulin dose is close to 1 IU/kg b.i.d.
Dietary management
or above, further work-up should be pursued
High protein, low carbohydrate diet; provided that no other disease has
priority Reevaluation 10 to 12 Weeks and 14 to 16 Weeks
45 to 60 kcal/kg/day after Diagnosis, Then Every 4 Months
If overweight, aim for 1% weight loss per week Repeat all procedures done 6 to 8 weeks after diagnosis (except further
Owner instruction (requires at least 1 hour) work-up if not needed)
Written instructions for owners Goals of Therapy
Reevaluation 1 Week after Diagnosis Good glycemic control
Administration of insulin and food at home, and then bring cat to hospital Clinical signs: Resolution of pu/pd, polyphagia, normal body weight
as soon as possible Blood glucose: Highest concentration between 180 to 270 mg/dL
History, physical examination, and body weight (10 to 15 mmol/L) and nadir between 80 to 140 mg/dL
Generation of a BGC (glucose measurement every 2 hours for the remain- (4.5 to 7.8 mmol/L)
der of the day, preferentially until next insulin injection, or even thereafter Fructosamine: Ideally between 350 and 450 mol/L
if nadir is not reached) Diabetic remission
Fructosamine measurement May be achieved in 25% to 50% of newly-diagnosed diabetic cats
Adjustment of insulin dosage if required: 0.5 IU/injection. In case of
Somogyi effect or overt hypoglycemia, dose reduction of 25% to 50%,
depending on the insulin dosage used
*1,2-0-dilauryl-rac-glycero-glutaric acid-ester (DGGR) lipase (part of routine biochemistry panel in some laboratories) or Spec fPL should be measured if clinically indicated.
b.i.d., Bis in die (twice a day); BGC, blood glucose curve; CBC, complete blood count; pu/pd, polyuria/polydipsia.
After diagnosing diabetes mellitus, the cat may be kept in the 28 (Lantus), 42 (Vetsulin/Caninsulin, Levemir) or 60 days (Pro
hospital for 1 to 2 days to complete the work-up. During this Zinc); however, true shelf-life is certainly longer and often own-
time, blood glucose concentration should be measured three to ers use the insulin for longer times. We routinely inform own-
four times throughout the day and the insulin dosage reduced if a ers about the potential risk of contamination and loss of activity
low glucose concentration (< 90 mg/dL, 5 mmol/L) is detected. If and that cloudy or discolored vials should be discarded. Simi-
the blood glucose concentration decreases only slightly, we do not larly the vial should be replaced if glycemic controls inexplicably
increase the insulin dose because it takes a few days for full insulin deteriorate.
action to develop (so-called equilibration). Adjustments in insulin
dosage are made on subsequent evaluations. The initial work-up Reevaluations and Adjustment of Insulin Dose
and start of treatment may also be done on an outpatient basis.
The approach is similar in cats that already receive insulin therapy After the initial work-up, the cat is discharged with insulin,
but in which the disease is not adequately controlled. If we consider syringes, diet, and, if needed, treatment for any concurrent dis-
the type of insulin to be the problem, we switch to a different type, ease. We inform the owner about the fact that during the next
using the same dosing schedule as for the newly-diagnosed diabetic 3 months, frequent reevaluations and close monitoring are
cats. The exception are cats that were shown to be prone to hypo- needed. Reevaluations are scheduled as a minimum after weeks 1,
glycemia with the previous insulin, those would not receive more 2 to 3, 6 to 8, 10 to 12, 14 to 16, and then approximately every
than 0.5 U/cat b.i.d. of the new insulin as a starting dose. 4 months (see Box 7-3). Additional appointments may be nec-
essary in some cats. It usually takes between 1 and 3 months
Insulin Handling and Owner Instruction until adequate glycemic control is achieved, and it is also during
the first 3 months that the likelihood of diabetic remission is
One of the most important periods in the owners care of a dia- greatest. The latter should not be overlooked, because serious
betic pet is the time during which the veterinarian or the techni- hypoglycemia may occur. We also introduce the general con-
cian teaches the technical aspects of the treatment and explains cept of home monitoring after initial work-up, and our written
the monitoring protocol. The owner should be instructed to mix instructions contain some more information and pictures about
the insulin correctly: the manufacturer of ProZinc recommends the technical aspects. However, we usually wait for 2 to 3 weeks
gently rolling of the vial, whereas Vetsulin/Caninsulin should be until teaching the technique. We first want to ensure that the
vigorously shaken. Lantus (and Levemir) are clear solutions and owner is able to handle the other parts of the disease (regular
need no mixing. It should be demonstrated how to load a syringe insulin injections, change in diet, weight management) until
without air bubbles, and the veterinarian may also refer the owner moving on to the next step. The exceptions are highly motivated
to one of the many administration videos available through the owners or diabetic owners being familiar with capillary glucose
Internet. We recommend injecting the insulin over the lateral measurements. Ideally, insulin injections should be given every
chest wall because perfusion is better there than in the neck area, 12 hours; however, this may not be possible for all owners.
which increases absorption of insulin. The spot should rotate each Therefore, we allow shifts of 1 to 2 hours. We always start
time. The owner must understand the differences between U-40 with the same insulin dose in the morning and in the evening.
and U-100/mL insulins: ProZinc and Vetsulin/Caninsulin are In some cats, different doses may be required during long term
U 40/mL, whereas Lantus and Levemir are U-100/mL prepa- management (e.g., a lower dose in the evening if recurrent epi-
rations. The use of the correct size of syringe is imperative. The sodes of hypoglycemia occur at night).
use of non-matching syringes based on conversion tables or the Clinical signs of diabetes usually resolve when blood glucose
owners own calculations is discouraged, because the risk of confu- concentrations can be kept below the renal threshold, ideally the
sion is high. The administration of small doses of insulin is dif- lowest glucose concentration (glucose nadir) should be between
ficult and requires particular attention. For the administration of 80 and 140 mg/dL (4.5 to 7.8 mmol/L), the highest glucose con-
Lantus (and Levemir) we routinely use 0.3 mL syringes, designed centration between 180 and 270 mg/dL (10 to 15 mmol/L). At
for the application of U-100 insulin preparations in 0.5 IU incre- each reevaluation, the owner is questioned about his/her opinion
ments (BD Micro-Fine+Demi U 100 syringes, 0.3 mL, Becton on the cats overall health, water intake, urine output, a thorough
Dickenson); however, for some people a pen designed to deliver physical examination is performed, body weight is recorded, and
0.5 IU increments may be an alternative. Lantus must not be a serial blood glucose curve (BGC) is generated. Fructosamine
diluted because dilution changes the time/action profile; Levemir measurement may also be informative. If glycemic control is
may be diluted with Insulin Diluting Medium for NovoRapid and considered unsatisfactory, the insulin dose is increased in steps of
Levemir supplied by Novo Nordisk (unfortunately it is not avail- 0.5 IU/cat per injection. It is possible that the insulin dose has
able in all countries). Dilution of other insulin preparations has to be increased several times until a reaction (clinically and with
been common practice; however, there are no studies on poten- regard to blood glucose concentration) is seen. We usually make
tial changes of pharmacokinetics and stability. We avoid dilution dose changes no more often than every 5 to 7 days. It is also pos-
whenever possible and never dilute Lantus. sible that the type of insulin has to be changed. If duration of
Unopened vials should generally be stored in the refrigerator, action is too short, a longer acting insulin should be used and
distant from the freezer compartment. Freezing and heating inac- vice versa. As mentioned earlier, Vetsulin/Caninsulin usually has
tivates the insulin; similarly direct exposure to sun light must a shorter duration of action than ProZinc and Lantus; in some
be avoided. We also recommend storage of in-use vials in the cats, ProZinc may have a longer duration of action than Lan-
refrigerator to ensure a consistent environment. However, insu- tus, although there is variability between cats. Levemir seems
lin is also stable at room temperature (as long as it is < 86o F, < to have a slightly longer duration of action than Lantus. How-
30o C, and light-protected) for approximately 4 weeks, which ever, there are substantial differences between diabetic cats, and
may be important for travelling. Insulin stored in the refrigerator the insulin dose has to be adapted according to the need of the
should be allowed to warm up a bit before injection. Manufac- individual cat. If hypoglycemia is noted at any time, the insulin
turers declare that opened (in use) vials have to be replaced after dose should be reduced and another reevaluation scheduled soon
|
thereafter. Most diabetic cats can be adequately controlled with diabetes, and therefore, oral hypoglycemic drugs and non-insulin
insulin doses between 0.5 and 3 IU/cat b.i.d. (i.e., usually with injectables may theoretically be of use. However, those classes have
less than 1.0 IU/kg b.i.d.). If the insulin requirement increases to not gained wide popularity, certainly due to two main reasons.
1 IU/kg b.i.d. or more without achieving adequate control, further First, it may be as difficult (or even more difficult) for a cat owner
work-up for any disease causing insulin resistance is indicated. to give life-long oral medication as to inject insulin. Secondly, for
Diabetic remission may occur in approximately 25% to 50% those drugs investigated in the cat, efficacy has been poor or mod-
of cases, usually during the first 3 months of therapy. Therefore, erate at best. Diabetic cats usually have symptoms of severe hyper-
an extended treatment goal is to increase the chance of diabetic glycemia and insulin secretion is low. As in humans with severe
remission. We do not use a specific remission protocol (meaning to disease, oral drugs and non-insulin injectables are usually unable
aim for lower glucose targets), because more aggressive insulin treat- to combat the profound metabolic derangements. Immediate and
ment is associated with a greater risk of hypoglycemia. However, we effective treatment should be initiated with the aim of preserving
always start insulin therapy immediately after diagnosis and aim for the remaining -cell mass and reversing the effects of glucotoxicity
good glycemic control. All of our owners are aware of the blood glu- on -cell function. We consider insulin treatment superior to any
cose targets mentioned earlier. If those targets are reached and the other currently available antidiabetic drug to increase the chance
owner is willing to perform home monitoring of blood glucose, we of diabetic remission. Insulin therapy is therefore highly recom-
consider to push treatment a bit further to see if diabetic remission mended to owners of cats with newly diagnosed diabetes. Oral
is possible (see details in the sections Home-Monitoring of Blood drugs and non-insulin injectables (e.g., the GLP-1 agonists) may
Glucose, Frequency of Monitoring, and Interpretation of Blood play a role in cats with mild forms of diabetes or as add-on treat-
Glucose Curves and Adjustment of Insulin Doses). The target for ment. The latter are also used when the owner absolutely refuses
the glucose nadir, however, is not altered (i.e., blood glucose con- to inject insulin or is unable to do so.
centration should not decrease to less than 80 to 120 mg/dL [4.5 to The currently available oral agents and non-insulin injectables
6.7 mmol/L]). If remission occurs unnoticed and the administra- can be divided by their mechanism of action into several groups:
tion of insulin is not discontinued, serious hypoglycemia may result. insulin secretagogues (sulfonylureas, glinides), insulin sensitizers
with predominant action on the liver (metformin), insulin sensitiz-
Oral Hypoglycemic Agents and Non-Insulin Injectables ers with predominant action in peripheral insulin-sensitive tissues
(glitazones), carbohydrate absorption inhibitors (-glucosidase
In humans with newly-diagnosed type 2 diabetes, initial thera- inhibitors), incretin-related therapies (DPP-4 inhibitors, GLP-1
peutic measures consist of lifestyle interventions and prescription agonists), and others/novel agents with less clear mechanisms (Buse
of an oral hypoglycemic agent. According to the latest position etal, 2011; Table 7-5). Not all agents are available in all countries,
statement of the American Diabetes Association and the European and the same drug may be named differently in different countries.
Association for the Study of Diabetes, metformin is the initial drug
of choice. If the glycemic target is not reached after approximately Sulfonylureas
3 months of metformin therapy, another antidiabetic drug should Sulfonylureas were introduced into human medicine in the 1950s
be added. This may be a sulfonylurea, thiazolidinedione, dipep- and are the oldest oral hypoglycemic agents. Early sulfonylureas
tidyl peptidase-4 (DPP-4) inhibitor, GLP-1 receptor agonist, or are referred to as first generation and include tolbutamide, car-
insulin. In newly-diagnosed human patients with severe diabetic butamide, acetohexamide, tolazamide, and chlorpropamide. They
symptoms and severe hyperglycemia (blood glucose > 300 to have largely been replaced by the more potent second generation
350 mg/dL, 16.7 to 19.4 mmol/L), insulin therapy should be sulfonylureas, such as glipizide, glyburide (glibenclamide), glicla-
started immediately (Inzucchi etal, 2012). In short, this means zide, and glimepiride. They act directly on the -cell to induce
that if -cell function has deteriorated beyond the capacity of oral insulin secretion; they do so by binding to the cytosolic surface of
agents to provide adequate glycemic control, the introduction of the sulfonylurea receptor, which causes closure of ATP-sensitive
insulin should not be delayed (Bailey and Krentz, 2010). It is cur- potassium channels, followed by depolarization of the plasma
rently assumed that the majority of diabetic cats suffer a type 2-like membrane, opening of calcium channels, and exocytosis of insulin
TABLE 7-5 C
LASSES OF ORAL HYPOGLYCEMIC AGENTS AND NON-INSULIN INJECTABLES AND THEIR MAIN
MODES OF ACTION
CLASS OF ANTIDIABETIC DRUG WITH EXAMPLES MAIN MODE OF ACTION PREDOMINANT SITE OF ACTION
Sulfonylureas Stimulate insulin secretion -cells
(glipizide, glyburide/glibenclamide, gliclazide, glimepiride)
Glinides/meglitinides Stimulate insulin secretion (faster onset and shorter -cells
(repaglinide, nateglinide) duration of action than sulfonylureas)
Biguanide Decrease of hepatic gluconeogenesis and glycogenolysis, Liver (muscle)
(metformin) increase of glucose-uptake
Glitazones/thiazolidinediones (pioglitazone, rosiglitazone) Increase insulin sensitivity Adipose tissue, muscle, (liver)
-glucosidase inhibitors (acarbose, miglitol, voglibose) Slow digestion of carbohydrate Small intestine
GLP-1 receptor agonists (exenatide, liraglutide, albiglutide) Enhance glucose-dependent insulin secretion -cells
DPP-4 inhibitors/gliptins (see also Table 7-10)
(sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin)
DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1.

(Bailey and Krentz, 2010). Sulfonylureas can only exert their for recommendations in case those adverse effects occur. One
effect if there is a sufficient reserve of -cells function left, and should be aware that glipizide is only effective in approximately
they usually become ineffective as -cell function declines during 30% of cases. In some of them, glipizide becomes ineffective after
the progression of the diabetic disease. They are contraindicated a few weeks to months; in others, good glycemic control can be
in individuals with an absolute insulin deficiency. Sulfonylureas maintained for a long period (years). Glipizide may have negative
can stimulate insulin release even if blood glucose concentrations effects on islets and may accelerate -cell loss. Under experimental
are low (< 90 mg/dL, 5 mmol/L), rendering hypoglycemia the conditions, increased amyloid deposition has been found in islets
most serious adverse effect. Another negative effect of sulfonylurea of cats treated with glipizide compared to cats treated with insulin;
therapy is weight gain. this is most likely due to the stimulatory effect of glipizide on both
Glipizide is the drug in this class most often used in cats and insulin and amylin secretion (Hoenig etal, 2000b). This finding
which has been studied best (Nelson etal, 1993; Feldman etal, is comparable to studies using human cell cultures, in which sul-
1997). There are no parameters to help the clinician identify cats fonylureas lead to increased -cell apoptosis (Maedler etal, 2005).
that will respond to glipizide therapy, and selection of patients One study investigated the efficacy of transdermal glipizide; unfor-
therefore relies on assessing the severity of disease. Glipizide tunately absorption was low and inconsistent (Bennet etal, 2005).
should only be used in diabetic cats that are in good physical con- There is very little to no experience with other sulfonylureas
dition, non-ketotic, have only mild to moderate signs of diabetes, in diabetic cats. Glyburide (glibenclamide) has a longer duration
and can be monitored closely. The starting dose of glipizide is 2.5 of action than glipizide and may be suitable for once daily use
mg/cat b.i.d. in conjunction with a meal. The dose is increased in some cats. Initial dose is 0.625 mg/cat b.i.d., which may be
to 5 mg/cat b.i.d. after 2 weeks provided that no adverse effects increased to 1.25 mg/cat b.i.d., if no effect is seen. Guidelines
have occurred and hyperglycemia is still present. The cat should and adverse effects are similar to those described for glipizide.
be reevaluated after another 1 to 2 weeks and at regular intervals Glimepiride is the most recently developed sulfonylurea for
thereafter. Therapy is continued as long as the drug provides good once daily use in humans. So far, it has been investigated only
glycemic control, i.e., resolution of clinical signs, stable body in healthy cats, in which a significant glucose lowering effect was
weight, blood glucose concentrations between 180 to 270 mg/dL demonstrated (Mori etal, 2009b).
(10-15 mmol/L) and 80 to 140 mg/dL (4.5-7.8 mmol/L). The dose Because sulfonylureas (e.g., glipizide) do not offer any medical
should be reduced or discontinued if normoglycemia or hypogly- advantage over insulin, we only use them if owners are unable
cemia occurs, and the cat should be reevaluated after a few days. If or unwilling to inject insulin. During the following weeks, confi-
hyperglycemia is again present, glipizide at a lower dose should be dence and willingness of owners often increase and a transition to
reintroduced. Glipizide should be discontinued and insulin ther- insulin will eventually be possible.
apy started when clinical signs and hyperglycemia are not under
control or worsen after a few weeks of treatment or ketoacidosis Glinides/Meglinides
develops. The dose of glipizide should not be increased above 5 mg/ Glinides/meglinides are insulin secretagogues, which also bind to
cat b.i.d. Adverse effects (besides hypoglycemia) occur in approxi- the sulfonylurea receptors, but on a different site from sulfonyl-
mately 15% of cats and include anorexia, vomiting, increased liver ureas. They induce a prompt, albeit short-lived insulin secretion
enzymes, and increased bilirubin with icterus. Please see Box 7-4 and are specifically designed to counteract postprandial hypergly-
cemia. As such, they are also termed short-acting prandial insulin
releasers. Adverse effects include hypoglycemia and weight gain;
BOX 7-4 A
dverse Reactions to Glipizide Treatment severity of both, however, is less than with sulfonylureas (Bailey
inDiabetic Cats and Krentz, 2010). Recently, nateglinide (one of the two mem-
bers of this class) was evaluated in healthy cats. It induced a more
Adverse Reaction Recommendation rapid and more pronounced increase in insulin secretion than the
Vomiting within 1 hour Vomiting usually subsides after 2 to sulfonylurea glimepiride, resulting in an earlier decrease in blood
of administration 5 days of glipizide therapy; decrease dose glucose concentrations (Mori etal, 2009b). There are no reports
or frequency of administration if vomiting on their use in diabetic cats, and because cats have unique nutri-
is severe; discontinue if vomiting persists tional characteristics (see Dietary Management), they may not be
longer than 1 week. helpful for glycemic control.
Increased serum hepatic Continue treatment and monitor enzymes
Biguanides
enzyme activities every 1 to 2 weeks initially; discontinue
glipizide if cat becomes ill (lethargy, inappe- Metformin is the only drug of the biguanide class in most coun-
tence, vomiting) or the alanine aminotrans- tries. According to the guidelines for the treatment of humans with
ferase activity exceeds 500 IU/L. type 2 diabetes, metformin should be considered as first line medi-
Icterus Discontinue glipizide treatment; reinstitute cal therapy, provided that there are no contraindications (Inzucchi
glipizide therapy at lower dose and etal, 2012). Its mechanisms of action are complex and not fully
frequency of administration once icterus understood. Some of the actions are achieved through enhanced
has resolved (usually within 2 weeks); insulin sensitivity, whereas others are independent of insulin,
discontinue treatment permanently if including activation of adenosine monophosphate-activated pro-
icterus recurs. tein kinase (AMPK) (Bailey and Davies, 2011). The primary site
Hypoglycemia Discontinue glipizide treatment; recheck of action is the liver, where it reduces gluconeogenesis and glycoge-
blood glucose concentration in 1 week; nolysis. Metformin also enhances glucose uptake and glycogenesis
reinstitute glipizide therapy at lower dose in skeletal muscle and promotes glycogen synthesis. The glucose-
or frequency of administration if lowering effect requires the presence of at least some circulating
hyperglycemia recurs. insulin, and therefore metformin is ineffective in patients with
complete lack of insulin. Metformin does not stimulate insulin
|
release, and although it reduces hepatic glucose production, the (Hoenig and Ferguson, 2003). Recently, the pharmacokinetics of
risk of hypoglycemia is minimal. Weight gain is also not a relevant pioglitazone, another member of the TZD class, was evaluated in
adverse effect. The main adverse effects in humans are gastrointesti- healthy cats. It was suggested that 1 to 3 mg/kg of pioglitazone
nal symptoms (anorexia, nausea, vomiting, abdominal discomfort, would be an appropriate oral dose for further studies on its effi-
diarrhea), and they are usually dose-related and may be reduced in cacy (Clark etal, 2011).
most patients by dose-titration or switching to a slow-release for-
mula. There are various contraindications, such as impaired renal Alpha-Glucosidase Inhibitors
function, cardiac or respiratory insufficiency, liver disease, and oth- Drugs of this class are competitive inhibitors of -glucosidase
ers. Metformin may also reduce vitamin B12 absorption (Bailey enzymes in the brush border of enterocytes, lining the intestinal
and Krentz, 2010; Bailey and Davies, 2011). The most frightening villi. Thereby, they prevent the final step of carbohydrate diges-
and serious potential adverse effect is lactic acidosis. An increase tion (i.e., cleavage of disaccharides and oligosaccharides into
in blood lactate concentration is a consequence of the effect of monosaccharides). As a result, glucose absorption is delayed.
metformin to inhibit hepatic gluconeogenesis, for which lactate It is not inhibited per se but moved distally in the gastrointes-
is an important substrate. Lactic acidosis, however, is a rare event tinal tract. These drugs can only be effective in the presence of
and mostly associated with the use of metformin in patients with a substantial amount of complex carbohydrate and when given
comorbidities and risk factors (e.g., renal insufficiency) (Krentz and with a meal. The main adverse effects are gastrointestinal signs
Nattrass, 2003; Renda et al, 2013). So far only very few studies (e.g., abdominal discomfort, flatulence, and diarrhea), which
have been performed in cats. Doses suggested to be necessary to often limit their use in humans. In humans, they may be used
reach plasma concentrations known to be effective in human dia- as monotherapy in patients with postprandial hyperglycemia but
betics varied between 2 mg/kg b.i.d. and 50 mg/cat b.i.d. (Michels only slightly increased fasting hyperglycemia. More often, how-
etal, 1999; Nelson etal, 2004). Unfortunately, results achieved in ever, they are considered as additive therapy with other antidia-
a small number of diabetic cats are not encouraging, because only betic drugs (Bailey and Krentz, 2010; Bailey and Davies, 2011).
one of five cats with diabetes responded to treatment. Clinical signs In cats, -glucosidase inhibitors may be useful in cases in which
improved 3 weeks after the metformin dose had been increased a high-carbohydrate diet is fed. In diabetic cats, the -glucosidase
to 50 mg/cat b.i.d. (from 10 mg/cat s.i.d., 10 mg/cat b.i.d., 25 inhibitor acarbose (12.5 mg/cat b.i.d. with a meal) had no appar-
mg/cat b.i.d.). Three diabetic cats failed to respond and one dia- ent positive effect when given with a low-carbohydrate diet
betic cat died unexpectedly some days after initiating therapy. The (Mazzaferro etal, 2003). This observation is consistent with the
responder was the only diabetic cat that had detectable insulin con- results of a study comparing the effects of acarbose in healthy cats
centrations prior to treatment, supporting the concept that some fed low- and high-carbohydrate diets. Cats on a high-carbohy-
circulating insulin has to be present for metformin to be effective drate diet had significantly lower blood glucose concentrations
(Nelson etal, 2004). when acarbose was added, although the same glucose-lowering
effect was seen with the low-carbohydrate diet. The acarbose dose
Glitazones was 25 mg/cat s.i.d. for cats fed once daily, and 25 mg/cat b.i.d. if
Glitazones are also known as thiazolidinediones (TZDs). Most fed several meals (Singh etal, 2006; Rand, 2012; Palm and Feld-
of their antidiabetic effect is achieved through stimulation of a man, 2013). As in humans, gastrointestinal side effects may occur,
nuclear receptor, the peroxisome proliferator-activated receptor- the severity of which may be reduced by slow dose titration. In
(PPAR-). PPAR- is highly expressed in adipose tissue and to a diabetic cats fed low-carbohydrate diets, acarbose is of no or negli-
lesser extent in muscle and liver. Stimulation results in differentia- gible use. Acarbose has been suggested for diabetic cats in which a
tion of preadipocytes into small, insulin-sensitive adipocytes that low-carbohydratehigh-protein diet may not be appropriate (e.g.,
take up fatty acids and reduce their availability for gluconeogen- in cats with concurrent renal failure). It should be noted, how-
esis. TZDs also increase insulin-mediated glucose uptake (insu- ever, that acarbose is considered contraindicated in humans with
lin sensitizer) into skeletal muscle and adipose tissue, reduce the impaired renal function (Yale, 2005; Tschpe et al, 2013); the
production of several proinflammatory cytokines (e.g., TNF) issue has not yet been investigated in cats.
and increase the production of adiponectin in adipose tissue.
They may also be of benefit in early stages of the disease and may Incretin-Related Therapeutics
slow the progression of -cell destruction. TZDs, like metformin, Incretins are hormones that are released from the gastrointesti-
require the presence of some circulating insulin to be effective; it nal tract during food intake and that potentiate insulin secretion
may take 2 to 4 months until the full effect is seen. They do not from the -cells. GIP and GLP-1 are the two currently known
stimulate insulin secretion and do not cause hypoglycemia. They incretin hormones. GIP is ineffective in diabetic individuals,
are often taken in combination with other antidiabetic drugs (e.g., whereas GLP-1 retains its stimulatory effect provided that there
metformin) to achieve an additive effect, but they may also be is still an adequate mass of -cells present. It also has benefi-
used as monotherapy. Adverse effects include weight gain due to cial effects on glucagon, gastric emptying, and satiety. GLP-1 is
fluid retention and accumulation of subcutaneous fat; they may be mainly produced in the L-cells in the intestinal tract. In the cat,
associated with an increased risk of heart failure and bone fractures the highest density of L-cells was recently shown to be in the
(Bailey and Krentz, 2010; Bailey and Davies, 2011; Buse et al, ileum (Gilor et al, 2013). Native GLP-1 is quickly degraded
2011). So far, no studies describe the use of TZDs in cats with dia- by the enzyme DPP-4, which has led to the development of
betes. The potential for this drug for the treatment of diabetic cats GLP-1 agonists with resistance to degradation and to inhibi-
is currently unknown. Healthy cats had significantly lower choles- tors of DPP-4 activity (Mudaliar and Henry, 2012). Although
terol, triglyceride, and leptin concentrations after 6 weeks of dar- both classes improve glycemic control, various differences exist
glitazone treatment (2 mg/kg s.i.d., orally) compared with control between them. From a practical standpoint, a major difference is
cats. A significant decrease in the area under the curve for NEFAs, the route of application: GLP-1 agonists have to be injected sub-
glucose, and insulin during an IVGTT was demonstrated; the lat- cutaneously, whereas DPP-4 inhibitors are oral agents. For both
ter suggested an increase in insulin sensitivity induced by the drug GLP-1 agonists and DPP-4 inhibitors, the risk of hypoglycemia
20
TABLE 7-6 C
OMPARISON OF GLP-1 RECEPTOR
AGONISTS AND
DPP-4 INHIBITORS
15
GLUCAGON-LIKE DIPEPTIDYL
Insulin U/mL
PEPTIDE-1 RECEPTOR PEPTIDASE-4
AGONISTS INHIBITORS
10
Administration Subcutaneous injection Orally
Glucose-dependent Enhanced Enhanced
insulin secretion
5
Glucose-dependent Reduced Reduced
glucagon secretion
Postprandial Reduced Reduced
hyperglycemia 0
0 15 30 60 120 300
Risk of hypoglycemia Low Low
Minutes
Gastric emptying Decelerated No effect
Appetite Suppressed No effect Prior to drug After drug
Satiety Induced No effect FIGURE 7-16 Insulin secretion before and 5 weeks after once weekly subcutane-
Body weight Reduced Neutral ous injection of exenatide long-acting (Bydureon). Samples for insulin measure-
ment were taken before and 15, 30, 60, 120, and 300 minutes after feeding a
Main adverse effects Nausea, vomiting Headache, nasophar- test meal. Results are mean values of three healthy cats. Prior to drug, Insulin
yngitis, urinary secretion before the start of the study. After drug, Insulin secretion after weekly
tract infection administration of 200 g/kg exenatide long-acting for 5 weeks. (From Padrutt I,
From Reusch CE, Padrutt I: New incretin hormonal therapies in humans relevant to etal.: Comparison of the GLP-1 analogues exenatide short-acting, exenatide
diabetic cats, Vet Clin North Am Small Anim Pract 43:417, 2013 (with permission). long-acting and the DPP-4 inhibitor sitagliptin to increase insulin secretion in
healthy cats, J Vet Int Med 26:1520, abstract, 2012.)
is low (Reusch and Padrutt, 2013; Table 7-6). In humans with signaling; its precise mode of action, however, is unclear. Trivalent
type 2 diabetes, incretin based therapy is currently used as mono- (3+) chromium is found in a wide range of foods and is available
therapy, as well as in combination with other antidiabetic drugs. as an inexpensive nutritional supplement. Chromium chloride,
In the rat and mouse, it has been shown that GLP-1 analogues chromium nicotinate, and chromium picolinate are formula-
preserve -cell mass by inducing -cell proliferation. There is tions of trivalent chromium; the absorption of the latter seems
hope that the same may be true for humans, because this would to be the most consistent. There is controversy as to whether
then be of great benefit to slow progression of the diabetic disease chromium supplementation should be routinely recommended
(Rutti etal, 2012). The same would be of course true for the cat. in diabetic humans without documented deficiency. Some stud-
GLP-1 agonists and DPP-4 inhibitors have thus far been inves- ies have found evidence in favor, others against a beneficial effect
tigated only in healthy cats. The GLP-1 agonist exenatide was (Wang and Cefalu, 2010). In cats, the effect of chromium was
shown to potentiate insulin secretion in association with a glu- so far investigated only in healthy animals and results also differ.
cose load, similar to its effect in other species (Gilor etal, 2011). In one study, using 100 g chromium picolinate for 6 weeks,
In a dose escalation study, the application of 0.2, 0.5, 1.0, and no effect on glucose tolerance was found (Cohn etal, 1999); in
2.0 g/kg exenatide b.i.d. for 5 days resulted in pronounced insu- another study, a small, but significant improvement in glucose
lin increase (area under the curve after a meal-response test) of tolerance was seen after chromium picolinate was supplemented
320%, 364%, 547%, and 198%. Exenatide is also available as for 6 weeks at mean concentrations of 22.9 g and 44.9 g
long-acting or extended-release preparation, which allows less fre- (Appleton et al, 2002). Adverse effects were not identified in
quent application (once per week instead of twice daily). Once any of the studies. It is not known if diabetic cats with ade-
weekly injection of exenatide long-acting (200 g/kg) for 5 weeks, quate dietary intake would benefit from additional chromium
resulted in a very efficient increase of meal-induced insulin secre- supplementation.
tion (Fig. 7-16). The application of the DPP-4 inhibitor sita- Vanadium is another trace element, which does have insulin-
gliptin in a dose-escalation manner (1, 3, 5, and 10 mg/kg s.i.d. mimetic properties in liver, skeletal muscle, and adipose tissue;
for 5 days) resulted in a less pronounced increase of insulin (43%, most likely it plays an activating role in the insulin signaling cas-
101%, 70%, and 56%). Transient gastrointestinal side effects were cade. The effects are similar, regardless of the type of vanadium salts
seen with all three drugs; however, well-being and appetite were used. Several clinical trials in human diabetics have documented
unaffected (Padrutt etal, 2012; Reusch and Padrutt, 2013). Clini- improvement in glycemic control; there is, however, a high inci-
cal studies in diabetic cats are under way, although the currently dence of gastrointestinal adverse effects (Smith etal, 2008; Clark
high costs of the drugs may be prohibitive for the routine use in etal, 2014). There is very little experience with vanadium supple-
practice. mentation in diabetic cats. Cats treated with insulin (PZI) and
oral vanadium dipicolinate (45 mg orally, s.i.d.) had a slightly bet-
Other Therapies ter glycemic control than cats treated with insulin alone. Adverse
Chromium is an essential trace element, required for normal effects included anorexia and vomiting (Fondacaro etal, 1999).
glucose metabolism. It is assumed that it may modulate insulin Further studies are needed to define the role of chromium and
|
vanadium supplementation in diabetic cats. So far, no dose rec- Dietary Carbohydrate and Protein
ommendation can be made due to the lack of dose finding studies. Several of the commonly manufactured cat foods (in particular
See Herbs, Supplements, and Vitamins in Chapter 6 for a discus- dry foods) contain high amounts of carbohydrates (up to 50%
sion on further alternative therapies. of ME). It has been debated whether long-term feeding of those
Oral hypoglycemic agents and non-insulin injectables are an diets contributes to the development of diabetes in cats. The rea-
area of intensive research in human medicine, and many new son behind those debates is the fact that the natural diet of cats
drugs have recently been developed. Amongst them are amylin in the wild includes mice and birds and is low in carbohydrates
analogues (pramlintide), dopamine agonists (bromocriptine), and and that the feline carbohydrate metabolism has some specif-
sodium-glucose-transporter-2 inhibitors. None of them have been ics. For instance, cats have low amylase activity in saliva and the
studied in cats so far. Many more will come, and the big chal- small intestinal tract, and their liver lacks glucokinase, which is an
lenge will be to critically evaluate them in a sufficient number of enzyme responsible for phosphorylation of glucose for subsequent
diabetic cats. oxidation or storage. Glucokinase operates when the liver receives
large amounts of glucose from the portal vein. Other glycolytic
enzymes, such as hexokinase (a constitutive enzyme), however,
Dietary Management
were found to be present in even higher concentrations than in the
Diet is an important component of the treatment plan. The goal liver of dogs (Washizu etal, 1999; Tanaka etal, 2005). Cats have
of dietary therapy is to provide a nutritionally complete and pal- a rather limited capacity to metabolize simple sugars, and experi-
atable food that is readily consumed. Regular eating is of particu- mental diets containing up to 40% of glucose and sucrose resulted
lar importance in the diabetic cat, because lack of food intake in hyperglycemia and glucosuria (Kienzle, 1994). After eating a
may lead to hypoglycemia. In addition, the diet should provide glucose enriched meal, healthy cats reveal significant higher blood
day-to-day consistency with regard to composition, ingredients, glucose concentrations than dogs with a later glucose peak and a
and calories so that an optimal body condition can be achieved later return to baseline. More physiological dietary studies used
and maintained. The diet should also reduce postprandial hyper- different levels of starch instead of adding simple sugars. Using a
glycemia and minimized fluctuations in blood glucose. Choos- high-starch diet (43% ME), blood glucose was significantly higher
ing an appropriate diet will also increase the chance of diabetic compared to baseline after 11 hours and remained significantly
remission. elevated until the end of the trial (19 hours after the meal) in cats;
in dogs, blood glucose increased only minimally. After feeding a
Obesity low or moderate starch diet (12% and 30% ME), glucose concen-
Obesity is an important risk factor for the development of diabe- trations did not increase in both species (Hewson-Hughes etal,
tes and the prevalence of both obesity and diabetes is increasing. 2011a; 2011b). Another study confirmed the finding that cats
Obesity is the result of excessive caloric intake, decreased energy may have a long postprandial increase in blood glucose concentra-
expenditure, or both. Neutering and physical inactivity (indoor tion. Hyperglycemia, albeit mild, was already seen after feeding
confinement) lead to a reduction in energy expenditure. Unfortu- a diet with moderate carbohydrate content (25% of ME). Mean
nately, those events are often combined with feeding highly pal- baseline glucose concentration was 90 mg/dL (5 mmol/L) and
atable, energy-dense diets in high amounts. Other factors, such increased to a mean of 130 mg/dL (7.2 mmol/L) after feeding.
as genetic background, epigenetic modulation of gene expression, The median time until blood glucose reached its peak was 6 hours
and the nature of the environment may also contribute (Zoran after feeding, and the median time until glucose returned to base-
and Buffington, 2011). line was 12.2 hours. Insulin concentrations returned to baseline
There is some debate on which macronutrients (fat or car- after a median of 12.3 hours (Farrow etal, 2012). Interestingly,
bohydrates) play the most important role in the development the use of a moderate starch diet lead to a postprandial glucose
of obesity. Recent studies showed that diets high in fat result increase in one of the studies, whereas no increase was seen in the
in weight gain and increase in body fat when fed ad libitum other study (Hewson-Hughes etal, 2011b; Farrow etal, 2012).
(Nguyen 2004; Backus et al, 2007). Body fat increased with It is possible that the differences are due to the use of different
increasing dietary fat and an obesity-promoting effect was seen carbohydrate sources in the diets.
when dietary fat exceeded 25% of metabolizable energy (ME). De-Oliveira, etal., (2008) fed diets containing 35% of starch
Because dietary fat was exchanged for carbohydrates, those diets from six different carbohydrate sources. Digestibility of the vari-
low in fat were high in carbohydrates (and vice versa), provid- ous carbohydrates varied slightly, but was generally very high. The
ing evidence that diets high in fat pose a greater risk for obesity time until the peak blood glucose was reached was quite different
than diets high in carbohydrates (Backus etal, 2007; Laflamme, between the diets and ranged between 2.5 and 7.2 hours. Interest-
2010). However, consumption of carbohydrates in excess of ingly, the overall maximum blood glucose concentration was only
energy needs will also contribute to obesity, meaning that any 93.3 mg/dL (5.2 mmol/L) (i.e., none of the cats had blood glu-
excess of calories poses a risk for obesity (Laflamme, 2010). Cats cose concentrations above the normal range). The highest blood
are strict carnivores and need larger amounts of dietary protein glucose was seen when corn was used as carbohydrate source, fol-
than dogs and humans. Although it is the restriction of calories lowed by brewers rice, and the lowest was with lentil and cassava
that ultimately leads to weight loss, it is important to minimize flour. From the studies mentioned, one may conclude the follow-
loss of lean body mass. Therefore, a weight-loss diet should be ing: healthy cats seem to be able to digest carbohydrate if prop-
calorie-restricted but provide an adequate amount of protein. erly processed; blood glucose and insulin concentrations increase
The minimum daily protein requirement for an adult cat was after dietary carbohydrate intake, the extent of which probably
recently reported to be at least 5.2 g/kg body weight per day. correlates with the carbohydrate concentration and carbohydrate
Dietary fiber is a helpful component of weight loss diets. It pro- source; the increase of blood glucose, if present, is usually mild,
vides little dietary energy and thereby reduces the caloric den- and it is unclear if this slight increase has any negative impact.
sity of the diet, and it also has a satiety effect (Laflamme, 2012; Currently, there are no studies showing that consumption of high
Laflamme and Hannah, 2013). dietary carbohydrates causes diabetes mellitus in cats. It is more
likely that excess intake of those diets leads to obesity, which in It has been shown that healthy cats may tolerate high amounts
turn is a risk factor. Other factors associated with the change in the of fat (up to 66% ME) well without negative impact on plasma
lifestyle of cats also play a role. Slingerland, etal., (2009) showed lipid concentrations (Butterwick et al, 2012). In diabetic cats,
that indoor confinement and physical inactivity was significantly however, it seems reasonable to avoid high fat diets (e.g., growth
correlated with the development of diabetes, whereas the percent- diets), because they may be associated with further weight gain
age of dry food (high in carbohydrates) was not. and possibly with increased risk of pancreatitis. Canned food has
The topic of diet is less controversial in cats with overt some advantages over dry food, such as a lower calorie density (the
diabetes and there is current agreement that a high-proteinlow- cat can eat more for the same caloric intake), and usually a lower
carbohydrate diet should be fed (Laflamme, 2010; Rucinsky etal, carbohydrate content and provision of additional water, which
2010; Zoran and Rand, 2013). High-fiber diets are no longer rec- increases hydration as well as satiety (Rucinsky etal, 2010; Zoran
ommended as diets of first choice in diabetic cats, because they and Rand, 2013). Many diets (in particular canned diets) fulfill
usually do not have a low carbohydrate content. They may, how- the aforementioned criteria. Most premium pet food companies
ever, be used if cats do not tolerate high-proteinlow-carbohy- offer diets specifically designed for diabetic cats (Table 7-7). We
drate diets or if weight loss is insufficient. It should be noted that routinely prescribe canned food with high protein and very low
the current dietary recommendation is based on a relatively small carbohydrate content to the owners of diabetic cats. If palatability
number of clinical studies (Frank et al, 2001; Mazzaferro et al, is a problem with our first choice diet, we switch to another diet
2003; Bennett etal, 2006). The most comprehensive study com- with comparable characteristics. In cats in which diabetic remis-
pared a moderate carbohydrate/high-fiber diet (26% carbohydrate sion is achieved after some time and insulin therapy is discon-
[CHO] ME) and a low carbohydrate/low fiber diet (12% CHO tinued, we recommend that the high-proteinlow-carbohydrate
ME) randomly assigned to cats with diabetes. After 4 months, diet is fed life-long. Similarly, in cats with prediabetes, weight
significantly more cats fed the low carbohydrate diet were in dia- reduction and feeding a high-proteinlow-carbohydrate diet is
betic remission compared with cats fed the moderate carbohydrate recommended.
diet (68% versus 41%); of the cats still requiring insulin, more
cats on the low carbohydrate diet were well regulated (40% ver- Calculation of Energy Requirement and Feeding Schedule
sus 26%) (Bennett etal, 2006). The positive effect on glycemic Energy requirement differs between individuals, and therefore,
control occurs before there is apparent loss of body weight. The guidelines should only be used as a rough estimate. The mainte-
exact mechanisms involved remain to be investigated (e.g., if low nance energy requirement of typical sized (4 to 5 kg), neutered
carbohydrate or high protein is the key factor and what roles the indoor cats is 45 to 55 kcal/kg body weight per day. For neutered
different sources of proteins and carbohydrates play). male cats, the lower number should be used (Zoran and Buffington,
Current recommendations state that the protein content in a 2011). In obese cats, the calculation of energy requirement
diet for diabetic cats should be more than 40% to 45% ME and should be based on ideal body weight. It is, however, possible
the carbohydrate content should be less than 12% to 15% ME, or that this amount is still too high and energy intake must be
as low as the cat will eat (Rucinsky etal, 2010; Zoran and Rand, reduced much further. A reduction of calories in steps of 10%
2013). No clear statements are made with regard to fat content. to 15% every few weeks may be necessary. To avoid loss of lean
TABLE 7-7 A
PPROXIMATE NUTRIENT CONTENT OF SOME COMMERCIALLY-AVAILABLE DIETS USED FOR
DIETARY MANAGEMENT OF DIABETES AND/OR WEIGHT LOSS IN CATS*
PROTEIN FAT CH FIBER PROTEIN

(% ME) (% ME) (% ME) (g/100 kcal ME) (g/100 kcal ME)
Purina DM (canned) 46.0 47.3 7.7 0.9 13.1
Purina DM (dry) 46.2 38.1 17.9 0.4 13.2
Hills Prescription Diet m/d (canned) 45.7 40.7 15.6 1.5 13.1
Hills Prescription Diet m/d (dry) 42.5 40.9 19.0 0.9 12.1
Royal Canin Diabetic DS (wet) 47.2 38.2 16.8 2.2 13.5
Royal Canin Diabetic DS 46 (dry) 45.2 28.6 30.0 1.0 12.9
Hills Prescription Diet w/d (canned) 39.2 37.9 26.1 2.9 11.2
Hills Prescription Diet w/d (dry) 39.2 37.9 26.1 2.3 11.2
Hills Prescription Diet r/d (canned) 41.0 24.3 39.6 4.8 11.7
Hills Prescription Diet r/d (dry) 40.7 27.9 35.9 4.1 11.6
Purina OM (canned) 51.1 36.8 13.9 1.9 14.6
Purina OM (dry) 53.7 21.7 28.1 2.4 15.3
Royal Canin Obesity Management (wet) 48.5 31.4 22.9 2.8 13.9
Royal Canin Obesity Management (dry) 45.4 26.2 32.5 2.1 13.0
Courtesy of Prof. Annette Liesegang, Institute of Animal Nutrition, Vetsuisse Faculty, Zurich, Switzerland.
*Metabolizable energy (ME) content was determined using the modified Atwater factors on the basis of data provided by the pet food companies. Results are calculated estimates
and the total energy in percent may therefore slightly deviate from 100%.
|
muscle mass, the diet has to meet the minimum daily protein Exercise
requirement. It is important to set realistic goals and avoid frus-
tration of the owner. Weight should decrease slowly; a loss of In humans, the positive effect of physical activity on glycemic
1% per week is considered optimal. Severely overweight cats control is well known. Exercise is associated with improved insu-
may never reach optimal body weight; however, a moderate lin sensitivity through various mechanisms (e.g., increased post-
weight loss may improve glycemic control. A small percentage of receptor insulin-signaling, increased GLUT protein, increased
diabetic cats are underweight. If insulin therapy does not lead to delivery of glucose to muscle, and decrease in body fat; Yardley
the desired weight gain, calories should be increased in steps of et al, 2010). According to the current recommendations of the
10% to 15%. Diabetic cats should be weighted once per week, American Diabetes Association, adult humans should perform at
providing that their owners have a precise scale. At each vet- least 150 min/week of moderate intensity aerobic physical activity
erinary visit, the notes of the owners should be reviewed, body with no more than 2 consecutive days without exercise (American
weight as well as body and muscle scoring should be evaluated, Diabetes Association, 2013). In dogs, comparable physical activ-
and amounts of calories should be amended if needed. It should ity can be achieved by daily walks of similar intensity; this kind of
be remembered that cats with untreated diabetes lose weight, therapeutic intervention is limited in the cat. However, so-called
which is stopped with adequate insulin therapy. Many cats gain environmental enrichment may increase the level of activity and
some weight with the start of insulin therapy (when calories are may also have positive psychological effects on the diabetic cat.
not restricted) as the body aims for its original weight. Persistent Enrichment strategies include structured play, use of toys (e.g.,
weight gain, however, should alert the clinician to consider high wire toys mimicking air-borne prey), food balls, cat trees, play
caloric intake, insulin overdose, or acromegaly as possible causes. tunnels, and others (Ellis, 2009; Hoyumpa Vogt etal, 2010).
Persistent weight loss may be caused by low caloric intake, inad-
equate insulin therapy, or any concurrent disease (e.g., pancre- Concurrent Problems
atitis, pancreatic insufficiency, hyperthyroidism, inflammatory
bowel disease, or lymphoma). The best feeding pattern for dia- Any concurrent disease (inflammatory, infectious, metabolic, or neo-
betic cats is unknown at the moment. We currently recommend plastic) can cause insulin resistance and can have a negative impact
to offer half of the cats daily calorie intake at the time of each on the management of diabetes. Insulin resistance may range from
insulin injection; any leftovers should remain available to the cat mild to severe or may fluctuate over time. A thorough evaluation of
until the next meal (Box 7-5). newly-diagnosed diabetic cats is of great importance, and any con-
current problem should be addressed appropriately. Similarly, glu-
Modifications in Dietary Therapy cocorticoids and progestagens have a negative influence on insulin
In cats with concurrent disease (e.g., pancreatitis, food allergy, or sensitivity, and their administration should be stopped immediately.
chronic renal failure) diets designed for diabetes management may If a concurrent disease requires immunomodulatory medication,
not be appropriate. Dietary therapy for the most serious disease alternative drugs should be used if possible (e.g., Ciclosporin). If
should take priority. Please see Modifications in Dietary Therapy glucocorticoids are absolutely required, the dose should be kept as
in Chapter 6. low as possible and administration as infrequent as possible. Insulin
dose will be higher in those cases and need to be adjusted whenever
the glucocorticoid dose is changed. Successful treatment of concur-
BOX 7-5 R
ecommendations for Dietary Treatment of Cats rent problems (e.g., oral care, eradication of urinary tract infection)
with Diabetes Mellitus and/or cessation of diabetogenic drugs oftentimes result in improved
glycemic control and improve the chance of diabetic remission.
Dietary Composition Some diseases, such as chronic renal failure and chronic pancreatitis,
First choice: High-protein and low-carbohydrate diet (protein > 40 to cannot be cured and require long-term management. Treatment of
45 ME, carbohydrate < 12% to 15% ME) diabetes in those situations is often very difficult because there may
Second choice: High-fiber and moderate carbohydrate diet be substantial fluctuations in insulin sensitivity. Owners should be
made aware that treatment may be very challenging and more fre-
Type of Food
quent monitoring and dose amendments than in the usual diabetic
First choice: Canned food
cat may be required. The presence of hyperadrenocorticism and
Second choice: Mixture of canned and dry food
acromegaly is oftentimes not suspected until large doses of insulin
Calculation of Quantity are required (see Concurrent Disorders Causing Insulin Resistance
Energy requirement for an average sized indoor neutered cat is 45 to and Drug-Induced Diabetes in this chapter and Concurrent Disor-
55 kcal/kg body weight per day (use lower number for neutered male cats) ders Causing Insulin Resistance in Chapter 6.
If cat is overweight, aim for loss of 1% of body weight per week
Adjust daily caloric intake on individual basis
TECHNIQUES FOR MONITORING DIABETIC
Reduce in steps of 10% to 15% if cat is overweight and no weight
CONTROL
loss is achieved
Increase in steps of 10% to 15% if cat is underweight and no The primary goals of therapy are to eliminate the clinical signs
weight gain is achieved during insulin therapy of diabetes while preventing short-term complications (hypogly-
Avoid loss of lean body mass by providing adequate amount of protein cemia, DKA). Concurrent problems also need to be controlled,
(5.2 g/kg body weight per day) because they may render glycemic control difficult. See Reevalu-
Feeding Schedule
ation and Adjustment of Insulin Dose and Box 7-3 for further
Half of daily caloric intake at time of each insulin injection; any
details on treatment goals, blood glucose targets, and times of
leftover should remain available for the rest of the day or the night
reevaluations. The monitoring techniques are similar for dogs and
cats. Different from dogs, however, cats may develop stress hyper-
ME, Metabolizable energy. glycemia when brought to an unfamiliar environment and/or
manipulated by a veterinarian. Stress hyperglycemia may render Fructosamine is also influenced by plasma protein concentra-
the interpretation of blood glucose concentrations and BGCs gen- tion and by protein turnover. It has been shown that cats suffering
erated in the hospital difficult. Measurement of blood glucose at from hypoproteinemia or hyperthyroidism have significantly lower
home is less stressful or even stress-free when done by experienced levels of fructosamine than healthy cats (Reusch and Tomsa, 1999;
owners, and results of home monitoring are usually more reliable Graham etal, 1999; Reusch and Haberer 2001). It is possible that
than results generated in the hospital. diabetic cats with concurrent hypoproteinemia or uncontrolled
hyperthyroidism may have normal (or even low) fructosamine
History and Physical Examination levels, which would then be misinterpreted as indicative for stress
hyperglycemia. In those situations (e.g., cats with concurrent
The most important parameters to assess glycemic control are the hyperthyroidism or hypoproteinemia), fructosamine should be
clinical signs observed by the owner: the stability of the body weight interpreted only if it is increased, which then indicates diabetes
and the findings during physical examination. Cats, in which the mellitus. There are arguments for and against correction of fruc-
initial clinical signs (e.g., polyuria, polydipsia, polyphagia, lethargy, tosamine for the serum protein level. Correction, however, may
and/or poor hair coat) have resolved, the body weight stays within lead to falsely high concentrations and is not recommended. In
the desired range, and physical examination reveals a good clinical the majority of situations, fructosamine is a helpful parameter to
condition are usually well controlled. In those cases, measurement differentiate between stress- and diabetes-related hyperglycemia.
of serum fructosamine concentration and generation of BGCs will After initiating insulin therapy, blood glucose concentrations
help to confirm the status of good glycemic control and are use- usually start to decrease, which is followed by a decrease in fructos-
ful for the fine-tuning of insulin therapy. The measurements also amine after a few days. We consider 50 mol/L to be the so-called
help to determine if diabetic remission has occurred. Persistence or critical difference (i.e., the difference between two consecutive
reoccurrence of clinical signs and unwanted weight loss is suggestive fructosamine measurements has to exceed 50 mol/L to reflect a
of inadequate glycemic control or the presence of another disease. change in glycemic control; Reusch, 2013). Another study found
Serum fructosamine and in particular generation of BGCs help a lower critical difference of 33 mol/L (Link and Rand, 2008).
to characterize the exact problem and to guide the amendment of Generally, fructosamine concentrations increase when glycemic
therapy. Additional tests may be needed in cases in which history or control worsens and decrease when glycemic control improves.
physical examination suggests the presence of a concurrent disease. As mentioned earlier, serum fructosamine concentration is not
affected by a short term increase in blood glucose concentration,
Serum Fructosamine Concentration which may be seen in cats in the hospital. It is also not affected
by lack of food intake, which is common in hospitalized cats and
Fructosamine is the product of an irreversible reaction between glu- often leads to much lower blood glucose concentrations than what
cose and the amino groups of plasma proteins. Its concentration is seen with food intake. Routine measurement of fructosamine is
mainly depends on the blood glucose concentration (e.g., extent and therefore helpful to clarify the effects of stress or lack of food intake
duration of hyperglycemia) and the lifespan of plasma proteins; it is (e.g., to clarify discrepancies between history and physical exami-
generally assumed that fructosamine reflects the mean blood glucose nation and blood glucose measurements). Most well-controlled
concentration of the preceding 1 to 2 weeks. The reference ranges diabetic cats are slightly hyperglycemic for some time during a
differ slightly between laboratories but are usually between approxi- 24-hour period, and consequently, fructosamine concentrations
mately 200 and 360 mol/L. To enable comparison between consec- will not become completely normal during therapy. In cats that
utive measurements, serum samples should always be sent to the same achieve diabetic remission, however, fructosamine concentrations
laboratory. Fructosamine is measured in serum using commercially- decrease into the normal range (Fig. 7-17).
available test kits adapted to autoanalysis. Shipping should be on cold
packs if samples will be in transit for more than 24 hours. Lean cats
have lower fructosamine concentrations than normal weight or obese
800
cats, whereas age has no influence. In two older studies, fructosamine
did not differ between male and female cats, whereas in the most
recent study, fructosamine was higher in male cats (Thoresen and
Bredal, 1995; Reusch and Haberer, 2001; Gilor etal, 2010b). In the 600
Fructosamine mol/L
vast majority of newly diagnosed diabetic cats, fructosamine levels

are more than 400 mol/L and may be as high as 1500 mol/L.
Fructosamine is not affected by short-term increases in blood glucose
concentration and thus is usually normal in cats with stress hypergly- 400
cemia (Reusch etal, 1993; Lutz etal, 1995; Crenshaw etal, 1996).
However, fructosamine is not a foolproof parameter, and certain
aspects need to be considered. In cats with a very recent onset of 200
diabetes or with mild diabetes, serum fructosamine may be in the
normal range, rendering the differentiation between stress and dia-
betic hyperglycemia impossible. In a recent study, two groups of
healthy cats were infused with glucose to maintain either a marked
0 1 2-3 6-8 12-16 24
or a moderate hyperglycemia (540 mg/dL, 30 mmol/L; or 300 mg/
dL, 17 mmol/L) for 42 days. In the group with marked hypergly- Time (weeks)
cemia, it took 3 to 5 days until fructosamine exceeded the upper FIGURE 7-17Serum fructosamine concentrations in six cats with diabetes
limit of the reference range; in the group with moderate hypergly- mellitus experiencing diabetic remission. Remission occurred during the first
cemia, fructosamine concentrations mostly fluctuated just below 12 weeks of therapy, and diabetes of all cats was still in remission after
the upper limit of the reference range (Link and Rand, 2008). 24 weeks. 0, Initial presentation; gray area, reference range (200 to 340 mol/L).
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As long as fructosamine is elevated (even if only slightly), we Feline hemoglobin differs considerably from human and
do not consider cats to be in diabetic remission. In those cases, canine hemoglobin, which limits the use of some of the human
insulin therapy is continued under close supervision. Fructos- assays. Successful measurement of glycated hemoglobin has been
amine concentrations between approximately 350 and 450 achieved by HPLC and affinity chromatography (Hasegawa etal,
mol/L reflect good glycemic control, concentrations between 1992; Hoyer-Ott etal, 1995; Elliott etal, 1997; 1999; Haberer
450 and 550 mol/L suggest moderate, and concentrations above and Reusch, 1998; Hoenig and Ferguson, 1999). Glycated hemo-
550 to 600 mol/L suggest poor glycemic control. In the latter globin was shown to be significantly higher in diabetic cats com-
situation, fructosamine is not helpful to identify the underlying pared to healthy cats and to cats with stress hyperglycemia. It was
problem because the various possible reasons for poor regulation also higher in poorly-controlled than in well-controlled diabetic
(e.g., application error, insulin underdose, too short duration cats. Its concentration decreased significantly after initiating insu-
of insulin effect, diseases causing insulin resistance, or Somo- lin therapy or after improvement of glycemic control respectively.
gyi phenomenon) are associated with high blood glucose con- Glycated hemoglobin is measured in ethylenediaminetetraacetic
centrations and therefore have the same impact. Generation of acid (EDTA) whole blood; the molecule is stable at 4o C for at
one or several BGCs and revision of the owners injection tech- least 1 week. As stability at room temperature differs between
nique are usually the next steps in those cases. Fructosamine assays, the instructions of the laboratory should be followed for
concentrations less than 350 mol/L suggest diabetic remission, shipping. We no longer use glycated hemoglobin mainly because
hypoglycemia or concurrent hypoproteinemia, or hyperthyroid- of the limited availability of assays validated for the cat and the
ism (Reusch, 2010). It is important to note that there are sub- lack of advantage over fructosamine, which is very easy to mea-
stantial differences in glycation between individuals. In healthy sure. Additionally, glycated hemoglobin in cats is substantially
cats in which blood glucose was maintained at 540 mg/dL lower than in dogs and humans, and the increase in case of dia-
(30 mmol/L), fructosamine concentrations ranged between 400 betes is less pronounced. Consequently, the difference between
and 633 mol/L when the plateau was reached (Link and Rand, well-, moderately-, and poorly-controlled cats is quite small, and
2008). The study underscores that diabetic cats with similar qual- the interpretation of results therefore is more difficult.
ity of glycemic regulation may have quite different fructosamine
concentrations. The ranges of interpretation listed earlier therefore Urine Glucose Monitoring
should only be used as rough guidelines. Fructosamine is useful if
followed in individual cats over time; however, it should never be Glucose is freely filtered by the glomerulus and reabsorbed in the
used as the sole indicator of the quality of metabolic control. The proximal tubules by the sodium-glucose cotransporter 2 (SGLT2).
parameter is less important than the evaluation of clinical signs The reabsorption capacity is limited, and when the blood glucose
and body weight and generation of BGCs. concentration exceeds the so-called renal threshold (approximately
DKA, dehydration, acidosis, and other unidentified factors may 17 mmol/L, 300 mg/dL in cats), glucose is excreted in the urine.
influence fructosamine concentrations. If a diabetic cat is hospi- The higher the blood glucose concentration is, the more glucose is
talized for any reason, fructosamine levels measured at the time found in the urine, which would render the urine test a valuable
of admission may be considerably different from concentrations monitoring tool in theory. However, measurement of urine glu-
measured a few days later. It is therefore reasonable to repeat the cose may be misleading for several reasons: (1) the result does not
measurement at the time of discharge and to use this concentra- reflect the actual blood glucose concentration, but is an average
tion as a reference point. See Serum Fructosamine Concentration over the time of urine accumulation in the bladder; (2) a negative
in Chapter 6 for additional information. urine test does not differentiate between hypoglycemia, normogly-
cemia, or mild hyperglycemia; and (3) hydration status and urine
concentration may affect the result. It should also be noted that
Glycated Hemoglobin Concentration
the renal threshold mentioned earlier is only an approximate num-
Glycated hemoglobin is formed by non-enzymatic, irrevers- ber. It is known from humans that there are substantial differences
ible binding of glucose to amino groups of the globin part of between individuals and the threshold may also change within
the hemoglobin molecule. Its concentration reflects the average the same individual. Therefore, marked hyperglycemia may exist
blood concentration over the lifespan of the erythrocytes, which without glycosuria, or glycosuria may occur with a normal blood
is approximately 70 days in the cat. In human diabetics, glycated glucose concentration (Pickup, 2003; Rave, 2006). Very few stud-
hemoglobin is one of the cornerstones of glycemic control, and ies have investigated the analytical aspects of urine glucose testing
its measurement in regular intervals is strongly recommended in cats. Recently, a commonly used test strip (Bayer Multistix) was
(American Diabetes Association, 2013). The matter is somewhat compared with a litter additive designed for monitor urine glucose
confusing because many different measuring methods are available at home (Purina Glucotest). The Multistix inaccurately classified
that measure different species of the molecule. Currently, consid- the degree of glycosuria in 24.2 of samples (19% overestimation,
erable effort is made in human medicine for an international stan- 5.2% underestimation). The Glucotest was read immediately after
dardization of glycated hemoglobin measurement (John, 2012). exposure to urine and at different time points thereafter over the
In humans, HBA1c is the component present in largest amounts course of 8 hours. At the initial reading, the test was inaccurate in
and results from binding of glucose to the N-terminal amino acid 22 % of samples (21% overestimation, 1% underestimation); the
valine of the -chain of hemoglobin. HBA1 is a series of glycated inaccuracy decreased to 10% and 3% when the test was read at
variants resulting from the binding of different carbohydrates to 30 minutes and 8 hours, respectively (Fletcher etal, 2011).
valine and includes HBA1a and HBA1b, as well as HBA1c. Total In summary, numerous biological and analytical factors render
glycated hemoglobin denotes the binding of all carbohydrates urine glucose testing unreliable. In our hospital, we do not adjust
at any site of the hemoglobin molecule. High-performance liq- insulin dosages based on urine glucose measurements, and we
uid chromatography (HPLC) mainly measures HBA1c as do the strongly discourage owners from doing so. Owners who are unable
newer immunoassays, whereas affinity chromatography methods to measure blood glucose but still want to do some type of monitor-
measure total glycated hemoglobin (Pickup, 2003). ing may be advised to use urine glucose measurements in all urine
300
400

300
200 1
2
3 200
100
4 100
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
A Hours after insulin administration B Hours after insulin administration
FIGURE 7-18 A, Variable glucose nadirs during blood glucose curves (BGCs) in four diabetic cats treated with
insulin glargine (Lantus) between 1 to 2.5 U/cat b.i.d. In cat 1 and 2, the nadirs are 2 and 4 hours, respectively,
after insulin administration. Cat 3 does not display an obvious nadir, and in cat 4, the nadir has not been reached
during the time of blood glucose measurements (e.g., the nadir is 10 hours after insulin administration). Insulin
glargine has been designed as a peakless insulin for humans. However, in a substantial percentage of cats, a clear
peak of action (associated with a clear nadir) is seen during BGCs. Some cats, in particular well-regulated cats, do
not show a nadir, and the BGC resembles a flat line as in cat 3. B, Two BGCs generated 4 weeks apart from each
other in the same cat at home showing different times of glucose nadirs (after 2 and 6 hours respectively). The cat
was treated with 1.5 U/cat insulin glargine (Lantus) at both points in time. 0, Time of insulin administration. To
convert mg/dL into mmol/L, multiply blood glucose concentration by 0.056.
samples voided throughout 1 day per week. Replacement of litter BGC) is the most important monitoring tool for diabetic cats.
by nonabsorbable material (e.g., aquarium gravel) facilitates urine BGCs are particular important during the initial phases of ther-
collection. Persistent glycosuria would suggest inadequate glycemic apy. During the first weeks to months, insulin doses usually need
control and the need for thorough evaluation in the hospital. If no to be adjusted several times; it is also most often during the first
glucose is detected in any of the samples, the cat is either very well 3 months of therapy that diabetic remission occurs. During long-
controlled, is in diabetic remission, or is overdosed with insulin term management regular, albeit less frequent generation of BGCs
and should be evaluated by a veterinarian. In cats prone to develop is helpful to ensure that the animal is still well-regulated. If clinical
DKA, we recommend that the owners check the urine for ketone signs of diabetes reappear at any time during long-term manage-
bodies on a regular basis (e.g., once to twice per week). ment, generation of BGCs helps to identify the underlying prob-
lem and allows informed dose amendments.
Single Blood Glucose Determination
Generation of Blood Glucose Curves in the Hospital
Measurement of a single blood glucose concentration is usually
insufficient to assess glycemic control. The exception may be cats We prefer that owners give insulin and food at home, and then
with long-standing diabetes in which clinical signs of diabetes bring the cat to the hospital as soon as possible (within 2 hours) for
mellitus have disappeared, physical examination is unremarkable, a BGC. This approach eliminates the effect of lack of food intake
and serum fructosamine concentration ranges between 350 and on blood glucose levelsat least in those cats that are fed only
450 mol/L. In these cases, the finding of a blood glucose concen- at the time of insulin administration. When technical difficulties
tration between 180 and 270 mg/dL (10 to 15 mmol/L) around are suspected, owners are asked to bring the cat to the hospital
the time of insulin injection is usually consistent with good glyce- before insulin application and to carry out the entire administra-
mic control and may render further glucose measurements unnec- tion procedure under supervision of a veterinarian or a technician.
essary. In cats with more recent onset of diabetes, achievement We generate BGCs by measuring the glucose concentration on
of diabetic remission is potentially possible and generation of a average every 2 hours throughout the day until the next insulin
BGC should be pursued. It is the glucose nadir measured dur- administration is due. Shorter intervals (i.e., 1 hour) are chosen
ing a BGC that mainly determines if there is room for further in cats with suspected hypoglycemia, and longer intervals (i.e.,
(slight) increase in insulin dose. Of note, the time of the glucose 3 hours) are sufficient in patients with stable disease. If the glu-
nadir varies between cats and also within the same cat (Fig. 7-18). cose nadir is not reached during this time, insulin administration
Therefore, determination of a single glucose concentration at the should be delayed and glucose measurements continued. The cat
time of the assumed nadir may be misleading. should be handled as carefully as possible and any unnecessary
A single low blood glucose concentration most often is due to manipulation should be avoided to reduce stress. Blood samples
insulin overdose, but may also be seen if there is lack of food intake. are not obtained by venipuncture but by collecting capillary blood
from the ear or the footpad using the same PBGM meter as the
Blood Glucose Curve owner at home. Usually, the cat can stay in the cage, and when
performed by an experienced technician, the procedure is usually
In addition to evaluation of clinical signs, serial measurement of well tolerated. With these precautions, we often achieve meaning-
blood glucose throughout the day (known as blood glucose curve, ful measurements (i.e., blood glucose concentrations that match
|
200 500

400
150
300
100
200
50
100
0 0
0 2 4 6 8 10 0 2 4 6 8 10
A Hours after insulin administration B Hours after insulin administration
FIGURE 7-19 A, Example of a good correlation between blood glucose curves (BGCs) generated in the hospital and
at home by the owner. The two curves were generated 3 days apart from each other. The cat (Domestic Short-Hair
[DSH], castrated male, 7 kg, 15 years old) received 1 U/cat insulin glargine (Lantus) b.i.d. at both points in time.
Clinical signs were well controlled and serum fructosamine concentration was 346 mol (reference range 200 to
340 mol/L). Open squares, BGC generated at home; closed squares, BGC generated in the hospital. B, Example of
a poor correlation between BGCs generated in the hospital and at home by the owner. The owner generated BGCs at
home for 2 consecutive days; another BGC was generated in the hospital 1 week thereafter. The cat (DSH, castrated
male, 4.4 kg, 11 years old) received 0.5 U/cat Lente-type insulin (Vetsulin/Caninsulin) b.i.d. at all three points in
time. Clinical signs of diabetes were well controlled, and serum fructosamine concentration was 358 mol/L (refer-
ence range 200 to 340 mol/L). The two home-BGCs show good agreement with each other and support the clinical
assessment of good glycemic control. The blood glucose concentrations in the hospital are substantially higher
and were attributed to stress. Insulin dose was not changed and the cat continued to do well. Open squares, BGCs
generated at home; closed squares, BGC generated in the hospital. 0, Time of insulin administration. To convert
mg/dL into mmol/L, multiply blood glucose concentration by 0.056.
very well with our clinical impression and the serum fructosamine
Home Monitoring of Blood Glucose
concentration; Fig. 7-19).
Generally, however, BGCs generated in the hospital are prone Treatment success depends largely on the active participation of
to be affected by stress, abnormal housing conditions (small cage the owner and on how well he or she is trained for this task by the
compared to free-roaming in the house), and decreased food veterinarian or the technician. The owner should assess the cat for
intake. Cats are particularly sensitive to stress caused by an unfa- clinical signs of diabetes on a daily basis, and body weight should
miliar environment and manipulation by the veterinarian or be measured at least once per week. Home monitoring of blood
technician. Consequently, blood glucose concentrations may rise glucose by the owner was developed approximately 15 years ago
during the BGC and never decrease again while the cat is in the and since then has been a routine part of our diabetic treatment
hospital, or glucose levels may be high from the beginning. Blood and monitoring protocol (Wess and Reusch, 2000). Home moni-
glucose concentrations in stressed cats in excess of 300 mg/dL toring enables frequent blood glucose measurements, and conse-
(17 mmol/L) are common and may even be higher than 400 quently the insulin dose can be amended more often and more
mg/dL (22 mmol/L). Stress hyperglycemia should be suspected precisely. The technique is of particular value in cats because stress
if the cat is obviously upset or aggressive, although it may also hyperglycemia and the potential of diabetic remission renders dia-
occur in cats appearing calm. The most reliable indicator of stress betic monitoring even more challenging than in dogs.
hyperglycemia is a discrepancy between the clinical impression, All of our cat owners are introduced to the option of home
body weight, and fructosamine concentration on the one hand monitoring of blood glucose, and many of them are willing and
and results of the BGC on the other. Lack of food intake has the able to generate BGCs on a long-term basis (e.g., for several years).
opposite effect because it may result in low blood glucose concen- Once owners are familiar with the technique, they highly appreci-
trations, a situation which is difficult to differentiate from insulin ate having more control over the disease. Major points mentioned
overdose. In addition, BGCs are time-consuming and expensive, by owners were that they could monitor blood glucose frequently
and therefore they are often not performed as often as required. It and were able to assess if changes in the cats well-being are associ-
is easy to overlook diabetic remission if blood glucose concentra- ated with hypo- or hyperglycemia. Owners also appreciate that
tions are not measured frequently. The veterinarian may also be home BGCs are less stressful for the cat than in-hospital BGCs
more reluctant to increase the insulin dose in cats in which BGCs (Kley etal, 2004).
are performed only sporadically, which may hamper achievement
of good glycemic control or diabetic remission. Close monitoring Introduction of Technique to Cat Owners
of blood glucose is also indicated in diabetic patients with concur- Owners are often worried when they learn that their cat is dia-
rent diseases, which may require frequent adjustments of the insu- betic. At first they need to gain confidence that they will be able to
lin dose. See the sections Home Monitoring of Blood Glucose, manage the disease, get some basic understanding about diabetes,
Frequency of Monitoring, and Interpretation of Blood Glucose and learn how to inject insulin and they need to adapt their own
Curves and Adjustment of Insulin Doses for more details. lifestyle to the new needs of their cat. The immediate introduction
to home monitoring may overburden many owners and should its use. Unfortunately, the lancing device Microlet Vaculance
therefore be delayed until the owner feels confident. We usually (Bayer Diagnostics) designed for use on alternative sites (i.e., not
introduce the general concept of home monitoring by the time of the fingertip) in humans is no longer available. The Microlet Vac-
discharge from the hospital after the diagnosis of diabetes has been ulance developed a vacuum after lancing, which helped to suck
made. Our written instructions on the various aspects of therapy out blood.
also contain pictures on how capillary blood glucose can be taken. The first PBGM device was the Ames Reflectance Meter, pat-
During the first reevaluation (approximately 1 week later), the ented in 1971 by the Ames company. It was almost 20 cm long
importance of BGCs in the control of the disease is emphasized, and required a very large drop of blood. Since then, numerous
and the owner is informed that the procedure of home monitor- models have been developed that are smaller, lighter, faster, and
ing can be started after the next reevaluation (2 to 3 weeks after easier to handle. Modern PBGM devices have a memory capac-
diagnosis). Owners who are very keen to perform home monitor- ity for the test results, and some allow data to be transferred to a
ing and those who are familiar with capillary blood sampling (e.g., personal computer. Various models require coding or calibration,
have another diabetic pet or are diabetics themselves) may start which is the process of matching the PBGM device with the test
home monitoring earlier. strips. Usually, this is done by inserting a code strip or a code num-
Teaching capillary blood sampling and the use of the PBGM ber into the meter each time a new batch of test strips is used. If
device takes at least 30 minutes and should be performed by an done incorrectly, the readings may be inaccurate. Some models use
experienced veterinarian or technician who has performed the a no coding technology, meaning that the device is automatically
procedure many times. The owner is taught how to use the lanc- calibrated and coded whenever a test strip is inserted. In human
ing device and all relevant technical aspects of the PBGM device. medicine, the quality control of PBGM devices is of continuous
Some PBGM devices come with very detailed information and concern because the success of diabetes management depends
an instructional DVD (e.g., the AlphaTRAK); the veterinarian largely on the reliability of the blood glucose measurements. The
can also refer the owner to one of the many websites demonstrat- analytical quality of measurements can be compromised by opera-
ing the technique. The owner should not leave the hospital before tor and other procedural errors (e.g., dirty meters), hematocrit,
being able to generate a blood drop and to work the PBGM device altitude, humidity, ambient temperature, and lot-to-lot variability
correctly. Along with the PBGM device and test strips, we provide of test strips (Farmer, 2010; Nerhus etal, 2011; Baumstark etal,
forms for recording the blood glucose values and show how the 2012). A number of accuracy standards have been proposed over
glucose concentration should be plotted. It is important that own- the past decades. The most recent International Organization
ers performing home monitoring have ready access to veterinary for Standardization (ISO) accuracy standards for PBGM devices
support if required. used in humans (known as ISO 15197 criteria) state that 95% of
the PBGM device measurements should fall within 15 mg/dL
Sampling Site, Lancing Device, and Portable Blood Glucose (0.84 mmol/L) of the reference method at blood glucose con-
Monitoring Device centrations < 100 mg/dL (5.6 mmol/L) and within 15% of
Capillary blood can be obtained from various sites. Initial stud- the reference method at blood glucose concentrations 100 mg/
ies showed that blood glucose concentrations obtained from the dL (Garg et al, 2013; International Organization for Standard-
ear correlated very well with those from venous blood (Wess and ization, 2013). However, those requirements are often not met.
Reusch, 2000). Recent comparison of blood glucose concen- A recent study in humans showed that only 18 of 34 PBGM devices
trations between different sampling sites (ear, metacarpal, and (52.9%) fulfilled those ISO standards (Freckmann etal, 2012).
metatarsal pads) revealed only minor, insignificant differences A huge number of different PBGM devices are currently avail-
(Zeugswetter etal, 2010). Sampling sites may therefore be rotated able, and most of them are made for use in humans. Unilke
(i.e., if no blood can be obtained at one site, another one can earlier times, most human PBGM devices are nowadays plasma-
be used). Our preferred site of sampling is the inner aspect of calibrated (i.e., they read the blood glucose concentrations from
the pinna. The tip of the ear is held between thumb and index capillary [whole] blood as if they were plasma glucose concentra-
finger, and the entire surface of the outer pinna is held flat using tions). The reason behind this calibration is to enable better com-
the remaining fingers of the same hand. One may also place a parison between laboratory and PBGM device measurements. As
cotton ball on the outside of the pinna. With the other hand, the amount of glucose within erythrocytes in cats (and dogs) is
the lancing device is placed on a non-haired area of the pinna lower than in humans, those PBGM devices may underestimate
and triggered. We aim for capillary, not for venous blood, and the true blood glucose concentration.
therefore avoid lancing a vein. No bleeding is expected after capil- Several companies are now marketing devices for veterinary use,
lary sampling, and therefore no pressure is needed after the punc- claiming that they give more accurate results in dogs and cats.
turing procedure. Shaving, warming, or any other preparation is We are currently using the PBGM meter, AlphaTRAK 2 (Abbott
hardly ever needed (Wess and Reusch, 2000; Casella etal, 2002; Animal Health), in the hospital and recommend its use to own-
Reusch, 2013). If the cat dislikes being touched at the ears, we ers. This PBGM meter is also plasma-calibrated, taking into
use the metacarpal, metatarsal, or digital pads (Fig. 7-20). Others account the difference of glucose distribution in whole blood in
prefer to sample from the lateral ear margin on the outside of the dogs and cats (see www.alphatrakmeter.com for more informa-
pinna or use nonweight-bearing pads (wrist pads) instead of tion). So far, a small number of studies have compared the per-
weight-bearing pads to avoid discomfort when walking or risk of formance of the AlphaTRAK meter with those of several human
infection with use of a litter box (Ford and Lynch, 2013). Several PBGM devices and demonstrated that quality parameters were
starter kits not only provide the PBGM device with test strips but better for the AlphaTRAK (Cohen etal, 2009; Zini etal, 2009b).
also a lancing device with a certain number of lancets. Pharmacies However, glucose readings from the AlphaTRAK may still differ
offer devices of different gauge sizes and various depth settings. considerably from the reference method, and differences increase
Which lancing device is used is a question of personal preference. as blood glucose concentrations increase. In contrast to many
The most important point is that the veterinarian or technician is human PBGM devices, which usually give readings in dogs and
familiar with the device and is able to convincingly demonstrate cats that are lower than the reference method, the AlphaTRAK
|
A B
C D
E
FIGURE 7-20 Capillary blood sampling from the ear (A to D) and pad (E) of a diabetic cat.
may either under- or overestimate the true glucose concentra- in the glucose categories < 100 mg/dL (5.6 mmol/L) and
tions. Therefore, unlike earlier times when the veterinarian could 100 mg/dL. Fortunately, precision of the AlphaTRAK is better at
assume the true glucose level to be a bit higher than what is blood glucose concentrations < 100 mg/dL (5.6 mmol/L), where
measured with the PBGM device, we now have to accept the con- exact measurements are most important, and approximately 90%
centration at face value. In most cases, the differences are small; of values fall within 15 mg/dL (0.85 mmol/L) of the reference
in rare instances, however, hypoglycemia may be overlooked. In method. At blood glucose above 100 mg/dL (5.5 mmol/L) impre-
our most recent evaluation, using 78 feline samples, no differ- cision is higher but is less serious. It is usually of lesser importance
ence between the AlphaTRAK reading and the reference method to distinguish a blood glucose concentration of 200 mg/dL from
was found in 7 samples (9%). In 40 samples (51%), the Alpha- 250 mg/dL (11 and 14 mmol/L) because treatment decision does
TRAK overestimated the glucose concentration; the differences to not change or is minor.
the reference method ranged between 1.8 to 72 mg/dL, median The bottom line is that according to currently available data,
4.4 mg/dL (0.1 to 4.0 mmol/L, median 0.8 mmol/L). In 31 samples the AlphaTRAK performs reasonably well in cats and dogs.
(40%), the AlphaTRAK underestimated the glucose concentra- Additional advantages are the very small sample volume (0.3 L)
tion by (1.8) to (122) mg/dL, median (12.6) mg/dL ([0.1] to and the wide measurement range of 20 to 750 mg/dL (1.1 to
[6.8] mmol/L, median [0.7]). Table 7-8 shows the differences 42 mmol/L). The influence of factors (e.g., hematocrit, ambient
temperature, and others) known to have an impact on the pre- does not seem to be painful, and the puncture sites are barely vis-
cision of human PBGM devices have not yet been investigated ible, even after numerous blood collections. The exceptions are
for the AlphaTRAK with feline blood. Other veterinary PBGM cats with very thin ears in which we have seen aural hematomas.
devices are on the market, and many more will certainly come. It In those cats, blood samples should be collected from the foot-
is very important that the veterinarian ensures that independent pads. Long-term compliance with home monitoring is usually
quality control studies have been performed before using them. A good, and many owners measure blood glucose on a regular basis
certain degree of deviation from the reference method, however, for many years. The vast majority of owners highly appreciate their
has to be accepted. active participation in the management of the disease. Periodic
reassessment of the entire procedure (capillary blood sampling,
Problems and Long-Term Compliance use of the PBGM device, and correct reading and interpretation of
Many of our clients call for advice one or more times after the start the measurements) in the hospital is highly recommended (Casella
of home monitoring. Some have specific questions regarding the etal, 2002; 2005; Kley etal, 2004; Reusch etal, 2006a). However,
procedure, and others just need reassurance that they are perform- home monitoring is an additional burden to owners that should
ing the procedure correctly. If support via telephone is insufficient, not be underestimated. The veterinarian must carefully determine
additionally, demonstration of the techniques should be provided. whether an owner is able (psychologically and time-wise) to cope
By watching an owner perform the procedure, the veterinarian or with home monitoring and should keep in mind that owners may
technician can identify and correct errors immediately. The most opt for euthanasia if they feel stressed. Owners should understand
frequently encountered problem is failure to generate an adequate that home monitoring is an additional tool in the management
amount of blood. If repeated demonstration is unsuccessful, an of diabetes, which provides valuable information. It is not an
alternative sampling site (e.g., switching form pinna to footpad) absolute requirement. On the other hand, there are also over-
may be helpful. Handling the PBGM device is usually not a prob- motivated owners who absolutely want to have a perfectly regu-
lem for owners, and most report that their cat tolerates the proce- lated cat. Those owners tend to contact the hospital whenever a
dure quite well. As little restraint as possible should be used to avoid blood glucose value is outside the target range, even if the devia-
the cat becoming stressed. Usually, cats become accustomed to the tion is only slight. They need to understand that the blood glucose
procedure with time and increasing experience of the owner. Many concentration in a diabetic individual is influenced by numerous
owners try different strategies for easier restraint and report that factors and can vary from day to day. It is important that those
their cats tolerate blood collection better when placed in a favorite owners learn to look at the general picture (well-being, stability
spot, such as bed, window sill, and/or a confined area such as a sink. of body weight, and most but not all glucose measurement within
Most owners are able to measure blood glucose without help, the target range) than on single glucose values. The exception is
but a second person may be required initially. The skin puncture the finding of a very low glucose concentration, which requires an
immediate reduction of the insulin dose. It has been assumed that
cat owners who perform home monitoring would visit the hospi-
TABLE 7-8 C
OMPARISON OF GLUCOSE tal less frequently. However, our experience over the past 15 years
CONCENTRATIONS MEASURED does not support this assumption. Frequency of veterinary visits
BY THE PORTABLE BLOOD does not differ to a relevant degree among cats with and without
GLUCOSE MONITORING home monitoring.
DEVICE, ALPHATRAK, AND THE
REFERENCE ANALYZER* Frequency of Monitoring
Our protocol for generation of a BGC at home is to have the
Glucose Concentration Obtained with Reference owner measure the glucose concentration before the morning insu-
Analyzer lin injection and every 2 hours thereafter until the evening insulin
< 100 mg/dL 100 mg/dL injection is due. One of the several advantages of home monitoring
(5.6 mmol/L) (5.6 mmol/L) is the fact that the veterinarian can ask for further blood glucose
measurements in cats in which the glucose nadir is not reached dur-
AlphaTRAK
ing this time (e.g., generation of a 14- or 16-hour BGC) without
Number of samples 4 (11%) 3 (7%) interfering with working hours of the practice. More frequent mea-
with no difference surement (hourly) may be suggested in cases with suspected hypo-
Overestimation glycemia so that the lowest glucose concentration is not missed. In
Number of samples 17 (49%) 23 (53%) cats in which the diabetes is well controlled, the intervals may be
prolonged to approximately every 3 hoursin particular during
Range (median) 1.8 to 27 mg/dL (7.2) 1.8 to 72 mg/dL (36) long-term management. Opinions on the question, How often
0.1 to 1.5 mmol/L (0.4) 0.1 to 4.0 mmol/L (2.0) owners should check their cats blood glucose? differ. Some inves-
Underestimation tigators have suggested that owners should perform measurements
Number of samples 14 (40%) 17 (40%) several times per day and adjust the insulin dose accordingly follow-
ing a very tight dosing algorithm. Those algorithms are sometimes
Range (median) (1.8) to (18) mg/dL (3.6) to (122) mg/dL called remission protocols, and it has been claimed that following
(5.4 mg/dL) (22 mg/dL) those protocols lead to higher remission rates (Roomp and Rand,
(0.1) to (1.0) mmol/L (0.2) to (6.8) mmol/L 2009; 2012). There is little doubt that early and adequate treat-
(0.3) (1.2 mmol/L) ment results in better diabetic control, fewer complications, and
*Data are given for glucose concentrations < 100 mg/dL (5.6 mmol/L) and 100 mg/dL. potentially to a higher remission rate compared with situations
A total of 78 feline samples were analyzed; in 35 samples, blood glucose measured with in which treatment is delayed and poorly done. However, those
the reference analyzer was < 100 mg/dL, and in 43 samples, blood glucose was intensive protocols require owners who have the time to measure
100 mg/dL. several times per day, and they bear a high risk of hypoglycemia,
|
even when performed under close supervision. The remission rate between cats and also within the same cat. Additionally, the type
in our hospital using the protocol described here ranges between of insulin influences the shape of a BGC. With Lente-type insu-
40% to 50% over the years; this is only slightly lower than the rate lins (Vetsulin/Caninsulin) and PZI oftentimes more or less bell-
of 51%, which was achieved with a remission protocol (Roomp shaped BGCs with a pronounced peak are seen (i.e., the fasting
and Rand, 2009), provided that cats with prior steroid treatment glucose concentrations are substantially higher than the glucose
were excluded from the analysis. In cats that develop diabetes dur- nadirs). Long-acting insulin analogues (insulin glargine/Lantus,
ing steroid treatment, remission is often easily achieved after cessa- insulin detemir/Levemir) are so-called peakless insulins, which
tion of the drug and initiating insulin therapy, and remission rates in theory should keep the blood glucose concentration at a fairly
may therefore appear to be high if many of those cats are included constant level. In fact, in some cats treated with insulin glargine,
in a study. Our protocol foresees that owners generate a BGC once the BGC is flat. In others, however, a clear peak is seen. The shape
a week during the first months of therapy. After stabilization (and of the BGC may change with time in the same cat. Initially, when
if no remission is achieved), the time intervals are prolonged to glycemic control is still poor, blood glucose concentrations may
approximately every 3 to 4 weeks. We also ask owners to measure just fluctuate in the high glycemic range; with improved glycemic
the fasting blood glucose (pre-insulin glucose) twice weekly and to control, a true curve is often seen, which again changes into
perform a spot glucose check whenever they feel uncertain about a more or less flat line when good glycemic control or diabetic
the well-being of the cat. Although many of our owners work full- remission is achieved (Fig. 7-21).
time, this protocol is feasible for most of them, because they gener- The glucose nadir is an important parameter because it is the
ate the BGC during the weekend. There are cases in which we ask major determinant of dose adjustment. We titrate the insulin
for additional BGCs (e.g., in an extremely unstable diabetic), but dose in steps of 0.5 U/cat b.i.d. until the glucose nadir is between
those are rare exceptions. 80 to 140 mg/dL (4.5 to 7.8 mmol/L). Dose requirements dif-
fer substantially between cats. Some are adequately controlled
Interpretation of Blood Glucose Curves and Adjustment with an insulin dose as low as 0.5 U/cat b.i.d., and others need
of Insulin Doses up to 1 U/kg b.i.d. or more. The majority of diabetic cats need
Owners can certainly be taught how to interpret BGCs and to between 0.5 and 3.0/cat b.i.d. Insulin requirements > 1.0 U/kg
make adjustments in insulin dose. However, we prefer that deci- should raise suspicion for the presence of concurrent disease, and
sions are made by the veterinarian and BGCs be sent to the hos- further work-up should be considered. However, some diabetic
pital, especially during the first 3 months of therapy. This initial cats without concurrent disease may need quite high insulin doses
treatment period needs particular attention, because most cats (1.0 to 1.5 U/kg b.i.d.) during the initial phases of treatment,
require several dose adjustments. It is also during this time that and oftentimes the dose can be cut back after some time. The
either diabetic remission occurs or the presence of insulin resis- reason is unclear; it is possible that those cats suffer from more
tance becomes apparent, requiring further work-up. During long- serious glucose toxicity and/or insulin resistance, which may be
term management, owners may take more responsibility and make
(slight) dose adjustments on their own.
BGCs are extremely helpful for the titration of the insulin dose, 700
1
either upward or downward. Interpretation of BGCs generated

at home follows the same rules as BGCs generated in the hospi- 600
tal. Our goal is to achieve blood glucose concentrations that are
500
below the renal threshold by avoiding hypoglycemia. The highest 2
glucose concentration, which is usually (but not always) the fast- 400 3
ing/pre-insulin concentration, should not exceed 180 to 270 mg/
dL (10 to 15 mmol/L); the lowest glucose concentration (glucose 300
nadir) should ideally be between 80 and 140 mg/dL (4.5 to 7.8
mmol/L). Lower nadirs may be due to insulin overdose (including 200
sudden improvement of insulin-resistant states), excessive overlap
100 4
of insulin actions, or lack of food intake. They may also be found
in cats in which diabetes is ready to go into remission or is already 0
in remission. Finding a nadir below 70 mg/dL (3.9 mmol/L) 0 2 4 6 8 10 12
should always lead to a reduction of the insulin dose. We toler- Hours after insulin administration
ate the occasional occurrence of a nadir between 70 and 80 mg/ FIGURE 7-21 Change of blood glucose curve (BGC) shape in a diabetic cat
dL (3.9 to 4.5 mmol/L) if the cat is doing well and is monitored (Devon Rex, castrated male, 9 years old, 4.5 kg) during treatment with insulin
closely. In general and in the long-run, however, nadirs should glargine (Lantus). BGC 1: 1 week after initiating treatment, insulin dose was
not be lower than 80 mg/dL (4.5 mmol/L). The dose reduction 2.0 U/cat b.i.d.; BGC 2: 6 weeks after start of therapy, insulin dose was 4.5 U/cat
should be 0.5 to 1.0 U/cat b.i.d. if the cat is on a low to moderate b.i.d.; BGC 3: 10 weeks after start of therapy, insulin dose was 6.0 U/cat b.i.d.;
dose of insulin (0.5 to 3/cat b.i.d.) or 25% to 50% if the cat is on BGC 4: 20 weeks after start of therapy, insulin dose was 0.5 U/cat s.i.d. Insulin
a higher dose. administration was stopped at that time; diabetes is still in remission (2 years
BGCs allow assessment of the insulin efficacy, the glucose nadir, after cessation of insulin administration). The increase and decrease in insulin
and duration of the insulin effect. Insulin efficacy means the effec- dose was done in steps of 0.5 U/cat b.i.d., and before each step, a BGC curve
tiveness of insulin to lower the blood glucose concentration, and was generated. Here, only four BGCs are shown to demonstrate that the shape
it may be evaluated by determining the difference between the of the BGC may change during treatment. All BGCs were generated by the owner
highest and lowest glucose concentration of a BGC. A small dif- at home. Generally, although insulin glargine is considered a peakless insulin,
ference is acceptable when all blood glucose concentrations are some cats display a clear glucose nadir, whereas in others, the BGC resembles
well within the target range; however, it is not acceptable if this more a flat line. 0, Time of insulin administration. To convert mg/dL into mmol/L,
is not the case. Of note, the shape of BGCs differs considerably multiply blood glucose concentration by 0.056.
overcome with treatment. The duration of effect is defined as the 0.5 U/cat s.i.d. is reached; if the blood glucose is still normal,
time from the insulin injection through the glucose nadir until insulin administration is terminated.
the blood glucose concentration exceeds 180 to 270 mg/dL (10 to Close clinical monitoring and regular glucose measurement
15 mmol/L), and it should be evaluated when the glucose nadir is (e.g., fasting blood glucose twice per week) is recommended to
within the target range and be ideally approximately 12 hours. If ensure that there is no relapse of the disease. Reduction is done
the duration is less than 8 to 10 hours, the cat usually reveals signs in larger steps than 0.5 U/cat if hypoglycemia is seen. Besides
of diabetes; and if the duration is longer than 14 hours, the risk the nadir, the fasting/pre-insulin blood glucose concentration
of hypoglycemia or the occurrence of the Somogyi effect increases is an important variable. Fasting blood glucose below the target
(see Complications of Insulin Therapy). range may be due to insulin overdose, improvement of an insulin-
Dose adjustments are generally done once a week after receiving resistant state, overlap of insulin actions, or in case of diabetic
the weekly BGC from the owner. The numbers of dose adjust- remission. In those situations, we use the following as a rough
ments differ widely between diabetic cats. In some, one or two guideline. If the fasting blood glucose is between 140 and 180
adjustments are sufficient to achieve the target glucose range, and mg/dL (7.8 to 10 mmol/L), the cat should be fed, and in case the
in others, it takes several weeks. It is not uncommon that the need cat can be monitored throughout the day, the normal insulin dose
to increase the dose alternates with the need of dose reduction. should be administered; otherwise, the dose should be reduced
In cats that continue to be severely hyperglycemic after the first by 0.5 U/cat. If the fasting blood glucose is between 80 and 140
2 to 3 weeks, the process of dose increase is hastened slightly, and mg/dL (4.5 to 7.8 mmol/L), the cat should be fed and the insulin
the intervals are shortened to approximately every 5 days. We do dose reduced by 0.5 U/cat. If the fasting blood glucose is < 80 mg/
not change the dose more often than every 5 to 7 days (except in dL (4.5 mmol/L), the cat should be fed and no insulin be given.
the case of hypoglycemia) because the insulin needs some time to Another glucose measurement should be performed after 1 to
equilibrate. Insulin glargine, which is currently our preferred insu- 2 hours. If the blood glucose is still < 80 mg/dL (4.5 mmol/L),
lin, is designed as intermediate/long-acting insulin. In humans, it no insulin should be given; if the blood glucose is > 80 mg/dL,
is very often used in a treatment regimen, called basal-bolus or mul- a small dose ( of the normal dose) should be administered. It
tiple daily injection regimen. Therewith, it is attempted to mimic should be understood that those cats need to be evaluated with
the normal physiological secretion of insulin as close as possible regard to the cause of the low fasting blood glucose and to decide
by providing background basal insulin coverage (with insulin on the further insulin dose. It also needs to be understood that
glargine) along with a bolus injection of short-acting insulin at the protocol is a guideline and all decisions have to be made on an
each mealtime. In humans, it is recommended not to make changes individual basis. Insulin sensitivity varies between cats and there-
more frequently than every 3 days, particularly for the basal insu- fore some cats may require a more pronounced dose reduction.
lin (Gough and Narendran, 2010). This means that intermediate/ Reduction may also be more pronounced in cats receiving high
long-acting insulins are not designed for daily dose changes. doses of insulin.
Basal-bolus regimens are usually not suitable for cats, and treat-
ment is limited to the use of the basal insulin preparation. Due to Variability of Blood Glucose Curves
the small size of our feline patients, the percentage of dose adjust- In humans, it is well known that blood glucose concentrations
ment (even when done in small steps such as 0.5 U) is much big- can vary markedly from day to day. These variations are associated
ger than what is done in humans. We therefore include a safety with different levels of activity, emotional stress, and differences in
margin to avoid hypoglycemia by using a somewhat longer equili- meal size and composition. However, even when these factors are
bration phase. When the blood glucose targets are reached in a held constant, day-to-day variability may persist. Causes include
particular cat, the question arises whether remission of the disease variable rate of insulin absorption, variation in length of insulin
can be achieved or not. One may decide to leave the situation as activity, variation in insulin sensitivity, and remaining -cell func-
it is and wait and see. We sometimes consider to push it a bit tion. There is also substantial variability among BGCs of diabetic
further, and we discuss the pros and cons (chance of remission cats. When BGCs generated at home were compared with those
versus risk of hypoglycemia) with the owner. The decision mainly generated in the hospital within the same week under the same
depends on the glucose nadir. If the nadir is in the lower range of conditions (i.e., same insulin dose and diet, same blood sampling
what we regard ideal (e.g., 80 to 90 mg/dL, 4.5 to 5.0 mmol/L), conditions), treatment decisions would have been identical regard-
we do not increase the dose. However, if the nadir is 95 to 140 less of the BGC used in approximately 60% of cases, whereas in
mg/dL (5.3 to 7.8 mmol/L), we suggest increasing the dose by approximately 40% of cases, the decisions would have been differ-
0.5 U/cat b.i.d. The cat should be supervised closely during the ent (Casella etal, 2005).
following days, fasting blood glucose concentrations should be In a follow-up study, BGCs generated on 2 consecutive days
measured, and a BGC should be generated within a few days. If at home and on 1 day in the hospital within the same week were
hypoglycemia occurs (blood glucose < 70 mg/dL, 3.9 mmol/L), compared. In some cats differences between the consecutive home
the insulin dose is cut back again to the previous one. BGCs were also relatively high and often not smaller than between
The next challenge is to decide if remission has occurred. home and clinic BGC. In cats with good glycemic control, vari-
Remission is defined as the situation in which the clinical signs ability between BGCs was less than in cats with moderate or poor
of diabetes have resolved, serum fructosamine and blood glucose glycemic control (Alt etal, 2007; see Fig. 7-19, B; Fig. 7-22). The
concentration are in the normal range, and insulin therapy can bottom line is that single BGCs may not be totally reliable for
be ceased. In cats in which all blood glucose measurements of a treatment decisions, even when they are generated at home. How-
BGC range between 80 and 120 mg/dL (4.5 to 6.7 mmol/L) and ever, one of the major advantages of home monitoring is that the
serum fructosamine concentration is < 350 mol/L, we start to veterinarian can ask the owner for more than one BGC before a
reduce the insulin dose in steps of 0.5 U/cat b.i.d. every 5 to 7 treatment decision is made. This is of particular importance in cats
days. The owner is advised to monitor the cat closely with regard that are difficult to regulate. Treatment decisions should never be
to reappearance of clinical signs, and a BGC is performed prior made on the basis of glucose measurements alone, but they should
to each reduction step. The insulin is reduced until a dose of always include the interpretation of the clinical situation.
|
Blood glucose concentration (mg/dL) 500 Thereafter, the sensor is connected to a transmitter that is also fixed
to the patient with tape, and that sends data in a wireless fashion to
400
a pager-sized monitor. Data are collected every 10 seconds, and a
mean glucose value in the sensor is computed every 5 minutes and
seen on the monitor (Figs. 7-23 and 7-24). Wireless transmission
300 of data is only possible if the monitor is within 2 to 3 meters of the
patient (e.g., is fixed to the cage). This is the major limiting factor
200
of the device, because it limits the use for home monitoring. Theo-
retically, one could affix the monitor to the patient; however, the
well-being of the cat would most likely be compromised. There are
100 a few other limitations of the system. It requires a 2-hour period
for initialization, and no data are provided during this time. The
0
system then has to be calibrated; however, only glucose concentra-
0 2 4 6 8 10 12 tions between 40 and 400 mg/dL (2.2 to 22.4 mmol/L) can be used
Hours after insulin administration for calibration. If the glucose is higher or lower, calibration has to
FIGURE 7-22 Variability of blood glucose curves (BGCs) generated at home be postponed until the blood glucose concentration is within the
and in the hospital in a cat (Siamese, castrated male, 14 years old, 6.1 kg) working range. Changes of blood glucose are followed by changes
receiving 3.0 U Lente-type insulin (Vetsulin/Caninsulin) b.i.d. The two home- in interstitial blood glucose with a delay of approximately 11 min-
BGCs were generated on 2 consecutive days; the clinic-BGC was gener- utes in cats (Moretti etal, 2010). Therefore, calibration should not
ated within the same week. The nadir in one of the home-BGCs was 54 mg/ be performed during times when blood glucose changes rapidly.
dL, which is too low. The nadir of the other home-BGC was 130 mg/dL, which Further calibration is needed 6 hours after initial calibration and
is acceptable; however, several of the glucose concentrations measured then every 12 hours thereafter, which requires capillary or venous
throughout the day were too high. The nadir of the clinic-BGC was too high blood sampling. The sensor, which is quite expensive, has a lim-
(210 mg/dL), as were all the other glucose concentrations. The cat was suf- ited sensor life; however, a complete restart of the system after the
fering from chronic pancreatitis, which may have been the cause of the vari- official lifespan of 72 hours allows another 72 hours of monitor-
ability. At the time the BGCs were generated, the cat had polyuria and poly- ing. Recently, a new sensor generation was marketed (Enlite Sen-
dipsia and reduced appetite, and serum fructosamine concentration was sor, used with a different transmitter), which has a lifespan of 144
560 mol/L. The dose was not changed at this point in time, but had to be hours. The monitor displays glucose concentrations between 40
amended thereafter a few times (dose increase and decrease). With time, the and 400 mg/dL (2.2. to 22.4 mmol/L); concentrations outside this
clinical situation stabilized, blood glucose concentrations became more consis- range are correctly recorded but have to be downloaded to be seen.
tent, and serum fructosamine decreased to 427 mol/L. In this case, a change Cats usually tolerate sensor placement and the bandage well,
to an insulin with a different activity profile (e.g. insulin glargine /Lantus) may and usually no adverse skin reactions occur. Accuracy of measure-
have been a good alternative. These BGCs demonstrate that blood glucose con- ments is an important issue, and none of the systems provides
centrations should always be interpreted in conjunction with clinical signs. The 100% accuracy. With the Guardian REAL-Time system, under-
advantage of home monitoring is that one or more additional BGCs can be gen- estimation of blood glucose is more frequent than overestimation.
erated before a treatment decision is made. 0, Time of insulin administration. Fig. 7-25 shows scatterplots of the differences between measure-
To convert mg/dL into mmol/L, multiply blood glucose concentration by 0.056. ments with the CGM system and the PBGM device, AlphaTRAK,
derived from 448 samples from diabetic (n = 39) and healthy cats
(n = 5). Almost all measurements in the normo- and hyperglyce-
Continuous Glucose Monitoring mic range are clinically accurate (i.e., CGM system readings do
not lead to a treatment error). In the hypoglycemic range, CGM
Continuous glucose monitoring (CGM) systems were developed system measurements deviate to a slightly larger extent from the
approximately two decades ago, and they have been introduced reference measurement (Moretti et al, 2010). When simultane-
more recently into veterinary medicine (Davison et al, 2003; ous BGCs were generated with the Guardian REAL-Time system
Wiedmeyer et al, 2003; Ristic, 2005). Those systems measure and the AlphaTRAK and analyzed in a blinded fashion by three
glucose concentrations in the subcutaneous interstitial fluid by internal medicine specialists, treatment decisions did not differ,
using transcutaneous sensors. Interstitial fluid is easily accessible supporting adequate accuracy for clinical use (Dietiker-Moretti
with transcutaneous sensors and has rapid equilibration with the etal, 2011). Readings differ depending on the site of the sensor
blood, resulting in a good correlation of interstitial and blood placement. In cats, readings from the neck area have been shown
glucose concentrations. Various different CGM systems are cur- to be more accurate than those from the lateral chest area or the
rently available, and as with the PBGM devices, many more are knee fold. Additionally, initial calibration is more often successful
expected to become available in the future. The first systems (and when the neck is used. Technical problems include failure to suc-
some of the systems used until today) offered only retrospective cessfully calibrate after the initialization period, discontinuation
analysis of the glucose concentrations after disconnecting the sen- of recordings at some time during the long-term measurement
sor and uploading the data, whereas newer generations measure (usually due to calibration errors) and loss of proper placement of
and display the data immediatelyreal-time continuous glucose the sensor underneath the skin (Hafner etal, 2013).
monitoring (RT-CGM). Immediate availability of results is a Currently, our main indication for the use of CGM system is
major advantage because it allows direct intervention. We evalu- blood glucose monitoring in diabetic cats that are hospitalized for
ated various aspects of one of those real-time systems (Guardian several days (e.g., in case of DKA). The costs of the sensor and the
REAL-Time system) and consider it to be a highly valuable addi- 2-hour initialization period are major limitations for generation
tional monitoring tool. The system uses a small electrode, which is of BGCs on a routine basis. The great potential of those systems,
inserted in the subcutaneous tissue by means of a 22 G needle and however, is the possibility to continuously record blood glucose
fixed with tape after clipping and disinfecting a small area of skin. at home and thereby giving valuable information on the glycemic
A B
C D
FIGURE 7-23 Use of the continuous glucose monitoring (CGM) system Guardian REAL-Time in a cat. A, Placement
of the sensor in the subcutaneous neck area; the sensor is connected to the transmitter (white). B and C, Attach-
ment with tape and bandage. D, Glucose concentrations are transmitted wirelessly to the monitor and displayed in
real time. Here, the glucose given is 18.4 mmol/L (331 mg/dL).
situation during the night. With the current Guardian REAL- duration of insulin effect, inadequate absorption of insulin, cir-
Time device, home monitoring is difficult, because the monitor culating insulin antibodies, fluctuating insulin requirements, and
has to be within 2 to 3 meters away from the patient. Various concurrent diseases causing insulin resistance.
other wireless CGM systems also have a limited transmission Recurrence or persistence of clinical signs is a common prob-
range. The iPro system uses the same electrochemical sensor; how- lem requiring a logical and stepwise approach. The first step is to
ever, the wireless transmitter used with the Guardian REAL-Time confirm that the cat indeed is poorly regulated (i.e., has clinical
system is replaced by a recording device for data storage. Data are signs of diabetes such as polyuria, polydipsia, polyphagia, progres-
not recorded real-time but have to be downloaded. The device sive weight loss, lethargy and decreased interaction with family
might be suitable for home monitoring, but it has not yet been members, lack of grooming behavior, and poor hair coat). High
evaluated in cats or dogs (Surman and Fleeman, 2013). blood glucose levels may have been incorrectly interpreted to
be the result of poor glycemic control when, in fact, they were
stress induced. Fructosamine concentration is also not always a
Insulin Therapy During Surgery
reliable parameter and is sometimes moderately or even markedly
The approach to managing diabetic dogs and cats is similar and increased, although the cat is clinically well. Box 7-6 gives a step-
is discussed in Chapter 6 (see Insulin Therapy During Surgery). wise approach to the work-up. Complications of insulin therapy
are similar for diabetic dogs and cats; see Chapter 6 for a more
comprehensive discussion.
COMPLICATIONS OF INSULIN THERAPY
Although the majority of diabetic cats can be adequately stabilized Stress Hyperglycemia
during the first 3 months of therapy, problems may occur any time
during management. They usually fall within one of the following Cats are prone to stress hyperglycemia, which develops as a result
categories: stress hyperglycemia, hypoglycemia, technical errors, of an increase in catecholamines or may be due to increased glu-
insulin underdose, insulin overdose with glucose counterregula- coneogenesis stimulated by lactate release in struggling cats (Rand
tion (Somogyi effect), short duration of insulin effect, prolonged et al, 2002). Stress-induced hyperglycemia not only renders
|
25
20
X
Glucose (mmol/L) 15
X
10 X X
0
0
0
0
0
0
0
0
0
10 0
11 0
12 0
00
14 0
15 0
16 0
00
18 0
00
20 0
21 0
22 0
23 0
00
0
10
20
30
40
50
60
70
80
90
0
0
0
0
0
0
0
0
0
0
17
24
13
19
Time
FIGURE 7-24 Blood glucose curve (BGC) over 24 hours generated by the continuous monitoring system Guard-
ian REAL-time in a newly diagnosed diabetic cat after the start of insulin therapy. The curve is generated by the
continuous glucose monitoring (CGM) system; X marks the glucose concentrations measured by the AlphaTRAK. To
convert mmol/L to mg/dL, multiply by 18.
160 300

120 200

Difference (mg/dL)
Difference (mg/dL)
80
100

40 0

0

100

40

200

80
300

120 400
160 500
60 90 120 150 180 210 90 180 270 360 450 540
A Reference method (mg/dL) B Reference method (mg/dL)
80
60
Difference (mg/dL)
40

20

0

20

40

60
90
30 45 60 75 90 105
C Reference method (mg/dL)
FIGURE 7-25 Scatterplots of the differences between blood glucose concentrations obtained by the use of the Guard-
ian REAL-Time continuous glucose monitoring (CGM) system versus concentration obtained with the reference por-
table blood glucose monitoring (PBGM) meter AlphaTRAK at (A) normal, (B) high, and (C) low glucose concentrations
in cats. To convert from mg/dL to mmol/L, multiply by 0.056. (From Moretti S, etal.: Evaluation of a novel real-time
continuous glucose-monitoring system for use in cats, J Vet Intern Med 24:120, 2010 [with permission].)
elevated blood glucose concentrations, they are most likely stress-

BOX 7-6 S
tepwise Work-Up in Diabetic Cats with induced. In those cats, treatment decisions cannot be based on blood
Persistence or Recurrence of Clinical Signs glucose levels. In our hospital, blood glucose is usually obtained from
the pinna (as described earlier for home monitoring) by an experi-
Step 1 enced technician. The technique is usually well tolerated, and it is
Confirm that the cat has clinical signs of diabetes. our impression that stress hyperglycemia is less of a problem with this
Determine whether work-up and previous treatment has been done technique. Stress hyperglycemia may also occur in the home environ-
according to the protocol (see Box 7-3). ment if the owner has difficulty performing the procedure. However,
Step 2 in most cases, home monitoring is a good alternative to generation
Determine whether insulin used by owner is outdated, has been of BGCs in the hospital. See Establishing a Diagnosis of Diabetes
diluted, frozen, or heated. Mellitus for more details on stress hyperglycemia.
Determine whether appropriate syringes are being used (U 40/mL vs.
U 100/mL). Hypoglycemia
Assess owners method of mixing, drawing up the correct dose, and
injecting insulin. Hypoglycemia is the most serious complication of insulin therapy.
Review diet regimen. It is the major factor that prevents achievement of near normo-
These points in problem-solving are often overlooked. However, techni- glycemia in diabetic patients with more tight glycemic control
cal errors are a frequent cause of difficulty in regulating a diabetic pet. (i.e., increase of insulin dose), the risk of hypoglycemia increases.
In humans, it is well established that the risk of hypoglycemia
Step 3
increases in proportion to the reduction of glycated hemoglobin.
Increase insulin dose every 5 to 7 days until the cat receives a dose of
The positive effect of tight glycemic control is counterbalanced
approximately 1.0 U/kg twice daily (intermediate/long-acting insulin).
by fear and anxiety of hypoglycemia, reduction in quality-of-life,
Step 4 reduced productivity, and increased healthcare costs (Bilous and
Generate blood glucose curves (BGCs) to determine whether there is Donnelly, 2010; Fidler etal, 2011). Similarly, cat owners worry
the Somogyi effect or short duration of insulin effect. Blood glucose about hypoglycemia, and a survey identified fear of hypoglyce-
should be measured at home every 1 to 2 hours for at least 12 hours. mia as one of the main factors having a negative impact on the
Step 5
quality of the owners life (Niessen etal, 2010). In a physiological
If no problem has been identified thus far, carry-out work-up for
state, hypoglycemia is prevented by inhibition of insulin secre-
diseases causing insulin resistance. In principle, any other concurrent
tion from the -cells that occurs when the blood glucose declines
disease (e.g., inflammatory, infectious, or neoplastic) may cause insu-
in the postabsorptive phase. If the glucose level falls just below
lin resistance. The most relevant problems are pancreatitis, pancreatic
the normal range, secretion of counterregulatory hormones (in
neoplasia, hyperadrenocorticism, hypersomatotropism (acromegaly),
particular glucagon and epinephrine) is triggered. In humans, the
infections (e.g., of oral cavity or urinary tract), chronic renal failure,
threshold for the latter is a blood glucose concentration between
and obesity.
65 to 70 mg/dL (3.6 to 3.9 mmol/L). If these defenses fail to
As a last resort, poor absorption of insulin and circulating insulin
abort an episode of developing hypoglycemia, lower blood glu-
antibodies should be considered. The relevance of the latter is contro-
cose levels lead to a more intense sympatho-adrenal response that
versial. Although insulin antibodies are produced (in particular when
causes neurogenic symptoms. Those symptoms cause awareness
insulin of a different species is used), it is not yet clear to what extent
of hypoglycemia that prompts the behavioral defense mechanism
they interfere with the action of the injected insulin. At this stage of the
of carbohydrate ingestion. In humans with diabetes, all of those
work-up, however, a switch to insulin of a different species is indicated.
defense mechanisms are typically compromised, a phenomenon
known as hypoglycemia unawareness or hypoglycemia-associated
autonomic failure (Cryer, 2010; 2013). An impaired counterregu-
latory response has also been documented in diabetic dogs (see
diagnosis of diabetes difficult but also complicates the accurate Insulin Overdosing and Glucose Counterregulation [Somogyi
evaluation of blood glucose concentrations measured during Response]). If this phenomenon exists in diabetic cats, it has not
long-term management. Increases in blood glucose can range yet been investigated. However, quite a substantial percentage of
from mild to severe. Blood glucose levels may remain extremely diabetic cats do not seem to sense hunger even if the blood glu-
elevated throughout the day despite insulin therapy or may start cose concentration decreases to quite low levels (e.g., < 50 mg/
in an acceptable range and then steadily increase. Blood sampling dL, 2.8 mmol/L); therefore, one should bear the possibility of
can be extremely stressful for cats and is, therefore, a common failing defense mechanisms in mind. Hypoglycemia in diabetic
cause of stress hyperglycemia. Failure to recognize the effect of cats is caused by an absolute or relative insulin excess. It results
stress on the blood glucose concentrations may lead to the errone- from insulin overdose, sudden increase in insulin sensitivity due
ous assumption that the diabetic cat is poorly controlled. If insulin to cure or improvement of concurrent disorders, diabetic remis-
therapy is adjusted by increasing the dose, hypoglycemia or the sion that goes unnoticed, long duration of insulin action resulting
Somogyi effect may result. in excessive overlap (mainly with PZI or insulin glargine, insulin
Stress hyperglycemia should be suspected, if there is a disparity detemir), or lack of food intake. Hypoglycemia may be a recur-
between the assessment of glycemic control based on the owners rent problem, most often seen in cats with concurrent disease in
observations, body weight, results of physical examination, and the which phases of insulin sensitivity and insulin resistance alternate.
results of BGCs. Evaluation of serum fructosamine can provide addi- Diabetic cats with chronic renal failure are notoriously difficult to
tional valuable information, because the parameter is not influenced regulate because insulin resistance due to uremic toxins coexists
by a short-term increase of blood glucose. A fructosamine concentra- with reduced insulin clearance by the kidneys.
tion within an acceptable range in a cat with no or little clinical signs Hypoglycemia may be asymptomatic (biochemical) or symp-
is consistent with adequate glycemic control. If such a cat has highly tomatic (clinical). There is no well-defined cutoff of blood glucose
|
below which hypoglycemia will become symptomatic. The lower The hyperglycemic period can last 24 to 72 hours; the diagnosis
the blood glucose and the more rapid the glucose level drops, the may therefore be missed with a single BGC and accordingly, the
more likely clinical signs will be apparent. In cats, clinical hypo- incorrect assumption is made that the insulin dose is too low.
glycemia is more difficult to identify than in dogs. Hypoglycemic Rebound hyperglycemia and the Somogyi effect should always
cats oftentimes just become quiet, withdraw from family life, and be considered as a differential diagnosis when BGCs show per-
hide away. More obvious signs include restlessness, aggression, sistently elevated blood glucose levels. To identify the problem,
hunger, lethargy, weakness, salivation, muscle twitching, ataxia, a series of BGCs is often needed, which may be best performed
seizures, and coma. Severe hypoglycemia may be fatal. Owners by home monitoring. If the Somogyi effect is documented or is
should be advised to treat symptomatic hypoglycemia depending assumed to be present, the insulin dose should be reducedthe
on its severity either by offering food or administration of any degree of which is somewhat arbitrarily (0.5 to 1.0 U/cat b.i.d. in
of the various oral glucose gels (over-the-counter medication) or cats on a low to moderate dose, approximately 25% in cats on a
sugar water. Our owners do not inject glucagon in case of sus- higher dose of insulin). If no change is seen, a further slight dose
pected hypoglycemia, although this option may be worth explor- reduction may be pursued. If clinical signs worsen, the approach
ing (Niessen, 2012). If signs do not resolve immediately, the cat was incorrect. Of note, classic glucose changes affiliated with
should be brought to the hospital and treatment performed as this problem are not as apparent today as they were two to three
described in Chapter 9. Owners should also be advised to measure decades ago, and this may reflect the changes in type of insulin
the blood glucose concentration in any of those situations. Docu- used. We have seen a substantial number of cats in which the
mentation by the owner that hypoglycemia was present is very Somogyi effect was assumed to be the cause of the problem, but
helpful for the veterinarian, because it may have resolved when the the cats were in fact suffering from a short duration of insulin
cat arrives in the hospital. effect. Lente-type insulins in particular may exert a pronounced
We consider blood glucose concentrations < 70 mg/dL peak with a quite fast decline in blood glucose concentration, but
(3.9 mmol/L) as too low, although clinical signs usually only the effect is short lasting. In the latter situation, the shape of the
occur when glucose levels are lower than 50 to 60 mg/dL (2.8 to BGC resembles a BGC showing the Somogyi effect. Close moni-
3.4 mmol/L). In cats showing symptomatic hypoglycemia, insu- toring and generation of BGCs after the change of the insulin
lin administration should be discontinued until the blood glucose dose is therefore important. See the discussion on the Somogyi
levels are > 180 mg/dL (10 mmol/L). Thereafter, insulin should be effect in Chapter 6 and the discussion on counterregulation in
restarted with a dose reduced by approximately 50% per injection. response to hypoglycemia in Chapter 9.
In the case of asymptomatic hypoglycemia (e.g., hypoglycemia
found by chance), the calculation of the dose reduction depends
Technical Problems
on the previous dose. If the cat was on a low to moderate insulin
dose (0.5 to 3.0 U/cat b.i.d.), the dose should be reduced by 0.5 to Errors in injecting and handling insulin are frequent causes of
1.0 U/cat b.i.d.; if the cat was on a higher dose, reduction should poor glycemic control and include failure to mix the insulin
be somewhat arbitrarily between 25% to 50%. Further monitor- correctly (if it is a suspension such as Vetsulin/Caninsulin or
ing and glucose measurements are mandatory to ensure that there ProZinc), diluting, freezing or heating, use of outdated insulin,
are no further episodes of hypoglycemia and for the fine-tuning drawing up air instead of insulin, inappropriate insulin dose and
of the insulin dose. Some cats only need an insulin dose as low as timing, poor injection technique, and use of the wrong syringe
0.5 U/cat s.i.d. size (U-40 mL vs. U-100/mLa frequent error). Careful his-
tory taking, asking the owners to bring their own insulin and
Insulin Overdose and Glucose Counterregulation syringes, and watching the owner during the procedure will usu-
(Somogyi Effect) ally unravel the problem.
The Somogyi effect is defined as rebound hyperglycemia due

Insulin Underdose
to hypersecretion of counter-regulatory hormones (mainly epi-
nephrine, glucagon) during hypoglycemia, induced by a (slight) Most cats are well regulated with insulin doses between 0.5 and
overdose of insulin. The phenomenon received its name after 3.0 U b.i.d. (usually with 1 U/kg b.i.d.). Some diabetic cats may
Michael Somogyi, a Hungarian biochemist. He postulated in need insulin doses > 1.0 U/kg b.i.d.; however, this is oftentimes
1959 that nocturnal hypoglycemia provokes rebound hyper- only temporarily during the initial phases of therapy and require-
glycemia and fasting hyperglycemia on the following morning ment decreases thereafter, which is most likely due to improve-
in diabetic humans (Somogyi, 1959). In cats, the first descrip- ment of glucose toxicity. In general, insulin underdose should be
tion of the phenomenon was published in 1986 (McMillan and considered if the insulin dose is considerably less than 1.0 U/kg
Feldman, 1986). Thereafter not much work on the Somogyi effect b.i.d., and the dose should be increased. As mentioned earlier, we
has been done, although it is frequently mentioned as an impor- increase the insulin dose in steps of 0.5 U/cat b.i.d. every 5 to 7
tant cause of poor glycemic control. For the effect to occur, blood days, and a BGC is generated before each step. The higher the
glucose levels must decrease to less than 65 mg/dL (3.6 mmol/L); insulin requirement, the more likely a concurrent disease is pres-
however, it may also occur when the blood glucose concentra- ent, which causes insulin resistance. Further work-up should be
tion decreases rapidly regardless of the nadir (Fig. 7-26). Clinical pursued when the dose requirement is > 1.0 U/kg b.i.d.
signs of hyperglycemia are obvious, whereas signs of hypoglyce- Insulin underdose should always be considered if the cat receives
mia often go unnoticed. Owners may report that days of good the insulin only once daily. Duration of effect is usually never as
glycemic control are followed by several days of poor control, long as 24 hours, independent of the type of insulin used, leav-
which should raise the suspicion of the Somogyi effect. Diagnosis ing the hepatic glucose production unopposed for a long time. In
requires the documentation of hypoglycemia or a very rapid drop those cats, administration should be changed from s.i.d. to b.i.d.,
in blood glucose concentration followed by hyperglycemia (blood starting with a dose as recommended for the initial treatment (see
glucose > 300 mg/dL, 17 mmol/L) within a 12-hour period. Box 7-3).
400 the problem; if the cat is on insulin glargine and duration is too
short, a change to PZI (ProZinc) or insulin detemir (Levemir)
should be considered. Lente-type insulin is more potent than

300 PZI and the long-acting insulin analogues, and therefore the
change should be accompanied by a slight dose reduction (0.5 to
1.0 U/cat b.i.d.).
200
Prolonged Duration of Insulin Effect
100 Prolonged duration of insulin effect is a rather uncommon prob-
lem in diabetic cats. It is usually not seen with NPH or Lente-type
insulin (Vetsulin/Caninsulin). It may, however, occur occasion-
0 ally in cats treated with twice daily application of PZI, insulin
0 2 4 6 8 10 12 glargine, or detemir. If duration of effect is longer than 12 hours,
Hours after insulin administration an overlap in insulin action results, which eventually leads to the
FIGURE 7-26 Blood glucose curve (BGC) 1 (squares): Suspected Somogyi ef-
Somogyi effect or to overt hypoglycemia. Indications for a pro-
fect in a diabetic cat (Domestic Short-Hair [DSH], spayed female, 12 years old,
longed duration of effect are a glucose nadir occurring 10 or more
5.9 kg) receiving 4.5 U/cat insulin glargine (Lantus) b.i.d. The blood glucose
hours after insulin administration and constantly decreasing glu-
dropped to a nadir of 46 mg/dL within 4 hours of insulin administration, followed
cose concentrations beyond the time of the next insulin adminis-
by an increase to 350 mg/dL within 8 hours. The effect did not reappear after
tration. An extended BGC (glucose measurements every 2 hours
reduction of the insulin dose to 3.5 U/cat b.i.d. BGC 2 (dots): Short duration of in-
for 14 to 18 hours) will usually unravel the problem. In some cats,
sulin effect in a diabetic cat (DSH, castrated male, 12 years old, 4.3 kg) receiving
a slight dose reduction can counterbalance the prolonged effect.
1 U/cat Lente-type insulin (Vetsulin/Caninsulin) b.i.d. Short duration of effect is
If this is unsuccessful or results in worsening of glycemic control,
quite common in cats using this type of insulin. The change to another type of
one should switch to an insulin preparation with shorter duration
insulin with longer duration of action (e.g., insulin glargine) should be consid-
of effect. In exceptional cases, switching from twice daily to once
ered. Please note that BGCs displaying short duration of effect or the Somogyi
daily administration is possible; however, duration of effect should
effect may look quite similar. It is important to reevaluate the patient soon after
be at least 20 hours.
amendment of treatment (e.g., dose reduction, change to another type of insulin)
to make sure that the decision was correct. 0, Time of insulin administration. To Impaired Absorption of Insulin
convert mg/dL into mmol/L, multiply blood glucose concentration by 0.056.
Slow absorption was a frequent problem with Ultralente insulin,
which is no longer available. The problem is not considered to be
Short Duration of Insulin Effect important with the insulin preparations used today.
However, insulin absorption is influenced by various factors,
A short duration of insulin effect is a common cause of difficult to including hydration status, local blood flow in the area where
regulate diabetes in cats. It is almost always seen if the insulin is the insulin is injected, obesity, size of the insulin dose, exercise,
given once daily; however, it is also frequently encountered when and environmental temperature. The unpredictability of insulin
given twice daily. NPH insulin preparations are notorious for their absorption was the stimulus for development of the new genera-
short duration of effect, and their use in cats is not recommended. tion of insulins, the insulin analogues. Insulin analogues were
However, short duration is also quite common in cats treated with designed for humans mainly to provide more consistent absorp-
Lente-type insulin (Vetsulin/Caninsulin). PZI insulin (ProZinc) tion kinetics. The currently available insulin analogues are still
and the long-acting insulin analogues (insulin glargine/Lantus, not perfect, and new analogues are under development. Repeated
insulin detemir/Levemir) have longer duration of action, although injection of insulin at the same location are known to result in
twice daily administration is needed in the vast majority of cases local hypertrophy of adipose tissue in humans (called lipohypertro-
(see also Long-Acting Insulin Analogues and Table 7-4). If dura- phy), which may result in slower and more erratic insulin absorp-
tion of action is less than 8 to 10 hours, the cat usually has signs tion (Gough and Narendran, 2010). The same may be true for
of diabetes. Diagnosis of duration of action requires generation cats and therefore, the injection sites should be rotated. However,
of one or several BGCs, which is best done by home monitoring. as blood flow differs, we advise that the body region should be
Stress and reduced food intake in the hospital have a major impact held constant (e.g., lateral thoracic wall).
on glucose values, rendering determination of duration of action
nearly impossible. Duration of action should be assessed only if the
Binding of Insulin by Insulin Antibodies
blood glucose nadir is within the target range (80 to 140 mg/dL,
4.5 to 7.8 mmol/L), and should ideally be 10 to 12 hours. Diag- Because the amino acid sequence of feline insulin differs to a vary-
nosis of short duration of action is confirmed by demonstrating extent from human, porcine, and bovine insulin (see Table
ing blood glucose concentrations more than 180 to 270 mg/dL 7-1), it is logical to assume that treatment will result in the pro-
(10 to 15 mmol/L) within less than 10 hours of the insulin injec- duction of anti-insulin antibodies. In principle, those antibodies
tion (see Fig. 7-26). Single glucose measurements (e.g., in the are capable of binding circulating insulin and reducing its free
morning) are unsuitable and may lead to the erroneous assump- concentration. If the antibody-insulin complex is subsequently
tion of insulin underdose. Fructosamine levels are usually moder- removed by the reticuloendothelial system, the requirement for
ately to severely increased. Treatment consists of changing to an exogenous insulin may be extremely high. Alternatively, insulin
insulin preparation with a longer duration of effect. For instance, may dissociate from the complex in an unpredictable manner,
if the cat is treated with Lente-type insulin (Vetsulin/Caninsulin), resulting in erratic concentrations of free insulin. Humans with
switching to PZI (ProZinc) or insulin glargine (Lantus) may solve diabetes produce anti-insulin antibodies even if they are treated
|
with human insulin. According to a comprehensive review, part, be reversible. Therefore, the administration of progesta-
there is little proof that the development of insulin antibodies in gens or glucocorticoids should be ceased. In case of obesity, a
humans affects glycemic control, insulin dose requirement, or the weight-reduction program should be instituted, and all treatable
incidence of hypoglycemia, although the matter is somewhat con- diseases should be managed as well as possible. Close monitor-
troversial (Fineberg etal, 2007). ing is mandatory, because the insulin requirement may decrease
The relevance of anti-insulin antibodies in the management of substantially. With some disorders, such as chronic renal failure
diabetic cats has not been extensively investigated. Two studies and chronic pancreatitis, insulin resistance persists or continues
identified antibodies in 14% and 37% of cats treated with recom- to fluctuate, and glycemic control usually remains challenging.
binant human, beef, and beef/pork insulins. There was no cor- In those cases, teaching the owner about the latter will help to
relation between glycemic control and the presence or absence of avoid frustration. The glucose targets should be set less tight,
antibodies (Harb-Hauser etal, 1998; Hoenig etal, 2000a). Studies and the insulin dose chosen with the aim of avoiding hypoglyce-
evaluating potential antibody production during therapy with the mia, very severe hyperglycemia, and DKA. Home monitoring of
long-acting insulin analogues have not yet been performed in cats. blood glucose is helpful to amend the insulin dose during acute
The currently available data allow the assumption that problems flares or worsening of the disease.
in regulating diabetic cats are only rarely (if at all) due to anti-
insulin antibodies. We consider the possibility that anti-insulin Obesity
antibodies are the reason for the difficulty to regulate diabetes only See Obesity under Dietary Management, and also see Obesity,
as a last resort (i.e., we switch to an insulin preparation of a differ- Gender, and Other Risk Factors.
ent species only after excluding the other causes of poor control).
Chronic Pancreatitis
Acute flares of chronic pancreatitis may need in-hospital treatment
Allergic Reaction to Insulin
including IV fluid therapy (with potassium supplementation),
Allergic reactions to insulin have not been documented in the cat. plasma transfusions, pain management, nutritional support (tube
See Allergic Reaction to Insulin in Chapter 6. feeding), antiemetic, and antibiotic therapy. Long-term treatment
of chronic pancreatitis is difficult, and a complete cure is often not
possible. Suggested measures include the use of appetite stimula-
Concurrent Disorders Causing Insulin Resistance
tors (mirtazapine, cyproheptadine), cobalamine supplementation
and Drug-Induced Diabetes
(if deficient), and supplementation with antioxidants (S-adenosyl-
Most diabetic cats can be regulated with insulin doses (interme- methionine [SAMe], vitamin C, vitamin E, and/or selenium). In
diate-/long-acting insulin) between 0.5 and 3.0 U b.i.d. (usually humans with acute pancreatitis, the use of glucocorticoids is cur-
with doses 1.0 U/kg b.i.d.). In cats with insulin requirements rently under investigation. There are anecdotal reports on clinical
above this threshold, concurrent disorders should be sus- improvement when used in cats with chronic or chronic relapsing
pected provided that the problems discussed earlier (i.e., tech- pancreatitis (Armstrong and Williams, 2012). However, there are
nical problems, short duration of effect) have been excluded. currently no criteria that would help the clinician to decide which
No insulin dose clearly defines insulin resistance. Insulin cat would potentially benefit from a short-term steroid adminis-
resistance should be suspected when glycemic control is poor tration and in which cases it would cause harm.
despite insulin doses of more than 1.0 U/kg b.i.d., high doses
(> 1.5 U/kg) are required to maintain blood glucose less than Chronic Kidney Disease
270 mg/dL (15 mmol/L), and when glycemic control is erratic See Concurrent Disorders Causing Insulin Resistance in Chapter 6.
and insulin requirements constantly change. It is important to
note that severity of insulin resistance can vary widely. Resis- Hyperthyroidism
tance can be mild and easily counterbalanced by some increase See Serum Thyroxine Concentration.
in insulin dose; however, it can also be severe requiring very high
insulin doses or can fluctuate with time. See Concurrent Disor- Exogenous Glucocorticoids and Progestins
ders Causing Insulin Resistance in Chapter 6 for more details on Glucocorticoids were named for their hyperglycemic effects,
mechanism of insulin resistance and on insulin dose adjustment. and they have the potential to exert strong diabetogenic prop-
Any inflammatory, infectious, neoplastic, and endocrine disor- erties. They may induce hyperglycemia in previously normo-
der can cause insulin resistance, as well as obesity and adminis- glycemic patients as well as worsen glycemic control in patients
tration of insulin-antagonistic drugs. In cats, insulin resistance is already known to have diabetes mellitus. Glucocorticoids induce
most commonly caused by severe obesity, chronic renal failure, or worsen diabetes mellitus by increasing insulin resistance in
chronic pancreatitis, stomatitis/oral infections, hyperadrenocor- peripheral tissues (muscle, fat) and by increasing hepatic glucose
ticism, and hypersomatotropism (acromegaly). The latter two production. Additionally, they may inhibit insulin release from
diseases are the ones with the potential of the most severe insulin the -cells (Delaunay etal, 1997; Gittoes etal, 2010; Lowe etal,
resistance. Some of the causes will be obvious after obtaining 2009). In humans, overt diabetes or impaired glucose tolerance
a detailed history (e.g., administration of progestagens or glu- is seen in 14% to 28% of individuals receiving long-term glu-
cocorticoids) and performing a thorough physical examination cocorticoids. Humans who are not able to increase their insulin
(obesity, stomatitis/oral infection). If history and physical exam- secretion to counterbalance the effects of the glucocorticoid (i.e.,
ination are fruitless, CBC, serum biochemical panel, lipase/fPLI have an intrinsically low insulin secretion capacity) are particularly
serum T4 concentration, measurement of insulin-like growth susceptible (Wajngot etal, 1992; Gittoes etal, 2010). In cats, the
factor-1 (IGF-1), urinalysis and urine culture, and abdominal prevalence of overt diabetes during glucocorticoid therapy has not
ultrasonography should be the next steps. Additional tests (e.g., yet been systematically evaluated. Steroid diabetes can occur after
biopsy of a mass or organ abnormality, low-dose dexametha- oral or parenteral as well as after topical administration of any of
sone test) may be required. Insulin resistance may, at least in the currently available glucocorticoids. Glucocorticoid sensitivity
varies between individual cats and therefore dose, duration, and initiating insulin therapy. Low IGF-1 levels have also been seen
frequency of application that will ultimately lead to hyperglyce- initially in untreated diabetic cats with acromegaly (Reusch etal,
mia, cannot be predicted. Experimental studies have shown that 2006b). In our hospital, IGF-1 is measured 6 to 8 weeks after
abnormalities may already become apparent after short-term initiating insulin therapy. Because IGF-1 measurements are not
therapy. Administration of 2 mg/kg prednisolone s.i.d. for 8 days 100% reliable, the final diagnosis requires documentation of a
resulted in reduced glucose tolerance after an IV glucose load in all pituitary mass by CT or magnetic resonance imaging (MRI) scan.
six cats, and three of the six developed hyperglycemia (Middleton See Chapter 2 for more details.
and Watson, 1985). It has been suggested that dexamethasone has
greater diabetogenic effects than equipotent doses of prednisolone Hyperadrenocorticism
(Lowe etal, 2008; 2009). Steroid diabetes often goes into remis- Hyperadrenocorticism is considered to be a rare disease and is
sion, provided that the glucocorticoid application is ceased imme- associated with diabetes mellitus in approximately 80% of cats.
diately and insulin treatment is initiated. Careful monitoring of Pituitary-dependent disease is present in 75% to 80%, and 20%
blood glucose levels is important. After the effect of the gluco- to 25% suffer from a cortisol-secreting adrenocortical tumor. In
corticoid on insulin sensitivity wears off, the insulin requirement rare circumstances, adrenocortical tumors secrete steroid hormones
decreases, resulting in the need to also decrease the insulin dose. other than cortisol. Progesterone-producing tumors result in clini-
Remission may fail to appear if treatment is inadequate or if the cal signs that are identical to those caused by hypercortisolism,
cat has substantial islet pathology. If glucocorticoid therapy can- and they may also be associated with diabetes mellitus (Boord and
not be terminated and no alternative drug can be used, the insulin Griffin, 1999; Rossmeisl etal, 2000; Quante etal, 2009). In addi-
dose has to be adjusted on the severity of the insulin resistance. In tion to polyuria/polydipsia (pu/pd) and weight loss, which are usu-
those cases, glycemic control oftentimes remains difficult. ally due to concurrent diabetes mellitus, typical clinical signs are
Progestins are known to exert glucocorticoid activity, and they abdominal enlargement, an unkempt seborrheic hair coat, thin-
have similar effects to glucocorticoids on insulin sensitivity. Treat- ning of the hair coat, failure of hair to regrow or alopecia, and
ment with progestins (e.g., megestrol acetate) may therefore also muscle weakness. Severe cases may have thin fragile skin that tears
result in glucose intolerance or overt diabetes (Peterson, 1987; easily. Cats with large pituitary masses may have CNS distur-
Middleton and Watson, 1985; Middeleton et al, 1987). Other bances. However, clinical signs may also be mild, and hyperad-
glucocorticoid-like side effects including skin atrophy, alopecia, renocorticism is often not suspected until it becomes evident that
and skin lacerations may be seen as well. Similar to glucocorti- the diabetes is difficult to regulate. The dexamethasone suppres-
coids, it is not possible to predict which cat will develop diabetes, sion test is the preferred screening test. Whether poorly-regulated
and therefore, regular reevaluations are mandatory. Remission of diabetics have hyperactivity of the hypothalamus-pituitary-adrenal
diabetes may occur after discontinuation of progestin administra- gland axis that leads to false positive test results is controversial. We
tion and the initiation of insulin therapy. recently investigated the dexamethasone test in a group of diabetic
cats 6 weeks after initiating insulin therapy. In 20 of 22 cats, the
Hypersomatotropism (Acromegaly) cortisol concentration was completely suppressed at 4 and 8 hours
Hypersomatotropism is a disease that is almost always associated after the application of 0.1 mg/kg dexamethasone IV. The results
with diabetes mellitus. It has the potential to cause very severe insu- did not differ between cats with good glycemic control and those
lin resistance and requirements of insulin doses more than 2 U/ with moderate to poor control. In two cats, the test was abnor-
kg b.i.d. are no exception. Insulin resistance, however, can also be mal and hyperadrenocorticism was confirmed by histopathology
quite mild, in particular in the initial phases of the disease. Hyper- (Kley et al, 2007). Based on our results, the dexamethasone test
somatotropism in cats is caused by a GH-producing tumor (usu- appears to be a suitable part of the diagnostic work-up in diabetic
ally an adenoma) in the pars distalis of the pituitary gland. GH has cats suspected of having hyperadrenocorticism. In our hospital, we
catabolic and anabolic effects; the latter are in part mediated by perform testing for hyperadrenocorticism in cats in which glycemic
IGF-1. The catabolic effects are mainly due to insulin antagonism control remains difficult after several weeks of therapy and other
and are the reason for the diabetes mellitus. The anabolic effects problems have been excluded. Usually, the test is carried out 6 to
include proliferation of bone, cartilage, soft tissue, and organs 8 weeks after initiating insulin therapy. Further details on feline
resulting in a large body size, broad head and large paws, weight hyperadrenocorticism can be found in Chapter 11.
gain, prognathia inferior, respiratory difficulties because of thick-
ening of pharyngeal tissues, degenerative arthropathy, and organo- Fluctuating Insulin Requirements (Glycemic Instability)
megaly with potential organ dysfunction. Growth of the tumor
may lead to signs of a central nervous system (CNS) disease. Of One of the most frustrating problems encountered with insu-
note, clinical signs may also be very subtle or even absent, and the lin therapy is the inability to maintain glycemic control. For
disease may therefore be overlooked. Acromegaly has long been instance, previously well-regulated cats on a stable dose of insulin
considered a rare disorder. However, it was recently suggested that suddenly develop clinical signs of diabetes and severe hyperglyce-
acromegaly occurs more frequently than previously thought and mia; an increase in insulin dose may solve the problem for a short
is most likely underdiagnosed (Niessen etal, 2007). Because the time, after which further dose amendments (either increase or
availability of a validated GH assay for cats is a problem, diagnosis decrease) are required. Other cats suffer from recurrent flares of
is usually based on the finding of a high IGF-1 concentration. DKA, despite being closely monitored, and have to be brought
A few important points should be kept in mind. First, circulat- to the hospital as an emergency frequently. Another subset of
ing IGF-1 is bound to proteins, which must be removed before diabetic cats suffers from frequent episodes of hypoglycemia that
measurement. Not all methods are equally effective, and intra- alternate with phases of adequate control or hyperglycemia. In
assay inference of binding proteins may lead to falsely high IGF-1 humans, the same problems occur and the term brittle diabe-
levels (Tschuor etal, 2012). Therefore, only assays validated for tes is used for individuals with glycemic instability sufficient to
the cat should be used. Second, IGF-1 concentrations are often disrupt the patients lifestyle. Causes of brittleness are numer-
low in newly diagnosed diabetic cats and increase markedly after ous and include failure to follow treatment regimen correctly,
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inappropriate lifestyle and dietary management, recurrent infec- cortical cataracts or posterior subcapsular plaques. Severity of dia-
tions, gastrointestinal diseases, chronic pancreatitis, concur- betic cataracts differs substantially between dogs and cats, as none
rent endocrinopathies or administration of diabetogenic drugs, of the cats was blind (Williams and Heath, 2006). Therefore, dif-
impaired counterregulatory hormone secretion, delayed gastric ferent from diabetic dogs, cataract formation in diabetic cats is usu-
emptying due to autonomic neuropathy, genetic defects in or ally of limited clinical relevance. More severe cataract with potential
beyond the insulin receptor, and psychiatric and psychological blindness may develop in diabetic kittens (Thoresen et al, 2002).
problems. In some patients, no obvious cause is found, which The enzyme aldose reductase and the sorbitol pathway seem to play
is then called idiopathic brittle diabetes (Voulgari et al, 2012). an important role in formation of diabetic cataract. (See Chronic
Most of those causes are also known to cause difficulties regu- Complications of Diabetes Mellitus in Chapter 6.) It has been
lating diabetes in cats and have already been discussed. Most shown that aldose reductase activity is significantly lower in lenses
commonly, glycemic instability in cats is due to acute flares of of older cats than in younger cats and dogs, which may prevent seri-
chronic pancreatitis or the development of another concurrent ous cataract formation (Richter etal, 2002).
disease (infections, neoplasia, chronic renal disease), severity of
which can range from mild (and may be overlooked) to severe.
Diabetic Nephropathy
Any disease may increase insulin resistance, and if insulin dose
is not adequately increased, signs of diabetes reoccur and DKA In humans, diabetic nephropathy is a well-known and extremely
may develop. After improvement or resolution of the concurrent serious complication of diabetes. It is a chronic disease develop-
disease, insulin resistance decreases, which may result in hypo- ing over many years and is characterized by gradually increasing
glycemia if the insulin dose is not amended. Cats with glycemic urine protein excretion and blood pressure, which is later fol-
instability need a thorough work-up as discussed earlier (see also lowed by a decline in glomerular filtration rate and azotemia.
Box 7-6). If a cause cannot be identified, close monitoring is Urine protein excretion itself gradually increases from microal-
mandatory, and regular home monitoring of blood glucose is of buminuria to overt proteinuria, and the development of overt
great help to decide on insulin dose amendments. nephropathy takes many years (Marshall and Flyvberg, 2010).
Histopathological lesions affect predominantly the glomeruli,
CHRONIC COMPLICATIONS OF DIABETES but there may also be severe interstitial and vascular involve-
MELLITUS ment. Findings include thickening of the glomerular basement
membrane, mesangial expansion, nodular sclerosis (Kimmelstiel-
Systemic Hypertension Wilson lesions), tubular basement membrane thickening, mono-
nuclear cell infiltrates in the interstitium, interstitial fibrosis and
There is currently no convincing evidence that diabetes in cats atrophy, and arteriolar hyalinosis (Tervaert etal, 2010). Chronic
is associated with clinically relevant hypertension. Of eight cats renal disease is common in the elderly, non-diabetic cat popula-
with recently-diagnosed diabetes, two had increased systolic blood tion, and its cause is usually unknown. Diabetes is also relatively
pressure of 170 and 180 mm Hg. However, values of 170 and common in elderly cats. So far, it is unclear if diabetes in cats
180 mm Hg were also found in two of 20 healthy control cats leads to kidney damage and chronic renal failure or if the coex-
(Sander et al, 1998). Similar findings were described in 14 cats istence of the two diseases is just coincidence. In recent studies,
with a median diabetes duration of 18 months. None of the cats the prevalence of chronic renal disease in diabetic cats ranged
had systolic blood pressures more than 180 mm Hg, and blood between 17% and 63% (Roomp and Rand, 2009; 2012; Cal-
pressures of healthy controls and diabetic cats did not differ. None legari etal, 2013). In a group of newly diagnosed diabetic cats,
of the cats had proteinuria or retinopathy (Senello etal, 2003). 13.3% developed chronic renal failure during a 6-month follow-
These findings are in agreement with two other studies, in which up study (Hafner etal, 2013).
the duration of diabetes was not specified; however, none of the 13 Proteinuria is assumed to be a marker for progression of
cats examined had hypertension (Bodey and Sansom, 1998; Nor- chronic renal disease and high urine protein-to-creatinine
ris etal, 1999). In a more recent study, the prevalence of hyper- (UPC) ratios have been shown to predict the development of
tension was not different in diabetic cats compared to control cats azotemia in non-diabetic cats (Jepson et al, 2009; Chakrab-
(Al-Ghazlat etal, 2011). Nevertheless, there may be exceptional arti etal, 2012). In diabetic cats, the prevalence of proteinuria
cases. In one study, two diabetic cats with hypertensive retinopa- was recently shown to be significantly higher than in healthy
thy were described; one had evidence of renal dysfunction, which and sick, non-diabetic controls (75%, 18%, 34%). None of
may have been the cause of hypertension, but the other cat had the cats were azotemic by the time of urinalysis, and no fol-
no other concurrent disease (Maggio etal, 2000). Further studies low-up information with regard to potential progression to
using larger cohorts of diabetic cats are needed to evaluate ques- chronic renal failure was given (Al-Ghazlat et al, 2011). One
tions, such as the definitive prevalence of hypertension and the small study reported histopathological findings in six diabetic
risk of kidney-damage when blood pressure is in the upper end of cats, which consisted of mesangial proliferation in two cats,
normal (Reusch etal, 2010). and glomerular sclerosis and interstitial inflammation in one
cat each (Nakayama etal, 1990). We recently compared histo-
pathological findings in 32 diabetic cats to those of 20 matched
Diabetic Cataracts
control cats. Glomerular lesions were observed in 17 (53%) of
For a long time it was believed, that diabetic cataract does not diabetic cats and 12 (60%) of the controls and consisted mainly
develop in cats. A recent study demonstrated, however, that cataract of increased mesangial matrix, glomerular basement membrane
formation is in fact a frequent event in feline diabetics. Forty-eight thickening, and thickening of the Bowman capsule. Tubulo-
of 50 cats (96%) with diabetes had some degree of lens opacifica- interstitial lesions were demonstrated in 26 (81%) of the dia-
tion. In 22 of them (46%), the findings were limited to linear poste- betic and 16 (80%) of the controls and included interstitial
rior cortical opacification, which is similar to what is seen in normal, fibrosis, inflammation, atrophy, and necrosis; vascular abnor-
elderly cats. Twenty-six cats (54%), however, had more pronounced malities were found in 3 (9.4%) of the diabetic and 2 (10%) of
the controls. Statistical analysis revealed no difference between factors, and inflammatory as well as immunological processes
the groups. Of note, tubule-interstitial necrosis tended to be (Ziegler, 2010). Data in cats are scarce. One study demon-
more frequent in diabetic cats than in controls (50% and 25%); strated an increase in nerve glucose and nerve fructose suggest-
however, the difference did not reach significance. Based on ing increased polyol pathway activity (Mizisin etal, 2002). The
those results, it is very likely that cats do not develop diabetes- first step in the polyol-pathway is the reduction of glucose to
induced nephropathy. The short life expectancy of diabetic cats sorbitol by the enzyme aldose reductase; thereafter, the enzyme
and the low prevalence of hypertension may be main reasons sorbitol dehydrogenase oxidizes sorbitol to fructose. It is cur-
for the difference from human diabetics (Zini etal, 2014). If rently assumed, that those enzymatic steps consume NADPH,
proteinuria is found in a diabetic cat, the next step is to exclude which is an important cofactor to regenerate reduced glutathi-
urinary tract infection and hypertension as possible causes. one. The latter in turn is an important scavenger of reactive
Thereafter, one should aim for good glycemic control and per- oxygen species (ROS); thus reduction in NADPH could induce
form regular reevaluations. If severity of proteinuria increases, or worsen oxidative stress (Giacco and Brownlee, 2010). Inter-
treatment with angiotensin converting enzyme (ACE) inhibi- estingly, in humans with type 1 diabetes, intensive treatment
tors may be considered, although data on their benefit in cats and enhanced glycemic control significantly reduces the risk for
are scarce. Treatment of chronic renal failure in diabetic cats developing diabetic neuropathy, whereas in type 2 diabetics,
should follow the same guidelines as in non-diabetic cats. glucose control has only small effects on the prevention of neu-
ropathy (Callaghan etal, 2012). These data suggest that other
factors (e.g., obesity, hyperlipidemia, and hypertension) are
Diabetic Neuropathy
important contributors to the risk of diabetic neuropathy. Once
Diabetic neuropathy is one of the most common chronic com- diabetic neuropathy is established, intensive treatment and
plications of diabetes in cats. The vast majority (90%) of dia- even diabetic remission does not result in significant improve-
betic cats reveal nerve abnormalities if peripheral nerves are ment in humans. Various drugs have been studied (including
examined by electron microscopy (Dahme etal, 1989). Overt aldose reductase inhibitors), but no major breakthrough has
neurological signs, however, are seen in only approximately been achieved. Treatment is therefore mainly limited to pain
10% of cats. Clinical signs range from very mild to severe and relief; reduction in neuropathic pain has been seen with the use
include hind limb weakness, difficulty or inability to jump, a of antioxidants, such as alpha lipoic acid, acetyl-L carnitine,
base-narrow gait, ataxia, muscle atrophy most noticeable in the and benfotiamine (Smith and Singleton, 2012; Singleton and
distal pelvic limbs, and a plantigrade posture when standing Smith, 2012). There is currently no recommended treatment
and walking, postural reaction deficits and decreased tendon for neuropathy in diabetic cats. In some cats, good glycemic
reflexes, and irritability when the feet are touched or manipu- control results in improvement of neurological signs, in others,
lated. Clinical signs may progress to include the front legs with however, no effect is seen. Complete reversal of diabetic neu-
a palmigrade stance and gait (Mizisin etal, 2002; see Box 7-2). ropathy is a rare event. Lipoic acid may also show some effects
By means of electrophysiological testing, decreased motor and in diabetic cats, however, it is associated with an increased risk
sensory nerve conduction velocities can be demonstrated with of hepatotoxicity and should not be used until further studies
more severe decrease in diabetic cats with severe clinical neu- on dosing regimens are available (Hill etal, 2004).
ropathy. Thoracic limbs tend to be less severely affected than
the pelvic limbs, and sensory nerve conduction is less severely
PROGNOSIS
affected than motor nerve conduction. Electromyographic
abnormalities are usually absent or if identified, are consistent The prognosis depends in part on owner commitment to treat
with denervation (Mizisin etal, 2002; 2007). the diabetes, presence of concurrent diseases (e.g., pancreatitis,
Histological evaluations of nerve biopsies display concurrent chronic renal disease, and acromegaly), and the ease of glycemic
injury to both Schwann cells and axons of myelinated fibers, control including the avoidance of complications such as DKA.
which is remarkably similar to lesions in human diabetic neuropa- In a recent study, survival time and prognostic factors were eval-
thy. Schwann cell injury is mainly characterized by splitting and uated in 114 cats with newly diagnosed diabetes (Callegari etal,
ballooning of the myelin sheath and subsequent demyelination. 2013). Mortality rate during the first 10 days was 16.7%, and
Additionally, disproportionally thin myelin sheath can be found, the main causes of death were severe concurrent diseases. The
being indicative of episodes of remyelination following demyelin- rate compares quite well with mortality rates of 11% seen dur-
ation and suggests ongoing metabolic dysfunction. Axonal injury ing the first weeks in previous studies (Kraus etal, 1997; Goos-
consists of axoplasmic dystrophic accumulation of membranous sens etal, 1998). Median survival time was 516 days (range 1
debris and glycogen as well as degenerative fibre loss. Similar axo- to 3468 days), 70%, 64%, and 46% lived longer than 3, 6, and
nal injuries can be found in unmyelinated fibers (Dahme et al, 24 months, respectively. Survival time was shorter for cats with
1989; Mizisin etal, 1998; 2002; 2007). Recently, it was shown concurrent diseases; increased serum creatinine concentrations
that nerve fibre injury in diabetic cats is also associated with endo- at diagnosis was significantly associated with a poor outcome.
neurial microvascular abnormalities, some of which parallel those Cats that achieved diabetic remission had longer survival times
in human diabetic neuropathy (Estrella etal, 2008). than cats that were persistently diabetic (Callegari etal, 2013).
The pathogenesis of diabetic neuropathy is only incom- From those data, one may conclude that prognosis of diabetes
pletely understood and most likely multifactorial. Most data in cats is moderate at best. However, two points have to be con-
are derived from studies with diabetic rodent models. Potential sidered. First, cats are usually already quite old when diabetes
mechanisms include increased flux through the polyol pathway, is diagnosed, and second, the studies mentioned earlier were
accumulation of advanced glycation end products on nerve performed in referral centers, and data therefore are most likely
and/or vessel proteins, disturbances in n-6 essential fatty acids associated with a negative selection bias. In cats without severe
and prostaglandin metabolism resulting in abnormal nerve concurrent diseases, good quality of life can often be achieved
membranes and microvasculature, depletion of nerve growth for several years.
|
REFERENCES
Al-Ghazlat SA, etal.: The prevalence of micro- Bennett N, etal.: Comparison of a low Chakrabarti S, etal.: Clinicopathological vari-
albuminuria and proteinuria in cats with carbohydrate-low fiber diet and a moderate ables predicting progression of azotemia
diabetes mellitus, Top Companion Anim carbohydrate-high fiber diet in the in cats with chronic kidney disease, J Vet
Med 26:154, 2011. management of feline diabetes mellitus, Intern Med 26:275, 2012.
Alsahli M, Gerich JE: Abnormalities of insulin J Feline Med Surg 8:73, 2006. Chen N, etal.: The complex exocrine-endocrine
secretion and -cell defects in type 2 Bilous R, Donnelly R, editors: Handbook of relationship and secondary diabetes in
diabetes. In Holt RIG, Cockran CS, Flyvb- diabetes, ed 4, Wiley-Blackwell, 2010. exocrine pancreatic disorders, J Clin Gas-
jerg A, Goldstein B, editors: Textbook of Biourge V, etal.: Effect of weight gain and sub- troenterol 45:850, 2011.
diabetes, ed 4, Chichester, 2010, Wiley- sequent weight loss on glucose tolerance Clark MH, etal.: Pharmacokinetics of pio-
Blackwell. and insulin response in healthy cats, J Vet glitazone in lean and obese cats, J Vet
Alt N, etal.: Day-to-day variability of blood Intern Med 11:86, 1997. Pharmacol Therap 35:428, 2011.
glucose concentration curves generated at Boari A, etal.: Glargine insulin and high- Clark TA, etal.: Alternative therapies for diabe-
home in cats with diabetes mellitus, J Am protein-low-carbohydrate diet in cats tes and its cardiac complications: role of
Vet Med Assoc 230:1011, 2007. with diabetes mellitus, Vet Res Commun vanadium, Heart Fail Rev, 2014.
American Diabetes Association: Standards of 32(Suppl. 1):243, 2008. Cohen TA, etal.: Evaluation of six portable
medical care in diabetes2013, Diabetes Bodey AR, Sansom J: Epidemiological study of blood glucose meters for measuring blood
Care 36(Suppl. 1):11, 2013. blood pressure in domestic cats, J Small glucose concentration in dogs, J Am Vet
Appleteon DJ, etal.: Insulin sensitivity de- Anim Pract 39:567, 1998. Med Assoc 235:276, 2009.
creases with obesity, and lean cats with Boord M, Griffin C: Progesterone secreting Cohn LA, etal.: Effects of chromium supple-
low insulin sensitivity are at greatest risk adrenal mass in a cat with clinical signs of mentation on glucose tolerance in
of glucose intolerance with weight gain, hyperadrenocorticism, J Am Vet Med Assoc obese and nonobese cats, Am J Vet Res
J Feline Med Surg 3:211, 2001. 214:666, 1999. 60:1360, 1999.
Appleton DJ, etal.: Dietary chromium tripico- Brennan CL, etal.: GLUT4 but not GLUT1 Concannon P, etal.: Genetics of type 1A dia-
linate supplementation reduces glucose expression decreases early in the devel- betes, N Engl J Med 360:16, 2009.
concentrations and improves glucose toler- opment of feline obesity, Domest Anim Costes S, etal.: -cell failure in type 2 diabe-
ance in normal-weight cats, J Feline Med Endocrinol 26:291, 2004. tes: a case of asking too much of too few?
Surg 4:13, 2002. Breuer TG, etal.: Proinsulin levels in patients Diabetes 62:327, 2013.
Armstrong PJ, Williams DA: Pancreatitis in with pancreatic diabetes are associated Crenshaw KL, Peterson ME: Pretreatment clini-
cats, Topics in Compan An Med 27:140, with functional changes in insulin cal and laboratory evaluation of cats with
2012. secretion rather than pancreatic beta-cell diabetes mellitus: 104 cases (1992-1994),
Backus RC, etal.: Gonadectomy and high di- area, Eur J Endocrinol 163:551, J Am Vet Med Assoc 209:943, 1996.
etary fat but not high dietary carbohydrate 2010. Crenshaw KL, etal.: Serum fructosamine con-
induce gains in body weight and fat of Brmel, etal.: Determination of adiponectin, a centration as an index of glycemia in cats
domestic cats, Br J Nutr 98:641, 2007. novel adipocytes hormone, in healthy and with diabetes mellitus and stress hypergly-
Bailey CJ, Krentz AJ: Oral antidiabetic agents. diabetic normal weight and obese cats (ab- cemia, J Vet Intern Med 10:360, 1996.
In Holt RIG, Cockran CS, Flyvbjerg A, stract), J Vet Intern Med 18:403, 2004. Cryer PE: Hypoglycemia in diabetes. In Holt
Goldstein B, editors: Textbook of diabetes, Buse JB, etal.: How do we define cure of dia- RIG, Cockran CS, Flyvbjerg A, Goldstein
ed 4, Chichester, 2010, Wiley-Blackwell. betes? Diabetes Care 32:2133, 2009. B, editors: Textbook of diabetes, ed 4,
Bailey CJ, Davies MJ: Pharmacological therapy Buse JB, etal.: Type 2 diabetes mellitus. In Chichester, 2010, Wiley-Blackwell.
of hyperglycemia in type 2 diabetes mel- Melmed S, Polonsky KS, Larsen P, Kro- Cryer PE: Mechanisms of hypoglycemia-
litus. In Wass JAH, Stewart PM, Amiel nenberg HM, editors: Williams textbook of associated autonomic failure in diabetes,
SA, Davies MJ, editors: Oxford textbook of endocrinology, ed 12, Philadelphia, 2011, N Engl J Med 369:362, 2013.
endocrinology and diabetes, ed 2, Oxford, Saunders Elsevier. Dahme E, etal.: Diabetic neuropathy in dogs
2011, Oxford University Press. Butterwick RF, etal.: Effects of increases in and catsa bioptic electron microscopic
Bailiff NL, etal.: Frequency and risk factors for dietary fat intake on plasma lipid and study, Tierarztl Prax 17:177, 1989.
urinary tract infection in cats with diabetes lipoprotein cholesterol concentrations and Davison LJ, etal.: Evaluation of a continuous
mellitus, J Vet Intern Med 20:850, 2006. associated enzyme activities in cats, Am glucose monitoring system in diabetic
Baldwin K, etal.: AAHA nutritional assessment J Vet Res 73:62, 2012. dogs, J Small Anim Pract 44:435, 2003.
guidelines for dogs and cats, J Am Anim Callaghan BC, etal.: Diabetic neuropathy: one De Cock HE, etal.: Prevalence and histopatho-
Hosp Assoc 46:285, 2010. disease or two? Curr Opin Neurol 25:536, logic characteristics of pancreatitis in cats,
Baral RM, etal.: Prevalence of feline diabetes 2012. Vet Pathol 44:39, 2007.
mellitus in a feline private practice (ab- Callegari C, etal.: Survival time and prognostic Delaunay F, etal.: Pancreatic beta cells are
stract), J Vet Intern Med 17:433, 2003. factors in cats with newly diagnosed diabetes important targets for the diabetogenic
Barrett KE, etal.: Endocrine functions of the mellitus: 114 cases (2000-2009), J Am Vet effects of glucocorticoids, J Clin Invest
pancreas & regulation of carbohydrate Med Assoc 243:91, 2013. 100:2094, 1997.
metabolism. In Ganong WF, editor: Review Caney SM: Pancreatitis and diabetes in cats, Delli AJ, etal.: autoimmune type 1 diabetes.
of medical physiology, ed 24, McGraw Hill Vet Clin North Am Small Anim Pract In Holt RIG, Cockran CS, Flyvbjerg A,
Lange, 2012. 43:303, 2013. Goldstein B, editors: Textbook of diabetes,
Baumstark A, etal.: Lot-to-lot variability of test Casella M, etal.: Measurement of capillary ed 4, Chichester, 2010, Wiley-Blackwell.
strips and accuracy assessment of systems blood glucose concentrations by pet De-Oliveira LD, etal.: Effects of six carbo-
for self-monitoring of blood glucose ac- owners: a new tool in the management of hydrate sources on diet digestibility and
cording to ISO 15197, J Diabetes Sci diabetes mellitus, J Am Anim Hosp Assoc postprandial glucose and insulin responses
Technol 6:1076, 2012. 38:329, 2002. in cats, J Anim Sci 86:2237, 2008.
Bennett N, etal.: Evaluation of transdermal Casella M, etal.: Home-monitoring of blood De Silva NM, Frayling TM: Novel biological
application of glipizide in a pluronic glucose in cats with diabetes mellitus: insights emerging from genetic studies
lecithin gel to healthy cats, Am J Vet Res evaluation over a 4-month period, J Feline of type 2 diabetes and related metabolic
66:581, 2005. Med Surg 7:163, 2005. traits, Curr Opin Lipidol 21:44, 2010.
Dietiker-Moretti S, etal.: Comparison of a con- Ford SL, Lynch H: Practical use of home blood Gough S, Narendran P: Insulin and insulin
tinuous glucose monitoring system with a glucose monitoring in feline diabetics, Vet treatment. In Holt RIG, Cockran CS,
portable blood glucose meter to determine Clin North Am Small Anim Pract 43:283, Flyvbjerg A, Goldstein B, editors: Textbook
insulin dose in cats with diabetes mellitus, 2013. of diabetes, ed 4, Chichester, 2010, Wiley-
J Vet Intern Med 25:1084, 2011. Forman MA, etal.: Evaluation of serum feline Blackwell.
Dohan FC, Lukens FD: Experimental diabetes pancreatic lipase immunoreactivity and Graham PA, etal.: Serum fructosamine con-
produced by the administration of glucose, helical computed tomography versus concentrations in hyperthyroid cats, Res Vet
Endocrinol 42:244, 1948. ventional testing for the diagnosis of feline Sci 67:171, 1999.
Donath MY, Shoelson SE: Type 2 diabetes as pancreatitis, J Vet Intern Med 18:807, Haberer B, Reusch CE: Glycated haemoglobin in
an inflammatory disease, Nat Rev Immunol 2004. various pathological conditions: investiga-
11:98, 2011. Forman MA, etal.: Evaluation of feline pan- tions based on a new, fully automated
Elliott DA, etal.: Glycosylated hemoglobin creas-specific lipase (SPEC fPL) for the method, J Small Anim Pract 39:510, 1998.
concentration for assessment of glycemic diagnosis of feline pancreatitis (abstract), Hafner M, etal.: Intensive intravenous insulin
control in diabetic cats, J Vet Intern Med J Vet Intern Med 23:733, 2009. therapy in diabetic cats, J Vet Intern Med
11:161, 1997. Frank G, etal.: Use of a high-protein diet in 25:1493, 2011. abstract.
Elliott DA, etal.: Comparison of serum fructos- the management of feline diabetes mel- Hafner M, etal.: Evaluation of sensor sites
amine and blood glycosylated hemoglobin litus, Vet Ther 2:238, 2001. for continuous glucose monitoring in cats
concentrations for assessment of glycemic Freckmann G, etal.: System accuracy with diabetes mellitus, J Feline Med Surg
control in cats with diabetes mellitus, evaluation of 43 blood glucose monitor- 15:117, 2013.
J Am Vet Med Assoc 214:1794, 1999. ing systems for self-monitoring of blood Hall DG, etal.: Lymphocytic inflammation of
Ellis S: Environmental enrichment. Practical glucose according to DIN EN ISO 15197, pancreatic islets in a diabetic cats, J Vet
strategies for improving feline welfare, J Diabetes Sci Technol 6:1060, 2012. Diagn Invest 9:98, 1997.
J Feline Med Surg 11:901, 2009. Garg SK, etal.: Possible impacts of new accu- Hall TD, etal.: Effects of diet on glucose con-
Erlich H, etal.: HLA DR-DQ haplotypes and racy standards of self-monitoring of blood trol in cats with diabetes mellitus treated
genotypes and type 1 diabetes risk, Diabe- glucose, US Endocrinology 9:16, 2013. with twice daily insulin glargine, J Feline
tes 57:1084, 2008. Garvey WT: Mechanisms of insulin signal Med Surg 11:125, 2009.
Estrella JS, etal.: Endoneurial microvascular transduction. In DeFronzo RA, Ferrannini Hanley NA: Endocrine disorders that cause dia-
pathology in feline diabetic neuropathy, E, Kne H, Zimmet P, editors: International betes mellitus. In Holt RIG, Cockran CS,
Microvasc Res 75:403, 2008. textbook of diabetes mellitus, ed 3, Wiley, Flyvbjerg A, Goldstein B, editors: Textbook
Farmer AJ: Monitoring diabetes. In Holt RIG, 2004. of diabetes, ed 4, Chichester, 2010, Wiley-
Cockran CS, Flyvbjerg A, Goldstein B, edi- George K, etal.: Classification and diagnosis Blackwell.
tors: Textbook of diabetes, ed 4, Chiches- of diabetes mellitus. In Wass JAH, Stewart Harb-Hauser M, etal.: Prevalence of insulin
ter, 2010, Wiley-Blackwell. PM, Amiel SA, Davies MJ, editors: Oxford antibodies in diabetic cats, J Vet Intern
Farrow H, etal.: Postprandial glycaemia in cats textbook of endocrinology and diabetes, ed Med 12:245, 1998. abstract.
fed a moderate carbohydrate meal persists 2, Oxford, 2011, Oxford University Press. Hasegawa S, etal.: Glycated hemoglobin frac-
for a median of 12-hoursfemale cats Gerhardt A, etal.: Comparison of the sensitivity tions in normal and diabetic cats measured
have higher peak glucose concentrations, of different diagnostic tests of pancreatitis by high performance liquid chromatogra-
J Feline Med Surg 14:706, 2012. in cats, J Vet Intern Med 15:329, 2001. phy, J Vet Med Sci 54:789, 1992.
Feldman EC, etal.: Intensive 50-week evalua- German AJ, etal.: Obesity, its associated Havelund S, etal.: The mechanism of protrac-
tion of glipizide administration in 50 cats disorders and the role of inflammatory tion of insulin detemir, a long-acting, acyl-
with previously untreated diabetes melli- adipokines in companion animals, Vet J ated analog of human insulin, Pharm Res
tus, J Am Vet Med Assoc 210:772, 1997. 185:4, 2010. 21:1498, 2004.
Fidler C, etal.: Hypoglycemia: an overview of Giacco F, Brownlee M: Pathogenesis of micro- Hecht S, Henry G: Sonographic evaluation of
fear of hypoglycemia, quality-of-life, and vascular complications. In Holt RIG, Cock- the normal and abnormal pancreas, Clin
impact on costs, J Med Econ 14:646, 2011. ran CS, Flyvbjerg A, Goldstein B, editors: Tech Small Anim Pract 22:115, 2007.
Fineberg SE, etal.: Immunological responses Textbook of diabetes, ed 4, Chichester, Henson MS, etal.: Evaluation of plasma islet
to exogenous insulin, Endocrine Reviews 2010, Wiley-Blackwell. amyloid polypeptide and serum glucose
28:625, 2007. Gilor C, etal.: Pharmacodynamics of insulin and insulin concentrations in nondiabetic
Flatt PR: The hormonal and neural control of detemir and insulin glargine assessed by cats classified by body condition score and
endocrine pancreatic function. In Pickup an isoglycemic clamp method in healthy in cats with naturally occurring diabetes
JC, Williams G, editors: Textbook of diabe- cats, J Vet Intern Med 24:870, 2010a. mellitus, Am J Vet Res 72:1052, 2011.
tes, ed 3, Blackwell Publishing, 2003. Gilor C, etal.: The effects of body weight, body Hewson-Hughes A, etal.: Postprandial glucose
Fletcher JM, etal.: Glucose detection and con- condition score, sex, and age on serum fruc- and insulin profiles following a glucose-
centration estimation in feline urine samples tosamine concentrations in clinically healthy loaded meal in cats and dogs, Br J Nutr
with the Bayer Multistix and Purina Glu- cats, Vet Clin Pathol 39:322, 2010b. 106:101, 2011a.
cotest, J Feline Med Surg 13:705, 2011. Gilor C, etal.: The GLP-1 mimetic exenatide Hewson-Hughes AK, etal.: The effect of dietary
Fondacaro JV, etal.: Treatment of feline dia- potentiates insulin secretion in healthy cats, starch level on postprandial glucose and
betes mellitus with protamine zinc analine Domest Anim Endocrinol 41:42, 2011. insulin concentrations in cats and dogs, Br
insulin (PZI) alone compared with PZI and Gilor C, etal.: Distribution of K and L cells in J Nutr 106(Suppl. 1):105, 2011b.
oral vanadium dipicolinate, J Vet Intern the feline intestinal tract, Domest Anim Hill AS, etal.: Lipoic acid is 10 times more
Med 13:244, 1999. abstract. Endocrinol 45:49, 2013. toxic in cats than reported in humans,
Forcada Y, etal.: Determination of serum fPLI Gittoes NJL, etal.: Drug-induced diabetes. In dogs or rats, J Anim Physiol Anim Nutr
concentrations in cats with diabetes mel- Holt RIG, Cockran CS, Flyvbjerg A, Gold- (Berl) 88:150, 2004.
litus, J Feline Med Surg 10:480, 2008. stein B, editors: Textbook of diabetes, ed Hoenig M: The cat as a model for human obe-
Forcada Y, etal.: A missense mutation in the 4, Chichester, 2010, Wiley-Blackwell. sity and diabetes, J Diabetes Sci Technol
coding sequence of MC4R (MC4R:c.92 Goossens MM, etal.: Response to insulin 6:525, 2012.
C > T) is associated with diabetes mellitus treatment and survival in 104 cats with Hoenig M, Ferguson DC: Impairment of glucose
in DSH cats, J Vet Intern Med 24:1567, diabetes mellitus (1985-1995), J Vet tolerance in hyperthyroid cats, J Endocri-
2010. abstract. Intern Med 12:1, 1998. nol 121:249, 1989.
|
Hoenig M, Ferguson DC: Diagnostic utility of Kienzle E: Blood sugar levels and renal sugar ex- Link KR, etal.: The effect of experimentally
glycosylated hemoglobin concentrations in cretion after the intake of high carbohydrate induced chronic hyperglycaemia on serum
the cat, Domest Anim Endocrinol 16:11, diets in cats, J Nutr 124:2563, 1994. and pancreatic insulin, pancreatic islet
1999. Kitchell BE, etal.: Clinical and pathologic IGF-1 and plasma and urinary ketones
Hoenig M, Ferguson DC: Effect of darglitazone changes in experimentally induced acute in domestic cat (Felis felis), Gen Comp
on glucose clearance and lipid metabolism pancreatitis in cats, Am J Vet Res Endocrinol 188:269, 2013.
in obese cats, Am J Vet Res 64:1409, 27:1170, 1986. Lowe AD, etal.: Clinical, clinicopathological
2003. Kley S, etal.: Evaluation of long-term home and histological changes observed in 14
Hoenig M, etal.: Glucose tolerance and insulin monitoring of blood glucose concentra- cats treated with glucocorticoids, Vet Rec
secretion in spontaneously hyperthyroid tions in cats with diabetes mellitus: 26 162:777, 2008.
cats, Res Vet Sci 53:338, 1992. cases (1999-2002), J Am Vet Med Assoc Lowe AD, etal.: A pilot study comparing the
Hoenig M, etal.: Beta cell and insulin antibod- 225:261, 2004. diabetogenic effects of dexamethasone
ies in treated and untreated diabetic cats, Kley S, etal.: Evaluation of the low-dose and prednisolone in cats, J Am Anim Hosp
Vet Immunol Immunopathol 77:93, 2000a. dexamethasone suppression test and Assoc 45:215, 2009.
Hoenig M, etal.: A feline model of experi- ultrasonographic measurements of the Lutz TA, etal.: Fructosamine concentrations in
mentally induced islet amyloidosis, Am J adrenal glands in cats with diabetes mel- hyperglycemic cats, Can Vet J 36:155,
Pathol 157:2143, 2000b. litus, Schweiz Arch Tierheilkd 149:493, 1995.
Hoenig M, etal.: Activity and tissue-specific 2007. Maedler K, etal.: Sulfonylurea induced -cell
expression of lipases and tumor-necrosis Kley S, etal.: Development of a feline proinsu- apoptosis in cultured human islets, J Clin
factor in lean and obese cats, Domest lin immunoradiometric assay and a feline Endocrinol Metab 90:501, 2005.
Anim Endocrinol 30:333, 2006. proinsulin enzyme-linked immunosorbent Maggio F, etal.: Ocular lesions associated
Hoenig M, etal.: Insulin sensitivity, fat distri- assay (ELISA): a novel application to with systemic hypertension in cats: 69
bution, and adipocytokine response to dif- examine beta cell function in cats, Domest cases (1985-1998), J Am Vet Med Assoc
ferent diets in lean and obese cats before Anim Endocrinol 34:311, 2008. 217:695, 2000.
and after weight loss, Am J Physiol Regul Klinke DJ 2nd: Extent of beta cell destruction Marshall RD, etal.: Glargine and protamine zinc
Integr Comp Physiol 292:227, 2007. is important but insufficient to predict the insulin have a longer duration of action and
Hoyer-Ott MA, etal.: Glycosylated hemoglobin onset of type 1 diabetes mellitus, PLoS result in lower mean daily glucose concen-
in the cat: affinity chromatography deter- ONE 3:e1374, 2008. trations than lente insulin in healthy cats,
mination in healthy, permanent diabetes Kraus MS, etal.: Feline diabetes mellitus: a J Vet Pharmacol Ther 31:205, 2008a.
mellitus and transient hyperglycemic cats, retrospective mortality study of 55 cats Marshall RD, etal.: Insulin glargine has a long
Tierartzl Prax 23:155, 1995. (1982-1994), J Am Anim Hosp Assoc duration of effect following administration
Hoyumpa Vogt A, etal.: AAFP-AAHA: feline 33:107, 1997. either once daily or twice daily in divided
life stage guidelines, J Feline Med Surg Krentz AJ, Nattrass M: Acute metabolic doses in healthy cats, J Feline Med Surg
12:43, 2010. complications of diabetes: diabetic 10:488, 2008b.
Hull RL, etal.: Islet amyloid: a critical entity in ketoacidosis, hyperosmolar non-ketotic Marshall RD, etal.: Treatment of newly diag-
the pathogenesis of type 2 diabetes, J Clin hyperglycemia and lactic acidosis. In nosed diabetic cats with glargine insulin
Endocrinol Metab 89:3629, 2004. Pickup JC, Williams G, editors: Textbook improves glycaemic control and results
International Organization for Standardization: of diabetes, ed 3, Blackwell Publishing, in higher probability of remission than
Invitro diagnostic test systemsrequire- 2003. protamine zinc and lente insulins, J Feline
ments for blood-glucose monitoring sys- Laflamme DP: Development and validation of Med Surg 11:683, 2009.
tems for self-testing in managing diabetes a body condition score system for cats: a Marshall SM, Flyvbjerg A: Diabetic nephropa-
mellitus, ISO 15197, 2013 (E). clinical tool, Feline Pract 25:13, 1997. thy. In Holt RIG, Cockran CS, Flyvbjerg A,
Inzucchi SE, etal.: Management of hyperglycae- Laflamme DP: Focus on nutrition: cats and Goldstein B, editors: Textbook of diabetes,
mia in type 2 diabetes: a patient-centered carbohydrates: implications for health and ed 4, Chichester, 2010, Wiley-Blackwell.
approach. Position statement of the Ameri- disease, Compend Contin Educ Vet 32:E1, Martin GJ, Rand JS: Pharmacology of a 40 IU/
can Diabetes Association (ADA) and the Eu- 2010. ml porcine lente insulin preparation in
ropean Association for the Study of Diabetes Laflamme DP: Nutritional care for aging cats diabetic cats: findings during the first week
(EASD), Diabetologia 55:1577, 2012. and dogs, Vet Clin Small Anim 42:769, and after 5 or 9 weeks of therapy, J Feline
Jepson RE, etal.: Evaluation of predictors of 2012. Med Surg 3:23, 2001.
the development of azotemia in cats, J Vet Laflamme DP, Hannah SS: Discrepancy Martin GJ, Rand JS: Control of diabetes mel-
Intern Med 23:806, 2009. between use of lean body mass or nitrogen litus in cats with porcine insulin zinc
Jin Y, Lin D: Fungal urinary tract infections balance to determine protein requirements suspension, Vet Rec 161:88, 2007.
in the dog and cat: a retrospective study for adult cats, J Feline Med Surg 15:691, Masharani U, German MS: Pancreatic hormones
(2001-2004), J Am Anim Hosp Assoc 2013. and diabetes mellitus. In Gardner DG,
41:373, 2005. Laluha P, etal.: Stress hyperglycemia in sick Shoback D, editors: Greenspans basic &
John WG: Global standardisation of haemoglo- cats: a retrospective study over 4 years, clinical endocrinology, ed 9, San Francisco,
bin A(1c) using metrological principles, Schweiz Arch Tierheilkd 146:375, 2004. 2011, McGraw Hill.
Clin Biochem 45:1048, 2012. Lederer R, etal.: Frequency of feline diabe- Mayer-Roenne B, etal.: Urinary tract infections
Kahn SE, etal.: Interactions between genetic tes mellitus and breed predisposition in in cats with hyperthyroidism, diabetes mel-
background, insulin resistance and -cell domestic cats in Australia, Vet J 179:254, litus and chronic kidney disease, J Feline
function, Diabetes Obes Metab 14(Suppl. 2009. Med Surg 9:124, 2007.
3):46, 2012. Link KR, Rand JS: Glucose toxicity in cats (ab- Mazzaferro EM, etal.: Treatment of feline dia-
Kanaya AM, Vaisse C: Obesity. In Gardner DG, stract), J Vet Intern Med 10:185, 1996. betes mellitus using an alpha-glucosidase
Shoback D, editors: Greenspans basic & Link KR, Rand JS: Changes in blood glucose inhibitor and a low-carbohydrate diet, J
clinical endocrinology, ed 9, San Fran- concentration are associated with relatively Feline Med Surg 5:183, 2003.
cisco, 2011, McGraw Hill. rapid changes in circulating fructosamine McCann TM, etal.: Feline diabetes mellitus in
Kaufman FR: Type 2 diabetes in children and concentrations in cats, J Feline Med Surg the UK: the prevalence within an insured
young adults: a new epidemic, Clinical 10:583, 2008. cat population and a questionnaire-based
Diabetes 20:217, 2002.
putative risk factor analysis, J Feline Med Nelson R, etal.: Evaluation of the oral antihyper- Penninck D: Pancreas. In Penninck D, dAnjou
Surg 9:289, 2007. glycemic drug metformin in normal and dia- M-A, editors: Atlas of small animal ultraso-
McMillan FD, Feldman EC: Rebound hypergly- betic cats, J Vet Intern Med 18:18, 2004. nography, Blackwell Publishing, 2008.
cemia following overdosing of insulin in Nelson RW, etal.: Field safety and efficacy of Persaud SJ, Howell SL: The biosynthesis and
cats with diabetes mellitus, J Am Vet Med protamine zinc recombinant human insulin secretion of insulin. In Pickup JC, Williams
Assoc 12:1426, 1986. for treatment of diabetes mellitus in cats, G, editors: Textbook of diabetes, ed 3,
Michel KE, etal.: Correlation of a feline J Vet Intern Med 23:787, 2009. Blackwell Publishing, 2003.
muscle mass score with body composition Nerhus K, etal.: Effect of ambient temperature Peterson ME: Effects of megestrol acetate on glu-
determined by dual-energy X-ray absorption analytical performance of self-moni- cose tolerance and growth hormone secretion
ometry, Br J Nutr 106:57, 2011. toring blood glucose systems, Diabetes in the cat, Res Vet Sci 42:354, 1987.
Michels GM, etal.: Pharmacokinetics of the Technol Ther 13:883, 2011. Pickup JC: Diabetic control and its measure-
antihyperglycemic agent metformin in Nguyen PG: Effect of dietary fat and energy on ment. In Pickup JC, Williams G, editors:
cats, Am J Vet Res 60:738, 1999. body weight and composition after gonadec- Textbook of diabetes, ed 3, Blackwell
Michiels L, etal.: Treatment of 46 cats with por- tomy in cats, Am J Vet Res 65:1708, 2004. Publishing, 2003.
cine lente insulina prospective, multicen- Niessen SJ, etal.: Feline acromegaly: an un- Prahl A, etal.: Time trends and risk factors
tre study, J Feline Med Surg 10:439, 2008. derdiagnosed endocrinopathy? J Vet Intern for diabetes mellitus in cats presented to
Middleton DJ, Watson AD: Glucose intoler- Med 21:899, 2007. veterinary teaching hospitals, J Feline Med
ance in cats given short-term therapies of Niessen SJ, etal.: Evaluation of a quality-of- Surg 9:351, 2007.
prednisolone and megestrol acetate, Am J life tool for cats with diabetes mellitus, Pressler, etal.: Candida spp. urinary tract
Vet Res 46:2623, 1985. J Vet Intern Med 24:1098, 2010. infections in 13 dogs and seven cats: pre-
Middleton DJ, etal.: Suppression of cortisol Niessen SJM: Glucagon: Are we missing a disposing factors, treatment, and outcome,
responses to exogenous adrenocorticotrophic (life-saving) trick? J Vet Emerg Crit Care J Am Anim Hosp Assoc 39:263, 2003.
hormone, and the occurrence of side effects 22:523, 2012. Quante S, etal.: Hyperprogesteronism due to
attributable to glucocorticoid excess, in cats Norris CR, etal.: Serum total and ionized bilateral adrenal carcinomas in a cat with
during therapy with megestrol acetate and magnesium concentrations and urinary diabetes mellitus, Schweiz Arch Tierheilkd
prednisolone, Can J Vet Res 51:60, 1987. fractional excretion of magnesium in cats 151:437, 2009.
Minkus G, etal.: Pathological changes of the with diabetes mellitus and diabetic keto- Radin MJ, etal.: Adipokines: a review of
endocrine pancreas in dogs and cats in acidosis, J Am Vet Med Assoc 215:1455, biological and analytical principles and an
comparison with clinical data, Tierartzl 1999. update in dogs, cats, and horses, Vet Clin
Prax 19:282, 1991. OBrien TD: Pathogenesis of feline diabetes Pathol 38:136, 2009.
Mizisin AP, etal.: Myelin splitting, Schwann mellitus, Mol Cell Endocrinol 197:213, Rand J: Feline diabetes mellitus. In Mooney
cell injury and demyelination in feline 2002. CT, Peterson ME, editors: BSAVA Manual
diabetic neuropathy, Acta Neuropathol Oppliger S, etal.: Evaluation of serum spec of canine and feline endocrinology, ed 4,
95:171, 1998. FPL and 1,2-o-dilauryl-rac-glycero-3-glu- British Small Animal Veterinary Associa-
Mizisin AP, etal.: Neurological complications taric acid-(6-methylresorufin) ester (DGGR) tion, 2012.
associated with spontaneously occurring lipase in 40 cats with standardized pancre- Rand JS, etal.: Over representation of Bur-
feline diabetes mellitus, J Neuropathol Exp atic histopathological assessment (abstract), mese cats with diabetes mellitus, Aust Vet
Nerol 61:872, 2002. J Vet Intern Med 27:696, 2013a. J 75:402, 1997.
Mizisin AP, etal.: Comparable myelinated Oppliger, etal.: Agreement of the serum Spec Rand JS, etal.: Acute stress hyperglycemia
nerve pathology in feline and human fPL and 1,2-o-dilauryl-rac-glycero-3-glu- in cats is associated with struggling and
diabetes mellitus, Acta Neuropathol taric acid-(6-methylresorufin) ester lipase increased concentrations of lactate and
113:431, 2007. assay for the determination of serum lipase norepinephrine, J Vet Intern Med 16:123,
Moretti S, etal.: Evaluation of a novel real-time in cats with suspicion of pancreatitis, J Vet 2002.
continuous glucose-monitoring system for Intern Med 27:1077, 2013b. Rasouli N, Kern PA: Adipocytokines and the
use in cats, J Vet Intern Med 24:120, 2010. Owens DR: Insulin preparations with prolonged metabolic complications of obesity, J Clin
Mori A, etal.: Decreased gene expression of effect, Diabetes Technol Ther 13(Sup- Endocrinol Metab 93:64, 2008.
insulin signaling genes in insulin sensi- pl.1):5, 2011. Rave K: Renal glucose excretion as a function
tive tissues of obese cats, Vet Res Comm Padrutt I, etal.: Comparison of the GLP-1 of blood glucose concentration in subjects
33:315, 2009a. analogues exenatide (short-acting), exena- with type 2 diabetesresults of a hyper-
Mori A, etal.: Effect of glimepiride and tide (long-acting) and the DPP-4 inhibitor glycaemic glucose clamp study, Nephrol
nateglinide on serum insulin and glucose sitagliptin to increase insulin secretion in Dial Transplant 21:2166, 2006.
concentration in healthy cats, Vet Res healthy cats (abstract), J Vet Intern Med Rees CA, Boothe DM: Evaluation of the effect
Commun 33:957, 2009b. 26:1520, 2012. of cephalexin and enrofloxacin on clinical
Mudaliar S, Henry RR: The incretin hormones: Palm CA, Feldman EC: Oral hypoglycemics in laboratory measurements of urine glucose
from scientific discovery to practical thera- cats with diabetes mellitus, Vet Clin North in dogs, J Am Vet Med Assoc 224:1455,
peutics, Diabetologia 55:1865, 2012. Am Small Anim Pract 43:407, 2013. 2004.
Nakayama H, etal.: Pathological observation of Panciera DL, etal.: Epizootiologic pat- Renda F, etal.: Metformin-associated lactic
six cases of feline diabetes mellitus, Nihon terns of diabetes mellitus in cats: 333 acidosis requiring hospitalization. A
Juigaku Zasshi 52:819, 1990. cases (1980-1986), J Am Vet Med Assoc national 10 year survey and a systemic lit-
Nelson RW, etal.: Effect of an orally adminis- 197:1504, 1990. erature in review, Eur Rev Med Pharmacol
tered sulfonylurea, glipizide, for treatment Parent C, etal.: Serum trypsin-like immunore- Sci 17(Suppl. 1):45, 2013.
of diabetes mellitus in cats, J Am Vet Med activity, amylase and lipase in the diagno- Reusch CE: Feline diabetes mellitus. In Et-
Assoc 203:821, 1993. sis of feline acute pancreatitis (abstract), J tinger SJ, Feldman EC, editors: Textbook of
Nelson RW, etal.: Transient clinical diabetes Vet Intern Med 9:194, 1995. veterinary internal medicine, ed 7,
mellitus in cats: 10 cases (1989-1991), Peakman M: Immunology of type 1 diabetes. In St Louis, 2010, Saunders/Elsevier.
J Vet Intern Med 13:28, 1999. Wass JAH, Stewart PM, Amiel SA, Davies Reusch CE: Diabetic monitoring. In Bonagura
Nelson RW, etal.: Efficacy of protamine zinc MJ, editors: Oxford textbook of endocrinol- JD, Twedt DC, editors: Kirks current vet-
insulin for treatment of diabetes mellitus in ogy and diabetes, ed 2, Oxford, 2011, erinary therapy XV, ed 1, St Louis, 2013,
cats, J Am Vet Med Assoc 218:38, 2001. Oxford University Press. Saunders/Elsevier.
|
Reusch CE, Haberer B: Evaluation of fruc- Schfer S, etal.: Evaluation of insulin-like Thorens B, Mueckler M: Glucose transporters
tosamine in dogs and cats with hypo- or growth factor 1 (IGF-1), thyroxine (T4), in the 21st century, Am J Physiol Endocri-
hyperproteinaemia, azotaemia, hyperlipi- feline pancreatic lipase immunoreactiv- nol Metab 298:141, 2010.
daemia and hyperbilirubinaemia, Vet Rec ity (FPLI) and urinary corticoid creatinine Thoresen SI, Bredal WP: Determination of a
148:370, 2001. ratio (UCCR) in cats with diabetes mel- reference range for fructosamine in feline
Reusch CE, Padrutt I: New incretin hormonal litus in Switzerland and the Netherlands, serum samples, Vet Res Commun 19:353,
therapies in humans relevant to diabetic ECVIM-CA congress Liverpool, 2013. 1995.
cats, Vet Clin North Am Small Anim Pract Senello KA, etal.: Systolic blood pressure in Thoresen SI, etal.: Diabetes mellitus and
43:417, 2013. cats with diabetes mellitus, J Am Vet Med bilateral cataracts in a kitten, J Feline Med
Reusch CE, Tomsa K: Serum fructosamine Assoc 223:198, 2003. Surg 4:115, 2002.
concentration in cats with overt hyperthy- Sieber-Ruckstuhl NS, etal.: Remission of Tschpe D, etal.: The role of co-morbidity in
roidism, J Am Vet Med Assoc 215:1297, diabetes mellitus in cats with diabetic the selection of antidiabetic pharmaco-
1999. ketoacidosis, J Vet Intern Med 22:1326, therapy in type-2 diabetes, Cardiovascular
Reusch CE, etal.: Fructosamine. A new param- 2008. Diabetology 12:62, 2013.
eter for diagnosis and metabolic control in Singh R, etal.: Switching to an ultra-low Tschuor F, etal.: Remission of diabetes mel-
diabetic dogs and cats, J Vet Intern Med carbohydrate diet has a similar effect on litus in cats cannot be predicted by the
7:177, 1993. postprandial blood glucose concentrations arginine stimulation test, J Vet Intern Med
Reusch CE, etal.: Home monitoring of the to administering acarbose to healthy cats 25:83, 2011.
diabetic cat, J Feline Med Surg 8:119, fed a high carbohydrate diet, J Vet Intern Tschuor F, etal.: Evaluation of four methods
2006a. Med 20:726, 2006. abstract. used to measure plasma insulin-like growth
Reusch CE, etal.: Measurements of growth Singleton JR, Smith AG: The diabetic neuropa- factor 1 concentrations in healthy cats
hormone and insulin-like growth factor 1 thies: practical and rational therapy, Semin and cats with diabetes mellitus or other
in cats with diabetes mellitus, Vet Rec Neurol 32:196, 2012. diseases, Am J Vet Res 73:1925, 2012.
158:195, 2006b. Sjaastad OV, etal.: The endocrine system. In Utzschneider KM, etal.: Normal insulin
Reusch CE, etal.: Endocrine hypertension in Sjaastad OV, Sand O, Hove K, editors: secretion in humans. In DeFronzo RA,
small animals, Vet Clin North Am Small Physiology of domestic animals, Oslo, Ferrannini E, Kne H, Zimmet P, editors:
Anim Pract 40:335, 2010. 2010, Scandinavian Veterinary Press. International textbook of diabetes mellitus,
Richter M, etal.: Aldose reductase activity Slingerland LI, etal.: Indoor confinement ed 3, Chichester, West Sussex, 2004, John
and glucose-related opacities in incubated and physical inactivity rather than the Wiley & Sons Ltd.
lenses from dogs and cats, Am J Vet Res proportion of dry food are risk factors in Voulgari C, etal.: Brittleness in diabetes:
63:1591, 2002. the development of feline type 2 diabetes easier spoken than broken, Diabetes Tech-
Ristic JM: Evaluation of a continuous glucose mellitus, Vet J 179:247, 2009. nol Ther 14:835, 2012.
monitoring system in cats with diabe- Smith AG, Singleton JR: Diabetic neuropa- Wade C, etal.: Evidence of a genetic basis
tes mellitus, J Feline Med Surg 7:153, thy, Continuum Lifelong Learning Neurol for diabetes mellitus in Burmese cats
2005. 18:60, 2012. (abstract), J Vet Intern Med 13:269,
Robertson RP: -cell deterioration during Smith DM, etal.: A systematic review of 1999.
diabetes: whats in the gun? Trends in vanadium oral supplements for glycaemic Wajngot A, etal.: The diabetogenic effects of
Endocrinol Metabol 20:388, 2009. control in type 2 diabetes mellitus, Q J glucocorticoids are more pronounced in
Roomp K, Rand J: Intensive blood glucose Med 101:351, 2008. low- than in high-insulin responders, Proc
control is safe and effective in diabetic Smith JR, etal.: A survey of southeastern Natl Acad Sci USA 89:6035, 1992.
cats using home monitoring and treatment United States veterinarians preferences Wang J, Osei K: Proinsulin maturation disorder
with glargine, J Feline Med Surg 11:668, for managing cats with diabetes mellitus, is a contributor to the defect of subse-
2009. J Feline Med Surg 14:716, 2012. quent conversion to insulin in -cells,
Roomp K, Rand J: Evaluation of detemir in Somogyi M: Exacerbation of diabetes by Biochem Biophys Res Commun 411:150,
diabetic cats managed with a protocol for excess insulin action, Am J Med 26:169, 2011.
intensive blood glucose control, J Feline 1959. Wang ZQ, Cefalu WT: Current concepts about
Med Surg 14:566, 2012. Steiner JM: Exocrine pancreatic insufficiency chromium supplementation in type 2
Rossmeisl JH, etal.: Hyperadrenocorticism in the cat, Top Companion Anim Med diabetes and insulin resistance, Curr Diab
and hyperprogesteronemia in a cat with 27:113, 2012. Rep 10:145, 2010.
an adrenocortical adenocarcinoma, J Am Steiner JM, etal.: Development and analytical Washizu T, etal.: Comparison of the activities
Anim Hosp Assoc 36:512, 2000. validation of a radioimmunoassay for the of enzymes related to glycolysis and glu-
Rucinsky R, etal.: AAHA diabetes manage- measurement of feline pancreatic lipase coneogenesis in the liver of dogs and cats,
ment guidelines, J Am Anim Hosp Assoc immunoreactivity in serum, Can J Vet Res Res Vet Sci 67:203, 1999.
46:215, 2010. 23:476, 2004. Weaver KE, etal.: Use of glargine and lente
Rutti S, etal.: Invitro proliferation of adult Strage EM, etal.: Validation of an enzyme- insulins in cats with diabetes mellitus, J
human beta-cells, PLoS ONE 7:1, linked immunosorbent assay for measure- Vet Intern Med 20:234, 2006.
2012. ment of feline serum insulin, Vet Clin Wess G, Reusch C: Capillary blood sampling
Sander C, etal.: Indirect blood pressure mea- Pathol 41:518, 2012. from the ear of dogs and cats and use
surement in cats with diabetes mellitus, Surman S, Fleeman L: Continuous glucose of portable meters to measure glucose
chronic nephropathy and hypertrophic monitoring in small animals, Vet Clin North concentration, J Small Anim Pract 41:60,
cardiomyopathy, Tierarztl Prax Ausg K Am Small Anim Pract 43:381, 2013. 2000.
Kleintiere Heimtiere 26:110, 1998. Tanaka A, etal.: Comparison and expression of Whiting DR, etal.: IDF diabetes atlas: global
Scarlett JM, Donoghue S: Associations between glucokinase gene and activities of enzymes estimates of the prevalence of diabetes for
body condition and disease in cats, J Am related to glucose metabolism in livers 2011 and 2030, Diabetes Res Clin Pract
Vet Med Assoc 212:1725, 1998. between dog and cat, Vet Res Commun 94:311, 2011.
Schfer SA, etal.: New type 2 diabetes risk 29:477, 2005. Wiedmeyer CE, etal.: Evaluation of a continu-
genes provide new insights in insulin Tervaert TW, etal.: Pathologic classification of ous glucose monitoring system for use
secretion mechanisms, Diabetes Res Clin diabetic nephropathy, J Am Soc Nephrol in dogs, cats, and horses, J Am Vet Med
Pract 93:9, 2011. 21:556, 2010. Assoc 223:987, 2003.
Williams DL, Heath MF: Prevalence of feline Yale JF: Oral antihyperglycemic agents and Zini E, etal.: Pancreatic enzymes activity
cataract: results of a cross-sectional study renal disease: new agents, new concepts, J and ultrasonographic findings in diabetic
of 2000 normal animals, 50 cats with Am Soc Nephrol 16:S7, 2005. cats at diagnosis and during follow-up
diabetes and one hundred cats follow- Yardley JE, etal.: Lifestyle issues: exercise. In (abstract), J Vet Intern Med 25:1491,
ing dehydrational crises, Vet Ophthalmol Holt RIG, Cockran CS, Flyvbjerg A, Gold- 2011.
9:341, 2006. stein B, editors: Textbook of diabetes, ed Zini, etal.: Histological investigation of endo-
Williams JM, etal.: Ultrasonographic find- 4, Chichester, Wiley-Blackwell, 2010. crine and exocrine pancreas in cats with
ings of the pancreas in cats with elevated Yki-Jrvinen HE: Insulin resistance in type 2 dia- diabetes mellitus (abstract), J Vet Intern
serum pancreatic lipase immunoreactivity, betes. In Holt RIG, Cockran CS, Flyvbjerg A, Med 26:1519, 2012.
J Vet Intern Med 27:913, 2013. Goldstein B, editors: Textbook of diabetes, Zini E, etal.: Renal morphology in cats with
World Health Organization: Diabetes mellitus ed 4, Chichester, 2010. Wiley-Blackwell. diabetes mellitus, Vet Pathol
report of a WHO expert committee (Tech. Zeugswetter FK, etal.: Alternative sampling Feb 24, 2014 (Epub ahead of print).
Rep. Ser., no 310), (PDF online): Geneva, site for blood glucose testing in cats: Zoran DL: Pancreatitis in cats: diagnosis and
1965, World Health Org. http://whqlibdoc giving the ears a rest, J Feline Med Surg management of a challenging disease, J
.who.int/trs/WHO_TRS_310.pdf. Accessed 12:710, 2010. Am Anim Hosp Assoc 42:1, 2006.
May 22, 2014. Ziegler D: Diabetic peripheral neuropathy. In Zoran DL, Buffington CAT: Effects of nutrition
World Health Organization: WHO expert com- Holt RIG, Cockran CS, Flyvbjerg A, Gold- choices and lifestyle changes on the well-
mittee on diabetes mellitus: second report stein B, editors: Textbook of diabetes, ed being of cats, a carnivore that has moved
(Tech. Rep. Ser., no 646), (PDF online): 4, Chichester, 2010, Wiley-Blackwell. indoors, J Am Vet Med Assoc 239:596,
Geneva, 1980, World Health Org. http://w Zini E, etal.: Hyperglycaemia but not hyper- 2011.
hqlibdoc.who.int/trs/WHO_TRS_646.pdf. lipidaemia causes beta cell dysfunction Zoran DL, Rand JS: The role of diet in the
Accessed May 22, 2014. and beta cell loss in the domestic cat, prevention and management of feline dia-
World Health Organization: Definition, diagno- Diabetologia 52:336, 2009a. betes, Vet Clin North Am Small Anim Pract
sis, and classification of diabetes mellitus Zini E, etal.: Evaluation of a new portable glu- 43:233, 2013.
and its complications: report of a WHO cose meter designed for the use in cats,
consultation. Part 1: diagnosis and clas- Schweiz Arch Tierheilkd 151:448, 2009b.
sification of diabetes mellitus (WHO/NCD/ Zini, etal.: Predictors of clinical remission in
NCS/99.2), (PDF online): Geneva, 1999, cats with diabetes mellitus, J Vet Intern
World Health Org. http://whqlibdoc.who.int Med 24:1314, 2010.
/hq/1999/who_ncd_ncs_99.2.pdf.
Accessed May 22, 2014.
CHAPTER 8 Diabetic Ketoacidosis
Richard W. Nelson
CHAPTER CONTENTS PATHOGENESIS AND PATHOPHYSIOLOGY

Pathogenesis and Pathophysiology, 315
Generation of Ketone Bodies, 315 Generation of Ketone Bodies
Role of Insulin Deficiency, 315
Role of Glucose Counterregulatory Hormones, 316 Ketone bodies are derived from oxidation of nonesterified or free
Physiologic Consequences of Enhanced Ketone fatty acids (FFAs) by the liver and are used as an energy source by
Body Production, 317 many tissues during periods of glucose deficiency. FFAs released
Signalment, 318 from adipose tissue are assimilated by the liver at a rate depen-
History and Physical Examination, 318 dent on their plasma concentration. Within the liver, FFAs can
Establishing the Diagnosis of Diabetic Ketosis be incorporated into triglycerides, can be metabolized via the tri-
and Ketoacidosis, 320 carboxylic acid (TCA) cycle to CO2 and water, or can be con-
In-Hospital Diagnostic Evaluation, 322 verted to ketone bodies (Hood and Tannen, 1994; Kitabchi etal,
Urinalysis and Urine Culture, 322 2001; Fig. 8-1). Oxidation of FFAs leads to the production of
The Minimum Data Base (Ketoacidosis Profile), 323 acetoacetate. In the presence of NADH, acetoacetate is reduced
Completing the Data Base, 327 to -hydroxybutyrate. Acetone is formed by spontaneous decar-
Treatment of Healthy Dogs and Cats with Diabetic Ketosis, 330 boxylation of acetoacetate (see Fig. 8-1). These ketone bodies
Treatment of Sick Dogs and Cats with Diabetic Ketoacidosis, 331 acetoacetate, -hydroxybutyrate, and acetoneare substrates for
Fluid Therapy, 331 energy metabolism by most tissues. The metabolism of ketone
Bicarbonate Therapy, 336 bodies is integrated with that of other substrates of energy metabo-
Insulin Therapy, 337 lism, both in peripheral tissues and in the liver. However, excessive
Concurrent Illness, 340 production of ketone bodies, as occurs in uncontrolled diabetes,
Monitoring and Complications of Therapy, 341 results in their accumulation in the circulation and development
Prognosis, 343 of the ketosis and acidosis of ketoacidosis.
Hyperosmolar Hyperglycemic State, 343
Pathogenesis, 343 Role of Insulin Deficiency
Clinical Findings, 344
Therapy, 344 The most important regulators of ketone body production are
FFA availability and the ketogenic capacity of the liver (McGarry
etal, 1989; Zammit, 1994). For the synthesis of ketone bodies to
be enhanced, there must be two major alterations in intermediary
Diabetic ketoacidosis (DKA) is a serious complication of diabe- metabolism: (1) increased mobilization of FFAs from triglycer-
tes mellitus. Before the availability of insulin in the 1920s, DKA ides stored in adipose tissue and (2) a shift in hepatic metabo-
was a uniformly fatal disorder. Even after the discovery of insu- lism from fat synthesis to fat oxidation and ketogenesis (Hood
lin, DKA continued to carry a grave prognosis with a reported and Tannen, 1994; Kitabchi et al, 2001). Insulin is a powerful
mortality rate in humans ranging from 10% to 30%. However, inhibitor of lipolysis and FFA oxidation (Groop etal, 1989). A
with the expanding knowledge regarding the pathophysiology of relative or absolute deficiency of insulin results in increased activ-
DKA and the application of new treatment techniques for the ity of hormone sensitive lipase in adipocytes, which increases FFA
complications of DKA, the mortality rate for this disorder has release from adipocytesthus increasing the availability of FFAs
decreased to less than 5% in experienced human medical centers to the liver and in turn promoting ketogenesis. Insulin deficiency
(Kitabchi et al, 2008). We have experienced a similar decrease also reduces peripheral utilization of glucose and ketones. The
in the mortality rate for DKA in our hospital over the past two combination of increased production and decreased utilization
decades. DKA remains a challenging disorder to treat, in part leads to an accumulation of glucose and ketones in blood. Virtu-
because of the deleterious impact of DKA on multiple organ sys- ally all dogs and cats with DKA have a relative or absolute defi-
tems and the frequent occurrence of concurrent often serious dis- ciency of insulin (Fig. 8-2). In established diabetic animals after
orders that are responsible for the high mortality rate of DKA. insulin is discontinued and in newly-diagnosed diabetic animals
In humans, the incidence of DKA has not decreased, appropriate that are diagnosed with ketoacidosis on initial examination, cir-
therapy remains controversial, and patients continue to succumb culating insulin levels are low or undetectable. Some dogs and
to this complication of diabetes mellitus. This chapter summarizes cats have serum insulin concentrations similar to those observed
current concepts regarding the pathophysiology and management in healthy, fasted dogs and cats (i.e., within the reference range;
of DKA in dogs and cats. Durocher etal, 2008). However, such insulin concentrations are
315
inappropriately low (relative insulin deficiency) for the severity Moschen, 2006; Vick etal, 2008). The ability to maintain nor-
of hyperglycemia encountered. mal glucose homeostasis represents a balance between the bodys
Some diabetic dogs and cats develop ketoacidosis despite receiv- sensitivity to insulin and the amount of insulin secreted by the
ing daily injections of insulin, and circulating insulin concentra- beta-cell or injected exogenously. With the development of insulin
tions may even be increased. Insulin deficiency per se cannot be resistance, the need for insulin may exceed the daily injected insu-
the sole physiologic cause for the development of DKA. In this lin dose, and this leads to a predisposition for the development of
group, a relative insulin deficiency is present. Presumably these DKA (Fig. 8-3).
dogs and cats have insulin resistance potentially resulting from an
increase in circulating glucose counterregulatory hormones (i.e., Role of Glucose Counterregulatory Hormones
glucagon, epinephrine, cortisol, growth hormone), an increase
in proinflammatory cytokines (e.g., tumor necrosis factor alpha Circulating levels of glucagon, epinephrine, cortisol, and growth
[TNF] and interleukin-6 [IL-6]), an increase in plasma FFAs hormone are typically markedly increased in humans with DKA,
and amino acids, and development of metabolic acidosis (Tilg and as are plasma FFA and amino acid concentrations (Luzi et al,
MUSCLE
Protein EPINEPHRINE
ADIPOCYTE
CORTISOL Amino Lactate (TG)
acids Glucose
Triglyceride
Glycogen
Free fatty
Glycerol Glycerol acid
Alanine Lactate Free fatty
acid
(FFA)
EPINEPHRINE
Glycerol CORTISOL Glucose
GROWTH
Alanine Lactate FFA HORMONE
Pyruvate BLOODSTREAM
Fatty acyl-CoA
LIV
ER
Mitochondrion
TG
Acyl
CE
carnitine
LL
VLDL Very low density lipoprotein (VLDL)

Pyruvate Fatty acyl-CoA
Beta-hydroxybutyrate (-OHB)
Acetoacetate (AcAc)
CO2 oxidation
Acetone
AcCoA Oxalo- Acetyl-CoA
acetate
AcCoA -OHB -OHB Glucose
AcAc- NAD+
Tricarboxylic CoA
acid cycle HMG-CoA NADH
AcAc AcAc
G6P
CO2 GIP
Carbon Mevalonate
dioxide Acetone F6d
and water Glycogen
Cholesterol
Several
Several Oxalo- Phosphoenol
Steps FdP
Steps acetate pyruvate
2PG G3P DHAP
3PG 1,3dPG a-GP
ADP ATP
Glycerol
EPINEPHRINE
GLUCAGON
CORTISOL
FIGURE 8-1 In response to a wide variety of stress situations (e.g., sepsis, heart failure, and pancreatitis), the
body increases its production of the glucoregulatory hormonesinsulin, glucagon, epinephrine, cortisol, and
growth hormone. In diabetes, the lack of insulin allows the glucogenic effects of the stress hormones to be unop-
posed in liver, muscle, and adipose tissue. This results in excess ketone formation, fat and muscle breakdown, and
a classic catabolic state. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; DHAP, dihydroxyacetone phos-
phate; GIP, gastric inhibitory polypeptide; HMG, hydroxymethylglutaryl; NAD+, nicotinamide adenine dinucleotide;
NADH, nicotinamide adenine dinucleotide (reduced form).
|
CHAPTER 8 Diabetic Ketoacidosis 317
1988; Fig. 8-4). Increased circulating concentrations of these also important modulators of ketogenesis, primarily through stim-
counterregulatory hormones cause insulin resistance, stimulate ulation of lipolysis. Both epinephrine and glucagon contribute to
lipolysis and the generation of FFAs in the circulation, and shift insulin resistance by inhibiting insulin-mediated glucose uptake in
hepatic metabolism of FFAs from fat synthesis to fat oxidation muscle and by stimulating hepatic glucose production through an
and ketogenesis (McGarry etal, 1989; Zammit, 1994). Glucagon augmentation of both glycogenolysis and gluconeogenesis (Cher-
is considered the most influential ketogenic hormone. Increased rington etal, 1987; Cryer, 1993). Cortisol and growth hormone
concentrations accompany ketotic states, and low concentrations enhance lipolysis in the presence of a relative or absolute defi-
blunt ketogenesis in ketogenic conditions (Hood and Tannen, ciency of insulin (see Fig. 8-1), block insulin action in peripheral
1994). Glucagon can directly influence hepatic ketogenesis. A low tissues (Bratusch-Marrain, etal, 1982; Boyle, 1993), and potenti-
insulin-glucagon ratio has a direct effect on the liver that promotes ate the stimulating effect of epinephrine and glucagon on hepatic
increased production of ketones (Durocher etal, 2008). However, glucose output (Sherwin et al, 1980). An elevation in plasma
glucagons effects still depend on substrate availability, and keto- FFA concentration and FFA oxidation inhibits insulin-mediated
genesis can occur in the absence of glucagon. Catecholamines are glucose uptake in muscle and stimulates hepatic gluconeogenesis
(Thiebaud etal, 1982; Ferrannini etal, 1983). The combination
of insulin deficiency and excesses in counterregulatory hormones
25,000
also stimulates protein catabolism. Increased plasma amino acid
concentrations impair insulin action in muscle and provide sub-
Serum ketone concentration
20,000
strate to drive gluconeogenesis (Tessari etal, 1985). The net effect
15,000 of these hormonal disturbances is accentuation of insulin defi-
ciency through the development of insulin resistance, stimulation
(mol/L)
10,000 of lipolysis leading to ketogenesis, and stimulation of gluconeo-

genesis, which worsens hyperglycemia. All of these factors lead to
5000 the eventual onset of clinical manifestations associated with DKA.
The body increases its production of the glucose counterreg-
0 ulatory hormones in response to a wide variety of diseases and
stress situations. Although this response is usually beneficial, in
0
0 0 20 40 60 80 100 120 140 160 DKA the activity of these hormones as insulin antagonists usually
A Serum insulin concentration (U/mL) worsens hyperglycemia and ketonemia, provoking acidosis, fluid
depletion, and hypotension. This condition progresses in a self-
25,000 perpetuating spiral of metabolic decompensation (Fig. 8-5). It is
rare for the dog or cat with DKA not to have some coexisting
Serum ketone concentration
20,000 disorder, such as pancreatitis, infection, chronic kidney disease, or

concurrent hormonal disorder. These disorders have the potential
15,000
for increasing glucose counterregulatory hormone secretion. For
(mol/L)
example, infection causes a marked increase in the secretion of

10,000
cortisol and glucagon, heart failure and trauma result in increased
5000 circulating levels of glucagon and catecholamines, and fever
induces secretion of glucagon, growth hormone, catecholamines,
0 and cortisol (Kandel and Aberman, 1983; Feldman and Nelson,
1987). The recognition and treatment of disorders that coexist
0 with DKA are critically important for successful management of
0 0 100 200 300 400 500
DKA (see Fig. 8-3).
B Serum glucagon concentration (pg/mL)
FIGURE 8-2 Scatterplots of serum ketone concentrations versus serum insulin

Physiologic Consequences of Enhanced Ketone
concentration (A) and serum glucagon concentration (B) in 48 dogs with dia-
Body Production
betes mellitus. There was a significant (P < 0.001) linear relationship between
serum ketone concentration and serum glucagon concentration. (From Durocher The physiologic derangements that accompany DKA are a direct
LL, etal.: Acid-base and hormonal abnormalities in dogs with naturally occurring result of relative or absolute insulin deficiency, hyperketone-
diabetes mellitus, J Am Vet Med Assoc 232:1310, 2008.) mia, and hyperglycemia (Box 8-1). In a short-term situation,
PATHOGENESIS OF DKA
Electrolyte deficiency
Insulin Altered metabolic
withdrawal milieu
Relative Insulin Counterregulatory
Beta-cell
insulin DKA resistance hormones
failure
deficiency
Fixed insulin Hypertonicity
dose
Metabolic acidosis
FIGURE 8-3 The pathogenesis of diabetic ketoacidosis (DKA), illustrating the interaction of insulin deficiency and
insulin resistance necessary in the development of the ketoacidotic state.
(1.784ng/mL) as a result of repeated bouts of vomiting, diarrhea, or both com-

bined with a lack of fluid intake; problems that often develop as
the metabolic acidosis worsens (see Fig. 8-5). The excessive loss
in diabetic ketoacidosis
Plasma hormone conc.
(7.92.9ng/mL)
of electrolytes and water leads to further volume contraction,
(46164pg/mL) (727g/dL)
underperfusion of tissues, decline in the glomerular filtration
rate (GFR), and worsening prerenal azotemia and dehydration.
Hyperglycemic dogs and cats with reduced GFR lose the ability to
excrete glucose and, to a lesser degree, hydrogen ions. Glucose and
ketones then accumulate in the vascular space at a more rapid rate.
(123U/ml) The result is increasing hyperglycemia and ketonemia and worsen-
Normal ing metabolic acidosis (see Fig. 8-5). The increase in blood glu-
range cose concentration increases plasma osmolality, and the resulting
Insulin Glucagon Cortisol osmotic diuresis further aggravates the increase in plasma osmo-
Catechols Growth horm. lality by causing water losses in excess of salt loss. The increase in
FIGURE 8-4 Plasma insulin and counterregulatory hormone concentrations in plasma osmolality causes water to shift out of cells, leading to cel-
diabetic ketoacidosis (DKA) (mean standard error of the mean [SEM]). DKA is lular dehydration and the eventual development of obtundation
characterized by relative insulin deficiency and stress hormone excess. Plasma and coma. The severe metabolic consequences of DKA, which
cortisol concentration is characteristically elevated in all humans admitted to include severe acidosis, obligatory osmotic diuresis, hyperosmolal-
the hospital in severe DKA. Although the mean growth hormone concentration ity, dehydration, and electrolyte derangements, ultimately become
also tends to be elevated in ketoacidosis, in many humans this hormone does not life-threatening.
become elevated until therapy is begun with insulin and fluids. (Reprinted from
Schade DS, etal.: Diabetic ketoacidosis: pathogenesis, prevention, and therapy. SIGNALMENT
In Schade DS, etal, editors: Diabetic coma, Albuquerque, 1981, University of New
Mexico Press, p. 84.) DKA is a serious complication of diabetes mellitus that occurs
most commonly in dogs and cats with previously undiagnosed
diabetes. Less commonly, DKA develops in an insulin-treated
the conversion of FFAs to ketone bodies is actually a positive diabetic dog or cat that is receiving an inadequate dosage of insu-
metabolic development. Diabetes mellitus is interpreted physi- lin, which is often in conjunction with a concurrent infectious,
ologically as a state of starvation. With glucose deficiency, ketone inflammatory, or insulin-resistant hormonal disorder. Because of
bodies can be used as an energy source by many tissues. However, the close association between DKA and newly-diagnosed diabetes
increasing plasma glucose and ketone concentrations eventually mellitus, the signalment for DKA in dogs and cats is similar to
surpass the renal tubular threshold for complete reabsorption and that for non-ketotic diabetics (see Chapters 6 and 7). For the most
spill into the urine, inducing an osmotic diuresis. Each gram of part, DKA appears to be a disease of middle-aged and older dogs
glucose excreted via the kidneys adds a solute load of approxi- and cats, although DKA can be diagnosed at any age. In dogs,
mately 6 mOsm. The lower molecular weight of ketones accounts DKA is diagnosed more commonly in females, whereas in cats it
for a greater osmotic load per gram, and excretion of ketones is is more common in males. Any breed of dog or cat can develop
responsible for one-third to one-half of the osmotic diuresis in DKA.
humans with DKA (DeFronzo etal, 1994; Kitabchi etal, 2001).
The anionic charge on the ketones, even at a maximally acid HISTORY AND PHYSICAL EXAMINATION
urine pH, obligates the excretion of positively charged ions (e.g.,
sodium, potassium, calcium, and magnesium) to maintain electri- The history and findings on physical examination are variable, in
cal neutrality. This increased solute excretion impairs the reabsorp- part because of the progressive nature of the disorder and the vari-
tion of water throughout the proximal tubule and loop of Henle, able time between the onset of DKA and owner recognition of a
lowering the concentration of sodium and chloride in the tubu- problem. The spectrum ranges from ketonuric dogs and cats that
lar lumen, creating an increased concentration gradient for their are otherwise healthy, eating, and have not yet developed meta-
reabsorption, and thereby inhibiting their transport from lumen bolic acidosis (i.e., diabetic ketosis [DK]) to ketonuric dogs and
to blood. The result is an excessive loss of electrolytes and water cats that have developed severe metabolic acidosis (i.e., DKA),
with depletion of water roughly twice that of solutes, leading to have severe signs of illness, and are moribund.
volume contraction, underperfusion of tissues, and hypertonicity Polyuria, polydipsia, polyphagia, and weight loss develop ini-
of the extracellular fluid (ECF) compartment. Insulin deficiency tially but are either unnoticed or considered insignificant by the
per se also contributes to the excessive renal losses of water and owner. Systemic signs of illness (i.e., lethargy, anorexia, vom-
electrolytes. Physiologic increases in plasma insulin concentra- iting) ensue as progressive ketonemia and metabolic acidosis
tion augment salt and water reabsorption in both the proximal develop, the severity of systemic signs being directly related to
and distal portions of the nephron and enhance proximal tubular the severity of metabolic acidosis, hyperosmolality, and dehy-
phosphate reabsorption (DeFronzo etal, 1994). Conversely, insu- dration and the nature of concurrent disorders (e.g., pancre-
lin deficiency leads to enhanced water and electrolyte excretion. atitis, infection) that are often present. The time interval from
The formation of ketones by the liver is associated with the pro- the onset of initial clinical signs of diabetes to development of
duction of an equivalent number of hydrogen ions, which titrate systemic signs of illness caused by DKA is unpredictable and
the plasma bicarbonate concentration. As ketones continue to ranges from a few days to several months. Once ketoacidosis
accumulate in the blood, the bodys buffering system becomes begins to develop, however, severe illness typically becomes evi-
overwhelmed, causing an increase in arterial hydrogen ion con- dent within a week.
centration, a decrease in serum bicarbonate, and development of When a severely ill dog or cat is brought to a veterinarian, the
metabolic acidosis. Further loss of water and electrolytes occurs owner may not mention signs that were present prior to those most
INSULIN INSUFFICIENCY
PROTEIN CATABOLISM LIPOLYSIS

GLUCOSE
PRODUCTION
RELEASE OF
And RELEASE OF AA RELEASE OF K+, PO4 GLYCEROL
RELEASE OF FFA
GLUCOSE
UTILIZATION
BETA OXIDATION
HYPERGLYCEMIA HYPERLIPEMIA
KETOGENESIS FATTY LIVER
ABDOMINAL PAIN
GLYCOSURIA
+
[ -OHB]/[AcAc] [H ]
OSMOTIC DIURESIS ANION GAP
KETONURIA
+
+ K LOSS NAUSEA
LOSS OF H2O, K ,
HYPOTHERMIA FLUID INTAKE
Na+, & PO4
HYPERVENTILATION VOMITING
THIRST
DEHYDRATION
POLYDIPSIA
HYPOVOLEMIA
HEMOCONCENTRATION
CHAPTER 8 Diabetic Ketoacidosis

METABOLIC STRESS PRERENAL HYPERVISCOSITY SHOCK ALDOSTERONE CATECHOLAMINES
AZOTEMIA
|
GLUCAGON
CORTISOL K+ LOSS
[H+] [K+] THROMBOSIS ACUTE TUBULAR NECROSIS LIPOLYSIS
GROWTH HORMONE
(CNS, RENAL VEIN) LACTIC ACIDOSIS KETOGENESIS
GLUCOSE PRODUCTION
WBC
GLUCONEOGENESIS INSULIN RESISTANCE
PROTEOLYSIS
INSULIN RESISTANCE
FIGURE 8-5 The interrelationship of the pathophysiologic mechanisms that result in diabetic ketoacidosis (DKA). AA, Amino acids; AcAc, acetoacetate; -OHB, beta-
hydroxybutyrate; CNS, central nervous system; FFAs, free fatty acids; K, potassium; WBC, white blood cells.
319
7
BOX 8-1 P
athophysiologic Derangements in Diabetic
Ketoacidosis 6
hydroxybutyrate (mol/L/)
Hyperglycemia Hyperketonemia Insulin Deficiency 5
Handheld beta-
Osmotic diuresis Osmotic diuresis Electrolyte and fluid
4
Sodium Sodium losses
Potassium Potassium Sodium 3
Water Water Water
Calcium Calcium Phosphate 2
Phosphate Phosphate Negative nitrogen
1 Slope: 0.717 0.058
Intracellular dehydration Metabolic acidosis balance p 0.001
0
0 1 2 3 4 5 6 7 8 9 10
obvious and worrisome at the moment. If the owner is questioned
Laboratory beta-hydroxybutyrate (mol/L)
closely with regard to the past history, the changes noted before
severe illness include the classic history for diabetes mellitus (i.e., FIGURE 8-6 Comparison of -hydroxybutyrate measurements using a laborato-
polyuria, polydipsia, polyphagia, and weight loss). Because of the ry-based enzymatic assay and a handheld ketone meter in 16 dogs and 3 cats.
increased incidence of concurrent diseases, it is imperative that the (From Hoenig M, etal.: Use of a hand-held meter for the measurement of blood
clinician spend ample time obtaining a careful history concerning beta-hydroxybutyrate in dogs and cats, J Vet Emerg Crit Care 18:86, 2008.)
all organ systems. Some diseases (e.g., pyometra, kidney failure,
and hyperadrenocorticism) have historical signs resembling DKA allows the rapid confirmation of diabetes mellitus. The concur-
and can initiate the metabolic derangements leading to DKA in a rent documentation of ketonuria establishes a diagnosis of DK
previously unidentified or insulin-regulated diabetic. or ketoacidosis. The subsequent documentation of metabolic
A complete and careful physical examination is critically impor- acidosis differentiates DKA from DK. Commonly used nitro-
tant in any ketoacidotic animal. The initial physical examination prusside reagent test strips for ketonuria (e.g., Keto-Diastix,
should focus on an evaluation of the status of hydration, on the Ketostix) measure only acetoacetate and its byproduct acetone.
extent of central nervous system (CNS) depression, and on a care- Beta-hydroxybutyrate has no ketone group and is therefore not
ful search for any initiating cause for diabetic decompensation detected by conventional nitroprusside tests. Beta-hydroxybu-
and ultimate ketoacidosis. Diabetic dogs and cats frequently suf- tyrate is formed from acetoacetate in the presence of hydro-
fer from concurrent infections, pancreatitis, cholangiohepatopa- gen ions; the more acidic the diabetic dog or cat is, the more
thy, kidney disease, cardiac disease, or other insulin-antagonistic -hydroxybutyrate is formed. Urine ketone measurements do
disorders (Bruskiewicz etal, 1997; Hume etal, 2006). A careful not reflect the severity of increase in blood -hydroxybutyrate
history, physical examination, and judicious use of laboratory tests concentration, may not reflect the severity of the metabolic
can, in most circumstances, identify underlying concurrent disor- acidosis, and may be negative for ketones in dogs and cats in
ders, lead to appropriate treatment, and increase the likelihood of the early stages of DK and DKA. If ketonuria is not identified
a successful outcome. in a dog or cat with suspected DK or DKA, blood should be
Common physical examination findings suggestive of DKA tested for the presence of -hydroxybutyrate using a quanti-
include lethargy, dehydration, tachypnea, tachycardia, weakness, tative enzymatic assay or a portable blood glucose and ketone
and sometimes a strong odor of acetone on the breath. Slow deep analyzer (e.g., Precision Xtra, Abbott Diagnostics; Fig. 8-6), or
breathing (i.e., Kussmaul respiration) may be observed in ani- plasma from heparinized hematocrit tubes can be used to test
mals with severe metabolic acidosis. Gastrointestinal tract signs for the presence of acetoacetate using urine reagent strips used
(e.g., vomiting and abdominal pain) are common in dogs and to document ketonuria (Duarte etal, 2002; Brady etal, 2003;
cats with DKA; this is in part because of the common concur- Hoenig etal, 2008; Di Tommaso etal, 2009; Zeugswetter and
rent occurrence of pancreatitis. Other intraabdominal disorders Pagitz, 2009).
should also be considered and diagnostic tests (e.g., abdominal In human diabetics, the predominate ketone body produced
ultrasound) performed to help identify the cause of the gastro- during DKA is -hydroxybutyrate. The -hydroxybutyrate-
intestinal signs. Additional physical examination findings associ- to-acetoacetate ratio can range from 3:1 to 20:1 depending on
ated with uncomplicated diabetes mellitus (e.g., hepatomegaly, the severity of hypovolemia, tissue hypoxia, and lactic acidosis
cataracts, peripheral neuropathy) may also be identified (see (Li etal, 1980; Goldstein, 1995). In the presence of circulatory
Chapters 6 and 7). collapse, an increase in lactic acid can shift the redox state to
increase -hydroxybutyrate at the expense of readily detectable
ESTABLISHING THE DIAGNOSIS OF DIABETIC acetoacetate. Severe hyperketonemia could be underestimated or
KETOSIS AND KETOACIDOSIS even undetected if urine reagent test strips or blood tests that
only measure acetoacetate and acetone are used to identify DK
A diagnosis of diabetes mellitus requires the presence of appro- or DKA.
priate clinical signs (i.e., polyuria, polydipsia, polyphagia, and The predominate ketone body produced in diabetic dogs and
weight loss) and documentation of persistent fasting hypergly- cats is also believed to be -hydroxybutyrate. Although serum
cemia and glycosuria. Measurement of the blood glucose con- -hydroxybutyrate concentrations may be mildly increased in
centration using a portable blood glucose monitoring device sick non-diabetic dogs and cats in a negative energy balance,
(see Protocol for Generating the Serial Blood Glucose Curve documenting an increased serum -hydroxybutyrate concen-
in the Hospital in Chapter 6) and testing for the presence of tration in conjunction with hyperglycemia and glycosuria sup-
glycosuria using urine reagent test strips (e.g., Keto-Diastix) ports a diagnosis of DK or DKA, regardless of dipstick test
|
20
1.4 B
1.2
1.0
-Hydroxybutyrate (mmol/L)
12 0.8
0.6
10
0.4
8 0.2
0.0
6 NKD
0
DK DKA
FIGURE 8-7 Serum beta-hydroxybutyrate (-OHB) concentrations from dogs with diabetic ketoacidosis (DKA) and
diabetic ketosis (DK). The small plot (B) is a graphic depiction of serum -OHB concentrations from dogs with non-
ketotic diabetes mellitus (NKD) compared to the reference interval (shaded area). (From Duarte R, etal.: Accuracy
of serum -hydroxybutyrate measurements for the diagnosis of diabetic ketoacidosis in 116 dogs. J Vet Intern Med
16:411, 2002.)
results for ketonuria (Di Tommaso etal, 2009; Zeugswetter etal, 180
2010; Aroch et al, 2012). The magnitude of increase in serum
160
-hydroxybutyrate concentration correlates with the severity of
hydroxybutyrate (percent)
the metabolic acidosis with the highest concentrations identified 140

in dogs with DKA (Duarte et al, 2002; Fig. 8-7). However, a 120
recent study by Durocher, etal., (2008) suggested that acetoac- 100
etate may be the predominate ketone body in some dogs with
DKA. Serum -hydroxybutyrate and total ketone body concen- 80
trations were measured in 48 diabetic dogs. As expected, serum 60
-hydroxybutyrate concentrations were increased in the dogs, but
40
when expressed as a percentage of total serum ketone concen-
tration, serum -hydroxybutyrate concentration decreased from 20
approximately 60% to 20% as serum total ketone concentra- 0
tion (and presumably acetoacetate concentration) increased (Fig. 0 5000 10,000 15,000 20,000 25,000
8-8). These findings suggest that the predominate ketone body Serum ketone concentration (mol/L)
(-hydroxybutyrate versus acetoacetate) may differ between dogs.
FIGURE 8-8 Scatterplot of serum -hydroxybutyrate concentration, expressed as
Regardless, measurement of -hydroxybutyrate in blood is indi-
a percentage of serum ketone concentration, versus serum ketone concentra-
cated whenever DK or DKA is suspected but ketonuria is absent.
tion in 48 dogs with diabetes mellitus. (From Durocher LL, etal.: Acid-base and
In a recent study evaluating plasma and urine ketone mea-
hormonal abnormalities in dogs with naturally occurring diabetes mellitus, J Am
surements using dipstick methodology (Ketostix) in cats with
Vet Med Assoc 232:1310, 2008.)
DK and DKA based on increased plasma -hydroxybutyrate
concentrations, positive plasma and urine test results for ace-
toacetate were found in approximately 46% and 20% of the concentrations greater than 2.55 mmol/L had a sensitivity of 94%
cats, respectively (Zeugswetter and Pagitz, 2009). The sensitiv- but a specificity of 68% for diagnosing ketoacidemia. Many cats
ity of the plasma ketone dipstick test was 100%, and a negative with high -hydroxybutyrate concentrations and normal blood
plasma test result reliably excluded DKA, suggesting that the pH had an elevated chloride gap suggestive of superimposed
plasma ketone dipstick test may be a useful tool to rule out hypochloremic metabolic alkalosis. The authors concluded that
DKA in cats. the ketone meter was a valid tool for excluding DKA in sick dia-
A subsequent study evaluating a hand-held glucose and ketone betic cats and for identifying resolution of ketonemia when treat-
meter (Precision Xtra, Abbott) for measuring -hydroxybutyrate ing a DKA cat.
in whole blood in diabetic cats showed a good linear correla- The aggressiveness of the diagnostic evaluation and treatment
tion with a reference laboratory method at low to moderate of a dog or cat with DKA is dictated primarily by results of the
-hydroxybutyrate concentrations (Zeugswetter and Rebuzzi, history and physical examination. A diagnosis of severe DKA
2012). Unfortunately, a significant negative bias was identified at is indicated in dogs and cats with systemic signs of illness (i.e.,
high concentrations of -hydroxybutyrate. Beta-hydroxybutyrate lethargy, anorexia, and/or vomiting); a physical examination
revealing dehydration, depression, weakness, and/or Kussmaul

respiration; blood glucose concentration greater than 600 mg/ BOX 8-2 C
ommon Clinicopathologic Abnormalities
dL (34 mmol/L); and severe metabolic acidosis as diagnosed Identified in Dogs and Cats with Diabetic
by a total venous CO2 or arterial bicarbonate concentration Ketoacidosis
less than 12 mEq/L. History and physical examination find-
Neutrophilic leukocytosis, signs of toxicity if septic
ings are subjective, however, and a veterinarian may not be able
Hemoconcentration
to obtain quick acid-base information. Therefore, a diagnosis
Hyperglycemia
of severe DKA is often initially based on having an ill dog or
Hypercholesterolemia, lipemia
cat with glucose and ketones in the urine. Dogs and cats with
Increased alkaline phosphatase activity
severe DKA require hospitalization and immediate initiation of
Increased alanine aminotransferase activity
fluid therapy (see Fluid Therapy). Additional diagnostic tests
Increased blood urea nitrogen (BUN) and serum creatinine concentrations
are necessary to care for these animals properly (see the next
Hyponatremia
section), but therapy should proceed while remaining tests are
Hypochloremia
pending.
Hypokalemia
A tentative diagnosis of DK is reserved for diabetic dogs
Metabolic acidosis
and cats that are apparently healthy but have both glucose
Hyperosmolality
and ketones present in the urine. Systemic signs of illness are
Glycosuria
absent or mild, serious abnormalities are not readily identifi-
Ketonuria
able on physical examination, and metabolic acidosis has not
Urinary tract infection
yet developed or is mild (i.e., total venous CO2 or arterial
bicarbonate concentration greater than 16 mEq/L). Dogs and
cats with DK are not in need of immediate aggressive therapy
and must be distinguished from the pet with a critical meta- BOX 8-3 D
iagnostic Tests for Insulin Resistance
bolic emergency. The apparently healthy ketotic diabetic can inDiabetic Dogs and Cats
often be managed conservatively, usually without fluid therapy,
whereas the animal with severe DKA requires a much more Complete blood count (CBC), serum biochemistry panel, and urinalysis
intensive therapeutic plan involving treatments with a variety Bacterial culture of the urine
of contingency alternatives based on numerous assessments of Serum canine/feline pancreatic-specific lipase (SPEC cPL/fPL)
related parameters. (pancreatitis)
Serum trypsin-like immunoreactivity (TLI) (exocrine pancreatic
IN-HOSPITAL DIAGNOSTIC EVALUATION insufficiency)
Adrenocortical function tests
The laboratory evaluation of healthy ketotic diabetic dogs Urine cortisol-to-creatinine ratio (spontaneous hyperadrenocorticism)
and cats is similar to that for non-ketotic diabetics (see Clini- Low-dose dexamethasone suppression test (spontaneous
cal Pathologic Abnormalities in Chapter 6 and Establishing hyperadrenocorticism)
the Diagnosis of Diabetes Mellitus in Chapter 7). The healthy Adrenocorticotropic hormone (ACTH)-stimulation test (iatrogenic
ketotic diabetic can usually be managed conservatively, as hyperadrenocorticism)
contrasted with the needs of an extremely ill DKA pet. Criti- Thyroid function tests
cally important information for formulating the initial treat- Baseline serum total and free thyroxine (hypothyroidism and
ment protocol in the sick DKA pet include hematocrit and hyperthyroidism)
total plasma protein concentration; serum glucose, albumin, Serum thyroid-stimulating hormone (TSH; hypothyroidism)
creatinine, and urea nitrogen concentrations; serum electro- Serum progesterone concentration (diestrus in intact female dog)
lytes; venous total CO2 or arterial acid-base evaluation; and Fasting serum triglyceride concentration (hyperlipidemia)
urine specific gravity. Abnormalities frequently associated with Plasma growth hormone or serum insulin-like growth factor-1 (IGF-1)
DKA are listed in Box 8-2. Once treatment for DKA is initi- concentration (acromegaly)
ated, additional studies (e.g., a complete blood count [CBC], Serum insulin concentration 24 hours after discontinuation of insulin
serum biochemistry panel, urinalysis, urine culture, thoracic therapy (insulin antibodies)
radiographs, and abdominal ultrasound) or diagnostic tests for Abdominal ultrasonography (adrenomegaly, adrenal mass, pancreatitis,
pancreatitis, diestrus in the female dog, and hyperthyroidism pancreatic mass, inflammatory bowel disease, neoplasia)
in the cat are usually warranted to identify underlying concur- Thoracic radiography (cardiomegaly, neoplasia)
rent disorders (Box 8-3). Computed tomography or magnetic resonance imaging (pituitary mass)
From Nelson RW, Couto CG: Small animal internal medicine, ed 5, St Louis, 2014,
Urinalysis and Urine Culture Elsevier/Mosby.
The urinalysis can serve several purposes simultaneously. The
most obvious reason for obtaining a urine sample is to identify
glycosuria and ketonuria. Urinary tract infection is a common and dogs with DKA, we routinely culture urine, regardless of findings
important contributing factor in DKA. The presence of bacteri- on urinalysis (Bailiff etal, 2006). Proteinuria may be the result of
uria, hematuria, and pyuria on urinalysis supports the presence of urinary tract infection or glomerular damage secondary to disrup-
urinary tract infection and the need for culture of a urine sample. If tion of the basement membrane. Evaluation of a urine protein-to-
possible, urine should be obtained by cystocentesis. Because of the creatinine ratio performed on a urine sample void of infection or
high incidence of urinary tract infections in our cats and especially inflammation can help determine if the proteinuria is significant.
|
Azotemia is also common in DKA, and evaluation of urine 1200

specific gravity from a sample of urine obtained prior to initia-
tion of fluid therapy is helpful in differentiating prerenal azote-
mia from primary kidney failure. Urine specific gravity must be 800
assessed with the severity of glycosuria and the hydration status
of the dog or cat kept in mind. If the animal is clinically dehy-

drated and has normal kidney function, its urine specific gravity 600
should be greater than 1.030. Urine specific gravities that are less
than 1.020 are suggestive of primary kidney disease or concur-
rent polyuria/polydipsia disorder (e.g., hyperadrenocorticism). 400
Glycosuria will increase the urine specific gravity measured by
refractometers and should be considered when interpreting
urine specific gravity. As a general rule of thumb, 2% or 4+ gly- 300
cosuria as measured on urine reagent test strips will increase the
urine specific gravity 0.008 to 0.010 when urine specific gravity
is measured by refractometry. 200
Oliguric and anuric kidney failure is an infrequent but grave
complication of DKA. Severe hyperglycemia (> 600 mg/dL; 34
mmol/L) is not likely to occur without a significant reduction Normal
100 range
in the GFR due to primary kidney disease or severe dehydra-
tion and poor renal perfusion. It is critical that urine produc-
tion be closely monitored in the severely ill DKA animal.
Although diabetic dogs and cats are prone to develop infection, 0
72 dogs 20 cats
it is still strongly recommended that the animal with severe with DKA with DKA
DKA and concurrent azotemia have an indwelling urinary
catheter secured in the bladder and attached to a closed col- FIGURE 8-9 Mean and range of blood glucose concentration determined at the
lection system. The urine volume produced over the initial 12 time diabetic ketoacidosis (DKA) was diagnosed in 72 dogs and 20 cats.
hours of therapy can be assessed and oliguric or anuric kidney
failure quickly recognized. Rapid institution of appropriate
measures to improve GFR and urine production can then be
initiated. Urine production should increase once dehydration
900
is corrected and normovolemia restored in the dog or cat with
severe prerenal azotemia and decreased GFR. Once adequate 800
urine production is confirmed, the indwelling urinary catheter
can be removed. 700
600
The Minimum Data Base (Ketoacidosis Profile)
Blood Glucose 500
Although the average blood glucose concentration in dogs and 400

cats with DKA is approximately 500 mg/dL (28 mmol/L), values
can range from close to 200 mg/dL (11 mmol/L) to concentra- 300
tions greater than 1000 mg/dL (56 mmol/L) (Fig. 8-9). Because
hepatic production of glucose is excessive in dogs and cats with 200
DKA and relative or absolute deficiencies of insulin always exist, 100
it is likely that the degree of hyperglycemia is determined pri-
marily by the severity of dehydration and corresponding decrease
in GFR. Evidence suggests that blood glucose concentrations 0 10 20 30 40 50 60
become extremely elevated (i.e., > 600 mg/dL; 34 mmol/L) only Minutes of fluid therapy
when the ECF volume has decreased to the point that urine flow FIGURE 8-10 The effect of fluid therapy on four severely diabetic ketoacidotic
and the capacity to excrete glucose are impaired. Studies have dogs over a period of 1 hour, without insulin administration.
shown a marked reduction in the blood glucose concentration
when humans with DKA were treated solely with fluids (i.e.,
no insulin) (Owen et al, 1981); these findings have also been following a sudden decrease in plasma osmolality; therefore the
seen clinically in diabetic dogs and cats (Fig. 8-10). An associa- rate of blood glucose decline needs to be slower during the initial
tion has been made in diabetic humans between the maximum hours of treatment.
attainable blood glucose concentration and the severity of reduc-
tion in GFR (Kandel and Aberman, 1983). The initial blood Acid-Base Status
glucose concentration also dictates, in part, how aggressive the Metabolic acidosis is one of the hallmark clinical pathologic
initial fluid and insulin therapy should be. The higher the blood changes in DKA and is the direct result of an excess accumulation
glucose concentration, the higher the plasma osmolality, and of ketone bodies in the blood. Excessive serum ketones can over-
the more at-risk the animal is for developing cerebral edema whelm the bodys buffering system, causing an increase in arterial
28
TABLE 8-1 ARTERIAL pH, PCO2, AND HCO3
IN SIMPLE ACUTE ACID-BASE
DISORDERS
Plasma bicarbonate concentration (mmol/L) 24
CONDITION pH ARTERIAL PCO2 TOTAL VENOUS CO2*
Normal
range Acidosis
20
Respiratory
Metabolic
16 Alkalosis
Respiratory
12 Metabolic
Double arrows indicate primary change; HCO3, bicarbonate ion; PCO2, partial pressure
of carbon dioxide.
8 *The total venous CO2 concentration is equal to the arterial bicarbonate concentration.
DKA, 80% were hyponatremic and only 5% were hypernatremic

4
(Bruskiewicz etal, 1997).
Hyponatremia results from excessive urinary sodium loss caused
by the osmotic diuresis induced by glycosuria and ketonuria.
0
Because insulin enhances renal sodium reabsorption in the dis-
72 dogs 20 cats
with DKA with DKA tal portion of the nephron, its absence results in sodium wasting.
Hyperglucagonemia, vomiting, and diarrhea also contribute to
FIGURE 8-11 Mean and range of plasma bicarbonate concentration determined
the sodium loss in DKA (Foster and McGarry, 1983).
at the time diabetic ketoacidosis (DKA) was diagnosed in 72 dogs and 20 cats.
It is important to consider the severity of hyperglycemia when
assessing the severity of hyponatremia in the dog or cat with DKA.
hydrogen ion concentration, a decrease in serum bicarbonate, and Because glucose penetrates cells poorly in the absence of insulin,
a progressively worsening metabolic acidosis (Fig. 8-11). an increase in ECF glucose concentration creates a transcellular
Failure of the kidneys to compensate adequately for the acid osmotic gradient that results in the movement of water out of the
load in DKA is partly the result of the physicochemical proper- cells, a corresponding reduction in the plasma sodium concentra-
ties of -hydroxybutyrate and acetoacetate. The renal threshold tion, and a falsely decreased measured sodium value. In general,
for these acids is low, and appreciable excretion occurs at plasma for every 100 mg/dL of plasma glucose above the reference range,
concentrations only slightly above normal. Thus, the renal plasma sodium concentration decreases by approximately 1.6
tubules are easily overwhelmed when these acids are synthesized mEq/L (DiBartola, 2012). Conversely, as insulin therapy drives
in excessive quantities by the liver. This creates a situation in glucose into the cells, water will follow and the plasma sodium
which the amount of acid present surpasses the renal capacity for concentration will increase. The measured sodium value should
urine acidification. Furthermore, -hydroxybutyrate and aceto- be corrected to a sodium value that accounts for hyperglycemia by
acetate are relatively strong acids (pKa 4.70 and 3.58, respec- using the following formula:
tively). Even at the lowest urinary pH, they are excreted mostly
as sodium and potassium salts, resulting in the concomitant loss Corrected Na + = 1.6 (measured glucose [mg/dL] 100) /100 + measured Na +
of bicarbonate.
Recognition of acidosis is usually straightforward with the use of This reflects that the measured serum sodium value is decreased
arterial blood gas or venous total CO2 determinations (Table 8-1). by approximately 1.6 mEq for every 100 mg/dL increase in glu-
In DKA, the severity of changes in arterial blood gas or venous cose above 100 (Nugent, 2005).
total CO2 depends on the duration and severity of hyperketone- Severe hypertriglyceridemia may occasionally cause factitious
mia at the time of presentation to the veterinarian. Arterial pH can hyponatremia. Severe hypertriglyceridemia can be recognized
range from 7.2 to as low as 6.6. Dogs and cats with arterial blood by the presence of gross lipemia on visual inspection of serum
pH values less than 7.0 have life-threatening DKA and are often or plasma or by the presence of lipemia retinalis on ophthalmo-
difficult to treat successfully (Hume etal, 2006). A tremendous scopic examination and confirmed by measurement of triglyceride
amount of controversy surrounds therapy directed specifically at concentration in serum or plasma. Physiologic saline and Ringers
the acidosis component of DKA. A discussion on the pros and solutions have adequate sodium quantities for replacement of
cons of bicarbonate therapy for animals with severe DKA is found sodium deficiencies and are recommended as the initial fluids of
in the Bicarbonate Therapy section later in this chapter. choice for the treatment of severe DKA (see Fluid Therapy later
in this chapter).
Serum Sodium Concentration
The serum sodium concentration is a reflection of the relative Serum Potassium Concentration
amounts of water and sodium present in the body. With rare During DKA, intracellular dehydration occurs as hyperglycemia
exception, dogs and cats with DKA have significant deficits in and water loss lead to increased plasma and ECF tonicity and a
total body sodium, regardless of the measured serum concentra- shift of water out of cells. This shift of water is also associated
tion. In 72 dogs with DKA, 62% were hyponatremic and only with a shift of potassium into the extracellular space (Kitabchi
7% were hypernatremic (Fig. 8-12). Similarly, in 42 cats with etal, 2001; Fig. 8-13). Potassium shifts are further enhanced by
|
180 8
170 7
Serum potassium concentration (mEq/L)

Serum sodium concentration (mEq/L)
160 6
Normal
range 5
150
Normal
range
140 4
130 3
120 2
110 1
100 0
72 dogs 20 cats 72 dogs 20 cats
with DKA with DKA with DKA with DKA
FIGURE 8-12 Mean and range of serum sodium and potassium concentrations determined at the time diabetic
ketoacidosis (DKA) was diagnosed in 72 dogs and 20 cats.
ECF ECF ECF +

ICF ICF H
+
H+ ICF H H+
H+ H+
K+ K+ K+ K+ K+ K+
PO42 PO42 PO42 PO42 PO42 PO42
A Normal pH B Acidosis C Correction of acidosis

FIGURE 8-13 Redistribution of extracellular fluid (ECF) and intracellular fluid (ICF) hydrogen, potassium, and
phosphate ions in response to a decrease in ECF pH (i.e., acidosis); an increase in ECF glucose and osmolality;
and the translocation of water from the ICF to the ECF compartment and subsequent correction of acidosis and the
intracellular shift of glucose and electrolytes with insulin treatment. A, Normal ECF pH. B, ECF H+ concentration
increases during acidosis, causing H+ to move into cells and down its concentration gradient. Increase in ECF
glucose and osmolality causes extracellular shift of water, K+, and PO4+2. C, ECF H+ concentration decreases during
correction of acidosis, causing H+ to move out of cells. Insulin administration and correction of acidemia cause an
intracellular shift of glucose, K+, and PO4+2, decreasing ECF K+ and PO4+2 concentration.
the presence of acidosis and the breakdown of intracellular pro- were hyperkalemic, respectively, at the time DKA was diagnosed
tein secondary to insulin deficiency. Entry of potassium into cells (Bruskiewicz etal, 1997).
is also impaired in the presence of insulinopenia. The osmotic Knowing the serum potassium concentration and status of
diuresis induced by glycosuria and ketonuria causes marked kidney function is critical when deciding on the aggressiveness
urinary losses of potassium. Secondary hyperaldosteronism of potassium supplementation in the intravenous (IV) fluids.
induced by plasma volume contraction, gastrointestinal losses, Polyuric DKA animals are predisposed to severe hypokalemia,
and decreased dietary intake augment the potassium deficiency and oliguric/anuric animals are predisposed to severe hyperkale-
(Kitabchi etal, 2001). As a consequence, most dogs and cats with mia. Insulin treatment causes a marked translocation of potassium
DKA have a net deficit of total body potassium. Serum potassium from the ECF to the intracellular fluid (ICF) compartment, which
concentrations can be decreased, normal, or increased, depend- when combined with continuing kidney and gastrointestinal loss,
ing on the duration of illness, kidney function, and previous can cause severe hypokalemia during the initial 24 to 48 hours
nutritional state of the dog or cat. Most dogs and cats with DKA of treatment. DKA dogs and cats that are hypokalemic on initial
have either normal or decreased serum potassium concentrations evaluation require aggressive potassium supplementation to their
on pretreatment testing (see Fig. 8-12). In 72 dogs and 42 cats IV fluids to replace deficits and to prevent worsening hypokalemia
with DKA, 43% and 67% were hypokalemic and 10% and 7% (see Monitoring Fluid Therapy later in this chapter).
Blood Urea Nitrogen and Creatinine are permeable to potassium and urea and, as such, these solutes are
The blood urea nitrogen (BUN) and serum creatinine concentra- ineffective osmoles. Hyperosmolality, if present, usually resolves
tions are commonly elevated in DKA (Fig. 8-14) and are useful with IV isotonic fluid and insulin therapy, albeit correction of the
indicators of the severity of volume depletion. When evaluated in hyperosmolar state must be done slowly to minimize the shift of
conjunction with the urine specific gravity and serum calcium and water from the extracellular to the intracellular compartment.
phosphorus concentrations, they can also help to identify concur- Many veterinary hospitals, especially those with a large emer-
rent primary kidney failure versus prerenal azotemia. In addition, gency case load, have the necessary equipment to measure serum
the initial BUN or serum creatinine concentration can serve as a or plasma osmolality directly. One can calculate the approximate
measure of the success of fluid therapy. A rapidly falling BUN and effective osmolality of serum or plasma using the following formula:
serum creatinine concentration in an azotemic dog or cat is con- ( )
Effective ECF Osmolality (mOsm/kg) = 2 Na + + 0.05 (glucose [mg/dL])
sistent with proper fluid therapy, good urine output, and prerenal
azotemia. The increased BUN and serum creatinine concentration or
that is slowly declining or static suggests inadequate fluid therapy ( )
= 2 Na + + glucose (mmol/L)
or primary kidney failure. Serum creatinine concentrations may
also be falsely increased due to interference from acetoacetate with In an insulin deficient state, the intracellular movement of glu-
some automated creatinine assays (Molitch etal, 1980; Nanji and cose in insulin-dependent tissues is impaired and the increase in
Campbell, 1981). extracellular glucose creates an osmotic gradient between the ECF
and ICF compartments. For this reason, glucose is included in cal-
Serum Osmolality culations of effective osmolality. In contrast, potassium and urea
Hyperosmolality is a potentially serious development in DKA, one remain freely permeable across cell membranes regardless of insu-
that can have profound effects on CNS function and conscious- lin concentrations and therefore are not included in calculations of
ness. Of all the factors related to stupor or altered consciousness, effective serum osmolality. The approximate normal range for effec-
including the serum levels of glucose, ketones, or arterial pH, the tive serum osmolality in the dog and cat is 280 to 300 mOsm/kg.
serum osmolality correlates best with the level of consciousness in
humans with DKA. Clouded consciousness is an extremely sub- Anion Gap
jective finding in humans, making recognition of such a problem The metabolic acidosis stemming from hyperketonemia is an
guesswork in dogs or cats. Nevertheless, veterinarians and owners anion gap acidosis, which must be differentiated from other
can usually recognize depression in the dog and cat, and, in our causes of anion gap acidosis (e.g., lactic acidosis, kidney failure,
experience, the severity of this sign roughly correlates with the and/or ethylene glycol intoxication) and from hyperchloremic
severity of hyperosmolality. acidosis (Narins etal, 1994). The anion gap is calculated by sub-
Fortunately, severe hyperosmolality (> 350 mOsm/kg of H2O) tracting the negatively charged anions, chloride and bicarbonate,
occurs infrequently in dogs and cats with DKA, in part because of from the most important positively charged cations, sodium and
the concurrent prevalence of hyponatremia (see Fig. 8-12). Serum potassium. The normal anion gap for dogs and cats is 12 to 16
sodium concentration and, to a lesser extent, glucose are the pri- mEq/L (Feldman and Rosenberg, 1981). Anything greater than
mary determinants of effective serum osmolality. Cell membranes 16 mEq/L indicates the presence of an anion gap acidosis. The
200
1.05
Blood urea nitrogen concentration (mg/dL)
150 1.04
1.03
100
1.02
50
1.01
Normal
range
0 1.00
72 dogs 20 cats 72 dogs 20 cats
with DKA with DKA with DKA with DKA
FIGURE 8-14 Mean and range of blood urea nitrogen (BUN) concentration and urine specific gravity determined at
the time diabetic ketoacidosis (DKA) was diagnosed in 72 dogs and 20 cats.
|
unmeasured anions that comprise the normal anion gap include etal, 1997; Hume etal, 2006). The leukocytosis may occur sec-
albumin and other circulating proteins, sulfate, phosphate, lac- ondary to the release of stress hormones or severe inflamma-
tate, and a variety of organic acids. tion, especially if an underlying pancreatitis is present. White
The typical diabetic dog or cat in ketoacidosis has an anion gap blood cell counts greater than 30,000/L, the presence of toxic
that ranges from 20 to 35 mEq/L, and the increment in the anion or degenerative neutrophils, or a significant left shift toward
gap above baseline approximates the decrement in serum bicarbon- immaturity of the cells supports the presence of a severe inflam-
ate concentration (Adrogu etal, 1982). A number of factors can matory and/or infectious process as the cause of the leukocytosis.
disrupt the normal stoichiometry between acid retention, increment The red blood cell count and hematocrit should be consistent
in the anion gap, and decrease in serum bicarbonate concentration with hemoconcentration secondary to dehydration. A hemato-
(Box 8-4). Such disruption is common in DKA because urinary crit below 35% in these typically volume-contracted animals
loss of ketoanions causes a disproportionately greater decrease in should arouse suspicion that blood loss has occurred or that
serum bicarbonate concentration compared with the increment in significant bone marrow suppression or another problem has
anion gap. In these cases, chloride replaces the missing ketoanion, resulted in anemia.
and a component of hyperchloremic acidosis commonly accompa-
nies the anion gap acidosis (Adrogu etal, 1982; 1984; Table 8-2). Liver Enzymes and Total Bilirubin
Dogs and cats that are volume contracted tend to have a pure anion Clinical pathologic abnormalities associated with the liver are com-
gap acidosis, because the decrease in GFR and tubular avidity for mon in dogs and cats with DKA and are usually caused by hepatic
sodium reabsorption limit the urinary loss of ketone bodies. Con- lipidosis, pancreatitis, severe acidosis, hypovolemia, hypoxia, sep-
versely, animals with DKA able to maintain salt and water intake sis, and, less commonly, extrahepatic biliary obstruction caused by
avoid severe volume depletion. These animals have variable degrees acute severe pancreatitis, acute and chronic hepatitis, and chol-
of hyperchloremic acidosis due to the urinary excretion of ketone angiohepatitis. Serum alanine aminotransferase (ALT), aspartate
salts and a concomitant retention of chloride (see Table 8-2). aminotransferase (AST), and/or alkaline phosphatase (ALP) are
usually increased, even in a non-ketotic diabetic animal. A more
worrisome hepatopathy and/or acute severe pancreatitis should be
Completing the Data Base
suspected when icterus, a marked increase in serum liver enzyme
Complete Blood Count activities (higher than expected with hepatic lipidosis), or abnor-
The CBC in uncomplicated DKA usually reveals a neutrophilic malities involving endogenous liver function tests (e.g., hypoalbu-
leukocytosis without evidence of toxic neutrophils (Bruskiewicz minemia, hypocholesterolemia, increased bile acids) are identified.
Acute and chronic hepatitis and cholangiohepatitis should also be
considered in diabetic dogs and cats with persistent lethargy and
BOX 8-4 Influences of Common Metabolic Disorders anorexia despite correction of the metabolic derangements asso-
on the Calculated Anion Gap* ciated with DKA. Hepatitis and cholangiohepatitis often occur
in conjunction with pancreatitis. When appropriate, abdominal
Increased Anion Gap ultrasound and histologic evaluation of a liver biopsy specimen
Diabetic ketoacidosis (DKA) may be indicated to establish concurrent liver disease.
Lactic acidosis
Tissue ischemia and/or hypoxemia Pancreatic Enzymes
Sepsis Because acute and chronic pancreatitis is so common in dogs
Malignancy and cats with DKA, a diagnostic evaluation for its existence is
Drugs always warranted (Bruskiewicz et al, 1997; Hume et al, 2006).
Uremic acidosis In our experience, abdominal ultrasound is the single best diag-
Ethylene glycol intoxication nostic test for identifying acute and chronic pancreatitis in the
Salicylate intoxication dog or cat with DKA (Fig. 8-15); however, results are equipment
Normal Anion Gap
and operator dependent. Blood tests to assess for the presence of
Diarrhea
pancreatitis should also be considered in the newly-diagnosed dia-
Renal tubular acidosis
betic dog or cat with DKA and in dogs or cats with recurring
Hypoadrenocorticism
bouts of DKA, especially if abdominal ultrasound is not avail-
Hyperchloremic acidosis
able. Measurement of canine and feline pancreatic-specific lipase
Ammonium chloride
(SPEC cPL and SPEC fPL) is currently the blood test of choice for
Carbonic anhydrase inhibitors
identifying pancreatitis (Forman etal, 2004; Trivedi etal, 2011;
McCord etal, 2012). Preliminary studies evaluating a less expen-
*These disorders are frequently associated with metabolic acidosis. sive novel catalytic assay for colorimetric determination of serum
TABLE 8-2 E
XAMPLES OF SERUM ELECTROLYTE CONCENTRATIONS AND THEIR ASSOCIATED
ANION GAPS IN ACIDOSIS
SODIUM (mEq/L) POTASSIUM (mEq/L) CHLORIDE (mEq/L) BICARBONATE (mEq/L) ANION GAP* (mEq/L)
Normal 142 4 108 22 12
Hyperchloremic acidosis 142 4 118 12 12
Anion gap acidosis 142 4 108 12 22
*Anion gap = (Na + K) (Cl + bicarbonate); the normal anion gap is 12 to 16 mEq/L.
Pancreas
A B
FIGURE 8-15 Abdominal ultrasound images of the pancreas (arrows) in a 10-year-old, spayed female Calico cat
diagnosed with severe diabetic ketoacidosis (DKA) and acute pancreatitis. At presentation (A), the pancreas was
enlarged and diffusely hypoechoic. On the fifth day of treatment (B), the pancreas was enlarged with a mixed
echogenic pattern characterized by a hypoechoic center and a hyperechoic periphery, changes consistent with
resolving pancreatitis. The cat underwent diabetic remission 5 weeks after discharge but was euthanized 2 years
later because of reoccurring bouts of pancreatitis and insulin-requiring diabetes.
lipase activity in dogs and cats found substantial agreement with to hyperglycemia and hyperosmolality (Kitabchi et al, 2001; see
SPEC cPL and SPEC fPL results from the same blood samples, Fig. 8-13). Osmotic diuresis subsequently leads to enhanced uri-
suggesting that the novel catalytic assay may offer a cost-effective nary phosphate loss. Serum phosphorus concentrations can be
alternative diagnostic test for pancreatitis in dogs and cats (Graca decreased, normal, or increased, depending on the duration of
et al, 2005; Oppliger et al, 2013). Sensitivity and specificity of illness and kidney function. Most dogs and cats with DKA have
SPEC cPL and SPEC fPL varies between studies and is dependent either normal or decreased serum phosphorus concentrations on
on the severity of pancreatitis and the cutoff value (200 versus 400 pretreatment testing. Hypophosphatemia (< 3.0 mg/dL) was iden-
g/L in dogs; 6.8 versus 10 g/L in cats) used to differentiate nor- tified at initial presentation in 24% of 72 dogs and 48% of 42 cats
mal from pancreatitis (McCord etal, 2012; Bostrom etal, 2013). with DKA (Bruskiewicz etal, 1997). In contrast, hyperphosphate-
Serum SPEC cPL and SPEC fPL concentrations can be increased mia (> 6.0 mg/dL) was identified in 14% and 26% of DKA dogs
in dogs and cats with a histologically confirmed normal pancreas and cats, respectively, and usually occurred in conjunction with
and normal in dogs and cats with histologically confirmed inflam- kidney failure.
mation of the pancreas, especially when the inflammatory process Insulin treatment causes a marked translocation of phosphorus
is chronic and mild (Forman etal, 2004; McCord etal, 2012). from the ECF to the ICF compartment. Within 24 hours of ini-
Interpretation of serum SPEC cPL and SPEC fPL results should tiating treatment for DKA, serum phosphorus concentration can
always be done in context with the history, physical examination, decline to severe levels (i.e., < 1 mg/dL) as a result of the dilutional
and additional findings on laboratory tests. Recognition of con- effects of fluid therapy, the intracellular shift of phosphorus fol-
current pancreatitis in the dog or cat with DKA has important lowing the initiation of insulin therapy, and continuing kidney
implications regarding initial fluid therapy, subsequent dietary and gastrointestinal loss (Willard etal, 1987). Clinical signs usu-
therapy, and prognosis. Fortunately, fluid therapy is the corner- ally do not develop until the serum phosphorus concentration is
stone of treatment for both DKA and pancreatitis. less than 1.5 mg/dL, and even at these low levels many dogs and
cats remain asymptomatic. Hypophosphatemia primarily affects
Calcium and Phosphorus the hematologic and neuromuscular systems in the dog and cat
The serum calcium and phosphorus concentrations are usually (Forrester and Moreland, 1989). Hemolytic anemia is the most
normal in the diabetic dog or cat with uncomplicated DKA. If common and serious sequela to hypophosphatemia. Hypophos-
concurrent primary kidney failure is present, the serum calcium phatemia may decrease erythrocyte concentration of adenosine
concentration is typically normal, whereas the serum phosphorus triphosphate (ATP) and/or alter red blood cell membrane lipids,
concentration is increased. Hypocalcemia may occur in dogs and which increases erythrocyte fragility, leading to hemolysis (Shilo
cats with concurrent pancreatitis, hypomagnesemia, or hypopro- et al, 1985; Adams et al, 1993). Hemolysis is usually not iden-
teinemia. The hypocalcemia is usually mild and does not require tified until the serum phosphorus concentration is 1 mg/dL or
treatment per se. Hypercalcemia supports the existence of concur- less. Hemolytic anemia can be life threatening if not recognized
rent disease affiliated with the development of hypercalcemia (see and treated. Neuromuscular signs include weakness, ataxia, and
Chapter 15). seizures, as well as anorexia and vomiting secondary to intestinal
Attention has been directed to serum phosphorus concentra- ileus. Phosphate therapy is indicated if clinical signs or hemoly-
tions in dogs and cats with DKA, especially during the initial sis are identified or if the serum phosphorus concentration is less
24 hours of treatment. Phosphate, along with potassium, shifts than 1.5 mg/dL, especially if a further decrease is possible (see
from the intracellular to the extracellular compartment in response Phosphate Supplementation).
|
Magnesium
The osmotic diuresis of DKA may cause significant urinary losses BOX 8-5 E
lectrocardiographic Alterations Associated
of magnesium and the development of hypomagnesemia (serum with Hypokalemia and Hyperkalemia
total magnesium concentration < 1.5 mg/dL; serum ionized mag- in the Dog and Cat
nesium concentration measured by ion-selective electrode < 1.0
mg/dL; Norris etal, 1999a; Fincham etal, 2004). In addition, the Hypokalemia
nature of the translocation of magnesium between the ICF and Depressed T-wave amplitude
ECF compartments is similar to potassium in that factors that Depressed ST segment
promote a shift of potassium into the ICF compartment (e.g., Prolonged QT interval
alkalosis, insulin, and/or glucose infusion) promote a similar shift Prominent U wave
in magnesium. During therapy for DKA, the serum total and ion- Arrhythmias
ized magnesium concentration can decline to severely low levels Supraventricular
(i.e., less than 1 mg/dL and 0.5 mg/dL, respectively) as a result Ventricular
of the dilutional effects of fluid therapy and the intracellular shift Hyperkalemia
of magnesium after the initiation of insulin therapy (Norris etal, Spiked T waves
1999a; Hume etal, 2006). Clinical signs of hypomagnesemia do Flattened P waves
not usually occur until the serum total magnesium concentration Prolonged PR interval
is less than 1.0 mg/dL, and even at these low levels, many animals Prolonged QRS interval
remain asymptomatic. Decreased R-wave amplitude
A magnesium deficiency can result in several nonspecific clini- Bradycardia
cal signs, including lethargy, anorexia, muscle weakness (includ- Complete heart block
ing dysphagia and dyspnea), muscle fasciculations, seizures, ataxia, Ventricular arrhythmias
and coma (Abbott and Rude, 1993; Martin et al, 1993; Dhupa Cardiac arrest
and Proulx, 1998). Concurrent hypokalemia, hyponatremia, and
hypocalcemia occur in animals with hypomagnesemia, although
the prevalence of these electrolyte abnormalities may differ between during management of DKA, and magnesium supplementation
species. These electrolyte abnormalities may also contribute to is not recommended unless hypomagnesemia is documented in
the development of clinical signs. Magnesium is a cofactor for dogs and cats with complications that have been associated with
all enzyme reactions that involve ATP, most notably the sodium- hypomagnesemia (e.g., persistent lethargy and anorexia; refractory
potassium ATPase pump. Deficiencies in magnesium may cause hypokalemia, hypocalcemia, or both).
potassium-losing nephropathy and potassium wastage from the
body and the resultant hypokalemia may be refractory to appro- Diagnostic Imaging
priate potassium replacement therapy. Magnesium deficiency may Concurrent disorders (e.g., acute or chronic pancreatitis, pyome-
inhibit parathyroid hormone (PTH) secretion from the parathyroid tra, cholangiohepatitis, heart failure, bacterial pneumonia, and
gland, resulting in hypocalcemia (Bush et al, 2001). Magnesium concurrent endocrinopathies) are common in dogs and cats with
deficiency causes the resting membrane potential of myocardial cells DKA. Many of these disorders actually perpetuate the metabolic
to be decreased and leads to increased Purkinje fiber excitability, derangements of DKA. Successful treatment of DKA requires rec-
with the consequent generation of arrhythmias (Abbott and Rude, ognition and treatment of these concurrent disorders. Abdominal
1993). Electrocardiographic changes include a prolonged PR inter- and thoracic radiographs as well as abdominal ultrasonography
val, widened QRS complex, depressed ST segment, and peaked T are invaluable in confirming problems suspected after a review of
waves. Cardiac arrhythmias associated with magnesium deficiency the history and physical examination and in identifying problems
include atrial fibrillation, supraventricular tachycardia, ventricular previously unsuspected. In our hospital, thoracic radiography and
tachycardia, and ventricular fibrillation. Hypomagnesemia also pre- abdominal ultrasonography are routine components of the diag-
disposes animals to digitalis-induced arrhythmias. nostic evaluation of any sick DKA dog or cat. However, radio-
Unfortunately, assessing an animals magnesium status is prob- graphs and ultrasound scans are not usually obtained until more
lematic because there is no simple, rapid, and accurate laboratory critical laboratory data (i.e., the ketoacidotic profile) have been ana-
test to gauge total body magnesium status. Serum total magne- lyzed and appropriate treatment for DKA initiated.
sium represents 1% of the bodys magnesium stores, and serum
ionized magnesium represents 0.2% to 0.3% of total body mag- Electrocardiogram
nesium stores. As a result, serum total and ionized magnesium The electrocardiogram (ECG) can be used to document and charac-
concentrations do not always reflect total body magnesium status. terize suspected cardiac arrhythmias and for monitoring changes in
A normal serum magnesium concentration may exist despite an serum potassium concentration during treatment of DKA. Use of
intracellular magnesium deficiency. However, a low serum mag- the ECG is especially helpful for recognizing severe hypokalemia or
nesium concentration would support the presence of a total body hyperkalemia in hospitals where frequent monitoring of the serum
magnesium deficiency, especially when clinical signs or concurrent potassium concentration is difficult because of lack of a point-of-
electrolyte abnormalities are consistent with hypomagnesemia. care chemistry analyzer or because of economic constraints. The
Magnesium exists in three distinct forms in serum: an ionized primary concern prior to and during treatment of DKA is hypo-
fraction, an anion-complexed fraction, and a protein-bound frac- kalemia. It must be emphasized that hypokalemia usually causes
tion. A serum ionized magnesium concentration determined subtle changes in the ECG, especially when the serum potassium
using an ion-selective electrode more accurately assesses total concentration is above 3.0 mEq/L (Box 8-5; Fig. 8-16). Changes
body magnesium content than measurement of serum total mag- in the ECG are more obvious when the serum potassium concen-
nesium and is recommended (Norris etal, 1999b). Fortunately, tration is between 2.5 and 3.0 mEq/L, and alterations invariably
hypomagnesemia is not usually a clinically recognizable problem occur with serum potassium levels below 2.5 mEq/L.
Normokalemia (4.5 mEq/L)
QRS
P wave T wave
Moderate hypokalemia (2.8 mEq/L)
T wave U wave
ST segment depressed
Taller R Severe hypokalemia (1.8 mEq/L)
Wider QRS
U wave
Taller and wider P

prolonged PR
FIGURE 8-16 Profiles of serum potassium are reflected in the electrocardiogram (ECG). These changes are exag-
gerated here for illustration purposes. In practice, these changes can be quite subtle, indicating the necessity of a
baseline ECG with simultaneous laboratory serum potassium.
The basic electrophysiologic alteration with hypokalemia is a the insulin treatment regimen and evaluation for concurrent dis-
gradual shift of the repolarization wave away from systole into orders should be undertaken. If systemic signs of illness are absent
diastole. The most consistent change on the ECG is prolonga- or mild, inappetence is not present, serious abnormalities are not
tion of the QT interval. Additional findings include a progressive readily identifiable on physical examination, and metabolic acido-
sagging of the ST segment, a decreased amplitude of the T wave, sis is mild (i.e., total venous CO2 or arterial bicarbonate concen-
and a repolarization wave occurring after the T wave (U wave). In tration greater than 16 mEq/L), short-acting regular crystalline
advanced hypokalemia, the amplitude and duration of the QRS insulin can be administered subcutaneously three times daily until
complex are increased. It is believed that the QRS complex widens the ketonuria and ketonemia resolves. Fluid therapy and intensive
diffusely secondary to a generalized slowing of conduction in the care are usually not needed. Because regular crystalline insulin is
ventricular myocardium or Purkinje fibers. The amplitude and the potent insulin, the initial dosage (0.1 to 0.2 U/kg/injection) is
duration of the P wave increase, and the PR interval is slightly lower than that recommended for longer-acting insulin prepara-
prolonged with hypokalemia. Atrial and ventricular premature tions. To minimize hypoglycemia, the dog or cat should be fed
contractions may also occur. one-third of its daily caloric intake at the time of each insulin
A complete description of the ECG findings in hyperkalemia is injection. Subsequent adjustments in the insulin dose are based
available in Chapter 12. on clinical response and results of blood glucose measurements.
Urine ketone concentrations should be monitored and, if avail-
able, blood glucose and -hydroxybutyrate concentrations using a
TREATMENT OF HEALTHY DOGS AND CATS
portable glucose and ketone meter (e.g., Precision Xtra, Abbott).
WITH DIABETIC KETOSIS
A decrease in the blood glucose concentration implies a decrease
Diabetic dogs and cats that have ketonuria but not metabolic aci- in ketone production. This, in combination with metabolism of
dosis (i.e., DK) are often relatively healthy aside from the typical ketones and loss of ketones in urine, will usually correct keto-
clinical signs of uncontrolled diabetes mellitus. DK may be identi- sis within 48 to 96 hours of initiating insulin therapy. Prolonged
fied in newly-diagnosed diabetic dogs and cats or in diabetic dogs ketonemia and ketonuria is suggestive of a significant concurrent
and cats that are being treated with insulin. Identification of keto- illness (e.g., chronic pancreatitis) or inadequate blood insulin con-
nuria in insulin-treated diabetic dogs and cats indicates that insu- centrations to suppress lipolysis and ketogenesis. Once the ketosis
lin treatment has become ineffective, usually because of a problem has resolved, insulin therapy may be initiated using longer-acting
with the insulin treatment regimen, development of a concurrent insulin preparations (see Chapters 6 and 7). As a general rule of
disorder causing insulin resistance, or both. Critical evaluation of thumb, the initial dosage of the longer-acting insulin preparation
|
BOX 8-6 Initial Management of the Dog or Cat with Severe Diabetic Ketoacidosis
Fluid Therapy Low-dose IV infusion technique: To prepare infusion, add 2.2 U/kg (dogs)
Type: 0.9% saline solution if hyponatremia is severe (< 130 mEq/L); isotonic or 1.1 U/kg (cats) of regular insulin to 250 mL of 0.9% saline; run 50
crystalloid solution, such as Ringers, lactated Ringers solution, Plasma- mL through the drip set and discard; then administer via infusion or
Lyte 148, or Normosol-R if serum sodium concentration 130 mEq/L syringe pump through a line separate from that used for fluid therapy
Rate: 60 to 100 mL/kg/24 hours initially; adjust based on hydration status, at an initial rate of 10 mL/hr; adjust infusion rate according to hourly
urine output, persistence of fluid losses blood glucose measurements; switch to SC regular insulin every 6 to
Potassium supplement: Based on serum K+ concentration (see Table 8-4); if 8 hours once blood glucose is less than 250 mg/dL or continue insulin
unknown, initially add 40 mEq KCl to each liter of fluids infusion at a decreased rate to prevent hypoglycemia until the IV insu-
Phosphate supplement: Administer if serum phosphorus concentration < lin preparation is exchanged for a longer-acting preparation
1.5 mg/dL; initial IV infusion rate is 0.01 to 0.03 mmol phosphate/kg/hour Goal: Gradual decline in blood glucose concentration, preferably around 50
in calcium-free IV fluids mg/dL/hr (2.8 mmol/L/hr) until concentration is less than 250 mg/dL (14
Dextrose supplement: Not indicated until blood glucose concentration is mmol/L)
less than 250 mg/dL (14 mmol/L), then begin 5% dextrose infusion
Ancillary Therapy
Bicarbonate Therapy Concurrent pancreatitis is common in DKA; nothing by mouth and intensive
Indication: Administer if plasma bicarbonate concentration is less than 12 fluid therapy usually indicated
mEq/L or total venous CO2 concentration is less than12 mmol/L; if not Concurrent infections are common in DKA; use of broad-spectrum, parenteral
known, do not administer unless animal is severely ill and then only once antibiotics usually indicated
Amount: mEq HCO3- = body weight (kg) 0.4 (12 animals HCO3-) Additional therapy may be needed, depending on nature of concurrent
0.5; if animals HCO3- or total CO2 concentration is unknown, use 10 in disorders
place of (12 animals HCO3-)
Patient Monitoring
Administration: Add to IV fluids and give over 6 hours; do not give as bolus
Blood glucose measurement every 1 to 2 hours initially; adjust insulin
infusion
therapy and begin dextrose infusion when decreases below 250 mg/dL
Retreatment: Only if plasma bicarbonate concentration remains less than
(14 mmol/L)
12 mEq/L after 6 hours of therapy
Hydration status, respiration, pulse every 2 to 4 hours; adjust fluids accordingly
Insulin Therapy Serum electrolyte and total venous CO2 concentrations every 4 to 8 hours;
Type: Regular crystalline insulin adjust fluid and bicarbonate therapy accordingly
Administration technique: Urine output, glycosuria, urine and plasma ketones every 4 to 8 hours; adjust
Intermittent IM technique: Initial dose, 0.1 to 0.2 U/kg IM; then 0.1 U/ fluid therapy accordingly
kg IM hourly until blood glucose concentration is less than 250 mg/dL Body weight, packed cell volume, temperature, and blood pressure every 6 to
(14 mmol/L), then switch to IM regular insulin every 4 to 6 hours or SC 8 hours
regular insulin every 6 to 8 hours Additional monitoring, depending on concurrent disease
DKA, Diabetic ketoacidosis; IM, intramuscular; IV, intravenous; SC, subcutaneous.
is approximately the same as the dosage of regular crystalline insu- change. If all abnormal parameters can be slowly returned toward
lin being administered at the time the switch in insulin is made normal over a period of 24 to 48 hours, therapy is more likely to
with subsequent adjustments in the dosage based on the animals be successful.
response to the insulin.
Fluid Therapy
TREATMENT OF SICK DOGS AND CATS WITH
Fig. 8-17 shows a flowchart for fluid therapy.
DIABETIC KETOACIDOSIS
Intensive therapy is called for if the dog or cat has systemic signs of Composition and Rate of Administration
illness (e.g., lethargy, anorexia, and/or vomiting); physical exami- Initiation of appropriate fluid therapy should be the first step in
nation reveals dehydration, depression, weakness, or a combina- the treatment of DKA, and in most cases it should precede the
tion of these; or metabolic acidosis is severe (i.e., total venous initiation of insulin therapy by 2 hours or longer to minimize the
CO2 or arterial bicarbonate concentration less than 12 mEq/L). development of complications affiliated with insulin administra-
The five goals of treatment of a severely ill diabetic dog or cat tion (see Monitoring and Complications of Therapy). Replace-
with ketoacidosis are (1) to restore water and electrolyte losses; ment of fluid deficiencies and maintenance of normal fluid
(2) to provide adequate amounts of insulin to suppress lipolysis, balance are critical to ensure adequate cardiac output, blood pres-
ketogenesis, and hepatic gluconeogenesis; (3) to correct acidosis; sure, and blood flow to all tissues. Improvement of renal blood
(4) to identify the factors precipitating the present illness; and (5) flow is especially critical. In addition to the general beneficial
to provide a carbohydrate substrate (i.e., dextrose) when neces- aspects of fluid therapy in any dehydrated animal, fluid therapy
sary to allow continued administration of insulin without causing can correct the deficiency in total body sodium and potassium,
hypoglycemia (Box 8-6). Proper therapy does not mean forcing dampen the potassium-lowering effect of insulin treatment, and
a return to a normal state as rapidly as possible. Because osmotic lower the blood glucose concentration in diabetics, even in the
and biochemical problems can arise as a result of overly aggressive absence of insulin administration (see Fig. 8-10). Fluids enhance
therapy as well as from the disease itself, rapid changes in various glucose excretion by increasing glomerular filtration and urine
vital parameters can be as harmful as, or more harmful than, no flow, and they decrease secretion of the diabetogenic hormones
Fluid therapy
Initial fluid 0.9% (normal) saline

if serum Na 130mEq/L
Plasma-Lyte 148 or Ringers
If serum Na 130 mEq/L
Dose in mL for first 24 hrs:

(Percent dehydration x b.w. kg x 1000) + (20 mL/kg/day)+ (20-40 mL/kg/day)
Insensible loss Urine output
best to monitor direct
Monitor:
1. Direct or indirect doppler blood pressure
2. Urine output, glycosuria, urine, and plasma ketones every 4 to 8 hours
3. Hydration status, respiration, pulse every 2 to 4 hours
4. Serum electrolytes and blood gases every 4 to 8 hours
5. Blood glucose every 1 to 2 hours
Blood glucose is 250 mg/dL (14mmol/L) or less
Add glucose to
make 5% solution
Serum sodium Serum sodium Serum sodium

130 mEq/L 130-155 mEq/L 155 mEq/L
Continue normal Plasma-Lyte 148

Ringers lactate
saline or Ringers solution
FIGURE 8-17 Intravenous (IV) fluid treatment plans for the dog or cat in diabetic ketoacidosis (DKA).
that stimulate hyperglycemia. The gradual decline in blood glu- lactate, and Plasma-Lyte 148 and Normosol-R contain acetate.
cose combined with replacement of sodium for glucose in the Lactate and acetate are metabolized to bicarbonate. A theoreti-
ECF helps minimize the intracellular shift of water caused by a cal contraindication for the use of crystalloid solutions that con-
rapid decrease in ECF osmolality, thereby preventing cerebral tain lactate centers on the increase in serum lactate concentration
edema (see Central Nervous System Signs [Cerebral Edema] under that could occur with use of these fluids. Lactate is metabolized
Monitoring and Complications of Therapy). Unfortunately, fluid in the liver in a similar manner as ketones, and hyperketonemia
therapy alone does not suppress ketogenesis (Foster and McGarry, could reduce hepatic lactate metabolism. As such, administration
1983; Lebovitz, 1995). For this reason, insulin is always required of fluids containing lactate could increase lactate concentrations
to resolve the ketoacidotic state. in the circulation and, because lactate is a negatively charged ion,
The type of parenteral fluid initially used depends on the ani- promote further sodium and potassium loss in the urine as lactate
mals electrolyte status, blood glucose concentration, and osmo- is excreted (Macintire, 1995). However, in our experience, use of
lality. With rare exceptions, all dogs and cats with DKA have lactated Ringers solution has not had a recognizable deleterious
significant deficits in total body sodium, regardless of the measured impact on development of complications or resolution of DKA
serum concentration (see Serum Sodium Concentration earlier). in dogs and cats. Lactated Ringers solution can be used in lieu of
Ringers solution or Plasma-Lyte 148 (Baxter Healthcare Corp.) 0.9% saline to minimize the chloride load in animals that develop
can be used for mild hyponatremia (serum sodium concentration hyperchloremic acidosis during treatment of DKA.
of more than 130 mEq/L) and 0.9% (physiologic) saline solution Most dogs and cats with severe DKA usually are sodium
for more severe hyponatremia (serum sodium concentration of depleted and therefore not suffering from dramatic hyperosmo-
less than 130 mEq/L) with appropriate potassium supplementa- lality. Hypotonic fluids (e.g., 0.45% saline) are rarely indicated
tion (see Fig. 8-17). Alternative isotonic crystalloid solutions that in dogs and cats with DKA, even when severe hyperosmolality
could be used include lactated Ringers solution and Normosol-R is present. Hypotonic fluids do not provide adequate amounts of
(Abbott Laboratories). Each of these solutions has a slightly dif- sodium to correct the sodium deficiency, restore normal fluid bal-
ferent electrolyte composition; none contain as much sodium ance, or stabilize blood pressure. Rapid administration of hypo-
as 0.9% saline (Table 8-3). Lactated Ringers solution contains tonic fluids can also cause a rapid decrease in the osmolality of
|
TABLE 8-3 ELECTROLYTE COMPOSITION OF COMMERCIALLY AVAILABLE FLUIDS
NA+ CL K+ GLUCOSE BUFFER* OSMOLARITY

FLUID (mEq/L) (mEq/L) (mEq/L) (g/L) (mEq/L) (mOsm/L)
0.9% saline 154 154 0 0 0 308
0.45% saline 77 77 0 0 0 154
Ringers solution 147 156 4 0 0 310
Lactated Ringers solution 130 109 4 0 28 (L) 272
Plasma-Lyte 148 140 98 5 0 27 (A) 295
Normosol-R 140 98 5 0 27 (A) 296
Normosol-M 40 40 13 0 16 (A) 112
Plasma-Lyte 56 40 40 13 0 16 (A) 110
5% dextrose in water 0 0 0 50 0 252
*Buffers used: A, acetate; L, lactate.

Baxter Healthcare Corp., Deerfield, IL.
Abbott Laboratories, Chicago, IL.
ECF, which may result in cerebral edema, deterioration in menta- oliguric or anuric renal failure. Failure to produce urine within
tion, and eventually coma (see Monitoring and Complications of several hours of initiating fluid therapy is an alarming sign, and
Therapy). Hyperosmolality is best treated with isotonic fluids and one that demands rapid recognition and an aggressive course
the judicious administration of insulin. of action. If urine production is in doubt, an indwelling uri-
The initial volume and rate of fluid administration are deter- nary catheter should be secured in the bladder and attached
mined by assessing the degree of shock, the dehydration deficit, to a closed collection system. Palpation of the bladder is not
the animals maintenance requirements, plasma protein concen- an accurate method for assessing urine output. A minimum of
tration, and presence or absence of cardiac disease. Fluid adminis- 1.0 to 2.0 mL of urine per kilogram of body weight per hour
tration should be directed at gradually replacing hydration deficits should be produced following the initial phase of fluid therapy.
over 24 hours while also supplying maintenance fluid needs and If urine production is minimal, the patency of the urinary cath-
matching ongoing losses. Rapid replacement of fluids is rarely eter should be checked, the adequacy of fluid therapy evaluated
indicated unless the dog or cat is in shock. Once out of this critical (e.g., CVP, arterial blood pressure, subjective signs of excessive
phase, fluid replacement should be decreased in an effort to cor- or inadequate fluids), and then attempts should be made to
rect the fluid imbalance in a slow but steady manner. As a general induce or increase the volume of urine produced with diuretics,
rule of thumb, a fluid rate of 1.5 to 2 times maintenance (i.e., 60 mannitol, and/or dopamine.
to 100 ml/kg/24 hr) is typically chosen initially with subsequent Frequent assessment (ideally every 4 to 8 hours initially) of
adjustments based on frequent assessment of hydration status, serum electrolytes and total venous CO2 or arterial blood gases
urine output, severity of azotemia, and persistence of vomiting should be done and adjustments in fluid type and supplements
and diarrhea. made accordingly. Changes in serum electrolyte concentrations
and blood gases are common and unpredictable during the initial
Monitoring Fluid Therapy 24 hours of treatment and the type of fluid (e.g., 0.9% saline,
The rate of fluid administration and its effects on the animal Plasma-Lyte 148, lactated Ringers solution) and presence and
must be monitored. Overzealous fluid therapy can lead to over- amount of supplements (e.g., potassium, bicarbonate) in the flu-
hydration, pulmonary edema, and other third-space fluid loss ids typically need to be adjusted several times during this period
with potentially serious consequences. Inadequate fluid admin- of time.
istration can result in prolonged tissue underperfusion, hypoxia,
continuing pancreatitis (if present), persistent prerenal azote- Potassium Supplementation
mia, and the potential for development of primary kidney fail- Fig. 8-18 shows a flow chart of potassium therapy.
ure. Evaluation of fluid therapy should include subjective and Most dogs and cats with DKA have a net deficit of total body
objective assessments. Subjectively, the animals alertness, heart potassium due primarily to the marked urinary losses caused by the
rate, mucous membrane moisture, capillary refill time, pulse osmotic diuresis of glycosuria and ketonuria. Most dogs and cats
pressure, and skin turgor should be monitored and frequent pul- with DKA initially have either normal or decreased serum potas-
monary and cardiac auscultation performed. Objectively, serial sium concentrations (see Fig. 8-12). During therapy for DKA, the
evaluation of direct arterial or indirect Doppler blood pressure serum potassium concentration decreases because of rehydration
measurements, central venous pressure (CVP), urine output, (dilution), insulin-mediated cellular uptake of potassium (with
body weight, and serum osmolality should be considered or glucose), continued urinary losses, and correction of acidemia
completed. (translocation of potassium into the ICF compartment). Dogs and
Accurate assessment of urine output is extremely important cats with hypokalemia require aggressive potassium replacement
in the sick ketoacidotic dog or cat, especially if azotemia is therapy to replace deficits and to prevent worsening, life-threaten-
present. Diabetes-induced glomerular microangiopathy and/or ing hypokalemia after initiation of insulin therapy. The exception
the hemodynamic effects of ketoacidosis, concurrent necrotiz- to potassium supplementation of fluids is hyperkalemia associated
ing pancreatitis, or prolonged severe dehydration can lead to with oliguric kidney failure. Potassium supplementation should
POTASSIUM THERAPY
SUPPLEMENT WITH KCI; IF HYPOPHOSPHATEMIC,
USE KCI AND KPO4
PATIENT IS URINE PRODUCTION

PRODUCING URINE QUESTIONABLE
CHECK SERUM K+ AND AWAIT INITIAL FLUID THERAPY OR

OBTAIN LEAD II ECG RESPONSE TO DIURETIC THERAPY
+
BEFORE ANY K THERAPY
SERUM POTASSIUM SERUM POTASSIUM SERUM POTASSIUM

>5.5 mEq/L 4.0 to 5.5 mEq/L <4.0 mEq/L
WAIT 2 HOURS OF ADD 40 mEq K+

FLUID THERAPY PER LITER IV FLUIDS SEE TABLE 8-4
Add 20 mEq K+
per liter IV fluids
+ +
MONITOR SERUM K AND Na
(EVERY 4-8 HOURS)
+ SERIAL ECG
SERUM K (EVERY 1-2 HOURS)
NO CHANGE EVIDENCE OF EVIDENCE OF

IF ABNORMALLY IF STABLE AT HYPOKALEMIA HYPERKALEMIA
HIGH OR LOW 4.0-5.0 mEq/L (PROLONGING OF (SHORTENING OF
Q-T INTERVAL) Q-T INTERVAL)
SEE FLOW CHART ABOVE CONTINUE THERAPY
SEE CHANGES RECOMMENDED ABOVE
AFTER 6-8 HOURS, MAINTAIN AT 20
mEq KCI/L OF FLUIDS OR
ACCORDING TO PATIENT NEEDS
FIGURE 8-18 Potassium therapy in the management of diabetic ketoacidosis (DKA).
initially be withheld in these dogs and cats until glomerular filtra- every 4 to 8 hours until the dog or cat is stable and serum electro-
tion is restored, urine production increases, and hyperkalemia is lytes are in the reference range.
resolving.
Ideally the amount of potassium required should be based on Phosphate Supplementation
actual measurement of the serum potassium concentration (Table Serum phosphorus concentrations can be decreased, normal,
8-4). If an accurate measurement of serum potassium is not avail- or increased, depending on the duration of illness and kidney
able, potassium should be added to the liter of fluids to bring the function. Most dogs and cats with DKA have either normal or
potassium concentration to 40 mEq per liter. For example, 0.9% decreased serum phosphorus concentrations on pretreatment
saline solution does not contain potassium, and Ringers solution testing. Within 24 hours of initiating treatment for DKA, serum
contains 4 mEq of potassium per liter; thus these fluids should be phosphorus concentration can decline to severe levels (i.e.,
supplemented with 40 mEq and 36 mEq of potassium, respec- < 1 mg/dL) as a result of the dilutional effects of fluid therapy,
tively. Subsequent adjustments in potassium supplementation the intracellular shift of phosphorus following the initiation of
should be based on measurement of serum potassium, preferably insulin therapy, and continuing kidney and gastrointestinal loss
|
TABLE 8-4 G
UIDELINES FOR POTASSIUM phosphate administration, and overzealous phosphate adminis-
SUPPLEMENTATION IN tration may cause hypocalcemia with tetany (Becker etal, 1983;
INTRAVENOUS FLUIDS Fisher and Kitabchi, 1983; Masharani and Karam, 2001). The
use of low-dose insulin treatment regimens, as described in the
GUIDELINES FOR DIA- Insulin Therapy section, helps reduce the intracellular shift of
TYPICAL GUIDELINES BETIC KETOACIDOSIS phosphate, and the frequent monitoring of serum phosphorus
concentrations during therapy ensures early recognition of wor-
K+ SUPPLEMENT/LITER K+ SUPPLEMENT/LITER risome changes in the serum phosphorus concentration. Argu-
SERUM K+ (mEq/L) OF FLUIDS OF FLUIDS ments for routine phosphate administration, especially if the
> 5.0 Wait Wait pretreatment phosphorus concentration is low, center on con-
4.0-5.5 10 20 to 30 cerns with hemolytic anemia and the desire to avoid this serious
3.5-4.0 20 30 to 40 complication. Studies documenting the effect, if any, of prophy-
3.0-3.5 30 40 to 50 lactic phosphate supplementation on the prevalence of hemo-
2.5-3.0 40 50 to 60 lytic anemia have not been reported in dogs or cats with DKA.
2.0-2.5 60 60 to 80 If the decision is made to prophylactically administer phosphate,
< 2.0 80 80 it can be administered separately using the dosages discussed ear-
Total hourly potassium administration should not exceed 0.5 mEq/kg body weight.
lier or can be included as a component of potassium replacement
in the fluids. When the latter approach is used, 5 to 10 mEq of
the potassium supplement added to the liter of fluids should
be potassium phosphate and the remainder of the potassium
(Willard et al, 1987). Hypophosphatemia affects primarily the supplemented as potassium chloride. The serum phosphorus
hematologic and neuromuscular systems in dogs and cats (see concentration should be monitored every 8 to 12 hours and the
Calcium and Phosphorus earlier in the chapter; Forrester and phosphate supplement adjusted accordingly.
Moreland, 1989). Hemolytic anemia is the most common prob-
lem and can be life threatening if not recognized and treated. Magnesium Supplementation
Severe hypophosphatemia may be clinically silent in many Hypomagnesemia is common in dogs and cats with DKA, and it
animals. often worsens during the initial treatment of DKA but resolves
Phosphate therapy is indicated if clinical signs or hemolysis are without treatment as the DKA resolves (Norris et al, 1999a).
identified or if the serum phosphorus concentration decreases to Clinical signs of hypomagnesemia do not usually occur until
less than 1.5 mg/dL. Phosphate is supplemented by IV infusion. the serum total and ionized magnesium concentration is less
Potassium and sodium phosphate solutions contain 3 mmol of than 1.0 and 0.4 mg/dL, respectively, and even at these low
phosphate and either 4.4 mEq of potassium or 4 mEq of sodium levels, many dogs and cats remain asymptomatic (see Magne-
per milliliter. The recommended dosage for phosphate supple- sium under Completing the Data Base). What impact, if any,
mentation is 0.01 to 0.03 mmol of phosphate per kilogram hypomagnesemia has on morbidity and response to treatment of
of body weight per hour, preferably administered in calcium- DKA is not clear. To date there are no clinical studies that have
free IV fluids (e.g., 0.9% sodium chloride) (Willard, 1987). In yielded guidelines for magnesium replacement in dogs and cats;
dogs and cats with severe hypophosphatemia, the dosage may currently it is determined empirically. We do not routinely treat
need to be increased to 0.03 to 0.12 mmol/kg/hr (Nichols and hypomagnesemia in dogs or cats with DKA unless problems
Crenshaw, 1995). Because the dose of phosphate necessary to with persistent lethargy, anorexia, weakness, or refractory hypo-
replete an animal and the animals response to therapy can- kalemia or hypocalcemia are encountered after 24 to 48 hours
not be predicted, it is important to initially monitor the serum of fluid and insulin therapy and another cause for the problem
phosphorus concentration every 8 to 12 hours and adjust the cannot be identified.
phosphate infusion accordingly. Adverse effects from overzeal- Parenteral solutions of magnesium sulfate (8.12 mEq of mag-
ous phosphate administration include iatrogenic hypocalcemia nesium per gram) and magnesium chloride (9.25 mEq of mag-
and its associated neuromuscular signs, hypernatremia, hypo- nesium per gram) salts are available. The IV doses for rapid and
tension, and metastatic calcification (Forrester and Moreland, slow magnesium replacement are 0.5 to 1 mEq/kg/day and 0.3 to
1989). Serum total or preferably ionized calcium concentra- 0.5 mEq/kg/day, respectively, administered by constant-rate infu-
tion should be measured at the same time as serum phosphorus sion in 5% dextrose in water or 0.9% sodium chloride (Dhupa
concentration and the rate of phosphate infusion decreased if and Shaffran, 1995; Hansen, 2000). Kidney function must be
hypocalcemia is identified. Phosphorus supplementation is not assessed before the administration of magnesium, and the mag-
indicated in dogs and cats with hypercalcemia, hyperphospha- nesium dose must be reduced by 50% to 75% in azotemic ani-
temia, oliguria, or suspected tissue necrosis. If kidney function mals. The administration of magnesium to animals being treated
is in question, phosphorus supplementation should not be done with digitalis cardioglycosides may cause serious conduction dis-
until the status of kidney function and serum phosphorus con- turbances. Magnesium is incompatible with solutions containing
centration are known. sodium bicarbonate or calcium. Serum total or preferably ionized
The routine supplementation of IV fluids with phospho- magnesium, calcium, and potassium concentrations should be
rus during the initial 24 to 48 hours of treatment to prevent monitored every 8 to 12 hours and adjustments in the rate of
the development of severe hypophosphatemia, especially if the magnesium infusion made accordingly. The goal of therapy is the
pretreatment serum phosphorus concentration is low, is con- resolution of clinical signs or refractory hypokalemia or hypocal-
troversial and varies with the experiences of the veterinarian cemia. The parenteral administration of magnesium sulfate may
queried. Routine phosphate supplementation is seldom recom- cause significant hypocalcemia such that calcium infusion may
mended in treating DKA in humans, in part because several be necessary. Other adverse effects of magnesium therapy include
studies have failed to identify any apparent clinical benefit from hypotension, atrioventricular and bundle-branch blocks, and in
BICARBONATE THERAPY
TOTAL VENOUS CO2 OR

ARTERIAL BICARBONATE
11 mEq/L 12 mEq/L
A: NO BICARBONATE SUPPLEMENTATION
B: TREAT AS NEEDED:
ADMINISTER BICARBONATE PLACED INTO IV INFUSION, 1. FLUIDS
TO BE DELIVERED OVER A 6 HOUR PERIOD. DOSE: 2. INSULIN
body weight (kg) x 0.2 x (12 patient's bicarb.) 3. ELECTROLYTES
RECHECK IN 6 HOURS
BEGIN AT TOP
FIGURE 8-19 Bicarbonate treatment protocol for the management of diabetic ketoacidosis (DKA).
the event of overdose, respiratory depression and cardiac arrest. When the plasma bicarbonate concentration is 11 mEq/L or less
Overdoses are treated with IV calcium gluconate. (total venous CO2 < 12 mEq/L), bicarbonate therapy should be
initiated. Many of these animals have severe depression that may
be a result of concurrent severe CNS acidosis. These can be dif-
Bicarbonate Therapy
ficult dogs and cats to treat, and the only safe therapeutic protocol
Fig. 8-19 shows a flow chart of bicarbonate therapy. involves correcting the metabolic acidosis slowly in the peripheral
In humans with DKA, sodium bicarbonate treatment is circulation via IV fluid supplementation, thereby avoiding major
reserved for patients with arterial pH of 7.0 or less and only alterations in the pH of the CSF. As such, only a portion of the
with careful monitoring to prevent overcorrection. The primary bicarbonate deficit is given initially over a 6-hour period of time.
concerns with sodium bicarbonate treatment are the poten- The bicarbonate deficit (i.e., the milliequivalents of bicarbonate
tially harmful consequences with overly aggressive bicarbonate initially needed to correct acidosis to the critical level of 12 mEq/L
administration, including exacerbation of hypokalemia from a over a period of 6 hours) is calculated as:
rapid shift of potassium into cells, tissue anoxia from reduced
mEq bicarbonate = body weight (kg) 0.4 (12 animal's bicarbonate) 0.5
dissociation of oxygen from hemoglobin when acidosis is rapidly
reversed, and an exaggerated decrease in the cerebrospinal fluid or if the serum bicarbonate is not known:
(CSF) pH with resultant worsening of CNS function (Hale etal,
mEq bicarbonate = body weight (kg) 2
1984; Hood and Tannen, 1994; Kitabchi etal, 2001). The clini-
cal presentation of the dog or cat, in conjunction with the plasma The difference between the animals serum bicarbonate concen-
bicarbonate or total venous CO2 concentration, should be used tration and the critical value of 12 mEq/L represents the treatable
to determine the need for bicarbonate therapy. Bicarbonate sup- base deficit in DKA. If the animals serum bicarbonate concentra-
plementation is not recommended when plasma bicarbonate (or tion is not known, the number 10 should be used for the treatable
total venous CO2) is 12 mEq/L or greater, especially if the ani- base deficit. The factor 0.4 corrects for the ECF space in which
mal is alert. An alert dog or cat probably has a normal or nearly bicarbonate is distributed (40% of body weight). The factor 0.5
normal pH in the CSF. The acidosis in these animals is corrected provides one-half of the required dose of bicarbonate in the IV
through insulin and fluid therapy. Improvement in renal perfu- infusion. In this manner, a conservative dose is given over a 6-hour
sion enhances the urinary loss of ketoacid, and insulin therapy period. Bicarbonate should not be given by bolus infusion (Ryder,
dramatically diminishes the production of ketoacid. Acetoacetate 1984). After 6 hours of therapy, the acid-base status should be
and -hydroxybutyrate are also metabolically usable anions, and reevaluated and a new dosage calculated. Once the plasma bicar-
1 mEq of bicarbonate is generated from each 1 mEq of ketoacid bonate level is greater than 12 mEq/L, further bicarbonate supple-
metabolized. mentation is not needed.
|
Intravenous Subcutaneous Intramuscular
0 0
Ketone Ketone
Ketone bodies
bodies
Change in plasma glucose

bodies
Change in total ketones

200 4
(mg/dL)
(mM)
Glucose Glucose
400 Glucose 8
P < 0.05 IV versus SC and IM

600 12
P < 0.01 IV versus SC and IM
0 4 8 0 4 8 0 4 8
Hours of therapy
FIGURE 8-20 Effect of route of insulin therapy on reduction in plasma glucose and ketone concentrations in hu-
mans with diabetic ketoacidosis (DKA). Intravenous (IV) insulin was associated with a more rapid decline (initial 0
to 2 hours) in plasma glucose and ketone levels. Thereafter, no differences were noted between any of these groups.
(Redrawn from Fisher JN, et al.: Diabetic ketoacidosis: low-dose insulin therapy by various routes, N Engl J Med
297:238-241, 1977. In DeFronzo RA, etal.: Diabetic ketoacidosis: a combined metabolic-nephrologic approach to
therapy, Diabetes Rev 2:223, 1994; used with permission.) IM, Intramuscular; SC, subcutaneous.
Insulin Therapy
Regardless, insulin therapy is still indicated. The amount of insu-
Insulin therapy is critical for the resolution of ketoacidosis. Insulin lin needed by an individual animal is difficult to predict. There-
inhibits lipolysis and the mobilization of FFAs from triglycerides fore, an insulin preparation with a rapid onset of action and a brief
stored in adipose tissue, thereby decreasing the substrate necessary duration of effect is ideal for making rapid adjustments in the dose
for ketone production; shifts hepatic metabolism from fat oxidation and frequency of administration to meet the needs of that par-
and ketogenesis to fat synthesis; suppresses hepatic gluconeogenesis; ticular dog or cat. Rapid-acting regular crystalline insulin meets
and promotes glucose and ketone metabolism by tissues (Hood and these criteria and is recommended for the treatment of DKA (Nel-
Tannen, 1994; DeFronzo etal, 1994). The net effect is decreased son etal, 1990). Rapid-acting insulin analogs (e.g., insulin lispro
blood and urine glucose and ketone concentrations, decreased and insulin aspart) are also effective for treating DKA in humans,
osmotic diuresis and electrolyte losses, and correction of metabolic dogs, and presumably cats (Kitabchi etal, 2008; Sears etal, 2012).
acidosis. Overzealous insulin treatment can cause severe hypoka- Insulin protocols for the treatment of DKA include the hourly
lemia, hypophosphatemia, and hypoglycemia during the first 24 intramuscular (IM) technique (Chastain and Nichols, 1981), the
hours of treatment; these problems can be minimized by appropriate constant low-dose IV infusion technique (Macintire, 1993; Claus
fluid therapy, frequent monitoring of serum electrolytes and blood etal, 2010), and the intermittent IM then subcutaneous (SC) tech-
glucose concentrations, and delaying the start of insulin treatment nique (Feldman, 1980). All three routes (IV, IM, and SC) of insulin
and modifying the initial insulin treatment protocol as indicated. administration are effective in decreasing plasma glucose and ketone
Initiating appropriate fluid therapy should always be the first concentrations (Fig. 8-20). Arguments abound regarding the most
step in the treatment of DKA. Delaying insulin therapy allows the appropriate route for initial insulin administration, arguments that
benefits of fluid therapy to begin to be realized before the glucose, are primarily based on personal experiences and preferences. Success-
potassium, and phosphorus-lowering effects of insulin therapy ful management of DKA does not depend on route of insulin admin-
commence. The question is how long to delay insulin therapy. We istration. Rather, it depends on proper treatment of each disorder
typically delay insulin therapy for a minimum of 2 hours after ini- associated with DKA (see Box 8-6). All three protocols are effective.
tiation of fluid therapy. Additional delays and decisions on the ini-
tial dosage of insulin administered are based on serum electrolyte Hourly Intramuscular Insulin Technique
results. If the serum potassium concentration is within the normal Dogs and cats with severe DKA should receive an initial regu-
range after 2 hours of fluid therapy, insulin treatment should com- lar insulin loading dose of 0.1 to 0.2 U/kg followed by 0.1 U/
mence as described in the subsequent paragraphs. If hypokalemia kg every 1 to 2 hours thereafter (Fig. 8-21). The insulin dose can
persists, insulin therapy can be delayed an additional 2 hours to be reduced by 25% to 50% for the first two to three injections
allow fluid therapy to replenish potassium, the initial insulin dose if hypokalemia is a concern. The insulin should be administered
can be reduced to dampen the intracellular shift of potassium and into the muscles of the rear legs to ensure that the injections are
phosphorus, or both can be done. The more severe the hypokale- IM and do not go into fat or SC tissue where insulin absorption
mia, the more inclined we are to delay insulin therapy and reduce may be impaired in the dehydrated dog or cat. Diluting regular
the initial insulin dose. However, in our opinion, insulin therapy insulin 1:10 with sterile saline or special diluents available from
should be started within 4 hours of initiating fluid therapy. the insulin manufacturer and using 0.3 mL U100 insulin syringes
Insulin therapy may not be as effective if a concurrent insulin- are helpful when small doses of insulin are required. By means of
antagonistic disease is present, and it may be necessary to elim- this insulin treatment regimen, the serum insulin concentration is
inate the disease while the animal is still ill to improve insulin typically increased to and maintained at approximately 100 U/
effectiveness and resolve the ketoacidosis (e.g., a bitch in diestrus). mL (700 pmol/L) (Fig. 8-22), which is an insulin concentration
INSULIN THERAPY
INITIALLY
0.1 to 0.2 U/kg REGULAR
INSULIN IM
HOURLY
0.1 U/kg REGULAR INSULIN IM
MONITOR BLOOD
GLUCOSE EVERY
HOUR
BLOOD GLUCOSE BLOOD GLUCOSE BLOOD GLUCOSE

FALLING AT FALLING AT FALLING AT
>75 mg/dL/hr 50-75 mg/dL/hr <50 mg/dL/hr
DECREASE DOSE TO CONTINUE ORIGINAL INCREASE DOSE TO

0.05 U/kg/hr IM DOSE 0.2 U/kg/hr IM
BLOOD GLUCOSE
<250 mg/dL/hr
HOURLY INSULIN DOSE USUALLY CAN

BE CHANGED TO:
REGULAR INSULIN SC AT
0.1-0.3 U/kg EVERY
6-8 HOURS
LONGER ACTING INSULIN

STARTED WHEN PATIENT IS OFF IV
FLUIDS, IS EATING AND DRINKING, AND HAS
NO VOMITING OR KETOACIDOSIS
FIGURE 8-21 Hourly intramuscular (IM) insulin treatment protocol for the management of diabetic ketoacidosis
(DKA). Similar principles for adjusting insulin therapy based on changes in the blood glucose concentration are
used with the constant low-dose intravenous (IV) insulin infusion technique. SC, Subcutaneous.
that inhibits lipolysis, gluconeogenesis, and glycogenolysis and accordingly (see Fig. 8-21). The goal of initial insulin therapy is to
promotes utilization of glucose and ketones by tissues (Kitabchi slowly lower the blood glucose concentration to the range of 200
etal, 2008). to 250 mg/dL (11 to 14 mmol/L), preferably over a 6- to 10-hour
The blood glucose concentration should initially be measured time period. An hourly decline of 50 mg/dL (2.8 mmol/L) in the
every hour using a point-of-care chemistry analyzer or portable blood glucose concentration is ideal (Wagner etal, 1999). This pro-
blood glucose monitoring device and the insulin dosage adjusted vides a steady moderate decline, avoiding large shifts in osmolality.
|
200 fifteen cats with DKA, adapting the protocol using regular insulin
described earlier. All of the cats were initially administered 1 to 2
U of glargine IM, and for twelve cats 1 to 3 U of glargine SC. This
was followed by intermittent IM glargine at intervals of 2 hours or
more (range, 2 to 22 hours) and 1 to 3 U of glargine SC every 12
hours. Complications included hypoglycemia, hypokalemia, and
150
hypophosphatemia. All fifteen cats survived and were discharged a
median of 4 days after initiating treatment. The authors conclude
that glargine may provide an alternative to regular insulin for the
treatment of DKA in cats. Additional studies evaluating the safety
and efficacy of glargine for treating DKA are needed before we
100 would consider using basal insulin for the treatment of DKA.
Constant Low-Dose Intravenous Insulin Infusion Technique
Constant IV infusion of regular crystalline insulin is also effective
in decreasing blood glucose concentrations. The decision to use
50 the hourly IM technique versus constant IV insulin infusion is
based primarily on clinician preference and availability of techni-
cal support and infusion pumps. To prepare the infusion, regular
crystalline insulin (2.2 U/kg for dogs; 1.1 U/kg for cats) is added
to 250 mL of 0.9% saline and initially administered at a rate
of 10 mL/hr in a line separate from that used for fluid therapy
0 (Church, 1983; Macintire, 1993). This provides an insulin infu-
0 1 2 3 4 5 6 7 8
sion of 0.05 (cat) and 0.1 (dog) U/kg/hr, an infusion rate that has
been shown to produce plasma insulin concentrations between
100 and 200 uU/mL (700 to 1400 pmol/L) in dogs (Macin-
Time (hours) tire, 1993). Because insulin adheres to glass and plastic surfaces,
FIGURE 8-22 Mean serum insulin concentration in eight dogs with diabetic approximately 50 mL of the insulin-containing fluid should be
ketoacidosis (DKA) prior to and after the administration of regular crystalline run through the drip set before it is administered to the animal.
insulin, 0.2 U/kg of body weight intramuscular (IM) (time 0) and then 0.1 U/ The rate of insulin infusion can be reduced for the initial 2 to
kg IM hourly thereafter (solid line), and in six dogs with DKA prior to and after 3 hours if hypokalemia is a concern. Two separate catheters are
continuous intravenous (IV) infusion of regular crystalline insulin (dashed line), recommended for treatment: a peripheral catheter for insulin
using a pediatric drip set. Insulin treatment was discontinued after the fourth administration and a central catheter for fluid administration and
hour in both groups of dogs. , IM insulin administration; hatched area, IV insulin blood sampling. An infusion or syringe pump should be used to
infusion; shaded area, ideal serum insulin concentration for treatment of DKA. ensure a constant rate of insulin infusion. Insulin infusions using
pediatric drip sets may not provide a constant insulin infusion
rate, especially if frequent monitoring of fluid administration is
A declining blood glucose concentration also ensures that lipolysis not possible (see Fig. 8-22). The goal of therapy is identical to
and the supply of FFAs for ketone production have been effec- that described for the hourly IM techniqueto provide a con-
tively turned off. Glucose concentrations, however, decrease much tinuous source of insulin at a dosage that causes a gradual decline
more rapidly than ketone levels (Barrett and DeFronzo, 1984; in the blood glucose concentration. This goal is best attained with
Yeates and Blaufuss, 1990). In general, hyperglycemia is corrected use of infusion or syringe pumps.
within 12 hours, but ketosis often takes 48 to 72 hours to resolve. Adjustments in the infusion rate or the concentration of the
Once the initial hourly insulin therapy brings the blood glucose insulin in the infusion (increased or decreased) are based on hourly
concentration near 250 mg/dL (14 mmol/L), hourly administra- measurements of blood glucose concentration; an hourly decline
tion of regular insulin should be discontinued and regular insulin of 50 mg/dL (2.8 mmol/L) in the blood glucose concentration is
given every 4 to 6 hours IM or, if hydration status is good, every ideal (Wagner etal, 1999). Once the blood glucose concentration
6 to 8 hours SC. The initial dose is usually 0.1 to 0.3 U/kg, with approaches 250 mg/dL (14 mmol/L), the insulin infusion can be
subsequent adjustments based on blood glucose concentrations. discontinued and regular insulin given every 4 to 6 hours IM or,
In addition, at this point, the IV infusion solution should have if hydration status is good, every 6 to 8 hours SC, as discussed for
enough 50% dextrose added to create a 5% dextrose solution (100 the hourly IM protocol. Alternatively, the insulin infusion can be
mL of 50% dextrose added to each liter of fluids). The blood glu- continued (at a decreased rate or decreased insulin concentration
cose concentration should be maintained between 150 and 300 in the infusion to prevent hypoglycemia) until the insulin prepa-
mg/dL (8 to 17 mmol/L) until the dog or cat is stable and eating. ration is exchanged for a longer-acting product. Dextrose should
Usually a 5% dextrose solution is adequate in maintaining the be added to the IV fluids once the blood glucose concentration
desired blood glucose concentration. If the blood glucose concen- approaches 250 mg/dL, as discussed in the Hourly Intramuscular
tration dips below 150 mg/dL or increases above 300 mg/dL, the Insulin Technique section.
insulin dose can be decreased or increased accordingly. Dextrose Claus, et al., (2010) recently compared the efficacy of three
helps minimize problems with hypoglycemia and allows insulin regular insulin doses (1.1 U/kg/d, 2.2 U/kg/d, and an escalating
to be administered on schedule. Delaying the administration of dosage from 1.1 to 2.2 U/kg during the course of the cats stay)
insulin delays correction of the ketoacidotic state. given by continuous IV infusion in 29 critically ill diabetic cats.
Marshall, et al., (2013) recently evaluated the efficacy of IM There was no significant difference between groups regarding time
glargine with or without concurrent SC glargine administration in required to reach a blood glucose of 250 mg/dL (14 mmol/L),
change in serum potassium or phosphorus concentrations relative maintained with IV dextrose infusions. If concurrent insulin-
to baseline, length of time for resolution of ketonuria, or length antagonistic disease is present, it may be necessary to treat the
of hospital stay. Sears, etal., (2012) evaluated the efficacy of the disease while the animal is still ill to improve the effectiveness of
short-acting insulin analog lispro (Humalog, Eli Lilly) for the insulin and resolve the ketoacidosis (e.g., ovariohysterectomy in
treatment of DKA using an IV constant rate infusion technique. diestrual bitch).
Treatment with IV constant rate infusion of lispro was safe and as
effective as treatment with regular crystalline insulin. Use of lispro Pancreatitis
insulin is a viable option for treating DKA, especially if the pro- Pancreatitis, acute or chronic, should always be assumed to
duction of regular crystalline insulin is discontinued in the future. be present in the dog or cat with DKA until proven otherwise.
The diagnosis of pancreatitis should be based on a combination
Intermittent Intramuscular/Subcutaneous Insulin Technique of presence of appropriate clinical signs; physical examination
An intermittent IM followed by intermittent SC insulin tech- ndings; abnormalities on the CBC, serum biochemistry panel,
nique has been described (Feldman, 1980). Although this tech- and urinalysis; results of serum pancreatic lipase immunoreactivity
nique was used successfully by us for years, it has been replaced (see Pancreatic Enzymes earlier); radiographic evidence of a loss
with the hourly IM and constant IV insulin infusion techniques. of detail in the right cranial abdomen accompanied by gas-lled
The intermittent IM followed by intermittent SC insulin tech- duodenal ileus; and ultrasonographic evidence of enlargement of
nique is less labor-intensive than the other techniques for insulin the pancreas and a hypoechoic to mixed echogenic pattern with
administration, but the decrease in blood glucose can be rapid and or without mild to severe blockage of the bile duct (see Fig. 8-15).
the risk of hypoglycemia is greater. The initial regular crystalline The presence of pancreatitis impacts fluid therapy and nutritional
insulin dose is 0.25 U/kg, administered intramuscularly. Subse- support during hospitalization, the duration of hospitalization,
quent IM injections are repeated every 4 hours. Usually, insulin is dietary recommendations, response to insulin treatment, the
administered intramuscularly only once or twice. Once the animal probability for recurrence of ketonuria and ketoacidosis following
is rehydrated, the insulin is administered subcutaneously rather discharge from the hospital, and survival. Acute severe necrotizing
than intramuscularly every 6 to 8 hours. SC administration is not pancreatitis is a common cause of death during the initial days of
recommended initially because of problems with insulin absorp- treatment of DKA, and the inability to prevent recurring bouts of
tion from SC sites of deposition in a dehydrated dog or cat. The chronic pancreatitis is one reason owners eventually elect eutha-
dosage of IM or SC insulin is adjusted according to blood glucose nasia of their pet (Goossens etal, 1998). Avoidance of recurrent
concentrations, which initially should be measured hourly begin- bouts of pancreatitis is critical to the long-term survival of the
ning with the first IM injection. An hourly decline of 50 mg/dL diabetic dog and cat. In the dog, this is primarily accomplished
in the blood glucose concentration is ideal (Wagner etal, 1999). through appropriate dietary therapy. To date, inciting factors for
Subsequent insulin dosages should be decreased by 25% to 50% development of pancreatitis in the cat have been poorly character-
if this goal is exceeded. Dextrose should be added to the IV fluids ized, and the impact of diet, if any, on preventing recurrence of
once the blood glucose concentration approaches 250 mg/dL (14 pancreatitis has yet to be clarified.
mmol/L), as discussed in the Hourly Intramuscular Insulin Tech-
nique section. Bacterial Infections
The immunosuppressive effects of diabetes mellitus, in conjunc-
Initiating Longer-Acting Insulin Therapy tion with the increased blood glucose concentration in body
Longer-acting insulin (e.g., Lente, protamine zinc insulin [PZI], fluids, predisposes diabetic dogs and cats to bacterial infections
glargine) are administered once the dog or cat is stable, eating, (McMahon and Bistrian, 1995; Joshi etal, 1999). Urinary tract
maintaining fluid balance without any IV infusions, and no lon- infections are most common, followed by infections of the oral
ger acidotic, azotemic, or electrolyte-deficient. The initial dose cavity, skin, and pulmonary systems (Hess etal, 2000; Peikes etal,
of the longer-acting insulin is similar to the regular insulin dose 2001). Life-threatening sepsis may develop in debilitated diabet-
being used just before switching to the longer-acting insulin. Sub- ics, those with severe concurrent illness (e.g., necrotizing pancre-
sequent adjustments in the longer-acting insulin dose should be atitis), and those in which aseptic technique is not strictly followed
based on clinical response and measurement of blood glucose con- during diagnostic and therapeutic procedures (e.g., placement
centrations, as described in Chapters 6 and 7. of indwelling urinary or venous catheters). The clinician should
always suspect infection in the DKA dog or cat. Urine cultures
should be completed in all dogs and cats with DKA. Culture of
Concurrent Illness
blood and other fluids and tissues is usually dictated by the clini-
Therapy for DKA frequently involves the management of concur- cal signs and findings on the physical examination, routine blood
rent, often serious illness. Common concurrent illness in the dog tests, and diagnostic imaging. Whenever possible, the choice of
and cat with DKA include pancreatitis, bacterial infection, con- antibiotic therapy should be based on results of culture and sen-
gestive heart failure, chronic kidney disease, hepatobiliary disease, sitivity testing.
and insulin-antagonistic disorders, most notably hyperadrenocor-
ticism (dog), hyperthyroidism (cat), and diestrus (intact female Kidney Disease
dog) (Bruskiewicz etal, 1997; Hume etal, 2006); It may be nec- Chronic and less commonly acute kidney disease may occur con-
essary in such animals to modify the therapy for DKA (e.g., fluid currently in dogs and cats with DKA. Abnormal kidney function
therapy with concurrent heart failure) or implement additional may result from the deleterious effects of the diabetic state (i.e.,
therapy (e.g., antibiotics), depending on the nature of the con- diabetic nephropathy) or may be an independent problem that
current illness. Insulin therapy, however, should not be delayed has developed in conjunction with diabetes in the geriatric dog or
or discontinued. Resolution of ketoacidosis can only be achieved cat. Close monitoring of urine output and changes in BUN and
through insulin therapy. If nothing is to be given per os, insulin serum creatinine concentration in response to fluid therapy are
therapy should be continued and the blood glucose concentration warranted whenever azotemia is identified in the dog or cat with
|
newly diagnosed DKA. See the sections Urinalysis and Urine Cul- Exogenous Glucocorticoids.Insulin resistance induced by
ture, Blood Urea Nitrogen and Creatinine, and Monitoring Fluid exogenous glucocorticoid administration can antagonize treat-
Therapy for information on kidney function and DKA. ment of DKA. In general, glucocorticoids should not be given to
dogs and cats with DKA and should be discontinued in previously
Hormonal Disorders Causing Insulin Resistance undiagnosed diabetic ketoacidotic dogs and cats. This includes
Insulin resistance accompanies many of the concurrent disorders oral, ocular, aural, and skin preparations. The exceptions are those
present in dogs and cats with DKA. The severity of insulin resis- situations in which glucocorticoids are necessary to control life-
tance is quite variable and depends on the underlying cause (see threatening disorders (e.g., immune-mediated disease). In these
Table 6-11). Fortunately, most disorders cause mild insulin resis- situations, the lowest dosage of glucocorticoid needed to control
tance; that is, the dog or cat remains responsive to insulin therapy the disorder should be administered and alternatives to glucocor-
even at the low insulin dosages often employed during the initial ticoids (e.g., azathioprine or cyclosporine) should be sought. In
24 to 72 hours of therapy, and ketoacidosis progressively resolves. addition, the clinician should be willing to compensate for the
Two major exceptions are diestrus-induced insulin resistance in insulin-antagonistic effects of glucocorticoids by administering
the intact bitch and hyperadrenocorticism. Although acromegaly larger dosages of insulin than are typically required to control
also causes severe insulin resistance in the cat, ketonuria is an DKA.
infrequent finding and systemic illness from DKA is uncommon, Naturally-Acquired Hyperadrenocorticism.Hyperadreno-
despite an inability to establish any semblance of glycemic control corticism is a well-recognized disorder in diabetic dogs and cats
with massive doses of insulin. Seemingly, insulin is able to inhibit and is occasionally suspected in dogs and cats with newly diag-
lipolysis and the supply of FFAs for ketone production but unable nosed DK and DKA and insulin-treated dogs and cats with per-
to control hepatic glucose secretion and/or stimulate tissue glu- sistent ketonuria. For relatively healthy dogs and cats with DK,
cose utilization to control hyperglycemia in these cats. appropriate diagnostic tests should be undertaken and appropriate
Diestrus. Increased progesterone secretion during the diestrual treatment initiated once the diagnosis of hyperadrenocorticism is
phase of the estrus cycle in the bitch directly antagonizes insulin confirmed (see Chapters 10 and 11). Despite its impaired effi-
action and stimulates growth hormone secretion which, in turn, cacy, insulin should continue to be administered to inhibit lipoly-
causes severe insulin resistance and the potential for life-threaten- sis, suppress ketone production, and prevent deterioration of the
ing DKA. Diestrus-induced insulin resistance can be difficult if ketoacidotic state. Ketosis typically resolves once hyperadrenocor-
not impossible to override, despite the administration of massive ticism is controlled.
doses of regular crystalline insulin. As a consequence, the meta- Establishing a diagnosis of hyperadrenocorticism is more prob-
bolic derangements associated with DKA progressively worsen lematic in the ill ketoacidotic dog or cat, in part because of con-
ultimately resulting in death of the bitch. cerns regarding accuracy of results when the diagnostic tests used
Intact bitches in DKA should always be assumed to be in to diagnose hyperadrenocorticism are performed in dogs and cats
diestrus and should be assumed to have a pyometra, regardless with severe illness (Kaplan etal, 1995). Ideally, testing for hyper-
of owner statements regarding estrus activity or the lack thereof. adrenocorticism should be postponed until DKA has resolved
Once initial therapy for DKA is initiated, abdominal ultrasound and the dog or cat is stable in the home environment. We rely
scans or radiographs should be evaluated for pyometra and a on results of the urine cortisol-to-creatinine ratio, low dose dexa-
blood progesterone concentration should be determined. A blood methasone suppression test, and ultrasonographic examination of
progesterone concentration greater than 2 ng/mL is diagnostic for the adrenal glands to help confirm the diagnosis of hyperadreno-
ovarian luteal activity and supports the diagnosis of diestrus. The corticism. Interpretation of results of the low dose dexamethasone
bitch should undergo ovariohysterectomy as soon as safely pos- suppression test and especially the urine cortisol-to-creatinine
sible. Timing of surgery depends on the severity of clinical signs. ratio should be done with care because of the increased potential
Severely ill bitches with DKA should be stabilized as best as possi- for false positive test results in sick dogs and cats. Ideally, treat-
ble with IV fluids, regular crystalline insulin, and if indicated, par- ment for hyperadrenocorticism should not be initiated until the
enteral antibiotics for 6 to 24 hours prior to performing surgery. DKA has resolved with fluid and insulin therapy and the dog or
We rarely wait more than 24 hours from the time of diagnosis cat is stable and eating.
of pyometra or diestrus to ovariohysterectomy. Insulin resistance
usually begins to resolve within a week of ovariohysterectomy. In Monitoring and Complications of Therapy
some bitches, insulin-requiring diabetes mellitus may even resolve
(see Chapter 6, Other Specific Types and Diabetic Remission). Complications induced by treatment of DKA are common and
Diestrus-induced insulin resistance and its effect on respon- usually result from overly aggressive therapy, inadequate animal
siveness of DKA to insulin therapy are not commonly encoun- monitoring, and failure to reevaluate biochemical parameters in
tered in cats, because essentially all female diabetic cats have been a timely manner (Box 8-7). DKA is a complex disorder that car-
spayed at the time diabetes is diagnosed and progesterone does ries a high mortality rate if improperly managed. To minimize
not stimulate growth hormone secretion in the cat (Peterson, the occurrence of therapeutic complications and improve the
1987). Progesterone can cause insulin resistance, but the insulin chances of successful response to therapy, all abnormal param-
resistance that develops during diestrus in the queen rarely causes eters should be slowly returned toward normal (i.e., over a period
significant problems, presumably because the insulin resistance is of 24 to 48 hours), the physical and mental status of the animal
not severe and the increase in plasma progesterone is transient. must be evaluated frequently (at least three to four times daily),
In contrast, insulin resistance caused by chronic progesterone and fluid therapy, urine production, urine and plasma ketones,
excess, as occurs with exogenous progestagen administration or a serum electrolytes, and blood gases every 4 to 8 hours. During
progesterone-secreting adrenocortical tumor, can cause diabetes the initial 24 hours, blood glucose concentrations should be mea-
mellitus and a clinical syndrome that mimics feline hyperadre- sured every 1 to 2 hours. Fluid, insulin, and bicarbonate therapy
nocorticism (Boord and Griffin, 1999; Rossmeisl etal, 2000; see typically require modification three or four times during the initial
Chapter 11). 24 hours of therapy. A CBC and serum biochemistry panel that
effects of hypokalemia include hypokalemic nephropathy, which

BOX 8-7 C
ommon Complications Caused by Treatment is characterized by chronic tubulointerstitial nephritis, impaired
of Diabetic Ketoacidosis in Dogs and Cats kidney function, and azotemia and manifested clinically as poly-
uria, polydipsia, and impaired urine concentrating capability;
Hypoglycemia from excessive use of insulin or inadequate hypokalemic polymyopathy, which is characterized by increased
administration of glucose serum creatine kinase activity and electromyographic abnormali-
Hypokalemia from inadequate potassium supplementation ties; and paralytic ileus, manifested clinically as abdominal dis-
Hypophosphatemia and hemolytic anemia from inadequate phosphorus tention, anorexia, vomiting, and constipation (DiBartola and de
supplementation Morais, 2012). Hypokalemic nephropathy and polymyopathy are
Hypernatremia from excessive administration of physiologic saline or most notable in cats. Cats seem more susceptible to the delete-
inadequate fluid intake rious effects of hypokalemia than dogs. In dogs, signs may not
Persistent oliguria from inadequate or inappropriately slow be evident until the serum potassium concentration is less than
administration of fluids 2.5 mEq/L, whereas in cats signs can be seen with serum potas-
Persistent hypotension from inadequate or inappropriately slow sium concentrations between 3 and 3.5 mEq/L. Clinical signs
administration of fluids of hypokalemia can be mistakenly ascribed to other commonly
Cerebral edema and neurologic signs from too rapid decrease in blood encountered concurrent disorders (e.g., pancreatitis) and hypoka-
glucose and/or osmolality lemia overlooked as a possible cause. Initial aggressive potassium
Paradoxical cerebral acidosis and neurologic signs from too rapid replacement therapy, frequent monitoring of serum electrolytes,
administration of bicarbonate and subsequent adjustments in potassium replacement therapy are
necessary to identify and prevent hypokalemia.
includes plasma proteins, creatinine, calcium, phosphorus, and Central Nervous System Signs (Cerebral Edema)
magnesium should be evaluated every 24 hours until the dog or Cerebral edema may result from excessive free water accumulation
cat is stabilized and eating. Failure to recognize changes in the stain the intravascular space during therapy for DKA. This typically
tus of DKA and to respond accordingly invariably leads to poten- results from a rapid decrease in the blood glucose concentration
tially serious complications. The more common complications are or after infusion of large quantities of hypotonic solutions (e.g.,
discussed below. 0.45% saline). With insulin deficiency, the movement of glucose
from the ECF to the ICF compartment is impaired. Glucose
Hypoglycemia accumulation in the ECF causes a significant increase in ECF
Hypoglycemia is a common problem during the initial days of osmolality. A rapid increase in ECF glucose can result in cellular
treatment, especially when the dog or cat is anorectic and unable dehydration as water moves from the ICF to the ECF compart-
to ingest a dietary source of glucose to counter the glucose-lower- ment in response to the increase in ECF osmolality. Neurologic
ing effects of insulin. The goal of initial insulin therapy, regardless signs develop as a consequence of neuronal dehydration in the
of how the insulin is administered, is to slowly lower the blood CNS. Neurons in the CNS produce osmotically active substances
glucose concentration to the range of 200 to 250 mg/dL (11 to including lactate, sorbitol, myoinositol, and idiogenic osmoles to
14 mmol/L), preferably over an 8- to 10-hour time period. Unfor- compensate for the increasing osmolality of the ECF and prevent
tunately, this goal can be quite difficult to attain, and the blood cellular dehydration. These intracellular substances can cause water
glucose concentration may drop precipitously. To avoid hypo- to diffuse into the cell if the osmolality within the cell exceeds that
glycemia, it is imperative that the blood glucose concentration within the ECF space. Idiogenic osmols within the neurons of a
initially be measured every hour using a point-of-care chemistry severely hyperglycemic animal is not associated with an osmotic
analyzer, or a portable blood glucose monitoring device, or a con- gradient because of the equilibrium between the hyperosmotic
tinuous glucose monitoring system (see Chapter 6, Fig. 6-23). ECF space (induced by glucose) and the hyperosmotic intracellu-
Whenever the blood glucose concentration approaches 250 mg/ lar space (induced by idiogenic osmols). However, with aggressive
dL, 50% dextrose should be added to the IV infusion solution to fluid therapy and exogenous insulin administration, rapid reduc-
create a 5% dextrose solution. If hypoglycemia occurs (i.e., blood tion in blood glucose concentration and improved renal perfusion
glucose less than 80 mg/dL; 4.5 mmol/L) or the dog or cat is may cause a rapid reduction in ECF osmolality. A relative excess
symptomatic for hypoglycemia, 0.25 to 0.50 gm/kg body weight in free water accumulates in the ECF space. This water can then
of 50% dextrose should be administered IV as needed until the diffuse into the idiogenic osmol-induced hyperosmotic brain cells.
5% dextrose solution is able to maintain the blood glucose above A rapid decline in blood glucose concentration can thus result in
80 mg/dL. Insulin therapy should also be modified and, if neces- cerebral edema and worsening CNS function. For these reasons,
sary, discontinued but only for a few hours. Discontinuing insulin the veterinarian must be aware of the CNS status of the animal
therapy interferes with resolution of the ketoacidosis. prior to initiation of therapy. If the animal becomes depressed or
obtunded during treatment, it may be the result of the relatively
Severe Hypokalemia rapidly decreasing blood glucose concentration leading to cerebral
Dogs and cats with DKA are at risk for development of severe edema.
hypokalemia (< 2.0 mEq/L) during the initial 48 hours of therapy Mannitol is the most effective treatment for cerebral edema.
for reasons that are discussed in the Potassium Supplementation Dexamethasone is usually recommended, but its efficacy has not
section earlier in the chapter. The most common clinical sign of been reported in diabetic dogs and cats. Passive hyperventilation
hypokalemia is generalized skeletal muscle weakness. In cats, ven- to lower carbon dioxide pressure and diminish cerebral blood flow
triflexion of the neck, forelimb hypermetria, and a broad-based has also been recommended. Prophylactically avoiding cerebral
hind limb stance may be observed. Cardiac consequences of hypo- edema through slow but progressive improvement in blood glu-
kalemia include decreased myocardial contractility, decreased car- cose concentration, serum electrolytes, and metabolic acidosis is
diac output, and disturbances in cardiac rhythm. Other metabolic the key.
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Hemolytic Anemia for DKA include 29% of 21 dogs (Macintire, 1993), 30% of 127
Life-threatening hemolytic anemia may develop during the initial dogs (Hume etal, 2006), and 26% of 42 cats (Bruskiewicz etal,
72 hours of therapy as a consequence of hypophosphatemia (see 1997), primarily as a result of severe concurrent illness. During
Phosphate Supplementation earlier in this chapter) (Willard etal, the past decade in our hospital, the mortality rate has decreased
1987; Adams etal, 1993; Bruskiewicz etal, 1997). The mecha- to approximately 5%, and death has usually been attributed to
nism of hypophosphatemia-induced hemolysis is not known, but underlying medical disorders (e.g., pancreatitis) that precipitated
hemolysis may occur secondary to depletion of erythrocyte ATP, the DKA, client financial constraints, or both rather than to the
which is necessary for maintenance of cell membrane integrity; metabolic complications of ketoacidosis (Claus et al, 2010). It
malfunction of the sodium-potassium pump secondary to eryth- is worth reiterating that a careful search should always be made,
rocyte ATP depletion and subsequent osmotic lysis; or alterations both at the time of initial history and physical examination and
in red blood cell membrane lipids (Shilo etal, 1985; Adams etal, during therapy, for underlying problems that might have precipi-
1993). tated the episode of DKA or developed during treatment of DKA.
Hypophosphatemia-induced hemolytic anemia can be seri- In particular, pneumonia, sepsis, pancreatitis, and hormonal
ous, with hematocrits less than 15% reported in dogs and cats diseases causing insulin resistance are often silent at the time of
(Willard etal, 1987; Adams etal, 1993). Additional findings on presentation. Despite all precautions and diligent therapy, a fatal
a CBC include spherocytes, Heinz bodies, and hemoglobinemia. outcome cannot be avoided in some cases. Nevertheless, with
Treatment involves the IV administration of phosphate, and, if logical therapy and careful monitoring, the goal of therapy for
necessary, blood. Prevention of hypophosphatemia is the key to DKA (i.e., achieving a healthy diabetic dog or cat) is attainable.
avoiding hemolytic anemia. Frequent monitoring of serum phos- Diabetic remission is also possible in cats following resolution of
phorus concentration during the initial 24 to 48 hours of therapy DKA, especially in cats with concurrent pancreatic disease or cats
for DKA and supplementation of the IV fluids with potassium being treated with glucocorticoids at the time DKA is diagnosed
or sodium phosphate when hypophosphatemia is identified is the (Sieber-Ruckstuhl etal, 2008; Marshall etal, 2013).
cornerstone of prevention.
Severe Hypernatremia and Hyperchloremia HYPEROSMOLAR HYPERGLYCEMIC STATE

Occasionally, animals with DKA develop severe hypernatremia Diabetic hyperosmolar hyperglycemic state has historically been
and hyperchloremia (see Fig. 8-12) as a result of water depriva- referred to by many terms, including hyperosmolar non-ketotic
tion (i.e., inadequate fluid intake) in conjunction with urinary syndrome, hyperosmolar coma, hyperglycemic hyperosmolar syn-
loss of large amounts of water in excess of electrolytes. Loss of drome, and non-ketotic hyperosmolar syndrome. Hyperosmolar
water in excess of electrolytes creates hypertonic dehydration, a hyperglycemic state (HHS) is the nomenclature recommended
state of dehydration with few of the expected signs of severe fluid by the American Diabetes Association to emphasize the varying
depletion (Edwards et al, 1983). Worsening hypernatremia, in alterations in sensorium less than coma that are usually present in
combination with hyperglycemia, causes severe hyperosmolality humans and that HHS may occur with mild ketosis and acidosis
(> 400 mOsm/kg) and CNS dysfunction. The initial critical signs (Nugent, 2005). HHS is an uncommon complication of diabetes
of hypernatremia include irritability, weakness, and ataxia, but as mellitus in the dog and cat. This syndrome is characterized by
the hypernatremia worsens, stupor progresses to coma and sei- severe hyperglycemia (blood glucose concentration > 600 mg/dL;
zures. The progression and severity of these signs depend on the 34 mmol/L), hyperosmolality (> 350 mOsm/kg), and dehydra-
rate of onset, degree, and duration of hypernatremia. Therapy tion in the absence of significant ketosis. Progressively worsening
should be designed to replace fluid deficits, match continuing lethargy ultimately leads to obtundation and coma as hyperos-
fluid losses, and decrease those losses when possible. (See Com- molality becomes more severe. Concurrent disorders (e.g., kidney
plications of the Modied Water Deprivation Test: Hypertonic failure, congestive heart failure, infection, pulmonary disease and
Dehydration and Hypernatremia in Chapter 1 for details on the pancreatitis) are common, contribute to the progression of this
treatment of hypernatremic, hypertonic dehydration.) syndrome, and negatively impact the prognosis. HHS is a diag-
It is important to consider factors that can result in artifactual nostic and therapeutic challenge that is associated with a high
changes in serum sodium concentrations. Severe lipemia can fatality rate (Koenig etal, 2004).
appear to raise the serum sodium concentration because lipemia
displaces sodium into the non-lipemic volume of serum, making
Pathogenesis
a normal serum sodium concentration appear increased. Hyper-
glycemia can also alter the serum sodium concentration. For each The pathogenesis of HHS is similar to that of DKAa partial or
100 mg/dL increment of serum glucose above the normal range, relative insulin deficiency reduces glucose utilization by muscle,
the serum sodium concentration decreases approximately 1.6 fat, and the liver while at the same time inducing hyperglucago-
mEq/L (DiBartola, 2012). nemia and increasing hepatic glucose output. Concurrent infec-
tion, inflammation, and organ system failure promote insulin
PROGNOSIS resistance and secretion of counterregulatory hormones (e.g., cat-
echolamines, cortisol) that exacerbate hyperglycemia. One theory
DKA remains one of the most difficult metabolic therapeutic for the lack of ketosis with HHS is the existence of a small popula-
challenges in veterinary medicine. One must remain aware of all tion of functional beta-cells that are capable of secreting insulin,
the complicating factors in treatment and remember that fluid albeit in insufficient amounts to prevent hyperglycemia. However,
therapy, insulin, and potassium supplementation are the corner- the presence of small amounts of insulin is believed to prevent the
stones of successful management. Added to these factors are close development of ketosis by inhibiting lipolysis (see Role of Insu-
supervision and monitoring of the animal, without which failure lin Deficiency). Therefore, even though a low insulin-to-glucagon
rates are high, and identification and treatment of concurrent dis- ratio promotes ketogenesis in the liver, the limited availability
ease that is invariably present. Reported in-hospital mortality rates of precursor FFAs from the periphery restricts the rate at which
ketones are formed (Ennis etal, 1994). Hepatic resistance to glu- are typically lethargic, extremely depressed, or actually comatose.
cagon may also play a role in the lack of ketosis with HHS (Yen There is a direct relationship between the severity of the hyperos-
etal, 1980; Azain etal, 1985). molality and the severity of neurologic signs. Hypothermia and
If a dog or cat is unable to maintain adequate fluid intake slow capillary refill time are common. Kussmaul respirations are
because of an associated acute or chronic illness (e.g., pancreati- absent unless severe metabolic (lactic) acidosis is present.
tis, gastroenteritis) or has suffered excessive fluid loss (e.g., diuret-
ics for concurrent congestive heart failure), marked dehydration Laboratory Findings
results. As plasma volume contracts, glomerular filtration is Severe hyperglycemia is present, with blood glucose concentrations
impaired, limiting renal glucose excretion and contributing mark- ranging from 600 to as high as 1600 mg/dL (34 to 90 mmol/L).
edly to the rise in blood glucose. The measured serum sodium Severe prerenal or renal azotemia is a common finding. These ani-
concentration is usually decreased or within the reference range, mals typically have depleted body potassium stores, despite the fact
but the corrected serum sodium concentration is typically in the that serum potassium concentrations can be high, normal, or low.
reference range or increased and is contributing to the increase in Serum sodium concentrations are also variable and may be low,
plasma osmolality (see Serum Sodium Concentration earlier). As normal, or elevated despite total body sodium depletion. Because
plasma osmolality increases, water is drawn out of cerebral neu- glucose osmotically shifts water into the extracellular space, sodium
rons, resulting in mental obtundation and further impairment of is diluted and the measured value may be falsely decreased. The
water intake. A vicious cycle of worsening hyperosmolality, obtun- measured sodium value should be corrected to a sodium value that
dation, inadequate fluid intake, dehydration, and prerenal azote- accounts for hyperglycemia by using the formula in Serum Sodium
mia ensues, ultimately resulting in coma and death. Concentration earlier in the chapter. The formula reflects that the
The hyperglycemia of HHS (600 to 1600 mg/dL; 34 to 90 measured serum sodium value is decreased by approximately 1.6
mmol/L) tends to be more severe than the hyperglycemia of DKA mEq for every 100 mg/dL increase in glucose above 100 (Nugent,
(300 to 600 mg/dL; 17 to 34 mmol/L). The increase in blood glu- 2005). A mild hyponatremia or a normal serum sodium concentra-
cose concentration in HHS is, as in DKA, the result of increased tion usually suggests moderate dehydration. Hypernatremia despite
production of glucose by the liver coupled with its diminished hyperglycemia suggests significant water loss has occurred and
use by tissues. However, two additional factors in HHS allow severe volume contraction and dehydration are present.
the hyperglycemia to become more severe. First, impaired urine Hyperosmolality is a consistent finding in HHS and can exceed
output in HHS diminishes excretion of glucose in urine (Foster 400 mOsm/kg, especially in dogs and cats with hypernatremia
and McGarry, 1989). Second, low or undetectable concentrations and severe hyperglycemia. Plasma osmolality may be measured by
of ketoacid in the plasma and urine in HHS removes an impor- determination of its freezing point with an osmometer or calculated
tant and early contributor to clinical signs. As a consequence, the using the formula given in Serum Osmolality earlier in the chapter.
hyperglycemia of HHS progresses for a longer period of time, and Mild to moderate ketosis may occur with HHS in diabetic
it is not until signs of severe hyperosmolality (i.e., lethargy, obtun- humans. HHS and DKA are two disorders believed to represent
dation) or signs related to concurrent problems become evident to different points along a spectrum of emergencies caused by poorly-
the owner that veterinary care is sought. controlled diabetes (Kitabchi etal, 2006). Ketosis is usually absent
Some dogs and cats with HHS are acidotic despite low or unde- in dogs and cats with HHS, although trace ketonuria may occur.
tectable concentrations of ketoacid in the plasma or urine. One Ketoacidosis is not a part of HHS but metabolic acidosis may be
cause for this disparity in expected versus real results is the fact identified (usually in the form of lactic acidosis) owing to under-
that -hydroxybutyrate (one of two major ketoacids) is not assayed lying disorders commonly affiliated with HHS in dogs and cats.
by commonly used urine and plasma reagent strips or tablets (see Lactic acidosis depresses plasma bicarbonate concentrations and
Establishing the Diagnosis of Diabetic Ketosis and Ketoacidosis). the arterial pH. An anion gap is present (see Anion Gap earlier
Another cause for acidosis in non-ketotic diabetics is lactic acidosis. in the chapter). Other causes of anion gap metabolic acidosis
Lactic acid is the end product of anaerobic metabolism of glucose. should be excluded (see Box 8-4). The diagnosis of lactic acidosis
The principal sources of this acid are erythrocytes (which lack the can be confirmed by measuring plasma lactate concentration.
enzymes for aerobic oxidation), skeletal muscle, skin, and brain.
Lactic acid is removed via hepatic, and to some degree renal, uptake Therapy
with conversion first to pyruvate and eventually back to glucose,
a process that requires oxygen. Lactic acidosis occurs when excess The goals of therapy for HHS are similar to DKAthat is, to cor-
lactic acid accumulates in the blood. This can be the result of over- rect severe dehydration and restore electrolyte losses, to provide
production (tissue hypoxia), deficient removal (hepatic failure), or adequate amounts of insulin to normalize intermediary metabo-
both (circulatory collapse). Like humans, dogs and cats with lactic lism, to correct the hyperosmolar state, and to identify and treat
acidosis are usually severely ill, with problems such as sepsis, hemor- precipitating factors. Restoring intravascular volume and lost elec-
rhage, anemia, pulmonary disease, liver disease, and kidney failure. trolytes using isotonic fluids has the highest priority. Osmolality
is returned to normal by lowering the blood glucose concentra-
tion and by replacing water deficits. Initially, fluid therapy is used
Clinical Findings
to lower the blood glucose concentration; insulin should not be
Clinical Signs administered until intravascular volume is restored, electrolyte
The onset of HHS may be insidious, and it may be preceded for derangements improved, and blood pressure stabilized. Careful
days or weeks by the classic signs of diabetes mellitus (polyuria, and frequent monitoring of the dogs or cats clinical and labora-
polydipsia, polyphagia, and weight loss). Progressive weakness, tory response to therapy is essential.
anorexia, and lethargy develop, usually in conjunction with a Fluid therapy is of paramount importance in treating HHS and
reduction in water intake. Additional clinical signs depend on is the primary mode of therapy for the initial 4 to 6 hours or lon-
the underlying precipitating disorder(s). Physical examination ger. Derangements in total body water, sodium and potassium,
often reveals the presence of profound dehydration. These pets hyperglycemia, and hyperosmolality are usually severe, in part
|
because the lack of ketoacidosis and associated systemic signs of DKA; this is in part because ketone production and its metabolic
illness allows HHS to develop for a longer period of time before consequences are minimal to nonexistent with HHS. Metabolic
veterinary care is sought. Despite the severe hyperosmolality, the acidosis, if identified in HHS, is more likely caused by lactic aci-
initial fluid of choice is isotonic (0.9%) saline with appropriate dosis, which can be improved with fluid therapy. In addition,
potassium supplementation. Isotonic saline will correct dehydra- insulin can cause a rapid decrease in the blood glucose concentra-
tion and improve blood flow to tissues, stabilize blood pressure, tion and ECF osmolalitychanges that promote cerebral edema
improve GFR and promote glycosuria, decrease blood glucose (see Central Nervous System Signs [Cerebral Edema]). The tech-
concentration, and replace sodium for glucose in the ECF space. niques for insulin administration are similar to those discussed for
The net effect is a slow reduction in ECF hyperosmolality, thereby DKA (see Insulin Therapy). However, the insulin dosage used for
minimizing development of cerebral edema. The initial goal of the hourly IM technique or the insulin infusion rate used for the
fluid therapy is correction of dehydration deficits. Half of the esti- constant low-dose insulin infusion technique should be decreased
mated dehydration deficit plus maintenance requirements should by 50% initially to dampen the decrease in the blood glucose con-
be replaced in the first 12 hours and the remainder in the next 12 centration and avoid a rapid decrease in ECF osmolality. Subse-
to 24 hours. quent adjustments in the amount of insulin being administered
The principles of potassium and phosphorus supplementation are based on the rate of decline in the blood glucose concentra-
are similar to those discussed for DKA (see Potassium Supplemen- tion. The goal is a decrease of 50 mg/dL/hour (2.8 mmol/L/hour),
tation and Phosphate Supplementation earlier in the chapter). although the rate of decrease is hard to predict or control, in part
Many dogs and cats with HHS are also in kidney failure (often because of differences in insulin sensitivity between animals.
oliguric) and may have hyperkalemia, hyperphosphatemia, and/ Once the blood glucose concentration is less than 250 mg/dL (14
or impaired ability to excrete a potassium load. As such, potas- mmol/L), dextrose should be added to the IV fluids to make a 5%
sium and phosphorus supplementation should be based on mea- dextrose solution.
surement of serum concentrations and awareness of the status of Monitoring urine output, blood pressure, blood glucose, serum
kidney function and urine production. Usually, initial therapy electrolytes, creatinine, BUN, and urine glucose is imperative. As
consists of 20 mEq/L of potassium replacement (as potassium with ketoacidosis, the clinician must attempt to correct the hyper-
chloride) into the infusion fluids. Subsequent adjustments are osmolality, hyperglycemia, and dehydration steadily (not pre-
based on measurements of serum electrolytes, which should be cipitously) while stimulating diuresis to improve azotemia. These
done frequently to quickly identify problems in serum electrolyte animals are critically ill and require close supervision.
concentrations, should they arise. The prognosis for recovery is guarded to poor. In a retrospective
Insulin therapy should be delayed (typically 4 to 6 hours or study of 17 diabetic cats with HHS, 65% did not survive the ini-
longer) until the positive benefits of fluid therapy are documented tial hospitalization, with most dying or being euthanized within
(i.e., correction of dehydration, stabilization of blood pressure, 10 hours of presentation (Koenig etal, 2004). The long-term sur-
and improvement in urine production, hyperglycemia, hyperos- vival rate was low (12%). The most common concurrent disease
molality, and derangements in serum electrolyte concentrations). affiliated with death or euthanasia in our animals with HHS is
The need for insulin treatment is not as critical with HHS as with kidney failure.
REFERENCES
Abbott LG, Rude RK: Clinical manifestations Barrett EJ, DeFronzo RA: Diabetic ketoacido- Bruskiewicz KA, etal.: Diabetic ketosis and
of magnesium deficiency, Miner Electrolyte sis: diagnosis and treatment, Hosp Pract ketoacidosis in cats: 42 cases (1980-
Metab 19:314, 1993. 19:89, 1984. 1995), J Am Vet Med Assoc 211:188,
Adams LG, etal.: Hypophosphatemia and Becker DJ, etal.: Phosphate replacement dur- 1997.
hemolytic anemia associated with diabetes ing treatment of diabetic ketosis: effects Bush WW, etal.: Secondary hypoparathyroid-
mellitus and hepatic lipidosis in cats, J Vet on calcium and phosphorus homeostasis, ism attributed to hypomagnesemia in a dog
Intern Med 7:266, 1993. Am J Dis Child 137:241, 1983. with protein-losing enteropathy, J Am Vet
Adrogu HJ, etal.: Plasma acid-base patterns Boord M, Griffin C: Progesterone secreting Med Assoc 219:1732, 2001.
in diabetic ketoacidosis, N Engl J Med adrenal mass in a cat with clinical signs of Chastain CB, Nichols CS: Low-dose intra-
307:1603, 1982. hyperadrenocorticism, J Am Vet Med Assoc muscular insulin therapy for diabetic
Adrogu HJ, etal.: Diabetic ketoacidosis: 214:666, 1999. ketoacidosis in dogs, J Am Vet Med Assoc
Role of the kidney in acid-base homeo- Bostrom BM, etal.: Chronic pancreatitis in 178:561, 1981.
stasis reevaluated, Kidney Int 25:591, dogs: a retrospective study of clinical, Cherrington AD, etal.: Insulin, glucagon, and
1984. clinicopathological, and histopathological glucose as regulators of hepatic glucose
Aroch I, etal.: A retrospective study of serum findings in 61 cases, Vet J 195:73, 2013. uptake and production invivo, Diabetes
-hydroxybutyric acid in 215 ill cats: clini- Boyle PJ: Cushings disease, glucocorticoid Metab Rev 3:307, 1987.
cal signs, laboratory findings and diagno- excess, glucocorticoid deficiency, and Church DB: Diabetes mellitus. In Kirk RW,
ses, Vet J 191:240, 2012. diabetes, Diabetes Rev 1:301, 1993. editor: Current veterinary therapy VIII,
Azain MJ, etal.: Contributions of fatty acid and Brady MA, etal.: Evaluating the use of plasma Philadelphia, 1983, WB Saunders, p 838.
sterol synthesis to triglyceride and choles- hematocrit samples to detect ketones uti- Claus MA, etal.: Comparison of regular insulin
terol secretion by the perfused rat liver in lizing urine dipstick colorimetric methodol- infusion doses in critically ill diabetic cats:
genetic hyperlipemia and obesity, ogy in diabetic dogs and cats, J Vet Emerg 29 cases (1999-2007), J Vet Emerg Crit
J Biol Chem 260:174, 1985. Crit Care 13:1, 2003. Care 20:509, 2010.
Bailiff NL, etal.: Frequency and risk factors Bratusch-Marrain PR, etal.: The effect of Cryer PE: Catecholamines, pheochromocy-
for urinary tract infection in cats with dia- growth hormone on glucose metabolism toma, and diabetes, Diabetes Rev 1:309,
betes mellitus, J Vet Intern Med 20:850, and insulin secretion in man, J Clin Endo- 1993.
2006. crinol Metab 55:131, 1982.
DeFronzo RA, etal.: Diabetic ketoacidosis: a Forrester SD, Moreland KJ: Hypophosphatemia: Kitabchi AE, etal.: Thirty years of personal ex-
combined metabolic-nephrologic approach causes and clinical consequences, J Vet perience in hyperglycemic crises: diabetic
to therapy, Diabetes Rev 2:209, 1994. Intern Med 3:149, 1989. ketoacidosis and hyperglycemic hyper-
Dhupa N, Proulx J: Hypocalcemia and hypo- Foster DW, McGarry JD: The metabolic de- osmolar state, J Clin Endocrinol Metab
magnesemia, Vet Clin North Am Small rangements and treatment of diabetic ke- 93:1541, 2008.
Anim Pract 28:587, 1998. toacidosis, N Engl J Med 309:159, 1983. Koenig A, etal.: Hyperglycemic, hyperosmolar
Dhupa N, Shaffran N: Continuous rate infusion Foster DW, McGarry JD: Acute complications syndrome in feline diabetics: 17 cases
formulas. In Ettinger SJ, Feldman EC, of diabetes: ketoacidosis, hyperosmolar (1995-2001), J Vet Emerg Crit Care
editors: Textbook of veterinary internal coma, lactic acidosis. In DeGroot LJ, 14:30, 2004.
medicine, ed 4, Philadelphia, 1995, WB editor: Endocrinology, ed 2, Philadelphia, Lebovitz HE: Diabetic ketoacidosis, Lancet
Saunders, p 2130. 1989, WB Saunders, p 1439. 345:767, 1995.
DiBartola SP: Disorders of sodium and water: Goldstein DE: Tests of glycemia in diabetes, Li PK, etal.: Direct, fixed time kinetic assays
hypernatremia and hyponatremia. In Diabetes Care 18:896, 1995. for -hydroxybutyrate and acetoacetate
DiBartola SP, editor: Fluid, electrolyte, Goossens MM, etal.: Response to insulin with a centrifugal analyzer or a computer-
and acid-base disorders in small animal treatment and survival in 104 cats with baked spectrophotometer, Clin Chem
practice, ed 4, St Louis, 2012, Elsevier diabetes mellitus (1985-1995), J Vet 26:1713, 1980.
Saunders, p 45. Intern Med 12:1, 1998. Luzi L, etal.: Metabolic effects of low-dose
DiBartola SP, de Morais HA: Disorders of Graca R, etal.: Validation and diagnostic ef- insulin therapy on glucose metabolism in
potassium: hypokalemia and hyperkalemia. ficacy of a lipase assay using the substrate diabetic ketoacidosis, Diabetes 37:1470,
In DiBartola SP, editor: Fluid, electrolyte, 1,2-o-dilauryl-rac-glycero-3-glutaric acid- 1988.
and acid-base disorders in small animal (6methylresorufin) ester for the diagnosis Macintire DK: Treatment of diabetic keto-
practice, ed 4, St Louis, 2012, Elsevier of acute pancreatitis in dogs, Vet Clin acidosis in dogs by continuous low-dose
Saunders, p 92. Pathol 34:39, 2005. intravenous infusion of insulin, J Am Vet
Di Tommaso M, etal.: Evaluation of a portable Groop LC, etal.: Effect of insulin on oxidative Med Assoc 202:1266, 1993.
meter to measure ketonemia and compari- and non-oxidative pathways of glucose and Macintire DK: Emergency therapy of diabetic
son of ketonuria for the diagnosis of canine FFA metabolism in NIDDM: evidence for crises: Insulin overdose, diabetic keto-
diabetic ketoacidosis, J Vet Intern Med multiple sites of insulin resistance, J Clin acidosis, and hyperosmolar coma, Vet
23:466, 2009. Invest 84:205, 1989. Clin North Am Small Anim Pract 25:639,
Duarte R, etal.: Accuracy of serum - Hale RJ, etal.: Metabolic effects of bicarbon- 1995.
hydroxybutyrate measurements for the ate in the treatment of diabetic ketoacido- Marshall RD, etal.: Intramuscular glargine
diagnosis of diabetic ketoacidosis in 116 sis, Br Med J 289:1035, 1984. with or without concurrent subcutaneous
dogs, J Vet Intern Med 16:411, 2002. Hansen B: Disorders of magnesium. In Di- administration for treatment of feline dia-
Durocher LL, etal.: Acid-base and hormonal Bartola SP, editor: Fluid therapy in small betic ketoacidosis, J Vet Emerg Crit Care
abnormalities in dogs with naturally oc- animal practice, ed 2, Philadelphia, 2000, 23:286, 2013.
curring diabetes mellitus, J Am Vet Med WB Saunders, p 175. Martin L, etal.: Magnesium in the 1990s:
Assoc 232:1310, 2008. Hess RS, etal.: Concurrent disorders in dogs Implications for veterinary critical care, J
Edwards DF, etal.: Hypernatremic, hypertonic with diabetes mellitus: 221 cases (1993- Vet Emerg Crit Care 3:105, 1993.
dehydration in the dog with diabetes 1998), J Am Vet Med Assoc 217:1166, Masharani U, Karam JH: Pancreatic hormones
insipidus and gastric dilatation-volvulus, J 2000. and diabetes mellitus. In Greenspan FS,
Am Vet Med Assoc 182:973, 1983. Hoenig M, etal.: Use of a hand-held meter for Gardner DG, editors: Basic and clinical
Ennis ED, etal.: The hyperosmolar hyperglyce- the measurement of blood beta-hydroxy- endocrinology, ed 6, New York, 2001,
mic syndrome, Diabetes Rev 2:115, 1994. butyrate in dogs and cats, J Vet Emerg Crit McGraw-Hill, p 623.
Feldman BF, Rosenberg DP: Clinical use of Care 18:86, 2008. McCord K, etal.: A multi-institutional study
anion and osmolal gaps in veterinary Hood VL, Tannen RL: Maintenance of acid- evaluating the diagnostic utility of the
medicine, J Am Vet Med Assoc 178:396, base homeostasis during ketoacidosis and Spec cPL and SNAP cPL in clinical
1981. lactic acidosis: implications for therapy, acute pancreatitis in 84 dogs, J Vet Intern
Feldman EC: Diabetic ketoacidosis in dogs, Diabetes Rev 2:177, 1994. Med 26:888, 2012.
Comp Cont Educ 11:456, 1980. Hume DZ, etal.: Outcome of dogs with diabet- McGarry JD, etal.: Regulation of ketogenesis
Feldman EC, Nelson RW: Canine and feline ic ketoacidosis: 127 cases (1993-2003), J and the renaissance of carnitine palmito-
endocrinology and reproduction, Philadel- Vet Intern Med 20:547, 2006. yltransferase, Diabetes Metab Rev 5:271,
phia, 1987, WB Saunders. Joshi N, etal.: Infections in patients with dia- 1989.
Ferrannini E, etal.: Effect of free fatty acids on betes mellitus, N Engl J Med 341:1906, McMahon MM, Bistrian BR: Host defenses and
glucose production and utilization in man, 1999. susceptibility to infection in patients with
J Clin Invest 72:1737, 1983. Kandel G, Aberman A: Selected developments diabetes mellitus, Infect Dis Clin North Am
Fincham SC, etal.: Evaluation of plasma- in the understanding of diabetic ketoacido- 9:1, 1995.
ionized magnesium concentration in 122 sis, Can Med Assoc J 128:392, 1983. Molitch ME, etal.: Spurious serum creatinine
dogs with diabetes mellitus: a retrospec- Kaplan AJ, etal.: Effects of disease on the elevations in ketoacidosis, Ann Intern Med
tive study, J Vet Intern Med 18:612, results of diagnostic tests for use in de- 93:290, 1980.
2004. tecting hyperadrenocorticism in dogs, J Am Nanji AA, Campbell DJ: Falsely elevated serum
Fisher JN, Kitabchi AE: A randomized study Vet Med Assoc 207:445, 1995. creatinine values in diabetic ketoacido-
of phosphate therapy in the treatment of Kitabchi AE, etal.: Management of hypergly- sisclinical implications, Clin Biochem
diabetic ketoacidosis, J Clin Endocrinol cemic crises in patients with diabetes, 14:91, 1981.
Metab 57:177, 1983. Diabetes Care 24:131, 2001. Narins RG, etal.: The metabolic acidoses. In
Forman MA, etal.: Evaluation of serum pan- Kitabchi AE, etal.: Hyperglycemic crises in Maxwell MH, Kleeman CR, editors: Clinical
creatic lipase immunoreactivity and helical diabetes mellitus: diabetic ketoacidosis disorders of fluid and electrolyte metabo-
computed tomography versus conventional and hyperglycemic hyperosmolar state, lism, New York, 1994, McGraw-Hill,
testing for the diagnosis of feline pancreati- Endocrinol Metab Clin N Am 35:725, p 769.
tis, J Vet Intern Med 18:807, 2004. 2006.
|
Nelson RW, etal.: Absorption kinetics of regu- secretion in the cat, Res Vet Sci 42:354, Wagner A, etal.: Therapy of severe diabetic
lar insulin in dogs with alloxan-induced 1987. ketoacidosis: zero-mortality under very-
diabetes mellitus, Am J Vet Res 51:1671, Rossmeisl JH, etal.: Hyperadrenocorticism low-dose insulin application, Diabetes Care
1990. and hyperprogesteronemia in a cat with 22:674, 1999.
Nichols R, Crenshaw KL: Complications and an adrenocortical adenocarcinoma, J Am Willard MD, etal.: Severe hypophosphatemia
concurrent disease associated with dia- Anim Hosp Assoc 36:512, 2000. associated with diabetes mellitus in six
betic ketoacidosis and other severe forms Ryder RE: Lactic acidosis: high-dose or low- dogs and one cat, J Am Vet Med Assoc
of diabetes mellitus, Vet Clin N Amer dose bicarbonate therapy? Diabetes Care 190:1007, 1987.
Small Anim Pract 25:617, 1995. 7:99, 1984. Vick MM, etal.: Effects of systemic inflamma-
Norris CR, etal.: Serum total and ionized Sears KW, etal.: Use of lispro insulin for treat- tion on insulin sensitivity in horses and in-
magnesium concentrations and urinary ment of diabetic ketoacidosis in dogs, J flammatory cytokine expression in adipose
fractional excretion of magnesium in cats Vet Emerg Crit Care 22:211, 2012. tissue, Am J Vet Res 69:130, 2008.
with diabetes mellitus and diabetic keto- Sherwin RS, etal.: Epinephrine and the Yeates S, Blaufuss J: Managing the animal
acidosis, J Am Vet Med Assoc 215:1455, regulation of glucose metabolism: effect in diabetic ketoacidosis, Focus Crit Care
1999a. of diabetes and hormonal interactions, 17:240, 1990.
Norris CR, etal.: Effect of a magnesium-defi- Metabolism 29(Suppl 1):1146, 1980. Yen TT, etal.: Hepatic insensitivity to glucagon
cient diet on serum and urine magnesium Shilo S, etal.: Acute hemolytic anemia caused in ob/ob mice, Res Commun Chem Pathol
concentrations in healthy cats, Am J Vet by severe hypophosphatemia in diabetic Pharmacol 30:29, 1980.
Res 60:1159, 1999b. ketoacidosis, Acta Haematol 73:55, 1985. Zammit VA: Regulation of ketone body metabo-
Nugent BW: Hyperosmolar hyperglycemic state, Sieber-Ruckstuhl S, etal.: Remission of diabe- lism: a cellular perspective, Diabetes Rev
Emerg Med Clin N Am 23:629, 2005. tes mellitus in cats with diabetic ketoaci- 2:132, 1994.
Oppliger S, etal.: Agreement of the serum dosis, J Vet Intern Med 22:1326, 2008. Zeugswetter F, Pagitz M: Ketone measure-
Spec fPL and 1,2-o-dilauryl-rac-glycero- Tessari P, etal.: Hyperaminoacidemia reduces ments using dipstick methodology in cats
3-glutaric acid-(6-methylresorufin) ester insulin-mediated glucose disposal in with diabetes mellitus, J Sm Anim Pract
lipase assay for determination of serum healthy man, Diabetologia 28:870, 1985. 50:4, 2009.
lipase in cats with suspicion of pancreati- Thiebaud D, etal.: Effect of long chain triglyc- Zeugswetter F, Rebuzzi L: Point-of-care
tis, J Vet Intern Med 13:27, 2013. eride infusion on glucose metabolism in -hydroxybutyrate measurement for the
Owen OE, etal.: Renal function and effects of man, Metabolism 21:1128, 1982. diagnosis of feline diabetic ketoacidaemia,
partial rehydration during diabetic ketoaci- Tilg H, Moschen AR: Adipocytokines: mediators J Sm Anim Pract 53:328, 2012.
dosis, Diabetes 30:510, 1981. linking adipose tissue, inflammation and Zeugswetter F, etal.: Efficacy of plasma -
Peikes H, etal.: Dermatologic disorders in dogs immunity, Nat Rev Immunol 6:772, 2006. hydroxybutyrate concentration as a marker
with diabetes mellitus: 45 cases (1986- Trivedi S, etal.: Sensitivity and specificity of ca- for diabetes mellitus in acutely sick cats, J
2000), J Am Vet Med Assoc 219:203, nine pancreas-specific lipase (cPL) and other Fel Med Surg 12:300, 2010.
2001. markers for pancreatitis in 70 dogs with and
Peterson ME: Effects of megestrol acetate on without histopathologic evidence of pancre-
glucose tolerance and growth hormone atitis, J Vet Intern Med 25:1241, 2011.
CHAPTER 9 Beta-Cell Neoplasia: Insulinoma
Richard W. Nelson
CHAPTER CONTENTS Polycythemia, 358

Etiology, 348 Artifactual Hypoglycemia, 358
Malignant Versus Benign Potential, 348 Iatrogenic Hypoglycemia (Toxicities), 358
Pathophysiology, 349 Diagnostic Approach to Hypoglycemia: Prioritizing the Differentials, 359
Maintenance of Euglycemia in the Healthy Dog, 349 Confirming the Diagnosis of an Insulin-Secreting Beta-Cell Tumor: Serum
Hypoglycemia and the Counterregulatory Response, 350 Insulin Determination, 359
Insulin Secretion in Dogs with Beta-Cell Neoplasia, 351 Whipples Triad, 359
Mechanism for Insulin-Induced Hypoglycemia, 351 Determination of Baseline Insulin and Glucose Concentrations, 360
Origin of Clinical Signs, 351 Insulin-to-Glucose Ratios, 360
Clinical Features, 352 Serum Fructosamine Concentration, 361
Signalment, 352 Provocative Testing, 361
History, 353 Diagnostic Imaging, 361
Physical Examination, 353 Radiography, 361
Clinical Pathologic Abnormalities, 354 Ultrasonography, 361
Differential Diagnoses for Fasting Hypoglycemia, 355 Computed Tomography, 362
Congenital Hepatic Disease, 355 Scintigraphy, 363
Acquired Hepatic Dysfunction, 355 Treatment of Beta-Cell Neoplasia, 364
Adrenocortical Insufficiency (Addisons Disease), 356 Surgical Versus Medical Therapy, 364
Glucagon Deficiency, 356 Perioperative Management of Dogs Undergoing Surgery, 364
Hypopituitarism, 356 Medical Therapy for an Acute Hypoglycemic Crisis, 368
NonBeta-Cell Tumors, 357 Medical Therapy for Chronic Hypoglycemia, 369
Neonatal and Juvenile Hypoglycemia, 357 Prognosis, 372
Endotoxic or Sepsis-Induced Hypoglycemia, 358 Insulin-Secreting Beta-Cell Tumors
Kidney Failure, 358 in Cats, 372
Insulin-secreting beta-cell tumors (insulinomas) were first described beta-cell tumors has revealed a high incidence of multihormonal
in the dog by Slye and Wells in 1935. During the past seven production, including pancreatic polypeptide, somatostatin, glu-
decades, numerous publications have appeared in the veterinary cagon, serotonin, and gastrin (Hawkins etal, 1987; OBrien etal,
literature addressing the clinical manifestations, diagnosis, treat- 1987; Minkus etal, 1997). Recently, using quantitative real-time
ment, and pathology of beta-cell tumors in dogs. Insulin-secreting polymerase chain reaction (PCR), significantly higher expression
beta-cell neoplasia is an uncommon diagnosis in dogs and a rare of genes encoding for growth hormone (GH) and insulin-like
entity in cats. Despite excellent documentation of this disease, growth factor-1 (IGF-1) have been identified in metastases, com-
increased awareness of the clinical presentations, and well-estab- pared to the primary beta-cell tumor and immunohistochemical
lished methods for establishing the diagnosis, treatment options examination of the beta-cell tumor and its metastases revealed
remain limited and the prognosis remains guarded to poor. This expression of GH, IGF-1, and GH receptor in both primary beta-
chapter summarizes current concepts regarding the diagnosis and cell tumors and metastases (Buishand et al, 2012). The authors
treatment of insulin-secreting beta-cell tumors in dogs and cats. speculated that therapeutic intervention with agents that specifi-
cally antagonize the GH/IGF-1 axis or members of their signaling
cascade may inhibit beta-cell tumor growth.
ETIOLOGY
Functional tumors arising from the beta cells of the pancreatic Malignant Versus Benign Potential
islets are malignant tumors that secrete insulin independent of
the typically suppressive effects of hypoglycemia. Insulin is the Beta-cell tumors are notorious for masking their malignant ten-
most common product demonstrated in the neoplastic cells, and dencies in the dog. Discrepancy is noted between the orderly
the clinical signs in such animals are primarily those that result arrangement of well-differentiated cells, the rarity of mitotic
from insulin-induced hypoglycemia. Beta-cell tumors, however, figures in most islet cell tumors, and the frequent metastasis of
are not completely autonomous, and they respond to provocative beta-cell tumors at the time of diagnosis (Kruth etal, 1982). Clas-
stimuli, such as an increase in blood glucose by secreting insu- sifying beta-cell tumors as adenomas or adenocarcinomas based
lin, often in excessive amounts. Immunohistochemical analysis of on their morphology often does not reflect their biologic behavior
348
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CHAPTER 9 Beta-Cell Neoplasia: Insulinoma 349
in humans and dogs (Mehlhaff, etal, 1985; Minkus etal, 1997). Plasma glucose
Differentiation of malignant from benign neoplasia is usually and/or INSULIN
caloric intake
based on identification of metastasis at surgery or necropsy or the
recurrence of hyperinsulinism and hypoglycemia days to months
after surgical removal of a solitary pancreatic mass. Recent his- AA mobilization Glycogenolysis Lipolysis
Gluconeogenic enzymes
topathologic evaluation of beta-cell tumors in 26 dogs revealed
that 96% were highly cellular and exhibited nuclear atypia and
83% had an infiltrative growth pattern (Buishand et al, 2010).
Glucose production Glucose utilization
Vascular invasion was common, but the mitotic index was low (liver) (fat, muscle)
in most tumors. Increased stromal fibrosis within the tumor was
the only significant morphological prognostic marker identified in
the study, a finding that illustrates the general lack of prognostic EUGLYCEMIA
significance of histopathologic criteria in beta-cell tumors (Kruth FIGURE 9-1 Hormonal and substrate changes by which euglycemia is main-
etal, 1982; Mehlhaff etal, 1985; Caywood etal, 1988). tained (and hypoglycemia is prevented) in normal subjects during a fast. The
The malignant potential of beta-cell tumors is often underesti- fall in the plasma insulin concentration is the key hormonal change resulting in
mated in the dog. In our experience, virtually all beta-cell tumors increased glucose production and decreased glucose utilization. The decline in
in dogs are malignant, and most animals have microscopic or the plasma insulin concentration is, in turn, a result of a small decrease in the
grossly visible metastatic lesions at the time of surgery. The most plasma glucose level (5 to 10 mg/dL) and/or a decrease in caloric intake. AA,
common sites of tumor spread are the regional lymphatics and Amino acid.
lymph nodes (duodenal, mesenteric, hepatic, splenic), the liver,
and the peripancreatic omentum. Pulmonary metastasis is typi-
cally not recognized until very late in the disease process. Identi- glycerol) delivered to the liver from peripheral stores. Muscle
fication of distant metastasis such as the gastrointestinal tract or and other structural tissues supply amino acids, mainly alanine;
bone marrow or gross invasion of the tumor into major blood blood cell elements supply lactate, the end product of glycolytic
vessels with tumor thrombus formation is uncommon (Pickens metabolism; and adipose tissue supplies glycerol from lipolysis of
etal, 2005; Hambrook and Kudnig, 2012). In most dogs, hypo- triglycerides (Karam, 2001). Oxidation of free fatty acids released
glycemia recurs days to weeks after surgical excision of the tumor. from adipose cells during lipolysis supplies the energy required
The high incidence of metastasis at the time afflicted dogs are ini- for gluconeogenesis and provides ketone bodies (i.e., acetoacetate,
tially examined results in part from the typically protracted time -hydroxybutyrate), which can serve as alternative metabolic fuels
for worrisome clinical signs (e.g., collapsing episodes, seizures) for the brain during periods of prolonged fasting. Other require-
to develop and become apparent to the owner and the interval ments include a normal hepatic circulation, functioning hepato-
between the time an owner initially observes signs and when assis- cytes capable of removing substrates from the circulation, and a
tance is sought from a veterinarian. Most dogs are symptomatic complete complement of hepatic enzymes capable of converting
for 1 to 3 months before being brought to a veterinarian. these noncarbohydrate precursors into glucose.
The renal cortex also has the requisite enzymes for the produc-
tion and release of glucose into the circulation, albeit the con-
PATHOPHYSIOLOGY
tribution is only about 5% during fasting (Stumvoll etal, 1995;
Gerich etal, 2001). However, renal glucose production is regu-
Maintenance of Euglycemia in the Healthy Dog
lated and under certain circumstances (e.g., glucose counterregu-
Glucose is essentially the sole metabolic fuel for the brain under nor- lation, hepatic insufficiency) the contribution of glucose derived
mal physiologic conditions. Survival of the brain requires a continu- from renal gluconeogenesis can be as high as 40%. The kidney
ous supply of glucose from the circulation which, in turn, requires does not have glycogen stores and depends on gluconeogenesis
maintenance of blood glucose concentration within or above the as its only source of glucose production. Glutamine rather than
physiologic range. Glucose is derived from three sources: intestinal alanine is the predominant amino acid substrate for renal gluco-
absorption that occurs after digestion of dietary carbohydrates; gly- neogenesis. In addition to its contribution to glucose homeostasis
cogenolysis, which is the breakdown of glycogen; and gluconeogen- during fasting, the kidney has been shown to be an important
esis, which is the formation of glucose from precursors including contributor to increasing blood glucose (i.e., glucose counterregu-
lactate, amino acids (especially alanine and glutamine), and glycerol lation) in the event of hypoglycemia. Although glucagon does not
(Cryer, 2011). The liver is the major source of net endogenous glu- affect the kidney, the counterregulatory increase in epinephrine
cose production through glycogenolysis and gluconeogenesis. has been shown to stimulate gluconeogenesis in the renal cortex
Exogenously derived energy, in the form of ingested carbohy- (Stumvoll etal, 1995; Gerich etal, 2001).
drate, fat, and protein, provides enough fuel for 4 to 8 hours of A normally functioning endocrine system is also necessary to
cell metabolism. After this postprandial period, fuel for cellular maintain glucose homeostasis and prevent hypoglycemia. Rates of
metabolism must be derived from endogenous sources, primarily endogenous glucose influx into the circulation and glucose efflux
through production of glucose by the liver (Fig. 9-1). The liver out of the circulation into tissues other than the brain are regulated
initially provides glucose by the breakdown of stored hepatic gly- primarily by the blood glucose-lowering hormone insulin and the
cogen (glycogenolysis). Liver glycogen stores are exhausted slowly blood glucose-raising hormones, glucagon and epinephrine, such
in dogs, requiring 2 to 3 days of fasting, compared with only that systemic glucose balance is maintained, hypoglycemia and
24 hours of fasting in humans (de Bruijne etal, 1981). Hepatic hyperglycemia are prevented, and a continuous supply of glucose
glucose production is augmented by gluconeogenesis as the post- to the brain is ensured (Cryer, 2011). In humans, when the blood
prandial period increases and hepatic glycogen stores become glucose concentration exceeds approximately 110 mg/dL (6.2

depleted (Rothman et al, 1991). Gluconeogenesis is the forma- mmol/L), insulin is secreted and the blood glucose concentration
tion of glucose from precursors (e.g., alanine, glutamine, lactate, declines into the normal physiologic range (i.e., 70 to 110 mg/dL;
BOX 9-1 A
utonomic Nervous System Response BOX 9-2 Insulin and Counterregulatory Hormonal
to Hypoglycemia Response to Hypoglycemia
Alpha-Adrenergic Effects Insulin: Decreased Secretion

Inhibition of endogenous insulin secretion Reduced stimulation of beta cells by low glucose
Stimulation of peripheral vasoconstriction causing increase in cerebral Inhibition of insulin secretion by alpha-adrenergic nervous system and
blood flow adrenomedullary catecholamines
Primary glucose regulatory factor, first defense against hypoglycemia
Beta-Adrenergic Effects
Stimulation of hepatic and muscle glycogenolysis Glucagon: Increased Secretion
Stimulation of plasma glucagon secretion Direct stimulation of alpha cells by low glucose
Stimulation of lipolysis generating free fatty acids Stimulation of glucagon secretion by beta-adrenergic nervous system and
Impairment of glucose uptake by muscle adrenomedullary catecholamines
Increase in cardiac output causing increase in cerebral blood flow Primary glucose counterregulatory factor, second defense against
hypoglycemia
Adrenomedullary Catecholamine Effects
Augmentation of alpha- and beta-adrenergic effects Catecholamines: Increased Secretion
Direct stimulation of sympathetic nervous system by low glucose
Cholinergic Effects
Direct secretion from the adrenal medulla in response to low glucose
Stimulation of pancreatic polypeptide secretion
Involved, third defense against hypoglycemia
Increase gastric motility
Produce hunger Adrenocorticotropic Hormone and Cortisol: Increased Secretion
Direct stimulation of pituitary adrenocorticotropic hormone (ACTH) secre-
Adapted from Karam JH: Hypoglycemic disorders. In Gardner DA, Shoback D, editors:
tion in response to low glucose
Greenspans basic & clinical endocrinology, ed 9, New York, 2011, McGraw-Hill,
Stimulation of pituitary-adrenocortical axis by the sympathetic nervous
with permission.
system
Involved but not critical
3.9 to 6.2 mmol/L). When the blood glucose concentration decreases Growth Hormone: Increased Secretion
toward the lower limit of the normal physiologic range, insulin syn- Direct stimulation of growth hormone (GH) in response to low glucose
thesis and secretion is inhibited, which limits tissue utilization of glu- Involved but not critical
cose and allows the blood glucose concentration to increase. If the
blood glucose concentration decreases below the normal reference
range, increased secretion of glucose counterregulatory hormones,
most notably glucagon and epinephrine, increase the blood glucose events leading to endogenous glucose production is initiated by a
concentration back into the normal physiologic range. blood glucose concentration that decreases below the normal physi-
The signaling pathways in the pancreatic beta cell provide the ologic range and the hormonal and neurogenic response to hypo-
mechanism whereby insulin secretion rates respond to changes glycemia intensifies as the hypoglycemia becomes more severe.
in blood glucose concentration. Glucose enters the beta cell by Insulin is the dominant glucose-lowering hormone. Hypoglyce-
facilitated diffusion mediated by glucose transporter 2 (GLUT-2) mia suppresses insulin secretion, which facilitates the mobilization
(see Origin of Clinical Signs). Intracellular glucose is phosphory- of energy from existing energy stores (glycogenolysis, lipolysis), pro-
lated to glucose-6-phospate by the enzyme glucokinase. Evidence motes hepatic gluconeogenesis and ketogenesis, promotes renal glu-
suggests that glucokinase, by determining the rate of glycolysis, coneogenesis, and decreases glucose utilization by insulin-dependent
functions as the glucose sensor of the beta cell and is the pri- tissues (Cryer and Polonsky, 1998; Karam, 2001). Glucose-raising
mary mechanism by which the rate of insulin secretion adapts to or counterregulatory hormones include glucagon, epinephrine, GH,
changes in blood glucose (Buse etal, 2011). An increase in blood and cortisol (see Box 9-2). Insulin-induced hypoglycemia causes an
glucose levels results in an increase in the rate of glycolysis and a increase in plasma glucagon, epinephrine, and norepinephrine con-
corresponding increase in the rate of insulin secretion by the beta centrations at the onset of the glucose counterregulatory response,
cell, and vice versa. See the Insulin Synthesis, Structure, and Regu- with increases in plasma GH and cortisol occurring later. Glucagon
lation section in Chapter 7 for more information on this topic. is the key counterregulatory hormone affecting recovery from acute
hypoglycemia. In response to falling plasma glucose levels, glucagon
is secreted by the alpha cells of the pancreatic islets into the hepatic
Hypoglycemia and the Counterregulatory Response
portal circulation; it acts exclusively on the liver to activate glycoge-
The brain is wholly dependent on plasma glucose and counter- nolysis and gluconeogenesis (Cryer, 2011). Hepatic glucose produc-
acts declining plasma glucose concentrations with a carefully pro- tion increases almost immediately.
grammed neurogenic and hormonal response to mobilize storage The adrenergic-catecholamine response to hypoglycemia also
depots of glycogen and fat and raise the plasma glucose concen- plays a major role in recovery from hypoglycemia. Epinephrine has
tration (Boxes 9-1 and 9-2). Hepatic glycogen reserves and gluco- both direct and indirect effects, which stimulate hepatic glycoge-
neogenesis in the liver and kidney directly supply the brain with nolysis and hepatic and renal gluconeogenesis; provide muscle tis-
glucose, and the mobilization of fatty acids from triglyceride depots sue with an alternative source of fuel by mobilizing muscle glycogen
provides energy for the large mass of skeletal and cardiac muscle, the and stimulating lipolysis; mobilize gluconeogenic precursors (e.g.,
renal cortex, the liver, and other tissues that use fatty acids as basic lactate, alanine, and glycerol); and inhibit glucose utilization by
fuel; this spares glucose for use by tissues that remain dependent on insulin-sensitive tissues (e.g., skeletal muscle) (Cryer, 1993; Karam,
glucose, including the central nervous system (CNS), erythrocytes, 2001). The role of cortisol and GH in the acute response to hypo-
bone marrow, and renal medulla (Karam, 2001). The cascade of glycemia is minimal but cortisol and GH may play roles in the
|
defense against prolonged hypoglycemia (Boyle and Cryer, 1991). depends on a continuous supply of glucose from sources outside
Cortisol facilitates lipolysis, promotes protein catabolism and the the CNS. If the blood glucose concentration drops below a critical
conversion of amino acids to glucose by the liver and kidney, and level, nervous system dysfunction occurs. In mammals the cerebral
limits glucose utilization by insulin-dependent tissues. Similarly, cortex is the first area to be affected by a shortage of glucose. The
GH promotes lipolysis and antagonizes the action of insulin on metabolically slower vegetative centers in the brainstem have less
glucose utilization in muscle cells. However, the hyperglycemic demand for blood glucose and are affected after the cerebral cortex.
effects of cortisol and GH do not appear for several hours after the The entrance of glucose into the neurons of the CNS occurs
hypoglycemic episode (Cryer and Polonsky, 1998). primarily by diffusion and is not insulin dependent. Because
The adrenergic neurogenic response to hypoglycemia acts cell membranes are impermeable to hydrophilic molecules (e.g.,
directly to raise the blood glucose concentration and to stimulate glucose), all cells require carrier proteins to transport glucose
hormonal responses that augment the adrenergic mobilization of across the lipid bilayers into the cytosol. All cells except those in
energy stores (see Box 9-1). In dogs, hepatic glucose autoregula- the intestine and kidney have nonenergy-dependent transporters
tion is also an important glucose counterregulatory factor (Cryer that facilitate diffusion of glucose across cell membranes. To date,
and Polonsky, 1998). That is, the rate of hepatic glucose produc- fourteen facilitative transporters have been identified in humans,
tion is an inverse function of the blood glucose concentration and they include transporters for substrates other than glucose,
independent of hormonal and neural regulatory factors. including fructose, myoinositol, and urate (Thorens and Mueck-
ler, 2010). The primary transporters involved in facilitative dif-
fusion of glucose into cells are called GLUT-1 through GLUT-4,
Insulin Secretion in Dogs with Beta-Cell Neoplasia
with the numbers designating the order of their identity (Table
In the dog or cat with an insulin-secreting tumor, neoplastic beta 9-1). GLUT-1 is present in all tissues, has a very high affinity for
cells autonomously synthesize and release insulin despite hypogly- glucose, and appears to mediate basal glucose uptake. GLUT-1
cemia. As a result, tissue utilization of glucose continues, hypogly- is an important component of the brain vascular system (blood
cemia progressively worsens, and clinical signs eventually appear. brain barrier) that ensures adequate transport of plasma glucose
The onset of clinical signs is related to both the degree of hypo- into the CNS (Fig. 9-2). GLUT-2 has very high expression in
glycemia achieved and the rate at which it occurs. For example, a pancreatic beta cells and the basolateral membranes of intestinal
blood glucose concentration that gradually drops to 35 mg/dL (2 and renal epithelial cells and hepatocytes. GLUT-3 is the major
mmol/L) over an extended period (i.e., weeks) is much less likely glucose transporter on the neuronal surface, has a very high affin-
to result in signs of hypoglycemia than is a blood glucose concen- ity for glucose, and is responsible for transferring glucose from the
tration of 35 mg/dL that develops rapidly over a few hours. cerebrospinal fluid (CSF) into the neuronal cells. GLUT-4 is the
Failure of insulin secretion to decrease during periods of hypo- major glucose transporter in adipocytes and skeletal muscle.
glycemia predisposes a dog or cat with a beta-cell tumor to develop Blood insulin concentrations do not affect neuronal glucose
clinical signs of hypoglycemia during fasting and exercise. Insulin- transport or utilization. However, if hyperinsulinemia results in an
secreting beta-cell tumors also remain responsive to many of the inadequate glucose supply for intracellular oxidative processes in
stimuli that promote insulin secretion in the healthy dog or cat, neurons, a resultant decline occurs in energy-rich phosphorylated
but the secretory response is often exaggerated, resulting in severe compounds (adenosine triphosphate [ATP]) in neurons. This in
hypoglycemia. For example, clinical signs of hypoglycemia may turn results in cellular changes typical of hypoxia, increased vas-
occur after consumption of food that is easily digestible and rap- cular permeability, vasospasm, vascular dilation, and edema. Neu-
idly absorbed or rapid intravenous (IV) administration of glucose ron death from anoxia follows. In acute hypoglycemia, histologic
to correct hypoglycemia. alterations are most marked in the cerebral cortex, basal ganglia,
hippocampus, and vasomotor centers (see Feldman and Nelson
[1987] for references). Although most of the damage from hypo-
Mechanism for Insulin-Induced Hypoglycemia
glycemia occurs in the brain, peripheral nerve degeneration and
Insulin-secreting tumors and the associated hyperinsulinemia
interfere with glucose homeostasis by decreasing the rate of glucose
release from the liver and increasing the utilization of glucose by TABLE 9-1 GLUCOSE TRANSPORTERS
insulin-sensitive tissues (e.g., muscle, adipose tissue). Insulin inter- IDENTIFIED IN HUMANS
feres with mechanisms that promote hepatic glucose output by
limiting circulating concentrations of substrates needed for gluco- NAME MAJOR SITES OF EXPRESSION AFFINITY FOR GLUCOSE*
neogenesis. This effect is accomplished by inhibiting enzymes nec- GLUT-1 Brain vasculature, red blood High
essary for mobilizing amino acids from muscle and glycerol from cells, all tissues (Km = 1 mmol/L)
adipose tissue. In addition, insulin decreases the activity of hepatic GLUT-2 Liver, pancreatic B cells, serosal Low
enzymes used in gluconeogenesis and glycogenolysis. Insulin also surfaces of gut and kidney (Km = 15-20 mmol/L)
lowers blood glucose concentrations by stimulating glucose uptake
GLUT-3 Brain neurons, also found in all High
and utilization in the liver, muscle, and adipose tissue. In essence,
tissues (Km < 1 mmol/L)
insulin increases tissue utilization of glucose already present in the
extracellular space while interfering with hepatic production of GLUT-4 Muscle, fat cells Medium
glucose. The net effect is decreasing blood glucose concentrations (Km = 2.5 to 5 mmol/L)
because of increased tissue utilization of glucose.
From Masharani U, Karam JH: Pancreatic hormones and diabetes mellitus. In Greenspan
FS, Gardner DG, editors: Basic and clinical endocrinology, ed 6, New York, 2001, Lange
Origin of Clinical Signs Medical Books/McGraw-Hill, p. 630.
GLUT, Glucose transporter.
Glucose is the primary fuel used by the CNS. Carbohydrate *Km represents the level of blood glucose at which the transporter has reached one-half
reserves in neural tissue are limited, and function of these cells of its maximum capacity to transport glucose. It is inversely proportional to the affinity.
demyelination are sometimes encountered (Braund etal, 1987). neuroglycopenic signs common to dogs include lethargy, weak-
Other major organ systems, such as the heart, kidneys, and liver, ness, ataxia, disorientation, abnormal behavior, and seizures (Table
also depend on glucose. However, an acute decrease in the blood 9-2). Clinical signs resulting from stimulation of the sympathoad-
glucose concentration results in clinical signs that involve the renal system include muscle tremors, shaking, nervousness, and
CNS before signs of any other major organ system dysfunction restlessness. In humans, the symptoms related to release of cat-
become apparent. echolamines often precede those of neuroglycopenia and act as an
Prolonged, severe hypoglycemia may result in irreversible early warning sign of an impending hypoglycemic attack (Karam,
brain damage; however, it is uncommon for a dog to die during 2001). This illustrates the rapid response of catecholamine secre-
a hypoglycemic episode. Hypoglycemia is a potent stimulus for tion to hypoglycemia and partly explains why canine patients with
the release of the counterregulatory hormones that function to insulin-secreting tumors do not always progress to generalized sei-
antagonize the effects of insulin and stimulate an increase in the zure activity during a fast.
blood glucose concentration (see Hypoglycemia and the Counter-
regulatory Response). CLINICAL FEATURES
The clinical manifestations of hypoglycemia are believed to
result from both a lack of glucose supply to the brain (neurogly- Signalment
copenia) and stimulation of the sympathoadrenal system. The
Insulin-secreting tumors typically occur in middle-aged or older
dogs. The mean age at the time of diagnosis of an insulin-secreting
CHRONIC HYPERGLYCEMIA tumor in 123 dogs in our series at University of California, Davis
Blood brain (UC Davis), was 9 years, with a median age of 10 years and an age
barrier range of 3 to 14 years (Fig. 9-3). There is no gender predilection.
Glucose A variety of breeds have been diagnosed with an insulin-secreting
GLUT-3 tumor at our hospital (Table 9-3). Labrador Retrievers and Golden
Glucose Neurons
GLUT-3 Retrievers are the breeds most commonly diagnosed with this dis-
Glucose GLUT-1 Glucose ease, which is probably a reflection of breed popularity in our region
GLUT-3
Glucose rather than a breed predisposition per se. In general, insulin-secreting
Glucose
Glucose TABLE 9-2 C
LINICAL SIGNS ASSOCIATED
WITH INSULIN-SECRETING
NORMAL GLUCOSE LEVELS TUMORS IN 117 DOGS
Blood brain
barrier CLINICAL SIGN NUMBER OF DOGS PERCENT AGE
Glucose Weakness 73 62
GLUT-3
GLUT-1 Neurons Seizures 61 52
GLUT-3
Glucose GLUT-1 Glucose Collapse 38 32
GLUT-3
GLUT-1 Tremors, shaking 25 21
Glucose Ataxia 22 19
Disoriented, abnormal 22 19
behavior
FREQUENT HYPOGLYCEMIA Lethargy 21 15
Blood brain Polyphagia 6 5
barrier
Weight gain 6 5
GLUT-1
GLUT-3
GLUT-1 Neurons
GLUT-3 20
Glucose GLUT-1 Glucose
GLUT-3
GLUT-1 16
GLUT-1
Number of dogs
GLUT-1 12
FIGURE 9-2 Glycemic regulation of glucose transporters. The center panel de-
picts the normal component of the high-affinity glucose transporter 1 (GLUT-1) 8
on the vascular cells of the central nervous system (CNS) during euglycemia.
An appropriate amount of glucose diffuses across the blood brain barrier and
4
is transported into the neurons by another high-affinity glucose transporter,
GLUT-3. The upper and lower panels, respectively, show adaptation by either
downregulation of GLUT-1 in the face of chronic hyperglycemia (upper panel) or 0
upregulation of GLUT-1 in the presence of chronic hypoglycemia. (From Karam JH: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Hypoglycemic disorders. In Greenspan FS, Gardner DG, editors: Basic and clinical FIGURE 9-3 Age of 123 dogs at the time of initial diagnosis of an insulin-
endocrinology, ed 6, New York, 2001, Lange Medical Books/McGraw-Hill, p. 701.) secreting islet cell tumor.
|
TABLE 9-3 B
REED DISTRIBUTION OF 115 concentrations (i.e., 20 to 30 mg/dL; 1.1 to 1.7 mmol/L) for pro-
DOGS WITH ISLET CELL TUMORS longed periods without clinical signs, and only small additional
changes in the blood glucose concentration are then required
BREED NUMBER OF DOGS PERCENT to produce symptomatic episodes. In these dogs, fasting, excite-
ment, exercise, and eating may trigger the development of clinical
Labrador Retriever 17 15 signs. The adaptation process to chronic severe hypoglycemia
Golden Retriever 11 10 is believed to involve up-regulation of the high-affinity glucose
Mixed-breeds 9 8 transporter, GLUT-1, on the vascular cells forming the blood
brain barrier (see Fig. 9-2) (Karam, 2001).
German Shepherd dog 7 6
In the healthy, exercising dog, a balance between increased glu-
Boxer 7 6 cose utilization by muscle, decreased glucose utilization by other
Terriers (Fox, Kerry Blue, West 7 6 tissues, and increased glucose production by the liver maintains
Highland White, Norwich) the circulating blood glucose concentration in the normal range,
Poodle 6 5 allowing the brain to continue to function. The exercising dog
with an insulin-secreting tumor has continuing glucose utilization
Irish Setter 6 5 not just by muscle but by all tissues, owing to the autonomous
Cocker Spaniel 6 5 and continuing secretion of insulin. In addition, hepatic release of
Collie 5 4 glucose is impaired. The potential for severe hypoglycemia is great,
Rottweiler 5 4
and this fact is supported by the number of owners who associate
symptoms in their pets with jogging, play, or long walks. A similar
Border Collie 4 3 pathophysiology is thought to explain the development of symp-
Doberman Pinscher 3 3 toms during periods of excitement. Insulin-secreting tumors are
Samoyed 2 2 responsive to increases in the blood glucose concentration, and the
insulin-secretory response can be exaggerated if the dog consumes
Staffordshire Terrier 2 2
food that is easily digestible and rapidly absorbed.
Dachshund 2 2
Other breeds (one dog each) 16 10 Physical Examination
Physical examination findings in dogs with an insulin-secreting
tumor are often surprisingly unremarkable; dogs are usually free
tumors occur more commonly in large breeds of dogs. However, the of visible or palpable abnormalities. Most abnormalities identified
size of the dog should never preclude an investigation for an insulin- on the physical examination are nonspecific (Table 9-4). Weakness
secreting tumor in a hypoglycemic dog. We have diagnosed insulin- and lethargy, the most common findings, are identified in 29% and
secreting tumors in dogs as small as a Pomeranian. 17% of our cases, respectively. Episodes of collapse and seizures may
occur during the examination but are uncommon. Afflicted dogs
History are usually free of palpable abnormalities, aside from findings com-
monly associated with aging. Weight gain is evident in some dogs
Clinical signs of an insulin-secreting tumor may have been and is a result of the anabolic effects of excess insulin in a dog with
observed for more than a year or as briefly as 1 day before veteri- a normal or increased appetite. Failure to identify abnormalities on
nary care is sought. Most dogs, however, are symptomatic for 1 the physical examination, especially in an older, large-breed dog,
to 3 months before being brought to a veterinarian. In our most is an important finding supportive of an insulin-secreting tumor.
recent 30 dogs with an insulin-secreting tumor, clinical signs had
been observed by the owners for an average of 5 weeks (range, 2 Peripheral Neuropathy
days to 4 months) before veterinary care was sought. Peripheral neuropathies have been reported in dogs with insulin-
Clinical signs of an insulin-secreting tumor typically are caused secreting tumors (Shahar etal, 1985; Braund etal, 1987; Van Ham
by hypoglycemia and an increase in circulating catecholamine etal, 1997). Clinical signs and physical examination findings range
concentrations and include weakness, seizures, collapsing epi- from paraparesis to tetraparesis, facial paresis to paralysis, sciatic
sodes, tremors, ataxia, and disorientation (see Table 9-2). One hyporeflexia to areflexia, hypotonia, and muscle atrophy of the
characteristic of hypoglycemic signs, regardless of the cause, is appendicular, masticatory and/or facial muscles. Sensory nerves
their episodic nature. Signs are generally observed intermittently may also be affected. A subclinical polyneuropathy has also been
for only a few seconds to minutes because of the compensatory reported (Braund etal, 1987). The onset of clinical signs may be
counterregulatory mechanisms that usually increase the blood acute (days) or insidious (weeks to months). Abnormalities iden-
glucose concentration after the development of hypoglycemia. If tified on electrodiagnostic testing include abnormal spontaneous
these mechanisms are inadequate, seizures may occur as the blood potentials (e.g., positive sharp waves, fibrillation potentials) and
glucose concentration continues to decrease. Seizures are usually slowed motor nerve conduction velocities (Braund et al, 1987).
self-limiting, typically lasting from 30 seconds to a few minutes. CSF analysis is usually unremarkable (Van Ham et al, 1997).
The seizure may stimulate further catecholamine secretion and Histopathologic findings in motor and sensory nerves include
activation of other counterregulatory mechanisms that increase moderate to severe axonal necrosis, nerve fiber loss, and variable
the blood glucose concentration above critical levels (see Hypo- demyelination-remyelination (Braund et al, 1987; Schrauwen
glycemia and Counterregulatory Response). etal, 1996; Van Ham etal, 1997). Muscle changes reflect neu-
The severity of clinical signs depends on the duration and sever- rogenic atrophy. The pathogenesis of the polyneuropathy is not
ity of the hypoglycemia. Dogs with chronic fasting hypoglycemia known. Proposed theories include metabolic derangements of
or with recurring episodes appear to tolerate low blood glucose the nerves induced by chronic and severe hypoglycemia or some
TABLE 9-4 PHYSICAL EXAMINATION BOX 9-3 A

Partial Listing of the Numerous Disorders
FINDINGS ASSOCIATED WITH that may Result in Weakness
INSULIN-SECRETING TUMORS
IN 78 DOGS Neuromuscular Disorders
Infectious (e.g., canine distemper, bacterial, mycotic)
PHYSICAL EXAMINATION Inflammatory
FINDING NUMBER OF DOGS PERCENTAGE Neoplasia
Weakness 23 29 Cerebrovascular hemorrhage
Spinal disorders (e.g., type II disc disease; discospondylitis)
Lethargy 13 17
Degenerative myelopathy
Collapsing 6 8 Myasthenia gravis
Tremors 5 6 Peripheral neuropathy
Obtunded 5 6 Polymyopathy/polymyositis
Peripheral neuropathy 5 6 Polyarthritis
Seizures 4 5 Immune-mediated
Infectious (e.g., rickettsial)
No abnormalities 43 55 Degenerative
identified
Cardiorespiratory
Congestive heart failure
Tachyarrhythmias/bradyarrhythmias
other tumor-induced metabolic deficiency, an immune-mediated
Heartworm disease
paraneoplastic syndrome resulting from shared antigens between
Bacterial endocarditis
tumor and nerves, or toxic factors produced by the tumor that
Pneumonia (viral, bacterial, mycotic)
deleteriously affect the nerves (Kudo and Noguchi, 1985; Das and
Pleural effusions
Hochberg, 1999; Heckmann etal, 2000). Treatment is aimed at
surgical removal of the beta-cell tumor (Jeffery etal, 1994). Pred- Hematologic Disorders
nisone therapy (initially 0.5 mg/kg every 12 hours) may improve Anemia
clinical signs (Van Ham etal, 1997). Correction of hypoglycemia, Polycythemia
by itself, may or may not improve clinical signs caused by the Hemangiosarcoma
peripheral neuropathy (Bergman etal, 1994). In our experience, Coagulopathy (e.g., warfarin-induced)
the prognosis for improvement in clinical signs is guarded to poor, Metabolic Disorders
although the occasional dog shows remarkable improvement in Hypoglycemia
ambulation following removal of the tumor and reestablishment Hypokalemia
of a normal blood glucose concentration. Hyperkalemia
Hypercalcemia
CLINICAL PATHOLOGIC ABNORMALITIES Insulinoma
Hypothyroidism
Virtually all dogs with insulin-secreting tumors remain undiag- Hypoadrenocorticism
nosed and often unsuspected of having such tumors after com- Hyperadrenocorticism
pletion of the history and physical examination. Most afflicted Pheochromocytoma
dogs have a history of episodic weakness or seizuressigns that Hepatic encephalopathy
encompass a wide variety of disorders (Box 9-3). The minimum
diagnostic evaluation for dogs with these clinical signs should
include a complete blood count (CBC), serum biochemical panel, mmol/L). The median blood glucose concentration was 38 mg/dL
and urinalysis in an effort to identify abnormalities supportive of (2.1 mmol/L). One hundred and eleven of 123 dogs (90%) had
one of the disorders outlined in Table 9-3. Therapy other than a random blood glucose concentration less than 60 mg/dL (3.4
that required in an emergency situation should be withheld until mmol/L). Dogs with insulin-secreting beta-cell tumors may occa-
a diagnosis has been made. sionally have a blood glucose concentration between 60 and 70
Results of the CBC and urinalysis in dogs with an insulin- mg/dL (3.4 and 3.9 mmol/L) on random testing. Such a finding
secreting tumor are usually normal. Results of the serum biochem- does not eliminate hypoglycemia as a cause of episodic weakness
ical profile, aside from the blood glucose concentration, are also or seizure activity. Fasting, with hourly evaluation of the blood
usually normal. Hypoalbuminemia, hypophosphatemia, hypoka- glucose concentration, should be done to induce hypoglycemia
lemia, and increased activity in alkaline phosphatase and alanine in dogs with suspected insulin-secreting beta-cell tumor. The
aminotransferase have been reported (Leifer etal, 1986), but these time required to induce hypoglycemia with fasting depends in
findings are considered nonspecific and not helpful in achiev- part on the extent of disease at the time the dog is examined and
ing a definitive diagnosis. A correlation has not been established ranges from a few hours to longer than 24 hours. Hypoglycemia
between increased liver enzyme activity and obvious metastasis of (blood glucose < 60 mg/dL) will develop in most dogs with an
beta-cell tumors to the liver. insulin-secreting beta-cell tumor within 12 hours of withholding
The only consistent abnormality identified in serum biochemis- food. A fast of 8 or fewer hours was successful in demonstrating
try profiles is hypoglycemia. The mean initial blood glucose con- hypoglycemia in 33 of 35 trials in 31 dogs with insulin-secreting
centration in 123 of our dogs at UC Davis with an insulin-secreting tumor (Kruth etal, 1982). We have had a few dogs require 12 to
tumor was 42 mg/dL, with a range of 15 to 78 mg/dL (0.84 to 4.4 24 hours of fasting before hypoglycemia became apparent and a
|
couple of dogs that did not develop hypoglycemia after 30 hours common problem resulting from overzealous insulin administra-
of fasting. The clinical signs in these dogs were episodic and mild, tion in diabetic dogs and cats.
and the diagnosis of beta-cell tumor was not established until 2 to
3 months after initial presentation. Congenital Hepatic Disease
Portovascular anomalies are the most common congenital cause
DIFFERENTIAL DIAGNOSES FOR FASTING
of hepatic-induced hypoglycemia. Hypoglycemia develops despite
HYPOGLYCEMIA
an appropriate reduction in circulating insulin because of insuf-
Hypoglycemia is present if the blood glucose concentration is ficient hepatic glycogen stores and inadequate hepatocellular
less than 60 mg/dL (3.4 mmol/L). It typically results from the function to support gluconeogenesis. Abnormalities suggestive of
excessive uptake of glucose by normal cells (e.g., during periods this disorder include microcytosis, hypoalbuminemia, hypocho-
of hyperinsulinism, such as that which occurs with a beta-cell lesterolemia, decreased urea nitrogen, increased total bilirubin,
tumor or xylitol ingestion) or neoplastic cells, impaired hepatic ammonium biurate crystals in the urine, abnormal preprandial
gluconeogenesis and glycogenolysis (e.g., portal shunt, hepatic and postprandial bile acid concentrations, and small liver size on
cirrhosis), a deficiency in diabetogenic hormones (e.g., hypocor- abdominal radiography or ultrasonography. Confirmatory tests
tisolism), an inadequate dietary intake of glucose and other sub- include liver biopsy, angiography, nuclear scintigraphy, and iden-
strates required for hepatic gluconeogenesis (e.g., anorexia in the tification of the shunt during abdominal ultrasound, computed
neonate or toy breeds), or a combination of these mechanisms tomography (CT) scanning or exploratory celiotomy.
(e.g., sepsis; Box 9-4; Service, 1995). Iatrogenic hypoglycemia is a Glycogen storage diseases (GSDs) are rare autosomal recessive
disorders of glycogen metabolism that result from a congenital
absolute or relative deficiency of one of the enzymes necessary to
BOX 9-4 Causes of Hypoglycemia in Dogs and Cats convert glycogen to glucose. In dogs, four breed-specific types of
GSD have been described. Type Ia in Maltese terriers (von Gierke
Beta-cell tumor (insulinoma)*
disease) is a deficiency in glucose-6-phosphatase caused by a
Extra pancreatic neoplasia (see Box 9-5)
mutated, defective glucose-6-phosphatase gene (Brix et al, 1995;
Hepatocellular carcinoma, hepatoma*
Kishnani et al, 1997; 2001). Type II in Lapland dogs (Pompe
Leiomyosarcoma, leiomyoma*
disease) is a deficiency of lysosomal acid -glucosidase (Walvoort
Hepatobiliary disease*
etal, 1985). Type III in German Shepherd dogs and Curly-Coated
Portosystemic shunts
Retrievers (Cori disease) is a deficiency of glycogen debranching
Chronic fibrosis, cirrhosis
enzyme (amylo-1,6-glucosidase; Fig. 9-4) (Hardy, 1989; Gregory
Hepatic necrosis; toxins, infectious agents
etal, 2007). GSD in Curly-Coated Retrievers affects both liver and
Primary and metastatic neoplasia
muscle (GSD type IIIa) and is caused by a mutation of the glycogen
Sepsis*
debranching enzyme gene (AGL) (Gregory etal, 2007). Type VII in
Severe canine babesiosis
English Springer Spaniels (Tarui disease) is a deficiency in phospho-
Septic peritonitis
fructokinase (Giger etal, 1988; Smith etal, 1996). In cats, GSD
Hypoadrenocorticism*
type IV has been identified in Norwegian Forest cats, is caused by
Primary and secondary
a deficiency in a glycogen branching enzyme (alpha-1,4 glucan 6
Idiopathic hypoglycemia*
glycol transferase), and results in glycogen accumulation in skeletal
Neonatal hypoglycemia
and cardiac muscle and the nervous system (Fyfe etal, 1992).
Juvenile hypoglycemia (especially toy breeds)
Indicators for possible GSD in a juvenile dog include: clinical
Hunting dog hypoglycemia
signs suggestive of hypoglycemia; progressive hepatomegaly char-
Exocrine pancreatic neoplasia
acterized histologically by diffuse, marked hepatocellular vacu-
Pancreatitis
olation caused by glycogen accumulation; and hypoglycemia and
Glucagon deficiency (?)
increased hepatic enzyme activities identified on routine blood
Chronic kidney disease and urine tests. Serum glucose concentrations typically fail to
Hypopituitarism increase after injection of glucagon in dogs with type Ia and type
Severe polycythemia III GSDs. Confirmatory tests include histologic evaluation of
Hepatic enzyme deficiencies hepatic biopsies and specific hepatic enzyme assays.
Glycogen storage diseases (GSDs)
Severe malnutrition Acquired Hepatic Dysfunction
Prolonged storage of whole blood*
Iatrogenic Hypoglycemia may result from progressive and severe destruction
Insulin overdose* of the liver typically caused by primary or metastatic neoplasia or
Sulfonylurea therapy chronic inflammation leading to fibrosis, cirrhosis, and the devel-
Ethylene glycol ingestion opment of acquired hepatic vascular shunts. There are numerous
Xylitol ingestion potential causes of chronic hepatic fibrosis in older dogs and cats.
Alpha lipoic acid Hypoglycemia results from inadequate amounts of functional
Dried chicken jerky treats hepatic tissue for adequate storage of glycogen or for sufficient
Artifact* gluconeogenesis to sustain a normal blood glucose concentration
Portable blood glucose monitoring (PBGM) devices during a fast. Serum insulin concentrations decline appropri-
Laboratory error ately with worsening hypoglycemia, but this alone may be insuf-
ficient to prevent problems. Additional abnormalities suggestive
*Common cause. of hepatic insufficiency include microcytosis, hypoalbuminemia,
hypocholesterolemia, decreased urea nitrogen, increased total circulation, and it acts exclusively on the liver to activate glycoge-
bilirubin, ammonium biurate crystals in the urine, abnormal nolysis and gluconeogenesis (Cryer and Polonsky, 1998). Hepatic
preprandial and postprandial bile acid concentrations, abnormal glucose production is increased almost immediately. Abnormalities
liver size on abdominal radiography, or abnormal echotexture or in the production or secretion of glucagon prevent a normal coun-
liver size on ultrasonography. Liver biopsy is helpful in confirm- terregulatory response to decreasing blood glucose concentrations
ing severe fibrosis or cirrhosis and may even identify a cause (e.g., and predispose the animal to hypoglycemia. A classic example is
neoplasia). The etiology of hepatic fibrosis and cirrhosis goes undi- hypoglycemia unawareness in diabetic humans, which is a syn-
agnosed in most cases. drome caused by deficient glucagon and catecholamine secretion,
resulting in defective counterregulation, severe hypoglycemia, and
Adrenocortical Insufficiency (Addisons Disease) diabetic coma (Gerich etal, 1991; Mokan etal, 1994; Meyer etal,
1998). Isolated glucagon deficiency that causes hypoglycemia has
Hypoglycemia in dogs with hypoadrenocorticism is caused by been reported in humans but is rare (Cryer and Polonsky, 1998).
insufficient secretion of the glucocorticoids needed to stimulate Typically, glucagon deficiency occurs in conjunction with excess
hepatic mobilization and production of glucose (see Chapter insulin secretion, deficient catecholamine secretion, or increased
12). In this disorder, hypoglycemia occurs despite an appropri- tissue sensitivity to the actions of insulin; and this combination
ate reduction in the blood insulin concentration. Reduced insulin results in hypoglycemia. We have identified hypoglycemia in dogs
secretion must be accompanied by an increase in hepatic gluco- and cats with severe pancreatitis and exocrine pancreatic adenocar-
neogenesis to correct hypoglycemia. Glucose synthesis is normally cinoma, and we speculate that the destructive process associated
stimulated by gluconeogenic hormones. Without secretion of with these disorders may alter the production and/or secretion of
these hormones, as observed in hypoadrenocorticism, hypoglyce- glucagon and insulin.
mia is possible (Sherwin and Felig, 1981). Hypoadrenocorticism
is most common in young and middle-aged dogs, and there is
Hypopituitarism
a gender predisposition for the female. Abnormalities on screen-
ing tests supportive of this diagnosis include a relative increase GH and cortisol are glucose counterregulatory hormones involved
in the eosinophil and lymphocyte counts, mild nonregenerative in hepatic glucose synthesis and secretion. Failure of the pituitary
anemia, mild to severe prerenal azotemia, hyperkalemia, hypona- gland to secrete ACTH, GH, or both may impact maintenance of
tremia, and hypercalcemia. Hypoglycemia may also develop with glucose homeostasis and predispose the animal to hypoglycemia,
atypical hypoadrenocorticism, which is characterized by cortisol especially in the fasting state. As in primary hypoadrenocorticism,
but not mineralocorticoid deficiency and normal serum electro- insulin secretion diminishes appropriately for the degree of hypo-
lyte concentrations. The diagnosis of hypoadrenocorticism can be glycemia, but this alone may not be sufficient to prevent clinical
confirmed by abnormal results on adrenocorticotropic hormone signs. GH deficiency is a rare cause of hypoglycemia and is usu-
(ACTH) stimulation test. ally diagnosed in young German Shepherd dogs as a congenital
defect (see Chapter 2). Pituitary failure to secrete ACTH results
Glucagon Deficiency in atrophy of the zona fasciculata of the adrenal cortex, impaired
secretion of cortisol, and the development of secondary hypoad-
Glucagon is the key counterregulatory hormone affecting recovery renocorticism. No classic abnormalities are found on screening
from acute hypoglycemia (Cryer and Gerich, 1985). In response laboratory studies in animals with secondary hypoadrenocorti-
to falling plasma glucose concentrations, glucagon is secreted cism. These dogs may have a mild nonregenerative anemia and
by the alpha cells of the pancreatic islets into the hepatic portal fasting hypoglycemia, but serum electrolyte concentrations are
GLYCOGEN
2 9
Glucose-1-P
1 8
GLUCOSE Glucose-6-P GLUCOSE
1 Hexokinase/glucokinase Fructose-6-P
Glycogen synthase 3 7
2
Fructose-1,6-P
3 Phosphofructokinase TRIGLYCERIDES
4 Pyruvate kinase
Triose-P
5 Pyruvate carboxylase GLYCEROL
6 Phosphoenolpyruvate
carboxykinase
FATTY ACIDS
7 Fructose-1,6-bisphos- Phosphoenolpyruvate
phatase 4 6
8 Glucose-6-phosphatase Pyruvate
9 Phosphorylase
5
Acetyl CoA
Oxaloacetate FIGURE 9-4 Schematic representation of glucose
TCA metabolism. (From Cryer PE, Polonsky KS: In Wilson
Citrate
cycle KETONES JD, etal, editors: Williams textbook of endocrinology,
LACTATE -Ketoglutarate ed 9, Philadelphia, 1998, WB Saunders, p. 940.)
Acetyl CoA, Acetyl coenzyme A; TCA, tricarboxylic
ALANINE Glutamine acid.
|
usually normal. An ACTH stimulation test and determination of carcinoma, hepatocellular carcinoma, and pancreatic neuroendo-
a baseline endogenous ACTH concentration are used to establish crine tumor (Boari etal, 1995; Zini etal, 2007; Finotello etal,
the diagnosis of secondary hypoadrenocorticism (see Chapter 12). 2009; Rossi etal, 2010). Blood glucose and serum insulin concen-
trations were low and serum IGF-2 concentrations were increased
NonBeta-Cell Tumors at presentation to the veterinary hospital in all dogs. Blood glu-
cose and serum IGF-2 concentrations returned to the reference
In humans, nonbeta-cell tumors that cause hypoglycemia are range in three dogs that underwent surgical removal of the tumor
usually of mesenchymal origin (e.g., leiomyosarcoma, fibrosar- and results of immunohistochemical staining of tumor tissue were
coma). Hypoglycemia is caused less often by tumors of epithe- positive for IGF-2 in all four dogs. Interestingly, the dog with an
lial origin (e.g., hepatoma, carcinoid tumors) and hematopoietic IGF-2-secreting mammary carcinoma was an insulin-dependent
origin (e.g., lymphoma, multiple myeloma) (Cryer and Polonsky, diabetic dog prior to development of the mammary carcinoma;
1998). A variety of tumor types have also been reported to cause this dog developed problems with severe hypoglycemia as the
hypoglycemia in the dog (Box 9-5). In our hospital, hepatocellular tumor enlarged and became diabetic again after surgical removal
carcinoma, hepatoma, leiomyoma, leiomyosarcoma, and tumors of the tumor (Rossi etal, 2010).
with extensive hepatic metastasis are most commonly associated In another study involving four dogs with hypoglycemia caused
with hypoglycemia (Cohen etal, 2003). by smooth muscle tumors, the results of immunohistochemical
The pathogenesis of hypoglycemia associated with nonbeta- staining for insulin were negative in the four tumors but positive
cell tumors is undoubtedly multifactorial. Proposed mechanisms for glucagon in three of the four tumors (Beaudry etal, 1995). The
include excessive glucose utilization by the tumor, impaired three smooth muscle tumors that stained positive for glucagon
hepatic glycogenolysis and gluconeogenesis as a result of tumor- originated in either the stomach or jejunum, whereas the tumor
induced hepatic destruction or inhibition of normal counter- that stained negative for glucagon originated in the spleen. Immu-
regulatory responses that prevent hypoglycemia, and secretion of nohistochemical staining for glucagon was negative in smooth
an insulin-like molecule, specifically insulin-like growth factor-2 muscle cells in normal adjacent tissue. The clinical relevance of
(IGF-2) that lowers the blood glucose concentration by enhancing this finding remains unclear, especially considering that glucagon
glucose utilization by normal cells (Cryer and Polonsky, 1998). should increase, not decrease, the blood glucose concentration.
Although the major organ responsible for circulating insulin-like Dogs with hypoglycemia caused by a nonbeta-cell tumor may
growth factors is the liver, it has been demonstrated that these fac- be brought to the veterinarian with clinical signs of hypoglyce-
tors are produced ubiquitously, particularly by mesenchymal cells mia, or hypoglycemia may be a serendipitous finding on a serum
(DErcole etal, 1984; Barreca etal, 1992). IGF-2 is structurally biochemistry panel. In most dogs, nonbeta-cell tumors that
homologous to proinsulin, can bind to insulin receptors, and has cause hypoglycemia are located in the liver or abdomen. Iden-
direct insulin-like actions that result in hypoglycemia (de Groot tification of a nonbeta-cell tumor requires a thorough physical
etal, 2007). In addition, IGF-2 may suppress glucagon and GH examination of the dog or cat, thoracic and abdominal radiogra-
secretion, which may also contribute to hypoglycemia (Cryer and phy, abdominal ultrasonography, and histopathologic evaluation
Polonsky, 1998). Serum insulin concentrations are typically unde- of biopsy specimens from identifiable masses. The association
tectable or in the lower end of the reference range with nonbeta- between a nonbeta-cell tumor and hypoglycemia requires resolu-
cell tumors, in contrast to the high-normal to increased serum tion of hypoglycemia after surgical excision of the tumor.
insulin concentrations seen with hypoglycemia induced by a beta-
cell tumor (Beaudry et al, 1995; Bagley et al, 1996; Bellah and
Neonatal and Juvenile Hypoglycemia
Ginn, 1996).
Paraneoplastic hypoglycemia affiliated with IGF-2 secretion The fetus receives a continuous source of glucose via the placenta
has been reported in a dog with gastric leiomyoma, mammary and does not depend on its own gluconeogenic capabilities to
maintain an adequate blood glucose concentration. In contrast,
the neonate depends on glycogenolysis and gluconeogenesis to
BOX 9-5 H
istologic Classification of NonBeta-Cell maintain euglycemia during fasts, even if brief. Limited hepatic
Tumors Associated with Hypoglycemia glycogen stores, small muscle mass, lack of adipose tissue, and
decreased use of free fatty acids as an alternative energy source
Hepatocellular carcinoma, hepatoma
place the neonate at risk for developing hypoglycemia within
Leiomyosarcoma, leiomyoma
hours of fasting (Chastain, 1990). Impaired gluconeogenesis as
Hemangiosarcoma
a result of delayed induction of one or more of the rate-limiting
Adenocarcinoma
gluconeogenic enzymes is suspected in neonatal hypoglycemia of
Mammary
human infants (Cryer and Polonsky, 1998) and may play a role in
Nasal (horse)
neonatal hypoglycemia of puppies and kittens as well.
Pulmonary
Hypoglycemia often occurs in conjunction with hypothermia,
Salivary
sepsis, starvation, toxic milk syndrome, or a combination of these
Gastric
problems. The ill neonate should always be evaluated for hypogly-
Small intestine
cemia. Orally administered glucose (e.g., 0.01 mL of 5% to 10%
Splenic
solution per gram of body weight) and frequent nursing or bottle
Renal
feeding help correct and prevent hypoglycemia in the neonate.
Lymphoblastic leukemia
Hypoglycemia of toy and miniature breed dogs younger than 6
Plasmacytoma months of age is common. Alanine deficiency has been implicated
Metastatic melanoma in this syndrome, as it has in young children (Chew etal, 1982).
Pancreatic neuroendocrine tumor In humans, the rate of alanine release from muscle determines the
rate of gluconeogenesis during starvation. Puppies with juvenile
hypoglycemia are usually under extreme stress. They frequently may cause hypoglycemia in humans, kidney failure-induced hypo-
have a history of recently being purchased, with an associated glycemia is a very uncommon finding in dogs and cats (Edwards
change in environment and diet. Gastrointestinal upset (vomit- etal, 1987; Cryer, 2011). Proposed mechanisms for development
ing, diarrhea, and/or anorexia) is typical and may or may not be of hypoglycemia in kidney failure include decreased renal glu-
associated with parasites. These puppies are quite fragile and are coneogenesis in conjunction with impaired glucose production
brought to veterinarians with signs that may include weakness, by the liver as a consequence of defective hepatic glycogenolysis
collapse, depression, ataxia, stupor, convulsions, hypothermia, and gluconeogenesis, limited availability of glucogenic substrates,
and/or diarrhea. IV administration of glucose usually results in inadequate glucose counterregulatory responses, decreased caloric
rapid clinical improvement. Frequent feedings prevent recur- intake, decreased renal degradation, and/or excretion of insulin
rences. This disorder virtually disappears with attainment of adult (Fischer etal, 1986; Gerich etal, 2001).
height and weight. If signs persist, a search for another disease that
may be causing the hypoglycemia should be considered.
Polycythemia
Endotoxic or Sepsis-Induced Hypoglycemia Severe polycythemia (hematocrit > 65%) may cause artifactual
hypoglycemia secondary to increased glucose utilization by the
Endotoxic or sepsis-induced hypoglycemia is a relatively uncom- markedly increased number of red blood cells in the blood sample.
mon cause of hypoglycemia in the dog and cat (Breitschwerdt Polycythemia may be primary (i.e., polycythemia vera), or it may
etal, 1981). The pathogenesis of sepsis-induced hypoglycemia is occur secondary to disorders that cause chronic systemic hypoxia
not well characterized but is believed to result from increased tis- (e.g., congenital right-to-left shunting of blood in the heart), to
sue utilization of glucose in conjunction with decreased hepatic chronic renal hypoxia (e.g., renal neoplasia), or to erythropoietin-
glucose production (Naylor and Kronfeld, 1985; Hargrove etal, producing tumors.
1988a; 1988b). Proposed mechanisms for increased glucose uti-
lization include sepsis-induced production of insulin-like sub-
Artifactual Hypoglycemia
stances, interleukin-1enhanced insulin secretion by beta cells,
cytokine-enhanced increase in glucose transport into cells, and Prolonged storage of blood before separation of serum or plasma
increased glucose utilization by bacteria and neutrophils (Com- causes the glucose concentration to decrease at a rate of approxi-
mens etal, 1987; del Rey and Besedovsky, 1987). Increased glu- mately 7 mg/dL/h (0.4 mmol/L/h). Glycolysis by red and white
cose use by macrophage-rich tissues (e.g., the liver, spleen, and blood cells becomes even more apparent in dogs and cats with
ileum) is responsible for most of the glucose utilization (Meszaros erythrocytosis, leukocytosis, or sepsis. Therefore whole blood
et al, 1988), with skeletal muscle accounting for an additional obtained for the measurement of the glucose concentration should
25% (Meszaros etal, 1987). Decreased hepatic glucose production be separated soon after collection (within 30 minutes), and the
may result from impaired hepatic oxidative metabolism, increased serum or plasma should be refrigerated or frozen until the assay is
anaerobic glycolysis of liver glucose, hypoxic injury to hepatic performed to minimize artifactual lowering of the blood glucose
cells, or sepsis-induced interference with substrate delivery to the concentration. Glucose determinations from separated and refrig-
liver (see Feldman and Nelson [1987] for references). Endotoxin erated plasma or serum are reliable for as long as 48 hours after the
may also decrease glycogenolysis through depletion of hepatic and separation and refrigeration of the specimen. Alternatively, plasma
muscle glycogen stores and may impair hepatic gluconeogenesis. can be collected in sodium fluoride tubes; sodium fluoride inhibits
In our hospital, sepsis-induced hypoglycemia is most com- glycolysis by erythrocytes, leukocytes, and platelets. Unfortunately,
monly associated with parvovirus infection, abscesses, hemor- hemolysis is common in blood collected in sodium fluoride-treated
rhagic gastroenteritis, pyothorax, pyometra, and gram-negative tubes, which can result in slight decrements in glucose values owing
septicemia. Sepsis-induced hypoglycemia should be considered if to methodological problems in laboratory determinations.
a hypoglycemic animal is suffering from severe infection or sig- Blood glucose values determined by many portable blood glu-
nificant leukocytosis (> 30,000 cells/L). Artifactual hypoglyce- cose monitoring (PBGM) devices designed for use by human
mia caused by delays in measuring the glucose concentration in diabetics are almost always lower than actual glucose values deter-
a blood sample containing bacteria and marked leukocytosis may mined by bench-top methodologies (e.g., glucose oxidase and
contribute to the low blood glucose measurement. A diagnosis of hexokinase methods). A notable exception is the AlphaTRAK
sepsis-induced hypoglycemia is based on identification of infec- glucometer designed for use in diabetic dogs and cats. Blood glu-
tion by means of a physical examination, CBC, radiography and cose values obtained with the AlphaTRAK can be high or low
ultrasonography, appropriate bacterial cultures, and resolution of compared with actual glucose values (Cohen et al, 2009; Zini
hypoglycemia after initiation of appropriate antibiotic therapy. If etal, 2009; Fig. 9-5). Failure to consider this error when using
severe infection is diagnosed in a dog or cat with hypoglycemia, a PBGM device could result in an incorrect diagnosis of hypogly-
pursuit of other causes of hypoglycemia is usually not warranted cemia. Fortunately, for most PBGM devices, the more severe the
unless screening tests dictate otherwise or the hypoglycemia fails hypoglycemia, the more accurate the device becomes.
to resolve after initiation of appropriate antibiotic therapy. Laboratory error may also result in an incorrect value for any
assay. Therefore it is wise to confirm a finding of hypoglycemia
by means of evaluation of a second blood sample using bench-
Kidney Failure
top methodology before more expensive studies are performed to
The blood glucose concentration in dogs and cats with kidney identify the cause of hypoglycemia.
failure is usually within the reference range. Occasionally dogs and
cats develop hyperglycemia as a result of uremia-induced carbohy- Iatrogenic Hypoglycemia (Toxicities)
drate intolerance and insulin resistance or more commonly develop
problems with glycemic control in a dog or cat with concurrent Insulin and oral sulfonylurea drugs (e.g., glipizide, glyburide) are
diabetes mellitus. Although critical illness caused by kidney failure the only commonly available drugs that consistently lower the
|
100 usually caused by idiopathic hypoglycemia, starvation, congenital

portosystemic shunt, or sepsis. In young adult dogs or cats, hypo-
glycemia is usually caused by hepatobiliary disease, portosystemic
Percentage of blood samples
80
shunt, hypoadrenocorticism, or sepsis. In older dogs or cats, hepa-
tobiliary disease, beta-cell neoplasia, extrapancreatic neoplasia,
60 hypoadrenocorticism, and sepsis are the most common causes.
The blood glucose concentration tends to be greater than 45
40 mg/dL (2.5 mmol/L) and is often an incidental finding in dogs
and cats with hypoadrenocorticism or hepatobiliary disease,
20
although severe hypoglycemia causing neurologic signs may occa-
sionally occur. Additional clinical pathologic alterations are usu-
ally present (e.g., hyponatremia and hyperkalemia in animals with
hypoadrenocorticism or increased liver enzyme activities, hypo-
0
Dog/Cat Human Human Human Human cholesterolemia, hypoalbuminemia, and a low blood urea nitro-
PBGM PBGM PBGM PBGM PBGM
gen [BUN] concentration in animals with hepatobiliary disease).
Normal serum electrolyte concentrations do not rule out a corti-
#1 #2 #3 #4
sol deficiency as the cause for hypoglycemia; atypical hypoadre-
FIGURE 9-5 Frequency of low (solid) and high (hatched) blood glucose results nocorticism may be present. An ACTH stimulation test or liver
measured in the same blood sample by five portable blood glucose monitoring function test (i.e., preprandial and postprandial bile acids) may be
(PBGM) meters designed for use in human diabetics and one meter (AlphaTRAK) required to confirm the diagnosis. Severe hypoglycemia (less than
designed for use in diabetic dogs and cats, compared with reference analyzer re- 40 mg/dL; 2.2 mmol/L) may develop in neonates and juvenile
sults. One hundred fifty-eight blood samples obtained from 49 dogs were evalu- kittens and puppies (especially toy breeds) and in animals with
ated. Blood glucose concentrations measured by the reference analyzer ranged sepsis, beta-cell neoplasia, and extrapancreatic neoplasiamost
from 41 to 639 mg/dL (2.3 to 35.8 mmol/L). (From Cohen TA, etal.: Evaluation of notably hepatic adenocarcinoma and leiomyosarcoma. Sepsis is
six portable blood glucose meters for measuring blood glucose concentration in readily identified on the basis of physical examination findings
dogs, J Am Vet Med Assoc 235:279, 2009.) and abnormal CBC findings, which include a neutrophilic leu-
kocytosis (typically > 30,000/L), a shift toward immaturity, and
signs of toxicity. Extrapancreatic neoplasia can usually be identi-
blood glucose concentration. In small animal practice, the most fied on the basis of the physical examination, abdominal or tho-
common cause of symptomatic hypoglycemia is an overdose of racic radiography, and abdominal ultrasonography findings. Dogs
insulin in a diabetic dog and cata diagnosis that should always with beta-cell neoplasia typically have normal physical examina-
be suspected whenever a client reports signs resembling hypogly- tion findings aside from findings suggestive of hypoglycemia (e.g.,
cemia in a diabetic pet. weakness) and no abnormalities other than hypoglycemia identi-
Clinical hypoglycemia has been reported in dogs following the fied on routine blood and urine tests. Measurement of baseline
ingestion of alpha lipoic acid (Loftin and Herold, 2009), dried serum insulin concentration when the blood glucose is less than
chicken jerky treats (Hooper and Roberts, 2011; Thompson etal, 60 mg/dL (3.4 mmol/L) is used to confirm the diagnosis of a beta-
2013), and xylitol (Murphy and Coleman, 2012). Alpha lipoic cell tumor.
acid has antioxidant properties, is available as an over-the-coun-
ter supplement, and has been investigated as possible adjunctive
CONFIRMING THE DIAGNOSIS OF AN INSULIN-
treatment for various conditions, including diabetes mellitus and
SECRETING BETA-CELL TUMOR: SERUM
diabetic neuropathy. Ingestion of dried chicken jerky treats made
INSULIN DETERMINATION
in China caused Fanconi syndrome characterized by glucosuria
and euglycemia or hypoglycemia in addition to lethargy, inappe- The diagnosis of an insulin-secreting beta-cell tumor requires an
tence, and vomiting in dogs. Xylitol is a five-carbon sugar alcohol initial confirmation of hypoglycemia followed by documentation
used as a sweetener and sugar substitute in many products includ- of inappropriate insulin secretion and identification of a pancre-
ing chewing gums, candies, baked goods, jellies, drink powders, atic mass using ultrasonography, CT, or exploratory celiotomy.
vitamins, and nutritional supplements (Murphy and Coleman, Considering the potential differential diagnoses for hypoglycemia
2012). Xylitol ingestion in dogs stimulates insulin secretion lead- (see Box 9-4), a tentative diagnosis of insulin-secreting beta-cell
ing to potentially severe and life-threatening hypoglycemia, which tumor can often be made on the basis of the history, physical
may develop within 30 minutes to 12 hours after xylitol ingestion. examination findings, and an absence of abnormalities other than
Acute hepatic failure may develop 1 to 3 days later. Treatment for hypoglycemia shown by routine blood tests.
these toxicities included IV fluids with dextrose administration in
addition to supportive care.
Whipples Triad
DIAGNOSTIC APPROACH TO HYPOGLYCEMIA: In 1935, the report that established insulin-secreting tumors
PRIORITIZING THE DIFFERENTIALS of the pancreas as a clinical entity included a discussion of the
three criteria to be used in confirming the diagnosis (Whipple
Hypoglycemia should always be confirmed in a second blood and Grantz, 1935). These standards, now referred to as Whipples
sample before initiating diagnostic studies to identify the cause. triad, are: (1) the symptoms occur after fasting or exercise; (2)
Careful evaluation of the animals history, physical examination at the time of symptoms, the serum glucose concentration is less
findings, and results of routine blood and urine tests (i.e., CBC, than 50 mg/dL (2.8 mmol/L); and (3) the symptoms are relieved
serum biochemistry panel, and urinalysis) usually provide clues by administration of glucose. Unfortunately, this triad can result
to the underlying cause. Hypoglycemia in the puppy or kitten is from numerous causes of hypoglycemia and as such is nonspecific.
Determination of Baseline Insulin and Glucose BOX 9-6 Interpretation of Baseline Serum Insulin
Concentrations Concentration in Dogs with Hypoglycemia
Theory Believed to be Caused by Insulin-Secreting
The diagnosis of an insulin-secreting beta-cell tumor is established Beta-Cell Neoplasia
by evaluating the blood insulin concentration at a time when
hypoglycemia is present. Hypoglycemia suppresses insulin secre- SERUM INSULIN CONCENTRATION PROBABILITY OF BETA-CELL TUMOR*
tion in normal animals, with the degree of suppression directly Above reference range High
related to the severity of the hypoglycemia. Hypoglycemia fails Upper half of reference range Possible
to have this same suppressive effect on insulin secretion if the Lower half of reference range Low
insulin is synthesized and secreted from autonomous neoplastic Below reference range Ruled out
cells, because tumor cells that produce and secrete insulin are less
responsive to hypoglycemia than normal beta cells. Invariably *Ideally, the blood glucose concentration determined by a bench-top methodology (i.e.,
the dog with an insulin-secreting tumor will have an inappropri- glucose oxidase or hexokinase method) should be less than 50 mg/dL in the same blood
ate excess of insulin relative to that needed for a particular blood sample submitted to the laboratory for insulin determination. Interpretation of serum insulin
glucose concentration. The relative excess of insulin is easiest to concentration is unreliable if the blood glucose concentration is greater than 60 mg/dL.
recognize when the blood glucose concentration is low, preferably
less than 50 mg/dL (2.8 mmol/L). If the blood glucose concentra- 150

*
tion is low and the insulin concentration is in the upper half of 100
**
the reference range or increased, the dog has a relative or abso- ** *
lute excess of insulin that can be explained by the presence of an 80 *
**
insulin-secreting tumor that is insensitive to hypoglycemia. Con- 60
*
**
fidence in identifying an inappropriate excess of insulin depends * ***
**
on the severity of the hypoglycemia; the lower the blood glucose 40 * **
**
concentration, the more confident the clinician can be in identi- **********
20 * * *** *
fying inappropriate hyperinsulinemia, especially when the serum * * **
***********
insulin concentration falls in the reference range. 10 *** * *
* *** *
***
5 *** * * *
Protocol ****** *** * *** *
* ****
***
Most dogs with insulin-secreting neoplasia are persistently hypo- 0
glycemic. If the blood glucose concentration is less than 60 mg/dL Beta cell Hepatic Smooth muscle Sepsis
tumor tumor tumor
(3.4 mmol/L) and preferably less than 50 mg/dL (2.8 mmol/L),
serum should be submitted to a commercial veterinary endocrine FIGURE 9-6 Serum insulin concentrations in dogs with hypoglycemia caused
laboratory for determination of the glucose and insulin concen- by an insulin-secreting beta-cell tumor, hepatoma or hepatocellular carcinoma,
trations. The insulin assay must be validated for use in dogs, and leiomyosarcoma, or sepsis. Although a serum insulin concentration in the high
interpretation of insulin results should be based on the reference end of the normal range (i.e., > 10 U/mL) is consistent with a beta-cell tumor, a
interval established by the laboratory utilized (Madarame et al, serum insulin concentration in the low end of the normal range (i.e., 5 to 10 U/
2009; berg etal, 2011). If the dogs blood glucose concentra- mL) is not diagnostic for a beta-cell tumor. Shaded regions represent the high
tion is greater than 60 mg/dL, fasting may be necessary to induce (horizontal lines) and low (hatched area) ends of the normal range.
hypoglycemia. Blood glucose concentrations should be evaluated
hourly during the fast and blood obtained for glucose and insu- insulin concentration is in the upper half of the reference range.
lin determination when the blood glucose concentration is less Insulin values near the lower end of the reference range may be
than 60 mg/dL. It is important to remember that blood glucose found in animals with other causes of hypoglycemia, as well as in
results obtained from PBGM devices are often lower than results those with insulin-secreting tumors (Fig. 9-6). Careful assessment
obtained using bench-top methodologies (Cohn etal, 2000; Wess of the history, physical examination findings, and diagnostic test
and Reusch, 2000; Cohen etal, 2009; Zini etal, 2009). Ideally a results in relation to viable differentials for hypoglycemia in that
blood sample for submission to a commercial laboratory for glu- dog and, if necessary, repeating serum glucose and insulin measure-
cose and insulin determinations should not be obtained until the ments when hypoglycemia is more severe will usually identify the
blood glucose measured on these devices is less than 50 mg/dL. cause of the hypoglycemia. In 101 of our dogs with a histologically
Once fasting has induced hypoglycemia and the blood sample has confirmed beta-cell tumor and a blood glucose concentration less
been obtained for glucose and insulin determination, the dog can than 60 mg/dL, the serum insulin concentration was above the
be fed several small meals over the next 2 to 3 hours to minimize reference range in 74 dogs (73%); in the upper half of the reference
overstimulation of the tumor and rebound hypoglycemia. range in 21 dogs (21%); and in the lower end of the reference range
in 6 dogs (6%). No dog had a serum insulin concentration less
Interpretation than the reference range. Any serum insulin concentration below
The serum insulin concentration must be evaluated from the same the reference range is consistent with insulinopenia and does not
blood sample as and in relation to the blood glucose concentration indicate the presence of an insulin-secreting tumor.
(Box 9-6). A serum insulin concentration that exceeds the upper
limit of the reference range in a dog with a corresponding blood Insulin-to-Glucose Ratios
glucose concentration of less than 60 mg/dL (3.4 mmol/L), in
combination with appropriate clinical signs and clinical pathologic Several insulin-to-glucose ratios, including the insulin-to-glucose
findings, strongly supports the diagnosis of an insulin-secreting ratio, the glucose-to-insulin ratio, and the amended insulin-to-glu-
tumor. An insulin-secreting tumor is also possible if the serum cose ratio, have been recommended to evaluate the interrelationship
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between the blood glucose and insulin concentrations and to help test. By evaluating the response of blood glucose and insulin
establish the diagnosis of insulin-secreting tumor when the labo- concentrations for a period of time after administration of these
ratory results are ambiguous (e.g., hypoglycemia is marginal and agents, a differentiation between normal and neoplastic beta cells
serum insulin concentrations remain in the reference range). Of can potentially be made. We do not use any of these tests to estab-
these ratios, the amended insulin-to-glucose ratio is most com- lish the diagnosis of an insulin-secreting tumor, and they are not
monly used. The amended insulin-to-glucose ratio is determined recommended. See the first edition of Canine and Feline Endocri-
by entering the blood glucose and serum insulin concentrations in nology and Reproduction (Feldman and Nelson, 1987) for more
the following formula: information on the use of provocative testing in dogs suspected of
having beta-cell neoplasia.
serum insulin (U/mL) 10
blood glucose (mg/dL) - 30
DIAGNOSTIC IMAGING
The use of 30 in the formula is based on the theory that Diagnostic imaging is indicated to identify a pancreatic mass, to
in normal humans, serum insulin concentrations are undetect- identify metastatic disease, and to localize the site of the mass in
able when the blood glucose concentration is less than 30 mg/dL the pancreas (e.g., pancreatic body versus pancreatic limb); this
(1.7 mmol/L). Whenever the blood glucose concentration is less information provides support for the diagnosis of a beta-cell tumor
than 30 mg/dL, the number 1 is used as the divisor. Extrapolat- and a preliminary assessment of surgical resectability, likelihood
ing from the human literature, most authors have suggested that of postoperative complications (e.g., pancreatitis), and prognosis.
an amended insulin-to-glucose ratio greater than 30 is diagnostic Abdominal ultrasound is widely available and is the initial imag-
of an insulin-secreting tumor. However, this test is not specific; ing procedure used to assess the pancreas, peripancreatic tissues,
that is, some dogs with other causes of hypoglycemia may have and liver. Advanced diagnostic imaging, specifically dual-phase
abnormal amended ratios (Leifer etal, 1986). The most common CT, is currently the most sensitive imaging procedure for identi-
reason for lack of specificity is a detectable serum insulin con- fication of the primary mass and metastases and is recommended
centration, albeit usually in the lower end of the reference range, immediately prior to surgical exploration, if available.
despite hypoglycemia. This occurs most commonly with hepatic
tumors and sepsis. We do not rely on insulin-to-glucose ratios for
Radiography
interpretation of blood insulin and glucose results. Rather, we
interpret the absolute serum insulin concentration during hypo- Abdominal radiographs are not helpful in establishing the diagno-
glycemia (see Box 9-6) in conjunction with the history, physical sis of an insulin-secreting tumor, partly because of the location of
findings, and results of routine blood and urine tests. the pancreas and the small size of most insulin-secreting tumors.
Insulin-secreting tumors are typically less than 3 cm in diameter
Serum Fructosamine Concentration at the time the diagnosis is established. Displacement of viscera
or a visible mass in the right cranial quadrant of the abdominal
Serum fructosamines are glycated proteins found in blood that are cavity is extremely rare. Thoracic radiographs are of limited help
used to monitor control of glycemia in diabetic dogs and cats (see in documenting metastatic disease, primarily because beta-cell
Chapters 6 and 7). Fructosamines result from an irreversible, non- tumors rarely metastasize to the lungs until late in the course of
enzymatic, insulin-independent binding of glucose to serum pro- the disease. As such, thoracic radiographs are typically negative
teins and are a marker of the average blood glucose concentration for metastatic disease when obtained at the time the diagnosis is
during the circulating lifespan of the protein, which varies from 1 established, and surgery is contemplated. The most common sites
to 3 weeks depending on the protein. The extent of glycosylation of early metastasis are the liver, regional lymph nodes, and peri-
of serum proteins is directly related to the blood glucose concen- pancreatic omentum, which are regions where abdominal radio-
tration; the lower the average blood glucose concentration dur- graphs are also ineffective in identifying metastatic disease.
ing the preceding 2 to 3 weeks, the lower the serum fructosamine
concentration, and vice versa. Serum fructosamine concentrations
Ultrasonography
below the reference range support the existence of significant
periods of hypoglycemia and an insulin secreting tumor, assum- Abdominal ultrasonography can be used to identify a mass in
ing the history and findings on physical examination and routine the region of the pancreas and to look for evidence of potential
blood and urine test results are also consistent with the diagnosis. metastatic disease in the liver and surrounding structures (Fig.
A serum fructosamine concentration below the reference interval 9-7). Because of the small size of most beta-cell tumors and simi-
may also occur with other disorders that cause prolonged periods lar echogenicity of the tumor and the adjacent normal pancreas,
of hypoglycemia or that interfere with the assay (see Table 6-8). abdominal ultrasonographic findings are often interpreted as nor-
Documenting a low serum fructosamine concentration in a dog mal, although a pancreatic mass or metastatic lesion can be found
with suspected insulinoma and blood glucose concentrations that at surgery. A normal abdominal ultrasonographic finding does not
remain greater than 60 mg/dL despite fasting provides support rule out the diagnosis of a beta-cell tumor.
for additional diagnostics (e.g., diagnostic imaging) or exploratory Ultrasonic detection of a mass lesion in the region of the pan-
surgery (Mellanby and Herrtage, 2002). creas helps confirm the suspicion of beta-cell tumor in a dog with
appropriate clinical signs and clinical pathologic abnormalities
Provocative Testing (Fig. 9-8). Identification of mass lesions in the hepatic paren-
chyma or peripancreatic tissue suggests metastatic disease. Occa-
Several tests have been described that use agents that stimulate sionally only the metastatic sites are identified with ultrasound,
insulin secretion by normal and neoplastic beta cells; these include and the tumor in the pancreas goes undetected. Failure to identify
the glucagon tolerance test, the oral and IV glucose tolerance test, a mass lesion in the region of the pancreas or metastatic sites is
the tolbutamide tolerance test, and the epinephrine stimulation common and does not rule out the presence of a beta-cell tumor.
In one study evaluating 13 dogs, the sensitivity of ultrasonography

for detecting insulinomas was 69% and the sensitivity for detect-
ing hepatic and lymph node metastasis was 44% (Lamb et al,
1995). In a more recent study evaluating 14 dogs, the sensitiv-
ity of ultrasonography for detecting insulinomas was 35% and
ultrasonography was negative in all five dogs that had lymph node
metastasis at surgery, and it was negative in two of four dogs with
hepatic metastasis (Robben etal, 2005). Random evaluation of 58
dogs with surgically and histologically confirmed beta-cell neo-
plasia seen at UC Davis that underwent ultrasound evaluation of
the abdomen prior to surgery identified a mass lesion in only 24
dogs (41%). Ultrasonography failed to identify diffuse infiltration
A of the pancreas by the tumor in two dogs and a mass that was not
grossly visible at the time of surgery in two dogs. In one of these
dogs, a 2.3 1.3 cm pancreatic mass was identified 1 year after the
initial exploratory surgery. Tumors in the left limb of the pancreas
were identified by ultrasound more often than those in the body
or right limb. Similarly, larger tumors were more likely to be iden-
tified with ultrasonography although tumors greater than 2 cm
2 cm were not identified.
The accuracy of ultrasound depends on the experience of the
operator, quality of the ultrasound machine and sonogram images,
size of the pancreatic mass, and presence of extraneous factors that
affect results (e.g., bowel gas, obesity, movement of the dog). Fail-
ure to identify a pancreatic mass in a dog suspected of having a
beta-cell tumor does not rule out the diagnosis or the presence of
metastatic disease but is a further indication for exploratory sur-
B gery in the hopes of finding a small, excisable tumor.
FIGURE 9-7 Ultrasonogram of the pancreas, showing an islet beta-cell tumor
(arrow; A) and an enlarged hepatic lymph node (arrows; B) resulting from me- Computed Tomography
tastasis of the beta-cell tumor to the liver in a 9-year-old Cocker Spaniel. (From
Nelson RW, Couto CG, editors: Small animal internal medicine, ed 5, St Louis, Conventional pre- and postcontrast CT is reported to have bet-
2014, Elsevier, p. 817.) ter sensitivity than ultrasonography for the detection of beta-cell
A B
C
FIGURE 9-8 Ultrasonograms of the pancreas showing an islet beta-cell tumor (arrows) in a 13-year-old Borzoi (A)
and a 14-year-old Miniature Poodle (B). C, Ultrasonogram of the peripancreatic tissue showing a metastatic beta-
cell tumor (arrows) in a 5-year-old Golden Retriever.
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tumors in dogs. In a series of 14 dogs with insulinoma, the presence or absence of somatostatin receptors in tumor biopsy
sensitivity of conventional pre- and postcontrast CT for detec- samples. Five somatostatin receptor subtypes, designated sst1 to
tion of insulinoma and lymph node metastasis was 71% and sst5, are recognized in human tissue (Reubi et al, 2001). One
40%, respectively (Robben etal, 2005). Unfortunately, CT also variable influencing the success of somatostatin receptor scin-
identified 28 false-positive lesions in lymph nodes. Conven- tigraphy is the predominant somatostatin receptor subtype
tional pre-and postcontrast CT has been replaced by dual-phase expressed by the insulinoma, which dictates its affinity for pente-
computed tomographic angiography (CTA) for the identifica- treotide. Ligand binding studies on beta-cell tumors in humans
tion and localization of insulinomas and metastases in humans have identified different subtypes of somatostatin receptors, with
(Chatziioannou etal, 2001). Dual phase CTA techniques have variable binding capacities for somatostatin and somatostatin
been developed in dogs and preliminary studies in dogs with analogs, which may explain the variability of results (Lamberts
insulinoma have been promising (Caceres et al, 2006; Iseri etal, 1991; Bruns etal, 1994).
etal, 2007; Mai and Caceres, 2008). During dual-phase CTA, In the dog, the predominant somatostatin receptor containing
images are acquired during the arterial and venous phases after high-affinity binding sites for the somatostatin analog octreotide
IV injection of contrast medium. Most human insulinomas are and the radiopharmaceutical In-111 pentetreotide in insulin-
histopathologically hypervascular, and the CT images obtained secreting tumors has been sst2 (Robben etal, 1997; Garden etal,
during the arterial phase may clearly delineate enhancing tumor 2005). Somatostatin receptor scintigraphy using radio-labeled
lesions (Gritzmann et al, 2004). Insulinomas in dogs are also
assumed to be hypervascular. A study evaluating dual-phase
CTA of the pancreas in 10 healthy Beagle dogs identified an
arterial phase peak at 15 2 seconds after contrast medium
injection followed by a venous phase peak where the pancre-
atic parenchyma was clearly delineated at 28 9 seconds and
appearance of the equilibrium phase approximately 70 seconds
after injection (Fig. 9-9; Iseri etal, 2007). Caceres, etal., (2006)
identified a purely arterial pancreatic window of 5 to 6 seconds a
after contrast administration in nine healthy Beagles. Evaluation c
of a dog with insulinoma revealed a hyperattenuating mass at the p
arterial phase of the dual-phase CTA, and the size and location Sp
of the tumor observed on the CT images were consistent with
those seen at surgery (Iseri etal, 2007).
In a subsequent study involving three dogs with insulinoma, St
dual-phase CTA identified lesions not seen on ultrasonography,
including the primary insulinoma in two dogs (Mai and Caceres,
2008). Findings with dual-phase CTA were in agreement with the Liver
surgical findings in all three dogs. In two dogs, the insulinomas
had marked contrast enhancement during the arterial phase of
the study with less enhancement during the venous phase and was
L
isoattenuating to the rest of the pancreas during the delayed phase
of the study. In the third dog, a metastasized lymph node but not A
the pancreatic insulinoma had strong enhancement at the arterial
phase comparable to that seen in the primary insulinoma in the
other two dogs. Lack of arterial enhancement of an insulinoma L
has been reported in humans with up to 45% of pancreatic insu-
linomas being hypo- to isoattenuating to the rest of the pancreas St
during the arterial phase (Van Hoe et al, 1995). Occasionally
the tumor is hyperattenuating at the venous but not the arterial
phase of the study. Evaluation of the arterial and venous phase of
a contrast-enhanced CT is currently recommended immediately Sp
prior to surgery to identify the location of the primary insulinoma
and its metastatic sites. The decision to either pursue surgery with
medical treatment to follow, or cancel surgery and initiate medi- RK
cal treatment will be dependent, in part, on the findings of the
CT study.
L
B LK
Scintigraphy
FIGURE 9-9Transverse (A) computed tomography (CT) image and a maximum
Somatostatin receptor scintigraphy using the radiopharmaceuti- intensity projection CT image in the dorsal plane (B) of a pancreatic beta-cell
cal drug indium (In)-111 pentetreotide has been used to image tumor obtained during the arterial phase of dual-phase CT angiography in a dog
pancreatic islet cell tumors in humans (Kvols etal, 1993; Lam- that presented with severe hypoglycemia and inappropriate hyperinsulinemia.
berts et al, 1993). In humans, localization of beta-cell tumors Note the marked distinction between the beta-cell tumor (arrows) and the re-
with somatostatin receptor scintigraphy has been inconsistent maining normal pancreas (arrow heads). (Images courtesy of Dr. Eric Johnson.)
and of limited value (Lamberts etal, 1991; Buetow etal, 1997). a, aorta; c, caudal vena cava; p, portal vein; St, stomach, Sp, spleen; RK and LK,
Positive and negative scan results have been correlated with the right and left kidney.
octreotide or In-111 pentetreotide was used to identify beta-cell Perioperative Management of Dogs Undergoing Surgery
neoplasia in seven dogs with inconclusive findings on abdominal
ultrasonography (Robben etal, 1997; Lester etal, 1999). Soma- The intent of surgery should be to remove as much abnormal tis-
tostatin receptor scintigraphy was effective in identifying the sue as possible, including resectable sites of metastases. The success
primary insulin-secreting tumor in five of seven dogs and larger of surgery depends in part on providing appropriate fluid therapy,
metastases in the regional lymph nodes and liver in three of three dextrose, and supportive care during the perioperative period to
dogs and two of three dogs, respectively. Small metastases in the avoid severe hypoglycemia and postoperative pancreatitis and to
liver were not detected in one dog. In a subsequent study by Gar- improve the likelihood of an uneventful recovery. Euthanasia is
den, etal., (2005) using In-111 pentetreotide, scintigraphic scans not recommended regardless of the findings at surgery. Many
in four of five dogs with insulinoma showed that abnormal foci dogs with metastatic disease can be managed medically for several
of In-111 pentetreotide activity attributed to the insulinoma but months to more than a year.
the anatomic location of the tumors was correctly predicted in Until surgery is performed, the dog should be protected from
only one of these dogs. The scan in the fifth dog was equivo- episodes of severe hypoglycemia. This can usually be accomplished
cal; a 1.5 cm insulinoma was identified in the distal left limb of through frequent feeding of small meals and administration of
the pancreas at surgery. In a series of 14 dogs with insulinoma, glucocorticoids (Box 9-7). A continuous IV infusion of a balanced
the sensitivity of single-photon emission CT using radiolabeled
octreotide was 43% and lymph node metastasis was identified
in none of five dogs (Robben etal, 2005). Negative scan results BOX 9-7 L
ong-Term Medical Therapy for Dogs with
could reflect the expression of somatostatin receptors with low a Beta-Cell Tumor
affinity for pentetreotide, low expression density of sst2 receptors,
or small size of the tumor, rather than absence of the tumor itself Standard Treatments
(Garden etal, 2005). 1. Dietary therapy
Somatostatin receptor scintigraphy offers intriguing options for a. Feed canned or dry food in three to six small meals daily.
identifying insulin-secreting tumors and determining potential b. Dietary fat, complex carbohydrates, and fiber help prolong postpran-
responsiveness of the tumor to octreotide therapy. Presumably, dial glucose absorption.
positive scintigraphic scans would also predict a positive response c. Avoid foods containing monosaccharides, disaccharides, propylene
to treatment with the somatostatin analog octreotide (see Soma- glycol, and corn syrup.
tostatin Therapy). 2. Limit exercise to walks; avoid strenuous exercise.
3. Glucocorticoid therapy
a. Prednisone, 0.5 mg/kg divided into two doses initially.
TREATMENT OF BETA-CELL NEOPLASIA
b. Gradually increase dose and frequency of administration, as needed.
c. Goal is to control clinical signs, not to reestablish euglycemia.
Surgical Versus Medical Therapy
d. Consider alternative treatments if signs of iatrogenic hypercorti-
Treatment options for a beta-cell tumor include surgical explo- solism become severe or glucocorticoids become ineffective.
ration, medical treatment for chronic hypoglycemia, or both. Additional Treatments
Surgery offers a chance to cure dogs with a resectable solitary 1. Diazoxide therapy
mass. In dogs with nonresectable tumors or with obvious meta- a. Continue standard treatment; reduce glucocorticoid dose if polyuria
static lesions, removal or debulking of as much abnormal tissue and polydipsia is unacceptable.
as possible frequently results in remission, or at least alleviation, b. May initiate diazoxide early when glucocorticoid dose is low, or later
of clinical signs and an improved response to medical treatment. when glucocorticoids become ineffective or polyuria and polydipsia
Survival time is longer in dogs that undergo surgical exploration becomes unacceptable.
and tumor debulking followed by medical therapy, compared with c. Diazoxide, 5 mg/kg every 12 hours initially.
dogs only treated medically (Tobin et al, 1999). Despite these d. Gradually increase dose as needed, not to exceed 60 mg/kg/day.
benefits, surgery remains a relatively aggressive mode of diagnosis e. Goal is to control clinical signs, not to reestablish euglycemia.
and treatment, in part because of the high prevalence of metastatic 2. Somatostatin therapy
disease, the older age of many dogs at the time beta-cell neopla- a. Continue standard treatment; reduce glucocorticoid dose if polyuria
sia is diagnosed, the potential for postoperative pancreatitis, and and polydipsia is unacceptable.
the unpredictable response to surgery as it relates to improvement b. Octreotide (Sandostatin), 10 to 40 g/dog administered subcutane-
in hypoglycemia and clinical signs. As a general rule, we are less ously every 12 hours to every 8 hours.
aggressive about recommending surgery in aged dogs (i.e., older 3. Streptozotocin therapy
than 12 years of age), dogs with extensive metastatic disease iden- a. Effectiveness in improving hypoglycemia, controlling clinical signs,
tified by diagnostic imaging, and dogs with concurrent disease and prolonging survival is variable and potentially severe adverse
that significantly enhances the anesthetic risk. reactions are common (see Streptozotocin).
Medical management of chronic hypoglycemia should be initi- b. Continue standard treatment; reduce glucocorticoid dose if polyuria
ated when an exploratory celiotomy is not performed or when and polydipsia is unacceptable.
metastatic or inoperable neoplasia results in recurrence of clinical c. 0.9% saline diuresis for 3 hours, then streptozotocin, 500 mg/m2,
signs. Medical therapy revolves around nonspecific antihormonal in 0.9% saline and administered intravenously over 2 hours, then
therapy designed to increase the blood glucose concentration and 0.9% saline diuresis for 2 additional hours.
decrease the occurrence of clinical signs. Many dogs with met- d. Administer antiemetics immediately after streptozotocin adminis-
astatic disease can be managed medically for several months to tration to minimize vomiting.
more than a year. Medical therapy, however, has no potential for e. Repeat treatment every 3 weeks until hypoglycemia resolves or ad-
providing a cure or for preventing metastasis of malignant beta- verse reactions develop (e.g., pancreatitis, renal failure).
cell neoplasia.
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electrolyte solution containing 2.5% to 5% dextrose before, dur- development of severe hypoglycemia (i.e., a blood glucose con-
ing, and immediately after surgery is important. Although this centration < 40 mg/dL). Fortunately, it is uncommon for a dog
does not restore euglycemia, these solutions provide a substrate in stable condition with a beta-cell tumor to require more than
for CNS function, thereby minimizing CNS signs in most dogs. a 5% dextrose solution given intravenously during surgery. This
Concentrations of dextrose in excess of 5% should be avoided to infusion usually maintains the blood glucose concentration above
prevent overstimulation of the pancreatic tumor and rebound, 40 mg/dL. If a 5% dextrose infusion is ineffective in preventing
sometimes fatal, hypoglycemia. The IV dextrose infusion can be severe hypoglycemia during surgery, a constant-rate infusion of
initiated the evening before surgery, at the time food and water glucagon should be considered (see Medical Therapy for an Acute
are withheld, and continued throughout the perioperative period. Hypoglycemic Crisis).
Initiation of fluid therapy before surgery also helps ensure ade- Adequate fluid therapy just prior to, during, and immediately
quate circulation to the pancreas, thereby minimizing the risk of after surgery is extremely important for minimizing the devel-
postoperative pancreatitis. The goal of the dextrose infusion is to opment of pancreatitis. Digital manipulation and dissection of
prevent clinical signs of hypoglycemia and to maintain the blood the pancreas cause inflammation. The severity of inflammation
glucose concentration at greater than 40 mg/dL (2.2 mmol/L), depends on the gentleness of the palpation, circulation to the
not to reestablish a normal blood glucose concentration. If the pancreas, and surgical procedures performed. Providing adequate
dextrose infusion is ineffective at preventing severe hypoglycemia fluid therapy prior to and during surgery ensures that every means
during the perioperative period, a constant-rate infusion of glu- of maintaining circulation through the microvasculature of the
cagon should be considered (see Medical Therapy for an Acute pancreas has been used and helps minimize the development of
Hypoglycemic Crisis). Glucagon is a potent stimulant of hepatic pancreatitis. We routinely administer fluids at a rate of 60 to 100
gluconeogenesis and is effective in maintaining normal blood glu- mL/kg/24 hr during surgery and for 24 to 72 hours after the pro-
cose concentrations in dogs with an insulin-secreting tumor when cedure, unless concurrent problems (e.g., heart failure, hypopro-
administered by constant-rate infusion. teinemia) are present that may affect the dogs ability to handle
IV fluids.
Intraoperative Considerations During surgery, as much of the pancreas as possible should be
Attention to the patients blood glucose concentration and main- examined visually. A complete, gentle digital inspection of this
tenance of adequate fluid therapy during surgery are imperative organ should then be undertaken. The importance of gentle han-
for the dog with beta-cell neoplasia. In a recent study, the addition dling of the pancreas cannot be overemphasized; failure to handle
of medetomidine (5 g/kg IM) to the preanesthetic medication the organ gently may result in severe, potentially life-threatening
protocol significantly decreased plasma insulin concentrations, pancreatitis. A thorough examination of the liver, surrounding
increased plasma glucose concentrations, and decreased the intra- lymph nodes, and omentum for metastatic sites should also be
operative glucose administration rate in 12 dogs undergoing done.
surgery for beta-cell tumor, compared with 13 dogs that did not Frequency of Tumor Identification. Most dogs with insulin-
receive medetomidine prior to surgery (Guedes and Rude, 2013). secreting tumors have masses that are easily visible to the sur-
These findings support the judicious use of medetomidine at low geon inspecting the pancreas (Fig. 9-10). In a minority of dogs,
doses as an adjunct to the anesthetic management of dogs with the tumor is not visible but can be palpated during gentle but
beta-cell neoplasia. thorough digital examination of the pancreas. Multiple pancre-
Monitoring the blood glucose concentration every 30 to 60 atic masses may also occur. Ninety-nine (88%) of 111 dogs with
minutes during surgery using a point-of-care or PBGM device insulin-secreting tumors at UC Davis had an obvious mass in the
allows objective assessment of the dogs blood glucose status. The pancreas at the time of surgery.
goal is to maintain the blood glucose concentration greater than Tumor Location. There is no predisposition for tumor loca-
40 mg/dL (2.2 mmol/L), not to establish a normal blood glu- tion in the pancreas (Fig. 9-11). In our 99 dogs in which a mass
cose concentration per se. Moderate changes in the blood glu- was identified in the pancreas, the mass was located in the right
cose concentration can be monitored and adjustments made in (duodenal) limb of the pancreas in approximately 41%, in the left
the rate of IV dextrose administration, as needed, to prevent the (splenic) limb of the pancreas in 40%, and in the central region
A B
FIGURE 9-10 A and B, Photographs of pancreatic insulin-secreting islet beta-cell tumors (arrows).
(body) of the pancreas in 19%. In five of the remaining 12 dogs, and hypoglycemia typically recurs shortly after surgery. Prior to
a diffuse, microscopic islet cell carcinoma was recognized histo- surgery we routinely discuss with the client the possible locations
logically in an arbitrarily resected portion of the right limb of the of the tumor and the implications that location has on attain-
pancreas. Diffuse thickening of the pancreas was evident on digital ing a successful outcome. We strongly recommend against tumor
palpation of the pancreas at the time of surgery in three of these removal if the insulin-secreting tumor is located in the body of
five dogs; the pancreas was visually and digitally normal in two the pancreas because of the high probability of life-threatening
dogs. In three dogs, there was no visible mass and no metastatic postoperative complications. We inform the client that there is a
sites, the pancreas was normal on digital palpation, and histologic one in five chance of the dog having inoperable disease and that
examination of a portion of the right limb of the pancreas failed if such disease is found, we advise closing the abdomen and treat-
to identify an insulin-secreting tumor. One year later a pancreatic ing the dog medically rather than risk the development of severe
mass subsequently confirmed as an insulinoma was identified in pancreatitis by trying to remove the tumor.
one of the dogs. In two dogs, there was no visible mass and no Failure to Identify a Mass: Use of Methylene Blue. IV methy-
metastatic sites, the pancreas was normal on digital palpation, and lene blue infusion has been advocated for intraoperative identifica-
histologic examination of a portion of the right limb of the pan- tion of a beta-cell tumor in the dog (Fingeroth and Smeak, 1988;
creas failed to identify an insulin-secreting tumor but subjectively Fingeroth et al, 1988). Methylene blue is an azo dye that, when
there was marked increase in the number of islets and islands administered intravenously, is concentrated in the parathyroid glands
of beta cells scattered throughout the pancreas. Periodic evalua- and endocrine pancreas. Methylene blue intensely stains hyperfunc-
tions of the dogs identified persistent hypoglycemia and hyper- tional, adenomatous, or carcinomatous areas of these organs. Nor-
insulinemia but failed to identify a pancreatic mass. One dog was mal pancreatic endocrine tissue is stained a dusky slate blue, whereas
lost to follow-up at 18 months after surgery and a necropsy was hyperfunctioning tissue is stained more intensely, often a reddish
performed on the other dog approximately 5 years after surgery; blue. In one dog, methylene blue also successfully identified an
histologic changes suggestive of beta cell hyperplasia were still ectopic islet cell tumor and differentiated metastatic from nonmeta-
evident, and a pancreatic mass was not identified. Enlargement static nodules in surrounding tissue (Smeak etal, 1988).
of a mesenteric lymph node adjacent to the pancreas was evident Methylene blue is administered as an IV infusion by mixing
in two dogs, but a mass was not identified in the pancreas per appropriate volumes of methylene blue in 250 mL of normal iso-
se. Histologic examination of the excised lymph node confirmed tonic saline solution to obtain a total dose of 3 mg methylene
metastatic beta-cell tumor. Hyperinsulinism and hypoglycemia blue per kilogram of body weight (Fingeroth and Smeak, 1988).
persisted in both dogs after surgery. The entire solution is given over a period of 30 to 40 minutes.
Tumor location has important ramifications for the success of Maximal staining of the endocrine pancreas occurs approximately
surgery. In general, solitary tumors in the left or right limb of 30 minutes after initiation of the infusion. Complications with
the pancreas are readily excisable with minimal damage to the methylene blue infusion include Heinz body hemolytic anemia,
pancreas and a low prevalence of postoperative pancreatitis. In acute kidney failure, pseudo-cyanosis (i.e., blue-appearing oral
contrast, tumors in the body of the pancreas are often intimately mucous membranes), green-tinged urine, and possibly pancreati-
intertwined with the pancreatic ducts, blood vessels, and lymphat- tis. Hemolytic anemia is common, with the hematocrit declining
ics. Surgical removal often requires extensive manipulation and to less than 25% 2 to 3 days after surgery.
dissection of the pancreas. Severe and potentially life-threatening We do not routinely use methylene blue because of its postop-
pancreatitis that requires aggressive and often extended treat- erative complications, the routine use of dual-phase CTA prior to
ment is a common postoperative complication despite appropri- surgery, and the ability to grossly identify abnormal tissue in the
ate perioperative treatment aimed at preventing its development. vast majority of our dogs with beta-cell neoplasia. If our surgeon
In addition, complete excision of the tumor is almost impossible fails to recognize a mass and the diagnosis has been confirmed
by glucose and insulin measurements, the recommendation is to
remove the right or left limb of the pancreas in the hope of remov-
ing the portion that contains the tumor. In theory, 90% of the
pancreas could be removed without causing overt diabetes mel-
litus or exocrine pancreatic insufficiency.
Sites of Metastasis. Little correlation appears to exist between
18 tumor size or shape and its malignant potential. A complete
Stomach inspection of the abdominal contents is imperative to identify
unsuspected abnormalities as well as sites of metastasis. The most
common sites of tumor spread include the regional lymphatics and
lymph nodes (duodenal, mesenteric, hepatic, splenic), the liver,
and the peripancreatic omentum. Failure to identify metastatic
40 disease is common during surgery. A solitary pancreatic mass is
41 commonly removed in toto, with the belief that the dog has been
Pancreas cured, only to have clinical signs of hyperinsulinism recur weeks
to months later. In our experience, almost all beta-cell tumors
in the dog are malignant. Unfortunately, initial clinical signs are
often vague and not worrisome to the owner; weeks to months
may elapse between the onset of clinical signs and establishment
of the diagnosis, and as a result, the likelihood of metastasis at the
Duodenum time of exploratory surgery is high.
FIGURE 9-11 Diagram of tumor location in the pancreas in 99 dogs with an Recommendations if Metastasis Is Identified.Ideally, all
insulin-secreting islet beta-cell tumor. abnormal-appearing tissue should be removed, if possible, and
|
submitted for histologic evaluation. When abnormal tissue cannot neoplastic beta cells in the pancreas, liver, lymph nodes, or peri-
be entirely removed, debulking of the tumor mass may be benefi- pancreatic tissues that multiply and eventually reach a population
cial. Biopsy of suspected tumor tissue is the least a surgeon should density capable of secreting enough insulin to cause hypoglycemic
accomplish. The surgeon must always weigh the potential gains signs to recur. For these dogs, resolution of diabetes is followed
obtained with aggressive tumor removal and debulking against the by a variable period of euglycemia, which eventually progresses
potential complications that may develop as a result of the surgi- to hypoglycemia. Owner evaluation of the pets urine glucose is
cal procedure. This is especially important when dealing with the helpful in identifying when insulin therapy is no longer needed.
pancreas, because life-threatening pancreatitis can develop after Persistently negative urine glucose in conjunction with cessation
extensive manipulation and dissection of the gland. Because medi- of polyuria and polydipsia is an indication to discontinue insu-
cal treatment is a viable option after surgery, euthanasia at the time lin therapy. If hyperglycemia and glycosuria recur, insulin therapy
of surgery and heroic attempts to remove all abnormal tissue are can be reinstituted, but at a lower insulin dosage. The develop-
not recommended in a dog with metastatic disease, especially if ment of permanent insulin-requiring diabetes mellitus after sur-
the latter course increases the risk of postoperative complications. gical removal of a solitary insulin-secreting tumor is uncommon
Postoperative Complications. The most common postopera- and implies additional abnormalities involving the beta cells (e.g.,
tive complications are pancreatitis, hyperglycemia, and hypogly- beta-cell degeneration, islet hypoplasia; see Chapter 6). Perma-
cemia. The development of these complications is directly related nent diabetes mellitus has developed in only two of the dogs that
to the expertise of the surgeon in handling the pancreas and excis- underwent surgical removal of an insulin-secreting tumor at our
ing these tumors, the location of the tumor in the pancreas (i.e., hospital. Both dogs were lost to follow-up after 1 to 2 years, and
peripheral limb versus body), the presence or absence of func- at that time both dogs were still receiving insulin injections twice
tional metastases, and the adequacy of fluid therapy during the a day to control hyperglycemia.
perioperative period. Persistent Postoperative Hypoglycemia.Dogs that remain
Pancreatitis. IV administration of polyionic fluids with 2.5% hypoglycemic after surgical removal of an insulin-secreting tumor
to 5% dextrose (60 to 100 mL/kg/24 hr) and nothing by mouth have functional metastatic disease. Medical therapy should be initi-
prior to, during, and for 24 to 48 hours after surgery, followed by ated in dogs with persistent postoperative hypoglycemia. During
appropriate dietary therapy during the ensuing week, is helpful in the initial 48 to 72 postoperative hours, IV infusion of 2.5% to 5%
minimizing the development of pancreatitis. We rely on physical dextrose should be continued. The goal is to prevent clinical signs
examination findings in determining when to initiate oral water of hypoglycemia (especially seizures), not to reestablish a normal
and a bland diet. Circulating pancreatic enzyme concentrations blood glucose concentration. Additional therapy may be needed if
(e.g., canine pancreatic-specific lipase [cPL]) are usually not deter- hypoglycemic seizures occur (Box 9-8; also see Medical Therapy for
mined after surgery. Arbitrarily treating the dog for pancreatitis an Acute Hypoglycemic Crisis). Small meals should be fed every
without determining the serum pancreatic enzyme concentra- 4 to 6 hours, beginning as soon after surgery as possible. A diet
tions beforehand has produced excellent results. Despite gentle acceptable for the treatment of pancreatitis should be fed initially.
handling of the pancreas during surgery, aggressive fluid therapy Additional therapy may be needed, depending on the efficacy of
during the perioperative period, and appropriate dietary therapy the frequent feedings in maintaining remission of clinical hypo-
during the postoperative period, nine (13%) of 70 dogs undergo- glycemia (see Medical Therapy for Chronic Hypoglycemia). If a
ing surgery for beta-cell tumor at UC Davis still developed clinical dog becomes symptomatic despite the frequent feedings, medical
signs of acute pancreatitis. Three of the nine dogs died as a result therapy should be attempted before euthanasia is recommended.
of pancreatitis; the tumor was located in the body of the pancreas
and was difficult to excise in all three dogs.
Diabetes Mellitus. Occasionally dogs develop transient diabe-
BOX 9-8 M
edical Therapy for Hypoglycemic Seizures
tes mellitus after surgical removal of an insulin-secreting tumor.
Caused by an Insulin-Secreting Beta-Cell Tumor
Diabetes mellitus is believed to result from inadequate insulin
secretion by atrophied normal beta cells. Removal of all or a
Seizures at Home
majority of the neoplastic cells acutely deprives the animal of insu-
Step 1: Rub sugar solution on pets buccal mucosa.
lin. Until the normal beta cells regain their secretory capability, the
Step 2: Once pet is sternal, feed a small meal.
dog is hypoinsulinemic and may require exogenous insulin injec-
Step 3: Call the veterinarian.
tions to maintain euglycemia. It was once thought that postsurgical
hyperglycemia and glycosuria were excellent prognostic signs indi- Seizures in Hospital
cating total removal of insulin-secreting neoplastic cells. However, Step 1: Administer 1 to 5 mL (depending on dog size) of 50% dextrose
most of our dogs have required exogenous insulin only transiently (diluted) intravenously slowly over 1 to 2 minutes followed by continuous
after surgery and ultimately have required medical management IV infusion of 5% dextrose in water (i.e., D5W).
for an exacerbation of an insulin-secreting tumor several weeks to Step 2: Once animal is sternal, feed a small meal.
months after their need for insulin therapy dissipates. Step 3: Initiate long-term medical therapy (see Box 9-7).
Postsurgical insulin therapy is initiated only when hyperglyce- Intractable Seizures in Hospital
mia and glycosuria persist for 1 to 2 days after discontinuation Step 1: Administer 2.5% to 5% dextrose in water intravenously at 1.5 to 2
of all dextrose-containing IV fluids. Initial insulin therapy should times maintenance fluid rate.
be conservativethat is, 0.25 U of Lente or neutral protamine Step 2: Add 0.5 to 1 mg of dexamethasone/kg to IV fluids and administer
Hagedorn (NPH) insulin per kilogram of body weight given once over 6 hours; repeat every 12 to 24 hours, as necessary.
daily. Subsequent adjustments in dosage or frequency of admin- Step 3: If above fails, administer glucagon USP (Eli Lilly) intravenously by
istration should be based on clinical response and blood glucose constant rate infusion at an initial dosage of 5 to 10 ng/kg/min.
determinations (see Chapter 6). Step 4: If necessary, control seizure activity with diazepam or phenobarbital
The need for insulin treatment is usually transient, lasting until medical treatment becomes effective in controlling hypoglycemia.
from a few days to a few months. Most of these dogs still have
Evaluating the Long-Term Success of Surgery: Is the Dog Cured? increases blood glucose through stimulation of hepatic glycogenol-
The long-term success of surgery can be difficult to predict in ysis and gluconeogenesis. In a recent study, subcutaneous admin-
dogs with a solitary mass that is removed in toto and subse- istration of glucagon resulted in a rapid and significant increase
quent blood glucose concentration returns to normal. The most in serum glucose concentrations in healthy Beagles but the effect
efficient and logical initial method for evaluating these patients was short-lived (Zeugswetter et al, 2012; Fig. 9-12). Although
for recurrence of beta-cell neoplasia is periodic measurement (i.e., clinical trials are needed, at home glucagon emergency kits used
every month initially) of a fasting blood glucose concentration. to treat severe hypoglycemia in human diabetics may become a
The fasting blood glucose concentration should be consistently viable option for the short-term treatment of severe hypoglycemia
greater than 70 mg/dL (3.9 mmol/L) if beta-cell neoplasia has not in dogs or cats and provide the time needed to get the dog or cat to
recurred. Recurrence of beta-cell neoplasia should be suspected if an emergency veterinary hospital for care (Niessen, 2012).
the blood glucose concentration is less than 70 mg/dL. Confir- In the hospital, clinical signs of hypoglycemia can usually be
mation of recurrence requires measurement of the serum insulin alleviated initially with IV administration of 50% dextrose,
concentration when the blood glucose concentration is less than diluted, followed by continuous IV infusion of 5% dextrose (i.e.,
60 mg/dL (see Confirming the Diagnosis of an Insulin-Secreting dextrose 5% in water [D5W]). In dogs with beta cell neoplasia,
Beta-Cell Tumor: Serum Insulin Determination). dextrose should be administered in small amounts slowly (e.g., 1
to 5 mL increments depending on the size of the dog over a period
of 1 to 2 minutes) to effect. Rapid administration of large boluses
Medical Therapy for an Acute Hypoglycemic Crisis
of glucose to a dog with suspected or proven beta cell neoplasia
The acute onset of clinical signs caused by hypoglycemia typi- can result in severe rebound hypoglycemia caused by excessive
cally occurs at home after exercise or consumption of food that insulin secretion by the tumor in response to the rapid increase in
is easily digestible and rapidly absorbed; during the immediate the blood glucose concentration. The goal of therapy is to control
postoperative period in the dog with functioning metastases or neurologic signs (primarily seizures), not correct hypoglycemia.
inoperable neoplasia; or as a result of inadvertently aggressive Once neurologic signs have been controlled with judicious IV
IV dextrose administration at the time hypoglycemia is initially administration of dextrose, frequent feedings and glucocorticoids
identified. Therapy depends on the severity of clinical signs and can be initiated (see Box 9-7).
the location of the dog (i.e., home versus hospital) and initially If the dextrose infusion is ineffective in preventing severe hypo-
involves administration of glucose, either as food or sugar solution glycemia or breaking the cycle of hypoglycemia and hyperglyce-
by mouth or as an IV dextrose solution. mia, a constant-rate infusion of glucagon should be considered.
If an owner contacts a veterinarian by telephone and reports Glucagon is a potent stimulant of hepatic glycogenolysis and glu-
that the pet is having a hypoglycemic seizure, we do not recom- coneogenesis and is effective in maintaining normal blood glucose
mend transporting the dog to a veterinary hospital. Rather, the concentrations in dogs with beta-cell neoplasia when administered
owner should be instructed to rub a sugar solution on the pets by constant-rate infusion (Fischer et al, 2000; Fig. 9-13). One
buccal mucosa. Hypoglycemic dogs usually respond in 1 to 2 min- milligram of lyophilized glucagon USP (Eli Lilly) is reconstituted
utes. The owner should be instructed to never place fingers in, or with the diluent provided by the manufacturer, and the solution
pour the sugar solution down, the pets mouth. Once the dog or is added to 1 L of 0.9% saline, making a 1 g/mL solution, which
cat is sternal and cognizant of its surroundings, it should be fed a can be administered by syringe pump. The initial dosage is 5 to 10
small meal and brought to the veterinarian. ng per kilogram of body weight per minute. The dosage is adjusted
At home subcutaneous administration of glucagon is used to as needed to maintain the blood glucose concentration between
treat severe hypoglycemia in human diabetics. Glucagon quickly 60 and 100 mg/dL (3.4 and 5.6 mmol/L). When discontinuing
12 216
Group 1 (Intravenous)
a,b a,b a Group 2 (Subcutaneous)

10 Group 3 (Placebo) 180
Glucose (mmol/L)
Glucose (mg/dL)
8 144
FIGURE 9-12Mean glucose concentrations

6 108 (mmol/L and mg/dL) over 180 minutes after
the subcutaneous (SC) and intravenous (IV)
injection of synthetic glucagon or 0.9% saline
solution (placebo). (From Zeugswetter FK, etal.:
4 72 Metabolic and hormonal responses to subcuta-
neous glucagon in healthy beagles, J Vet Emer
Crit Care 22:558, 2012.) Bars indicate standard
deviations. a, Significant difference of SC versus
2 36 placebo injection; b, significant difference of
0 20 40 60 80 100 120 140 160 180 200 SC versus IV injection; P < 0.05 is considered
Sampling Points (minutes) significant.
|
Blood glucose (mg/dL) dogs benefit from surgical debulking after medical treatment has
150 become ineffective in controlling clinical signs of hypoglycemia.
Glucagon stopped
One of our dogs underwent surgical debulking on three separate
100
occasions; the dog survived 3 years before succumbing to meta-
Sx Glucagon
tapered
static disease involving the lungs.
Alloxan and streptozotocin are drugs with specific toxicity
50 directed at beta cells. The potential for serious adverse reactions
Glucagon infusion has limited the use of these drugs for the treatment of insulin-
0 secreting tumors in dogs. However, a viable treatment protocol
1 3 5 7 9 using streptozotocin in dogs has been described, and studies to
Days determine its value in the treatment of insulin-secreting tumors
FIGURE 9-13 Blood glucose concentrations in a 13-year-old female spayed Po- have been reported (Moore etal, 2002; Northrup etal, 2013).
meranian before and after surgical removal of an insulin-secreting islet beta-
cell tumor. Pancreatitis and severe hypoglycemia developed postoperatively. Frequent Feedings
The hypoglycemia resolved, and euglycemia was maintained after initiation of Dogs with insulin-secreting tumors have a persistent absolute or
a constant-rate intravenous (IV) infusion of glucagon. The dosage of glucagon relative excess of circulating insulin. Frequent feedings provide
was gradually tapered beginning on day 5, feeding of small amounts of food a constant source of calories as a substrate for the excess insulin
was begun on day 7, and the IV glucagon infusion was stopped on day 8. Severe secreted by the tumor and help to reduce the frequency of hypo-
hypoglycemia did not recur. Sx, Surgery. glycemic episodes. Diets high in fat, complex carbohydrates, and
fiber delay gastric emptying, slow intestinal glucose absorption,
and help minimize a rapid increase in the portal blood glucose
glucagon, the dose should be gradually decreased over 1 to 2 days concentration that could stimulate excessive pancreatic insu-
and the blood glucose concentration monitored for recurrence of lin secretion. Simple sugars are rapidly absorbed, have a potent
severe hypoglycemia. stimulatory effect on insulin secretion by neoplastic beta cells, and
Occasionally, a hypoglycemic dog with CNS signs fails to should be avoided. A combination of canned and dry food, fed
respond to glucose or glucagon administration. These signs in three to six small meals daily, is recommended. Daily caloric
could be the result of a disorder unrelated to hypoglycemia. intake should be controlled because hyperinsulinemia promotes
However, irreversible cerebral lesions may result from long- obesity. Exercise should be limited to walks on a leash.
term, severe hypoglycemia and the resultant cerebral hypoxia.
Cerebral hypoxia predisposes the nervous tissue to edema, caus- Glucocorticoid Therapy
ing increased CSF pressure and cell death. These animals have Glucocorticoid therapy should be initiated when dietary manipu-
a guarded to grave prognosis. Therapy is directed at providing lations are no longer effective in preventing clinical signs of hypo-
a continuous supply of glucose as a 5% solution given intrave- glycemia. Glucocorticoids antagonize the effects of insulin at the
nously or by stimulating hepatic glucose production with a con- cellular level, stimulate hepatic glycogenolysis, and indirectly pro-
stant-rate infusion of glucagon. Simultaneously, seizure activity is vide the necessary substrates for hepatic gluconeogenesis. Pred-
controlled with diazepam or stronger anticonvulsant medication nisone (dog) or prednisolone (cat) are the glucocorticoids most
(e.g., phenobarbital). Last, if cerebral edema is suspected, treat- often used. The initial dosage is 0.25 mg/kg by mouth every 12
ment with mannitol, furosemide, and/or dexamethasone should hours. Adjustments in the dose are based on clinical response. The
be considered (Fenner, 1995). dose of prednisone required to control clinical signs increases with
time in response to growth of the tumor and its metastatic sites.
Medical Therapy for Chronic Hypoglycemia Eventually, the adverse effects of prednisone, specifically polyuria
and polydipsia, become unacceptable to clients. This typically
See Box 9-7. occurs when the prednisone dosage approaches 1 mg/kg twice
daily, although there is dog to dog variability in development of
Background adverse effects and owner tolerance of the adverse effects. When
Medical management for chronic hypoglycemia should be initi- adverse effects become intolerable, the dose of prednisone should
ated when an exploratory celiotomy is not performed or when be reduced by 25% to 50% (not stopped) and additional therapy
metastatic or inoperable neoplasia results in recurrence of clinical considered.
signs. The goals of medical therapy are to reduce the frequency
and severity of clinical signs and to avoid an acute hypoglycemic Diazoxide Therapy
crisis, not to establish euglycemia per se. Medical therapy typi- Diazoxide (Proglycem) is a benzothiadiazide diuretic that inhibits
cally involves nonspecific antihormonal therapy. Antihormonal insulin secretion, stimulates hepatic gluconeogenesis and glyco-
therapy is palliative and should minimize hypoglycemia by pro- genolysis, and inhibits tissue use of glucose. The net effect is the
viding a continuous source of glucose from the gastrointestinal development of hyperglycemia. Diazoxide does not inhibit insu-
tract (frequent feedings), increasing hepatic glycogenolysis and lin synthesis and does not have cytotoxic (antineoplastic) effects.
gluconeogenesis (glucocorticoids), or inhibiting the synthesis, Diazoxide therapy can be initiated early in the medical treatment
secretion, or peripheral cellular actions of insulin (glucocorticoids, of a beta-cell tumor when the glucocorticoid dose is low and poly-
diazoxide, somatostatin). Antihormonal therapy consists primar- uria and polydipsia are acceptable to the client or can be initiated
ily of frequent feedings and glucocorticoids (see Box 9-7). Surgi- later when glucocorticoids are no longer effective in controlling
cal debulking of functional masses may enhance the effectiveness clinical signs of hypoglycemia or the severity of polyuria and poly-
of medical therapy. The best results are obtained when surgical dipsia has become unacceptable to the client. In the later situa-
debulking is performed shortly after the diagnosis of an insulin- tion, glucocorticoids should be continued but at a lower dose. The
secreting tumor has been established, although we have had a few initial dosage of diazoxide is 5 mg/kg by mouth every 12 hours.
The dosage may gradually be increased as needed to control signs receptors have been identified in humans (Patel, 1999). These sub-
of hypoglycemia but should not exceed 60 mg/kg/day. Thiazide types show a tissue-specific distribution and differences in affinity
diuretics may potentiate the effects of diazoxide. The two drugs for somatostatin and its analogs (Bruns etal, 1994). In humans,
can be administered together to enhance hyperglycemic effects if some insulin-secreting tumors have receptor subtypes that do not
diazoxide alone is not effective. The dosage of hydrochlorothiazide or only minimally bind octreotide, resulting in minimal to no
is 1 to 2 mg/kg by mouth every 12 hours. effect by the analog on serum insulin and glucose concentrations
The goal of diazoxide therapy is to establish a dosage at which (Lamberts etal, 1991; 1996). Autoradiography performed in dogs
hypoglycemia and its clinical signs are reduced or absent. In addi- with insulin-secreting neoplasia suggests the presence of only one
tion, the dosage should be low enough to avoid hyperglycemia somatostatin receptor (sst2 receptors) in canine insulin-secreting
(blood glucose concentrations > 180 mg/dL; 10 mmol/L) and its tumors (Robben etal, 1997). The somatostatin receptor identified
associated clinical signs. Reports of diazoxide use have appeared in canine insulin-secreting tumors contains high-affinity binding
in the veterinary literature only sporadically (Leifer et al, 1986; sites for octreotide and the radiopharmaceutical pentetreotide (see
Feldman and Nelson, 1987). Thirteen of 17 dogs with an insulin- Scintigraphy). In that study, baseline plasma insulin concentra-
secreting tumor in our series had a good clinical response, lasting tions, although varying widely, decreased significantly in all 10
6 weeks to 20 months. In another report, nine of 14 dogs had a dogs after octreotide administration. Unfortunately, octreotide is
good response to diazoxide therapy (Leifer etal, 1986). extremely expensive, must be administered by injection, has a rela-
The most common adverse reactions to diazoxide administra- tively short (< 6 hours) suppressive effect on serum insulin con-
tion are anorexia and vomiting. Administering diazoxide with a centrations in some dogs, clinical response to octreotide treatment
meal or decreasing the dosage, at least temporarily, is usually effec- is unpredictable, and some dogs that initially respond become
tive in controlling adverse gastrointestinal signs. Other potential refractory to octreotide treatment (Lothrop, 1989). Nevertheless,
complications include diarrhea, tachycardia, bone marrow sup- octreotide (10 to 40 g SC twice or three times per day) is well
pression, aplastic anemia, thrombocytopenia, pancreatitis, diabe- tolerated and can be used for the management of both acute and
tes mellitus, cataracts, and sodium and fluid retention (Feldman chronic hypoglycemia in some dogs with insulin-secreting neo-
and Nelson, 1987). Diazoxide is metabolized in the liver, and plasia. Adverse reactions have not been reported at these dosages.
the metabolites are excreted via the kidneys and biliary system. Streptozotocin. Streptozotocin is a naturally occurring nitro-
Adverse reactions or complications may develop more rapidly or sourea that is similar in structure to glucose and is taken up by
at a lower dosage of diazoxide in a dog with concurrent hepatic the GLUT-2 transmembrane carrier protein but not by other glu-
dysfunction. cose transporters (Schnedl et al, 1994). Because pancreatic beta
cells have high concentrations of GLUT-2 transporters, strepto-
Somatostatin Therapy zotocin selectively destroys pancreatic beta cells by depressing the
Octreotide (Sandostatin) is an analog of somatostatin that inhibits pyridine nucleotides nicotinamide adenine dinucleotide (NAD)
the synthesis and secretion of insulin by normal and neoplastic and reduced nicotinamide adenine dinucleotide (NADH). Two
beta cells. IV administration of octreotide can rapidly decrease the dogs with confirmed hyperinsulinism were treated with strepto-
serum insulin concentration, causing a corresponding increase in zotocin by Meyer in the 1970s. The first dog developed neph-
the serum glucose concentration in dogs with insulin-secreting rotoxicosis and was euthanized 3 weeks after a single treatment
neoplasia (Robben etal, 1997; Fig. 9-14). The inhibitory actions with streptozotocin at a dosage of 1000 mg/kg body weight given
of octreotide on insulin secretion can be maintained for several intravenously over a 1-minute period. The second dog developed
hours with subcutaneous administration (Fig. 9-15). The respon- temporary remission of hypoglycemia that lasted approximately
siveness of insulin-secreting tumors to the suppressive effects of 50 days after two treatments with streptozotocin at a dosage of
octreotide varies and depends on the presence of membrane recep- 500 mg/m2 given intravenously over a 30-second period. The
tors on the tumor cells that bind somatostatin (Lamberts et al, treatments were given 1 week apart, and mannitol was infused for
1990; Simpson etal, 1995). To date, five subtypes of somatostatin 20 minutes before and after each streptozotocin treatment. The
200 50
160 40
Serum insulin (U/mL)
Serum insulin (U/mL)
120 30
80 20
40 10
0 0
0 10 20 30 0 2 4 6 8
Time (minutes) Time (hours)
FIGURE 9-14 Mean ( SD) serum insulin concentration prior to and after intra- FIGURE 9-15 Serum insulin concentration prior to and after subcutaneous (SC)
venous (IV) administration of 100 g of octreotide in six dogs with an insulin- administration of 20 g of octreotide to a dog with an insulin-secreting islet cell
secreting islet cell tumor. Arrow, Octreotide administration; hatched area, normal tumor. Arrow, Octreotide administration; hatched area, normal range for fasting
range for fasting serum insulin concentration. serum insulin concentration.
|
dog developed a nephropathy and hepatopathy after a third treat- of hypoglycemia, detection of local recurrence or metastasis, or
ment administered at day 97 and was euthanized shortly there- death because of any cause, was 196 days (range, 20 to 840 days).
after. As a result of these clinical reports, streptozotocin was not Response rate to streptozotocin could not be determined from
considered a viable treatment for insulin-secreting tumors in dogs. the results of this study because there was no control group of
In 2002, Moore and colleagues described a fluid diuresis pro- dogs with comparable metastatic or nonresectable insulinoma that
tocol that allowed streptozotocin to be administered to dogs with were not treated, and survival times in the streptozotocin-treated
insulin-secreting tumors with a minimum of adverse reactions. dogs were confounded by concurrent symptomatic therapy, use of
Fluid diuresis has been reported to ameliorate the renal toxic- other cytotoxic therapies, and owner decision to euthanize. Bell,
ity of streptozotocin in humans, presumably as a result of less etal., (2005) reported on a Springer Spaniel treated with gluco-
contact time between the drug and the renal tubular epithelium corticoids and one treatment of streptozotocin for metastatic insu-
(Tobin et al, 1987; Kintzel, 2001). In Moores study, diuresis linoma that subsequently developed diabetes mellitus. The dog
with 0.9% sodium chloride at a rate of 18.3 mL/kg/hr adminis- was euthanized 118 days after streptozotocin treatment because of
tered through a peripherally located over-the-needle catheter was cervical pain caused by metastasis of the tumor.
performed for 7 hours. Streptozotocin (Zanosar) was adminis- In our experience, the effectiveness of streptozotocin in improv-
tered over a 2-hour period beginning 3 hours after initiation of ing hypoglycemia, controlling clinical signs, and prolonging
the saline diuresis. The dose of streptozotocin (500 mg/m2) was survival time has been unpredictable and adverse events to strep-
diluted in an appropriate volume of 0.9% saline to maintain tozotocin (severe vomiting, acute pancreatitis, potentially severe
the same rate of fluid administration for 2 hours. Saline diuresis kidney injury) are common and can be life-threatening. A thor-
was continued at the same fluid rate for an additional 2 hours ough discussion of potential complications with streptozotocin
after completion of the streptozotocin administration. Butorph- treatment should always be undertaken with the owner prior to
anol (0.4 mg/kg IV) was given immediately after streptozotocin initiating treatment.
administration as an antiemetic. Streptozotocin treatments were Phenytoin.Phenytoin is an anticonvulsant that inhibits the
repeated at 3-week intervals until there was evidence of tumor release of insulin by beta cells and may also directly impair the
progression (i.e., increase in tumor size by greater than 50%), effects of insulin on peripheral tissues (Haemers and Rottiers,
recurrence of hypoglycemia, or streptozotocin-induced toxicity 1981). Unfortunately, phenytoin is not usually successful in
that required supportive treatment. controlling clinical signs of hypoglycemia. Only 30% of human
Fifty-eight treatments were administered to 17 dogs with an patients with hyperinsulinism showed any beneficial effects after
insulin-secreting tumor at variable times after surgery (Moore phenytoin administration (Haemers and Rottiers, 1981). Con-
etal, 2002). Sixteen of 17 dogs had metastatic disease. One dog current diazoxide administration is not recommended, because it
developed azotemia, several dogs developed increases in serum ala- results in a decrease in blood concentrations of phenytoin. Phe-
nine aminotransferase activity that appeared to resolve with ces- nytoin has not been critically evaluated in dogs with beta-cell
sation of treatment, and vomiting occurred in 18 (31%) of 58 neoplasia.
streptozotocin treatments and was occasionally severe. Two dogs Propranolol.Propranolol is a nonselective beta-adrenergic
developed diabetes mellitus after receiving five treatments; two blocking drug that has no intrinsic sympathomimetic activity. Its
of three dogs had rapid resolution of paraneoplastic peripheral potential usefulness in patients with beta-cell neoplasia probably
neuropathy; and two dogs had a measurable reduction in tumor involves its ability to block insulin secretion by beta cells. Insu-
size. Although the median survival time was longer in dogs treated lin secretion is stimulated by the beta-adrenergic nervous system.
with streptozotocin than in 15 control dogs with a similar stage of However, propranolol may also induce hypoglycemia by impair-
disease (163 versus 90 days, respectively), this difference was not ing hepatic gluconeogenesis and glycogenolysis, normally induced
statistically significant. The range for survival time was also similar by endogenous catecholamines. Propranolol has not been criti-
between the two groups of dogs (streptozotocin-treated dogs, 16 cally evaluated in dogs with beta cell neoplasia.
to 309 days; control dogs, 0 to 426 days).
Because myelosuppression was not observed in the Moore study,
Northrup, etal., (2013) investigated increasing dose intensity by 100
decreasing the interval between streptozotocin dosing from 3 to
2 week intervals. Nineteen dogs with residual, local, metastatic,
80
or recurrent insulinoma were treated with the streptozotocin and
Percentage alive
saline diuresis protocol described by Moore, et al., (2002) but

administered biweekly rather than once every 3 weeks. Treatment 60
was initiated after surgery for insulinoma or at the time of recur-
rence. The planned treatment protocol was five treatments per dog; 40
however, 13 dogs received fewer than five treatments (median, 3;
range, 1 to 4) primarily because of development of adverse events.
20
Adverse events occurred in all dogs and included nausea, anorexia,
acute emesis or regurgitation, diarrhea, increased liver enzyme
activity, renal tubular injury, and hypoglycemic collapse or sei- 0
zure during treatment. Mild to moderate gastrointestinal toxicity 0 200 400 600 800 1000 1200 1400
was the most common adverse event. Myelosuppression was not Survival time (days)
identified. Eight dogs developed diabetes mellitus and six of these FIGURE 9-16 Kaplan-Meier curve depicting overall survival of 19 dogs with in-
dogs subsequently died or were euthanized. Median survival time sulinoma treated with streptozotocin at 2-week intervals. The median survival
for the 19 dogs was 308 days (range, 20 to 1404 days; Fig. 9-16). time was 308 days (range, 20 to 1404 days). (From Northrup NC, etal.: Prospec-
Median progression-free survival time, defined as the number tive evaluation of biweekly streptozotocin in 19 dogs with insulinoma, J Vet Intern
of days from the first streptozotocin treatment until recurrence Med 27:483, 2013.)
PROGNOSIS INSULIN-SECRETING BETA-CELL TUMORS

IN CATS
Owing to the extremely high likelihood of malignancy in any dog
with an insulin-secreting tumor (greater than 95%), the long- Insulin-secreting beta-cell tumors are rare in cats with only a few
term prognosis is guarded to poor at best because beta-cell tumors single cat case reports in the literature (McMillan, 1985; OBrien
almost always metastasize. The disease-free interval and survival et al, 1990; Hawks et al, 1992; Kraje, 2003; Greene and Bright,
time are difficult to predict. Survival time depends partly on the 2008) and one additional report in which the beta-cell tumor was
owners willingness to treat the disease. Predictors of disease free an incidental finding at necropsy in a cat with ductal pancreatic ade-
interval and survival time in dogs with an insulin-secreting beta- nocarcinoma (Carpenter etal, 1987). We have seen only two cats
cell tumor include tumor size, TNM (tumor, node, and metasta- with beta-cell neoplasia during the past three decades, in contrast to
sis) stage, stromal fibrosis within the tumor, and the Ki67 index more than 150 dogs with the disease during the same time interval.
(Caywood etal, 1988; Buishand etal, 2010). Ki67 is a prolifera- The clinical characteristics of insulin-secreting beta-cell tumors in
tion marker expressed during the active phases of the cell cycle cats appear to be similar to those in dogs. To date, the disorder has
and absent in resting cells (Scholzen and Gerdes, 2000). The Ki67 affected aged cats, 12 to 17 years old. Interestingly, three cats have
index has been correlated with clinical outcome in humans with been Siamese. Immunohistochemical analysis of the beta-cell tumor
insulinoma (La Rosa etal, 2009). in a few of these cats has revealed multihormonal productivity, with
Tobin and colleagues (1999) reported median survival time insulin and chromogranin A being the most common peptides dem-
after diagnosis of 74 days (range, 8 to 508 days) and 381 days onstrated in the neoplastic cells (Kraje, 2003; Jackson etal, 2009).
(range, 20 to 1758) in dogs treated medically versus dogs that ini- Clinical signs result from the effects of hyperinsulinism and included
tially underwent surgery followed by medical treatment, respec- seizures, weakness, ataxia, lethargy, disorientation, and muscle twitch-
tively. Polton and colleagues (2007) reported median survival time ing. Hypoglycemia (blood glucose concentration < 60 mg/dL; 3.4
after diagnosis of 196 days (95% confidence interval [CI] 0 to 549 mmol/L) was documented in each cat, and an inappropriately
days) and 785 days (95% CI: 190 to 1380 days) in dogs treated increased blood insulin concentration was documented in four cats in
medically versus dogs that initially underwent surgery followed which insulin was measured. Abdominal ultrasound failed to identify
by medical treatment, respectively. The shorter survival time for a 1.5 to 2.0 cm pancreatic mass in one cat and a 0.4 cm pancreatic
dogs treated medically in the Tobin study was partly due to a more mass in another cat in which ultrasound was performed prior to sur-
severe stage of the disease at the time of diagnosis and the own- gery. A pancreatic mass was identified in five cats that underwent sur-
ers feelings of hopelessness, which translated into early acceptance gery, and hypoglycemia and clinical signs resolved in four of five cats
of euthanasia when clinical signs recurred. Polton, etal., (2007) after surgical excision of the mass. Four cats died or were euthanized
reported a median disease free interval of 496 days (95% CI: 302 4 weeks, 5 weeks, 18 months, and 2 years after surgery, and three of
to 690 days) in 19 dogs that underwent partial pancreatectomy. these four cats were hypoglycemic at the time of death. Necropsy in
The median disease free interval in 31 dogs that underwent partial one of these cats revealed metastasis to the liver and pancreatic lymph
pancreatectomy at Utrecht University was 244 days (range, 0 to nodes. One cat was alive with no clinical signs suggestive of recur-
1116 days) and survival time was 258 days (range, 1 to 1146) rence of the insulinoma 32 months after surgical removal of a solitary
(Tryfonidou etal, 1998). 0.4 cm pancreatic carcinoma (Greene and Bright, 2008).
The extent to which surgery can alter the prognosis depends Until more experience is gained with beta-cell neoplasia in cats,
on the clinical stage of the disease, most notably the extent of it seems prudent to approach this disorder in a manner similar to
metastatic lesions. In one multi-university study, dogs with that used for dogs. Beta-cell neoplasia should be included in the list
tumors confined to the pancreas (stage I) were normoglycemic for of differential diagnoses for persistent hypoglycemia in the older cat
a median of 14 months after surgery, whereas dogs with metasta- (see Box 9-4). The index of suspicion for beta-cell neoplasia should
sis to regional lymph nodes (stage II) or distant metastasis (stage be heightened after a thorough review of the history, physical exam-
III) were normoglycemic for a median of approximately 1 month ination, and results of clinicopathologic tests and diagnostic imag-
(Caywood etal, 1988). Dogs with stage I or stage II disease had a ing. However, as with the dog, failure to identify a pancreatic mass
median survival time of approximately 18 months, whereas those with abdominal ultrasound does not rule out a beta cell tumor. The
with stage III disease had a median survival time of less than 6 diagnosis should be confirmed by documentation of an inappro-
months. Approximately 50% of dogs with metastases to the liver priate serum insulin concentration despite the presence of hypo-
were dead by 6 months, and all were dead by 18 months from the glycemia (see Confirming the Diagnosis of an Insulin-Secreting
time of diagnosis. Beta-Cell Tumor: Serum Insulin Determination). Many commer-
In our experience, approximately 10% to 15% of dogs under- cially available radioimmunoassays for insulin work well in the dog
going surgery for an insulin-secreting tumor die or are euthanized but do not work in the cat (Lutz and Rand, 1993). It is imperative
at the time of or within 1 month of surgery because of severe that the radioimmunoassay used to measure feline insulin is vali-
metastatic disease, uncontrollable postoperative hypoglycemia, or dated for cats and that species specific reference ranges are available.
complications related to pancreatitis. An additional 20% to 25% Surgical exploration should be the initial treatment of choice
of dogs die or are euthanized within 6 months of surgery because for beta-cell neoplasia in the cat. However, the age of the cat,
of severe metastatic disease and recurrence of clinical hypoglyce- identification of metastatic disease using ultrasonography, or the
mia. The remaining 60% to 70% live beyond 6 months postop- existence of concurrent disease that increases the anesthetic risk
eratively, many beyond 1 year after surgery, before uncontrollable may warrant a more conservative medical approach in some cats.
hypoglycemia develops, resulting in death or necessitating eutha- Frequent feedings and prednisolone therapy have been effective
nasia. Additional surgery to debulk metastatic lesions may improve in controlling clinical signs of hyperinsulinism and should be the
the animals responsiveness to medical therapy and prolong the mainstay of medical therapy for chronic hypoglycemia. The use
survival time in some dogs that become nonresponsive to medi- of diazoxide has not been reported in the cat and is not recom-
cal treatment after the initial surgery. Some dogs with metastatic mended until its safety and dosing schedule have been investi-
disease do remarkably well (i.e., survive longer than 2 years) after gated in cats. Similarly, the efficacy of octreotide for the treatment
aggressive surgical debulking of the tumor and its metastases. of feline beta-cell neoplasia remains to be reported.
|
REFERENCES
Bagley RS, etal.: Hypoglycemia associ- Chastain CB: Endocrine and metabolic Fenner WR: Diseases of the brain. In Ettinger
ated with intraabdominal leiomyoma and systems. In Hoskins JD, editor: Veterinary SJ, Feldman EC, editors: Textbook of veteri
leiomyosarcoma in six dogs, J Am Vet Med pediatrics, Philadelphia, 1990, WB nary internal medicine, ed 4, Philadelphia,
Assoc 208:69, 1996. Saunders, p 249. 1995, WB Saunders, p 578.
Barreca A, etal.: Invitro paracrine regulation Chatziioannou A, etal.: Imaging and localization Fingeroth JM, Smeak DD: Intravenous methylene
of human keratinocyte growth by fibroblast- of pancreatic insulinomas, Clin Imaging blue infusion for intraoperative identification
derived insulin-like growth factors, J Cell 25:275, 2001. of pancreatic islet cell tumors in dogs. II.
Physiol 151:262, 1992. Chew DJ, etal.: Hyperglycemia and hypoglyce- Clinical trials and results in four dogs, J Am
Beaudry D, etal.: Hypoglycemia in four dogs mia. In Klenner WR, editor: Quick reference Anim Hosp Assoc 24:175, 1988.
with smooth muscle tumors, J Vet Intern to veterinary medicine, Philadelphia, Fingeroth JM, etal.: Intravenous methylene
Med 9:415, 1995. 1982, JB Lippincott, p 432. blue infusion for intraoperative identifica-
Bell R, etal.: Treatment of insulinoma in a Cohen M, etal.: Gastrointestinal leiomyosarcoma tion of parathyroid gland and pancreatic
springer spaniel with streptozotocin, J Sm in 14 dogs, J Vet Intern Med 17:107, islet cell tumors in dogs. I. Experimental
Anim Pract 46:247, 2005. 2003. determination of dose-related staining
Bellah JR, Ginn PE: Gastric leiomyosarcoma Cohen TA, etal.: Evaluation of six portable efficacy and toxicity, J Am Anim Hosp
associated with hypoglycemia in a dog, blood glucose meters for measuring blood Assoc 24:165, 1988.
J Am Anim Hosp Assoc 32:283, 1996. glucose concentration in dogs, J Am Vet Finotello R, etal.: Pancreatic islet cell tumor
Bergman PJ, etal.: Canine clinical peripheral Med Assoc 235:276, 2009. secreting insulin-like growth factor type-II
neuropathy associated with pancreatic islet Cohn LA, etal.: Assessment of five portable in a dog, J Vet Intern Med 23:1289,
cell carcinoma, Prog Vet Neurol 5:57, 1994. blood glucose meters, a point-of-care ana- 2009.
Boari A, etal.: Hypoglycemia in a dog with a lyzer, and color test strips for measuring Fischer JR, etal.: Glucagon constant-rate infu-
leiomyoma of the gastric wall producing an blood glucose concentration in dogs, J Am sion: a novel strategy for the management of
insulin-like growth factor IIlike peptide, Vet Med Assoc 216:198, 2000. hyperinsulinemic-hypoglycemic crisis in the
Eur J Endocrinol 132:744, 1995. Commens PJ, etal.: Interleukin-1 is a potent dog, J Am Anim Hosp Assoc 36:27, 2000.
Boyle PJ, Cryer PE: Growth hormone, cortisol, modulator of insulin secretion from Fischer KF, etal.: Hypoglycemia in hospitalized
or both are involved in defense against but isolated rat islets of Langerhans, Diabetes patients: causes and outcomes, N Engl J
are not critical to recovery from prolonged 36:963, 1987. Med 315:1245, 1986.
hypoglycemia in humans, Am J Physiol Cryer PE: Catecholamines, pheochromocy- Fyfe JC, etal.: Glycogen storage disease type IV:
260:E395, 1991. toma and diabetes, Diabetes Rev 1:309, inherited deficiency of branching enzyme
Braund KG, etal.: Insulinoma and subclinical 1993. activity in cats, Pediatr Res 32:719, 1992.
peripheral neuropathy in two dogs, J Vet Cryer PE: Hypoglycemia. In Melmed S, Polonsky Garden OA, etal.: Somatostatin receptor imaging
Intern Med 1:86, 1987. K, Larsen PR, Kronenberg HM, editors: invivo by planar scintigraphy facilitates
Breitschwerdt EB, etal.: Hypoglycemia in four Williams textbook of endocrinology, ed 12, the diagnosis of canine insulinomas, J Vet
dogs with sepsis, J Am Vet Med Assoc Philadelphia, 2011, Elsevier, p 1552. Intern Med 19:168, 2005.
178:1072, 1981. Cryer PE, Gerich JE: Glucose counterregula- Gerich J, etal.: Hypoglycemia unawareness,
Brix A, etal.: Glycogen storage disease type tion, hypoglycemia, and intensive insulin Endocr Rev 12:356, 1991.
Ia in two littermate Maltese puppies, Vet therapy in diabetes mellitus, N Engl J Med Gerich JE, etal.: Renal gluconeogenesis: its
Pathol 32:460, 1995. 313:232, 1985. importance in human glucose homeostasis,
Bruns C, etal.: Molecular pharmacology of Cryer PE, Polonsky KS, etal.: Glucose homeo Diabetes Care 24:382, 2001.
somatostatin receptor subtypes, Ann N Y stasis and hypoglycemia. In Wilson JD, edi- Giger U, etal.: Metabolic myopathy in canine
Acad Sci 733:138, 1994. tor: Williams textbook of endocrinology, ed 9, muscle-type phosphofructokinase deficiency,
Buetow PC, etal.: Islet cell tumors of the pan- Philadelphia, 1998, WB Saunders, p 939. Muscle Nerve 11:1260, 1988.
creas: clinical, radiological, and pathologic Das H, Hochberg FH: Metastatic neoplasms Greene SN, Bright RM: Insulinoma in a cat, J
correlation in diagnosis and localization, and paraneoplastic syndromes. In Goetz Sm Anim Pract 49:38, 2008.
Radiographics 17:453, 1997. CG, Pappert EJ, editors: Textbook of clini Gregory BL, etal.: Glycogen storage disease
Buishand FO, etal.: Evaluation of clinico- cal neurology, Philadelphia, 1999, WB type IIIa in curly-coated retrievers, J Vet
pathological criteria and the Ki67 index as Saunders, p 957. Intern Med 21:40, 2007.
prognostic indicators of canine insulinoma, DErcole AJ, etal.: Tissue concentrations Gritzmann N, etal.: CT in the differentiation of
Vet J 185:62, 2010. of somatomedin C: further evidence for pancreatic neoplasms-progress report, Dig
Buishand FO, etal.: Expression of insulin-like multiple sites of synthesis and paracrine or Dis 22:6, 2004.
growth factor-1 by canine insulinomas and autocrine mechanisms of action, Proc Natl Guedes AG, Rude EP: Effects of pre-operative
their metastases, Vet J 191:334, 2012. Acad Sci USA 81:935, 1984. administration of medetomidine on plasma
Buse JB, etal.: Type 2 diabetes mellitus. In de Bruijne JJ, etal.: Fat mobilization and insulin and glucose concentrations in
Melmed S, Polonsky K, Larsen PR, plasma hormone levels in fasted dogs, healthy dogs and dogs with insulinoma, Vet
Kronenberg HM, editors: Williams textbook Metabolism 30:190, 1981. Anaesth Analg 40:472, 2013.
of endocrinology, ed 12, Philadelphia, de Groot JW, etal.: Non-islet cell tumor- Haemers S, Rottiers R: Medical treatment of
2011, Elsevier, p 1371. induced hypoglycaemia: a review of the insulinoma, Acta Clin Belg 36:199, 1981.
Caceres AV, etal.: Helical computed tomographic literature including two new cases, Endocr Hambrook LY, Kudnig ST: Tumor thrombus
angiography of the normal canine pancreas, Relat Cancer 14:979, 2007. formation in two dogs with insulinoma, J
Vet Radiol Ultrasound 47:270, 2006. del Rey A, Besedovsky H: Interleukin 1 Am Vet Med Assoc 241:1065, 2012.
Carpenter JL, etal.: Tumors and tumorlike affects glucose homeostasis, Am J Physiol Hardy RM: Diseases of the liver and their treat-
lesions. In Holsworth J, editor: Diseases of 253:R794, 1987. ment. In Ettinger SJ, editor: Textbook of
the cat: medicine and surgery, Philadelphia, Edwards DF, etal.: Hypoglycemia and chronic veterinary internal medicine, ed 3, Phila-
1987, WB Saunders, p 406. renal failure in a cat, J Am Vet Med Assoc delphia, 1989, WB Saunders, p 1479.
Caywood DD, etal.: Pancreatic insulin-secreting 190:435, 1987. Hargrove DM, etal.: Adrenergic blockade does
neoplasms: clinical, diagnostic, and Feldman EC, Nelson RW: Canine and feline en not abolish elevated glucose turnover
prognostic features in 73 dogs, J Am Anim docrinology and reproduction, Philadelphia, during bacterial infection, Am J Physiol
Hosp Assoc 24:577, 1988. 1987, WB Saunders. 254:E16, 1988a.
Hargrove DM, etal.: Adrenergic blockade Lamberts S, etal.: Parallel invivo and invitro Minkus G, etal.: Canine neuroendocrine tu-
prevents endotoxin-induced increases detection of functional somatostatin mors of the pancreas: a study using image
in glucose metabolism, Am J Physiol receptors in human endocrine pancreatic analysis techniques for the discrimina-
255:E629, 1988b. tumors: consequences with regard to tion of metastatic versus nonmetastatic
Hawkins KL, etal.: Immunocytochemistry of diagnosis, localization and therapy, J Clin tumors, Vet Pathol 34:138, 1997.
normal pancreatic islets and spontane- Endocrinol Metab 71:566, 1990. Mokan M, etal.: Hypoglycemia unaware-
ous islet cell tumors in dogs, Vet Pathol Lamberts SJW, etal.: The role of somatostatin ness in IDDM, Diabetes Care 17:1397,
24:170, 1987. and its analogs in the diagnosis and treat- 1994.
Hawks D, etal.: Insulin-secreting pancreatic ment of tumors, Endocrinol Rev 12:450, Moore AS, etal.: Streptozotocin for treatment
(islet cell) carcinoma in a cat, J Vet Intern 1991. of pancreatic islet cell tumors in dogs: 17
Med 6:193, 1992. Lamberts SJW, etal.: Octreotide and related cases (1989-1999), J Am Vet Med Assoc
Heckmann JG, etal.: Hypoglycemic senso- somatostatin analogs in the diagnosis and 221:811, 2002.
rimotor polyneuropathy associated with treatment of pituitary disease and soma- Murphy LA, Coleman AE: Xylitol toxicosis in
insulinoma, Muscle Nerve 23:1891, tostatin receptor scintigraphy, Neuro dogs, Vet Clin N Am Small Anim 42:307,
2000. endocrinology 14:27, 1993. 2012.
Hooper AN, Roberts BK: Fanconi syndrome in Lamberts SWJ, etal.: Somatostatin analogs: Naylor JM, Kronfeld DS: Invivo studies of hy-
four non-basenji dogs exposed to chicken future directions, Metabolism 45:104, poglycemia and lactic acidosis in endotoxic
jerky treats, J Amer Anim Hosp Assoc 1996. shock, Am J Physiol 248:E309, 1985.
47:178, 2011. Leifer CE, etal.: Insulin-secreting tumor: Niessen SJM: Glucagon: are we missing a
Iseri T, etal.: Dynamic computed tomography diagnosis and medical and surgical (life-saving) trick? J Vet Emerg Crit Care
of the pancreas in normal dogs and in management in 55 dogs, J Am Vet Med 22:523, 2012.
a dog with pancreatic insulinoma, Vet Assoc 188:60, 1986. Northrup NC, etal.: Prospective evaluation of
Radiol Ultrasound 48:328, 2007. Lester NV, etal.: Scintigraphic diagnosis of biweekly streptozotocin in 19 dogs with in-
Jackson TC, etal.: Cellular and molecular insulinoma in a dog, Vet Radiol Ultra sulinoma, J Vet Intern Med 27:483, 2013.
characterization of a feline insulinoma, sound 40:174, 1999. berg J, etal.: Validation of a species-
J Vet Intern Med 23:383, 2009. Loftin EG, Herold LV: Therapy and outcome optimized enzyme-linked immunosorbent
Jeffery ND, etal.: Letter to the editor, Prog of suspected alpha lipoic acid toxicity in assay for determination of serum concen-
Vet Neurol 5:135, 1994. two dogs, J Vet Emerg Crit Care 19:501, trations of insulin in dogs, Vet Clin Path
Karam JH: Hypoglycemic disorders. In 2009. 40:66, 2011.
Greenspan FS, Gardner DG, editors: Lothrop CD: Medical treatment of neuroen- OBrien TD, etal.: Canine pancreatic endocrine
Basic and clinical endocrinology, ed 6, docrine tumors of the gastroenteropan- tumors: Immunohistochemical analysis of
New York, 2001, Lange Medical Books/ creatic system with somatostatin. In Kirk hormone content and amyloid, Vet Pathol
McGraw-Hill, p 699. RW, editor: Current veterinary therapy 24:308, 1987.
Kintzel PE: Anticancer druginduced kidney X, Philadelphia, 1989, WB Saunders, p OBrien TD, etal.: Pancreatic endocrine
disorders, Drug Safety 24:19, 2001. 1020. tumor in a cat: clinical, pathological, and
Kishnani PS, etal.: Isolation and nucleotide Lutz TA, Rand JS: Comparison of five com- immunohistochemical evaluation, J Am
sequence of canine glucose-6-phospha- mercial radioimmunoassay kits for the Anim Hosp Assoc 26:453, 1990.
tase mRNA: identification of mutation in measurement of feline insulin, Res Vet Sci Patel YC: Somatostatin and its receptor family,
puppies with glycogen storage disease 55:64, 1993. Front Neuroendocrinol 20:157, 1999.
type Ia, Biochem Mol Med 61:168, Madarame H, etal.: Retrospective study of Pickens EH, etal.: Unique radiographic appear-
1997. canine insulinomas: eight cases (2005- ance of bone marrow metastasis of an
Kishnani PS, etal.: Canine model and genomic 2008), J Vet Med Sci 71:905, 2009. insulin-secreting beta-cell carcinoma in a
structural organization of glycogen storage Mai W, Caceres AV: Dual-phase computed dog, J Vet Intern Med 19:350, 2005.
disease type Ia (GSD Ia), Vet Pathol tomographic angiography in three dogs Polton GA, etal.: Improved survival in a retro-
38:83, 2001. with pancreatic insulinoma, Vet Radiol spective cohort of 28 dogs with insuli-
Kraje AC: Hypoglycemia and irreversible Ultrasound 49:141, 2008. noma, J Sm Anim Pract 48:151, 2007.
neurologic complications in a cat with in- McMillan F: Functional pancreatic islet cell Reubi J, etal.: Somatostatin receptor sst1-sst5
sulinoma, J Am Vet Med Assoc 223:812, tumor in a cat, J Am Anim Hosp Assoc expression in normal and neoplastic human
2003. 21:741, 1985. tissues using receptor autoradiography
Kruth SA, etal.: Insulin-secreting islet cell Mehlhaff CJ, etal.: Insulin-producing islet with subtype-selective ligands, Eur J Nucl
tumors: establishing a diagnosis and the cell neoplasms: surgical considerations Med 28:836, 2001.
clinical course of 25 dogs, J Am Vet Med and general management in 35 dogs, Robben JH, etal.: Invitro and invivo detec-
Assoc 181:54, 1982. J Am Anim Hosp Assoc 21:607, 1985. tion of functional somatostatin receptors
Kudo M, Noguchi T: Immunoreactive myelin Mellanby RJ, Herrtage ME: Insulinoma in in canine insulinomas, J Nucl Med
basic protein in tumor cells associated a normoglycaemic dog with low serum 38:1036, 1997.
with carcinomatous neuropathy, Am J Clin fructosamine, J Sm Anim Pract 43:506, Robben JH, etal.: Comparison of ultrasonog-
Pathol 84:741, 1985. 2002. raphy, computed tomography, and single-
Kvols LK, etal.: Evaluation of a radio-labeled Meszaros K, etal.: Increased uptake and photon emission computed tomography for
somatostatin analog (I-123 octreotide) in phosphorylation of 2-deoxyglucose by the detection and localization of canine
the detection and localization of carcinoid skeletal muscles in endotoxin-treated insulinoma, J Vet Intern Med 19:15,
and islet cell tumors, Radiology 197:129, rats, Am J Physiol 253:E33, 1987. 2005.
1993. Meszaros K, etal.: Invivo glucose utilization Rossi G, etal.: Paraneoplastic hypoglycemia
La Rosa S, etal.: Improved histologic and by individual tissues during nonlethal in a diabetic dog with an insulin growth
clinicopathologic criteria for prognostic hypermetabolic sepsis, FASEB J 2:3083, factor-2-producing mammary carcinoma,
evaluation of pancreatic endocrine tumors, 1988. Vet Clin Path 39:480, 2010.
Human Path 40:30, 2009. Meyer C, etal.: Effects of autonomic neuropa- Rothman DL, etal.: Quantitation of hepatic
Lamb CR, etal.: Ultrasonography of pancreatic thy on counterregulation and awareness of glycogenolysis and gluconeogenesis in
neoplasia in the dog: a retrospective review hypoglycemia in type 1 diabetic patients, fasting humans with 13C NMR, Science
of 16 cases, Vet Rec 137:65, 1995. Diabetes Care 21:1960, 1998. 254:573, 1991.
|
Schnedl WJ, etal.: STZ transport and cytotoxi Smith BF, etal.: Molecular basis of canine Van Hoe L, etal.: Helical CT for the preopera-
city; specific enhancement of GLUT2- muscle type phosphofructokinase defi- tive localization of islet cell tumors of the
expressing cells, Diabetes 43:1326, 1994. ciency, J Biol Chem 271:20070, 1996. pancreas: value of arterial and paren-
Scholzen T, Gerdes J: The Ki-67 protein: from Stumvoll M, etal.: Uptake and release of glucose chymal phase images, Am J Roentgenol
the known and the unknown, J Cell Physiol by the human kidney: postabsorptive rates 165:1437, 1995.
182:311, 2000. and responses to epinephrine, J Clin Invest Walvoort HC, etal.: Comparative pathology
Schrauwen E, etal.: Peripheral polyneuro 96:2528, 1995. of the canine model of glycogen storage
pathy associated with insulinoma in the Thompson MF, etal.: Acquired proximal renal disease type II (Pompes disease), J Inherit
dog: clinical, pathological, and electro tubulopathy in dogs exposed to a common Metabl Dis 8:38, 1985.
diagnostic features, Prog Vet Neurol dried chicken treat: retrospective study Wess G, Reusch C: Evaluation of five portable
7:16, 1996. of 108 cases (2007-2009), Aust Vet J blood glucose meters for use in dogs, J Am
Service FJ: Hypoglycemic disorders, N Engl J 91:368, 2013. Vet Med Assoc 216:203, 2000.
Med 332:1144, 1995. Thorens B, Mueckler M: Glucose transporters Whipple AO, Grantz VK: Adenoma of islet cells
Shahar R, etal.: Peripheral neuropathy in a in the 21st century, Am J Physiol Endocrinol with hyperinsulinism: a review, Ann Surg
dog with functional islet B-cell tumor and Metab 298:E141, 2010. 101:1299, 1935.
widespread metastasis, J Am Vet Med Assoc Tobin MV, etal.: Forced diuresis to reduce Zeugswetter FK, etal.: Metabolic and hormonal
187:175, 1985. nephrotoxicity of streptozocin in the treat- responses to subcutaneous glucagon in
Sherwin RS, Felig P: Hypoglycemia. In Felig P, ment of advanced metastatic insulinoma, healthy beagles, J Vet Emerg Crit Care
etal.: Endocrinology and metabolism, New Br Med J 294:1128, 1987. 22:558, 2012.
York, 1981, McGraw-Hill, p 869. Tobin RL, etal.: Outcome of surgical versus Zini E, etal.: Paraneoplastic hypoglycemia
Simpson KW, etal.: Evaluation of the long- medical treatment of dogs with beta-cell due to an insulin-like growth factor type-II
acting somatostatin analogue octreotide neoplasia: 39 cases (1990-1997), J Am secreting hepatocellular carcinoma, J Vet
in the management of insulinoma in three Vet Med Assoc 215:226, 1999. Intern Med 21:193, 2007.
dogs, J Small Anim Pract 36:161, 1995. Tryfonidou MA, etal.: A retrospective evaluation Zini E, etal.: Evaluation of a new portable
Slye M, Wells HG: Tumor of islet tissue with of 51 dogs with insulinoma, Vet Quart glucose meter designed for use in cats,
hyperinsulinism in a dog, Arch Pathol 20:114, 1998. Schweiz Arch Tierheilkd 151:448, 2009.
19:537, 1935. Van Ham L, etal.: Treatment of a dog with an
Smeak DD, etal.: Intravenous methylene insulinoma-related peripheral polyneuro
blue as a specific stain for primary and pathy with corticosteroids, Vet Rec 141:98,
metastatic insulinoma in a dog, J Am Anim 1997.
Hosp Assoc 24:478, 1988.

SECTION 4 THE ADRENAL GLAND
CHAPTER 10 Canine Hyperadrenocorticism

Ellen N. Behrend
CHAPTER CONTENTS Sudden Acquired Retinal Degeneration Syndrome, 394

Regulation of Glucocorticoid Secretion, 378 Blindness, 394
Corticotropin-Releasing Hormone, 378 Acute Weakness Due to Non-Traumatic Rupture of an Adrenal Mass, 394
Adrenocorticotropic Hormone, 378 Central Nervous System Signs, 394
Dopamine, 379 Routine Blood and Urine Evaluation, 395
Steroids, 380 General Approach, 395
Pathology and Pathophysiology, 381 Complete Blood Count, 395
Pituitary-Dependent Hyperadrenocorticism, 381 Serum Biochemical Profile, 396
Hyperadrenocorticism Due to Adrenal Tumor, 383 Urinalysis, 397
Ectopic Adrenocorticotropic Hormone Syndrome, 384 Complications Associated with Hyperadrenocorticism, 398
Adrenocortical Nodular Hyperplasia and Food-Dependent Urinary Crystals and Calculi, 398
Hyperadrenocorticism, 385 Hypertension, 398
Simultaneous Pituitary-Dependent and Adrenal-Dependent Hypothyroidism, 398
Hyperadrenocorticism, 385 Diabetes Mellitus, 398
Signalment, 385 Gallbladder Mucocele, 398
Age, 385 Pulmonary Thromboembolism, 399
Gender, 385 Specific Evaluation of the Pituitary-Adrenocortical Axis, 399
Breed/Body Weight, 385 Screening Tests: Confirming a Diagnosis of Hyperadrenocorticism, 400
History, 385 Sensitivity and Specicity, 400
Items of Importance Not in the History, 386 Special Considerations, 400
General Review, 386 Urine Cortisol-to-Creatinine Ratio, 401
Polyuria and Polydipsia, 386 Adrenocorticotropic Hormone Stimulation Test, 402
Appetite, 388 Low-Dose Dexamethasone Suppression Test, 404
Abdominal Enlargement, 388 Combined Dexamethasone Suppression/Adrenocorticotropic Hormone
Muscle Weakness and Lethargy, 388 Stimulation Test, 405
Cutaneous Markers, 389 Tests Not Recommended as Screening Tests, 405
Obesity, 391 Differentiating Pituitary-Dependent Hyperadrenocorticism and
Respiratory Signs, 392 Adrenocortical Tumor, 405
Reproductive Abnormalities, 392 Suppression Tests, 406
Myotonia (Pseudomyotonia), 392 Endogenous Adrenocorticotropic Hormone Measurement, 407
Facial Paralysis, 393 Corticotropin-Releasing Hormone and Vasopressin Response Testing, 409
Physical Examination, 393 Diagnostic Imaging, 409
General Review, 393 Radiography, 409
Hyperpigmentation, 393 Abdominal Ultrasonography, 410
Hepatomegaly, 393 Computed Tomography and Magnetic Resonance Imaging, 413
Gonadal and Sex HormoneRelated Alterations, 394 TreatmentGeneral Approach, 415
Ectopic Calcication, 394 To Treat or Not To Treat, 417
Bruisability, 394 Therapy Without Dening the Underlying Cause, 417
377
378 SECTION 4 THE ADRENAL GLAND
TreatmentSurgery, 417 Retinoic Acid, 436

Adrenalectomy, 417 Metyrapone and Aminoglutethimide, 436
Hypophysectomy, 421 TreatmentPituitary Irradiation, 436
TreatmentMedical Management Using Mitotane, 422 Spontaneous Remission of Hyperadrenocorticism, 437
Pituitary-Dependent Hyperadrenocorticism, 422 Primary Mineralocorticoid Excess: Primary Hyperaldosteronism, 438
Functioning Adrenocortical Tumors, 429 Unexpected Discovery of an Adrenal Mass, 439
TreatmentMedical Management with Trilostane, 431 Occult Hyperadrenocorticism, 441
TreatmentMedical Management with Ketoconazole, 434 Evidence for and Against the Existence of Occult
TreatmentOther Medications, 435 Hyperadrenocorticism as a Sex HormoneMediated Disease, 441
L-Deprenyl, 435 Indications for Diagnostic Testing, 443
Bromocriptine, 435 Treatment, 444
Cyproheptadine, 436
In 1932, Dr. Harvey Cushing described eight humans with a disorder biologic activity. Its primary function is to stimulate glucocorti-
that he suggested was the result of pituitary basophilism. Six of the coid secretion from the adrenal cortex. Stimulation of adrenocor-
eight humans had small, basophilic pituitary adenomas and clinical tical mineralocorticoid or sex hormone secretion is less important.
features of excess adrenocortical cortisol secretion. As other forms are During synthesis, ACTH is derived from a large precursor
now recognized for what was then considered a single condition, the molecule, pro-opiomelanocortin (POMC). In the pituitary cells
eponym Cushings syndrome is an umbrella term referring to the responsible for ACTH secretion (corticotrophs), POMC is syn-
constellation of clinical and chemical abnormalities that result from thesized and processed into smaller, biologically active fragments
chronic exposure to excessive concentrations of glucocorticoids (i.e., including -lipotropin (-LPH), melanocyte-stimulating hor-
hyperadrenocorticism [HAC]). Specifically, the term Cushings dis- mone (-MSH), -melanocyte-stimulating hormone (-MSH),
ease is applied to cases in which hypercortisolism occurs secondary -endorphin, and N-terminal fragment (Fig. 10-2). Two of the
to inappropriate excessive secretion of adrenocorticotropic hormone POMC fragments are contained within the structure of ACTH
(ACTH; corticotropin) by the pituitary (i.e., pituitary-dependent and, therefore, are byproducts of ACTH metabolism: -MSH is
hyperadrenocorticism [PDH]). Besides PDH, a pathophysiologic the first 13 amino acids of ACTH and corticotropin-like interme-
classication of HAC includes (1) autonomous secretion of cortisol diate lobe peptide (CLIP) is amino acids 18 to 39. Neither peptide
by an adrenocortical carcinoma or adenoma, (2) iatrogenic result- is secreted as a separate hormone in humans.
ing from exogenous glucocorticoid administration, (3) secretion of In dogs, CRH controls ACTH release (Kemppainen and Sar-
ACTH from an ectopic site (i.e., non-pituitary), (4) food-dependent tin, 1987; Kemppainen etal, 1992). Both CRH and ACTH are
cortisol secretion, and (5) pituitary hyperplasia caused by excess secreted in a pulsatile manner with a diurnal rhythm in humans
corticotropin-releasing hormone (CRH) secretion due to a hypotha- that results in a peak before awakening. Secretion of ACTH is epi-
lamic disorder and, secondarily, adrenocortical hyperplasia (which is sodic and pulsatile in healthy dogs and those with PDH (Kemp-
extremely rare in people and not yet reported in dogs or cats). painen and Sartin, 1984a; Kooistra et al, 1997a). A circadian
rhythm has not been convincingly demonstrated, although one
REGULATION OF GLUCOCORTICOID SECRETION study reported higher plasma ACTH concentrations in late after-
noon than in the morning (Castillo etal, 2009). Many types of
Corticotropin-Releasing Hormone stress (e.g., pain, trauma, hypoxia, acute hypoglycemia, cold expo-
sure, surgery, and inflammatory mediators) also stimulate ACTH
The hypothalamus, by secreting CRH into the hypophyseal por- secretion (Stewart, 2008).
tal system, exerts control over secretion of ACTH by the anterior The negative feedback effects of cortisol on the pituitary gland to
pituitary (pars distalis). In turn, ACTH stimulates adrenocortical diminish ACTH secretion occur within three time domainsfast,
secretion of cortisol. Cortisol completes the circle by inhibiting intermediate, and delayed. Fast feedback occurs within minutes in
secretion of hypothalamic and pituitary hormones (Fig. 10-1). response to a rising cortisol concentration. Intermediate feedback
The CRH-secreting neurons are located in the anterior por- occurs within 0.5 to 3 hours of cellular exposure to glucocorticoid
tion of the hypothalamic paraventricular nuclei. A polypeptide and is present until delayed feedback begins approximately 9 hours
containing 41 amino acid residues, CRH has a long plasma after glucocorticoid exposure (Phillips and Tashjian, 1982; Daya-
half-life (approximately 60 minutes). In humans, both arginine nithi and Antoni, 1989; Antoni and Dayanithi, 1990). Delayed
vasopressin and angiotensin II potentiate CRH secretion and, feedback appears to be mediated principally through suppression
in turn, ACTH; conversely, oxytocin inhibits CRH-mediated of the synthesis of both hypothalamic stimulatory peptides and
ACTH secretion. Roles for arginine vasopressin, oxytocin, and pituitary ACTH. Type II glucocorticoid receptors (GRs) in the
angiotensin II in regulating ACTH secretion have not been con- hypothalamus and pituitary likely interact with negative response
sistently demonstrated in dogs (Kemppainen and Sartin, 1987; elements in the gene for these peptides and decrease their transcrip-
Kemppainen etal, 1992). tion (Eberwine et al, 1987). Although negative feedback control
of ACTH secretion at the pituitary corticotroph within the inter-
mediate time domain is of fundamental biological (and potentially
Adrenocorticotropic Hormone
medical) importance, no one has yet ascertained how this process
ACTH is a 39 amino acid peptide hormone with a half-life in occurs. In addition to the negative feedback by adrenal steroid secre-
blood of approximately 10 minutes. The amino terminal end of tion, ACTH also exerts a negative feedback effect on (i.e., inhibits)
the ACTH molecule (amino acids 1 to 18) is responsible for its its own secretion (short loop feedback), as depicted in Fig. 10-1.
|
CHAPTER 10 Canine Hyperadrenocorticism 379
Stress Hypothalamus
Inhibits (e.g., physical,
emotional)
Stimulates
CRH
Dopamine
Pituitary
Exogenous
glucocorticoids
ACTH
Adrenal glands
Cortisol Aldosterone
FIGURE 10-1 The hypothalamic-pituitary-adrenal axis, il-

Liver Kidneys lustrating the various stimuli that enhance corticotropin-
releasing hormone (CRH) secretion as well as negative
feedback by cortisol at the hypothalamic and pituitary lev-
Major target organs els. ACTH, Adrenocorticotropic hormone.
Genome
mRNA
Pro-opiomelanocortin
N-terminal fragment (1131) ACTH (139) -LPH (191)
FIGURE 10-2 The processing of pro-opiomelanocortin (POMC) into

-MSH CLIP -LPH -Endorphin
its biologically active peptide hormones. -MSH, melanocyte-
(113) (1839) (158) (6191) stimulating hormone; -MSH, -melanocyte-stimulating hormone;
-LPH, -lipotropin; ACTH, adrenocorticotropic hormone; CLIP,
-MSH Met-Enk
corticotropin-like intermediate lobe peptide; mRNA, messenger
(4158) (6165) ribonucleic acid.
Dopamine
ACTH. The second population (B cells) stains strongly for ACTH
In humans and dogs, the pituitary gland is distinctly divided into and weakly for -MSH. The intense ACTH staining of pars inter-
an anterior section (pars distalis) and a posterior section (pars ner- media B cells is similar to the staining characteristics of ACTH-
vosa). However, dogs, unlike humans, also have a distinct area producing pars distalis cells (Halmi etal, 1981).
that separates the anterior and posterior lobes of the pituitary, the In comparison to regulation of the pars distalis, secretion of
pars intermedia or intermediate lobe (Halmi et al, 1981). The ACTH from the pars intermedia is under tonic negative regu-
pars intermedia has two distinct cell types. The predominant cells lation by dopamine secreted from the hypothalamic arcuate
(A cells) immunostain intensely for -MSH but weakly for nucleus, as well as by serotonin and CRH. Compared to the pars
TABLE 10-1 NOMENCLATURE OF Cholesterol

STEROIDOGENIC ENZYMES
Pregnenolone
ENZYME GENE SYMBOL TRIVIAL NAME
P450scc CYP11A1 Cholesterol side chain cleavage
enzyme
3- Hydroxysteroid HSD3B1 3-Hydroxysteroid dehydrogenase Progesterone
dehydrogenase HSD3B2
(3-HSD)
P450c17 CYP17 17-Hydroxylase; 17,20-lyase
P450c21 CYP21A2 21-Hydroxylase 11-Deoxycorticosterone
P450c11 CYP11B1 11-Hydroxylase
P450aldo
P450c11AS CYP11B2 P450aldo; aldosterone synthase;
corticosterone methyloxidase
Corticosterone
distalis, which is devoid of a nerve supply, the relatively avascular P450aldo

pars intermedia is innervated and controlled by dopaminergic and
serotoninergic bers from the brain (Peterson etal, 1982a). 18-Hydroxycorticosterone
Steroids P450aldo
Zones of the Adrenal Cortex and Their Products
The main hormones secreted by the adrenal cortex are cortisol, CH OH
2
corticosterone, and aldosterone. In dogs, cortisol and corticos-
terone are secreted in equal amounts. Histologically, the adrenal
cortex is composed of three zones: the zonae glomerulosa, fascicu- C=O
lata, and reticularis. Most adrenal steroidogenic enzymes belong O=CH
to the cytochrome P450 oxygenase family (Table 10-1). All zones HO
can synthesize and secrete corticosterone. However, due to enzy-
matic differences between the zona glomerulosa and the inner two
zones, the adrenal cortex functions as two separate units with dif-
fering regulation and secretory products.
The outer layer, the zona glomerulosa, produces aldosterone. It is
decient in 17-hydroxylase activity (CYP17), rendering the zone
incapable of making cortisol and sex hormones. In contrast, only
cells in the zona glomerulosa contain the enzyme necessary for syn-
thesizing aldosterone (i.e., aldosterone synthase) (Fig. 10-3).
O
The middle layer, the zona fasciculata, functions as a unit with the
innermost layer, the zona reticularis. The zona fasciculata, however,
secretes mostly glucocorticoids, and the zona reticularis secretes Aldosterone
mainly sex hormones. Due to the presence of 17-hydroxylase, FIGURE 10-3 Steroid biosynthesis in the zona glomerulosa. The steps from cho-
both zones can synthesize 17 -hydroxypregnenolone and lesterol to 11-deoxycorticosterone are the same as in the zona fasciculata and
17-hydroxyprogesterone, precursors of cortisol and sex hor- zona reticularis. Only the zona glomerulosa contains aldosterone synthase, which
mones (Fig. 10-4). catalyzes the conversion of 11-deoxycorticosterone to corticosterone and then to
18-hydroxycorticosterone and finally aldosterone.
Steroidogenesis
Cortisol, aldosterone, androgens, and estrogens are steroid
hormones; the precursor for all is cholesterol. Low-density Regulation of Cortisol Secretion
lipoprotein (LDL) particles account for approximately 80% Besides being a secretory factor, ACTH is also a trophic hormone
of cholesterol delivered to the adrenal glands. A small pool of for the zonae fasciculata and reticularis. Delivery of ACTH to the
free cholesterol is available within the glands for rapid response adrenal cortex leads to rapid synthesis and secretion of cortisol and
to stimulation. When stimulation occurs, hydrolysis of stored androgens. Plasma cortisol concentration increases within min-
cholesteryl esters to release cholesterol, cholesterol uptake from utes of ACTH administration. Chronic adrenocortical stimula-
plasma lipoproteins, and cholesterol synthesis also occurs within tion by elevated ACTH concentrations leads to hyperplasia and
the adrenal glands. The rate limiting-step in the production of hypertrophy; conversely, ACTH deciency results in adrenocorti-
adrenocortical steroid hormones is cholesterol transfer within cal atrophy and decreased steroidogenesis, adrenal gland weight,
mitochondria and is regulated by steroidogenic acute regula- and protein and nucleic acid content. Inflammatory mediators
tory protein (StAR). Virtually no steroids are stored within the (e.g., interleukin-1, interleukin-6, and tumor necrosis factor-)
adrenal glands; thus, synthesis is constant and secretion requires increase ACTH secretion either directly or by augmenting the
activation of the biosynthetic pathway. effect of CRH (Stewart, 2008).
|
CH3 5 P-450c17 CH3 6 P-450c17 7 Sulfokinase

Cholesterol C=O C=O O
OH DHEA
sulfate
1
17-Hydroxy-
Pregnenolone DHEA
P-450scc pregnenolone
HO CH3 HO CH3 HO
2 C=O C=O O
OH
3HSD/ISOM
17-Hydroxy- Androstenedione
Progesterone
progesterone
O CH2OH O CH2OH O
3 C=O C=O
OH
P-450c21
11-
11-Deoxycortisol
Deoxycorticosterone
O CH2OH O CH2OH
4 C=O C=O
HO HO OH
P-450c11
Corticosterone Cortisol
O O
FIGURE 10-4 Steroid biosynthesis pathway in the adrenal cortex. The branching pathways for glucocorticoids,
mineralocorticoids, and adrenal androgens and the structures of these steroids and their biosynthetic precursors
are shown. Names of the biosynthetic enzymes are shown in Table 10-1. DHEA, Dehydroepiandrosterone.
Regulation of Aldosterone Secretion capabilities and staining capacities of the laboratory performing
Regulation of aldosterone synthesis is primarily by the renin- the histologic examination; some tumors can be quite small. In
angiotensin system and serum potassium concentrations (see the authors experience, almost all dogs with PDH have a pituitary
Chapter 12). tumor. Functioning pituitary carcinomas occur rarely (Puente,
2003). Occasionally, more than one process may be present in the
pituitaryfor example, dogs with (1) two pituitary adenomas,
PATHOLOGY AND PATHOPHYSIOLOGY
each tumor apparently arising from a different pituitary lobe, or
(2) both a tumor and hyperplasia of the pituitary.
Pituitary-Dependent Hyperadrenocorticism
Approximately 71% to 80% of pituitary tumors arise in the pars
Pituitary Control, Feedback, and Cortisol Secretion distalis. The remaining tumors originate in the pars intermedia
In normal dogs, ACTH secretion is episodic. In dogs with PDH, (Peterson etal, 1982a; 1986a). Two types of pars intermedia tumors
typically both the frequency and amplitude of ACTH secretory exist: dexamethasone non-suppressible with disproportionately
bursts are increased. Chronic ACTH oversecretion drives excess elevated -MSH levels and relatively dexamethasone-suppressible
cortisol secretion and, eventually, adrenocortical hyperplasia. with normal to slightly elevated -MSH concentrations (Peterson
Dogs with HAC are exposed to more cortisol on a daily basis etal, 1986a). The two types appear to have identical clinical presen-
than healthy animals (Fig. 10-5), resulting in the clinical signs of tations; the cell type of origin has no known clinical significance.
HAC that are due to the effects of cortisol. Feedback inhibition
of ACTH secreted from a pituitary adenoma by physiologic or Microadenoma Versus Macroadenoma
excess levels of glucocorticoids is relatively ineffective (Fig. 10-6). Pituitary tumors less than 10 mm in diameter are classified as
If feedback inhibition of ACTH secretion by glucocorticoids microadenomas, whereas those more than 10 mm in diameter are
functioned normally, PDH would not evolve. classified as macroadenomas (Theon and Feldman, 1998). At the
time of diagnosis of PDH, 31% to 48% of dogs have tumors less
Incidence of Pituitary Tumors than 3 mm in diameter (Bertoy et al, 1995; Wood et al, 2007;
Eighty percent to 85% of dogs with naturally occurring HAC Auriemma etal, 2009).
have PDH (Feldman, 1983a; 1983b). The reported incidence of
histologically recognized pituitary tumors varies between 20% Pathology
and 100% (Peterson etal, 1982a; Feldman, 1983a; 1983b; McNicol, Histologic classication of endocrine tissue is challenging. It is
1987); the remainder of dogs reportedly has pituitary hyper- not unusual for pathologists to have difculty distinguishing
plasia. The variation in reported incidence may be due in part to between normal and hyperplastic tissue. It may also be difcult
the persistence of the pathologist, as well as the microdissection to distinguish diffuse hyperplasia from adenomas as well as some
7 16
Group I Dog 1
Group II 14
6 Dog 2
Group III
Plasma cortisol (g/dL)

12 Dog 3
5
10
4
8
3
6
2
4
1 2
0 0
8:00 9:00 10:00 11:00 Noon 1:00 2:00 3:00 4:00 8:00 9:00 10:00 11:00 Noon 1:00 2:00 3:00 4:00
A B
Time Time
7 10
Dog 1 Dog 1
6 Dog 2 Dog 2
8

Dog 3 Dog 3
5
6
4
3 4
2
2
1
0 0
8:00 9:00 10:00 11:00 Noon 1:00 2:00 3:00 4:00 8:00 9:00 10:00 11:00 Noon 1:00 2:00 3:00 4:00
C Time D Time
FIGURE 10-5 A, Mean plasma cortisol concentrations measured every 30 minutes for 8 hours in 15 normal dogs
(Group I), 30 dogs with pituitary-dependent hyperadrenocorticism (PDH) (Group II), and 18 dogs with hyperad-
renocorticism (HAC) secondary to an adrenocortical tumor (AT) (Group III). Demonstrating significant individual
variation in plasma cortisol concentrations over time are values from three healthy dogs (B), three dogs with PDH
(C), and three dogs with ATs (D).
adenomas from carcinomas. Thus, communication between cli- The histologic appearance of pars intermedia tumors is distinct
nician and pathologist, plus inclusion of laboratory and clinical from those of the pars distalis. Numerous colloid-filled follicles are
impressions, may help the pathologist. present. Nests of cells between the follicles are primarily chromo-
Grossly, larger adenomas often are attached to the base of the phobic, but occasional acidophilic or basophilic cells are present.
sella turcica but without invasion. As the diaphragma sellae is Adenomas that secrete ACTH have prominent groups of large
incomplete in dogs, pituitary growth occurs dorsad with invagina- corticotrophs with abundant eosinophilic cytoplasm interspersed
tion into the infundibular cavity and dilation of the infundibu- with variable numbers of smaller, more basophilic cells. Dense
lar recess and the third ventricle, with eventual compression or bands of fibrous connective tissue are occasionally interspersed
replacement of the hypothalamus. Larger neoplasms can have foci between the follicles and chromophobic cells. Compression and
of hemorrhage, necrosis, mineralization, and liquefaction. Due to invasion of the posterior pituitary is often present. If the tumor
the ACTH secretion, bilateral adrenal gland enlargement is pres- arises in the pars intermedia, the pars distalis is readily identifiable
ent. Nodules of yellow-orange cortical tissue can be found outside and sharply demarcated from the tumor. The pars distalis may
the adrenal capsule in the periadrenal fat and extending into the have compression atrophy (Capen, 2007).
adrenal medulla. The corticomedullary junction is irregular and
the medulla is compressed (Capen, 2007). Etiology of Pituitary-Dependent Hyperadrenocorticism
Histologically, pituitary corticotroph adenomas arising from the Two main theories exist regarding the pathogenesis of pituitary
anterior pituitary are composed of well-differentiated chromophobic tumors: (1) Excess stimulation by hypothalamic CRH secretion
cells supported by fine connective tissue septa (see Chapter 2). Secre- leading to corticotroph hyperplasia, and a somatic mutation of
tory cells are polyhedral to round. Secretory granules are not visible hyperplastic cells then leads to adenoma formation (i.e., the poly-
with standard light microscopy, but the cells will stain for ACTH and clonal theory), and (2) somatic mutation of a single corticotroph
MSH; secretory granules can be demonstrated by electron microscopy. leading to clonal expansion (i.e., the monoclonal theory) (Castillo
For tumors of the pars distalis, the demarcation between the neoplasm and Gallelli, 2010). The former is not widely believed; most pituitary
and pars distalis is often not distinct, and the pars distalis is either partly tumors are monoclonal in humans, and hyperplastic areas are not
replaced by the neoplasm or severely compressed (Capen, 2007). detected surrounding adenomas. In addition, it would be difcult
|
explain resistance of corticotrophic adenomas to negative gluco-

corticoid feedback allowing continued ACTH secretion.
( )
In humans and mice, the T-box transcription factor Tpit
(Tbx19) is a marker of corticotrophs and melanotrophs and is
Cortisol
Cortisol
ACTH
ACTH
necessary for POMC expression. Similarly, Tpit is expressed in
normal and adenomatous canine pituitary tissue. Using adenoma-
tous tissue from 14 dogs with PDH, the Tpit gene was screened
for a tumor-specific mutation (e.g., a gain-of-function mutation),
but none was identified. Interestingly, a missense polymorphism
Normal Adrenal cortical adenoma was discovered in the highly conserved DNA-binding domain
or carcinoma
for Tpit, the T-box, in one tumor sample, but the significance
Adenoma remains unknown (Hanson etal, 2008).
Hypothalamus
(?)
Leukemia inhibitor factor (LIF), a cytokine of the interleukin-6
family, activates the hypothalamic-pituitary axis and promotes
corticotroph differentiation. Most cells of the canine pars dista-
Cortisol
Cortisol
ACTH
ACTH
lis express LIF protein at low levels compared to rare cells in the
pars intermedia; co-localization with ACTH is partial. Expression
within 13 adenomas varied from high to almost undetectable. The
LIF receptor (LIFR) is co-expressed with ACTH in cells of the
Corticotroph adenoma, Idiopathic cortical pars intermedia and pars distalis. No mutations were identified in
adenohypophysis hyperplasia the LIFR gene of 14 corticotroph adenomas. Due to strong co-
localization of LIFR and ACTH within adenomas, the possibility
exists that LIFR pathway activation could play a role in tumor
( ) ( ) formation or progression (Hanson etal, 2010).
Activation of epithelial growth factor receptor (EGFR) occurs
Cortisol
Cortisol
ACTH
ACTH
Lung in a variety of human cancers, and epithelial growth factor (EGF)

is a pituitary cell growth factor. Expression of EGFR is variable
in canine pituitary corticotroph adenomas; however, for tumors
ACTH expressing EGFR, treatment of cells in vitro with gefitinib, a
+ +
tyrosine kinase inhibitor targeting the EGFR, decreased POMC
Iatrogenic
expression. Thus, the EGFR may play a role in POMC overex-
Ectopic ACTH secretion pression in some corticotroph adenomas (Fukuoka etal, 2011).
In humans, KI-67 and proliferating cell nuclear antigen
FIGURE 10-6 Multiple pathogenic mechanisms of cortisol excess in dogs. (In (PCNA) predict pituitary adenoma behavior and surgical out-
Maxie MG, editor: Jubb, Kennedy and Palmers pathology of domestic animals, come. The cell-cycle inhibitor p27kip1 is correlated with tumor
Philadelphia, 2007, Saunders, p. 339.) ACTH, Adrenocorticotropic hormone. recurrence after hypophysectomy. In one study in dogs, no signifi-
cant differences in Ki-67, PCNA, and p27kip1 labeling indices
for one hypothalamic disorder to account for tumors arising in both were found between enlarged and non-enlarged pituitaries (van
the pars distalis and pars intermedia, because regulation of the two Rijn etal, 2010). Ishino and colleagues did find greater expression
lobes is so different. Cerebrospinal fluid CRH concentrations are sig- of Ki-67 in larger adenomas (Ishino etal, 2011). However, expres-
nificantly lower in dogs with PDH than in healthy dogs (van Wijk sion of minichromosome maintenance-7 (MCM-7) was signifi-
et al, 1992). In addition, approximately 77% of dogs with PDH cantly higher than that of Ki-67 in canine pituitary corticotroph
have no recurrence following hypophysectomy (Hanson etal, 2007); adenomas. The MCM proteins are part of the DNA replication
tumor regrowth should be common if the underlying problem were system and may be potential markers of neoplastic cell prolifera-
hypothalamic because the pituitary would continue to be stimulated. tion. Due to the higher expression of MCM-7, it may be a better
Potential alterations in gene expression, oncogenes, and pro- proliferation marker than Ki-67 (Ishino etal, 2011).
liferation markers have been evaluated in canine corticotrophic
tumors. Within 10 pars distalis adenomas, expression of the genes Hyperadrenocorticism Due to Adrenal Tumor
for POMC, CRH receptor 1 (CRHR1), glucocorticoid receptor,
mineralocorticoid receptor (MR), and 11- hydroxysteroid dehy- Tumoral Secretion
drogenase (11-HSD) type 1 and type 2 were determined. The Primary adrenocortical tumors (ATs), both adenomas and carci-
messenger ribonucleic acid (mRNA) levels for POMC, CRHR1, nomas, develop autonomously. Functioning, cortisol-secreting
and 11-HSD2 were significantly increased approximately ATs secrete excessively, independent of pituitary control and in an
fourfold to fivefold, and for MR and 11-HSD1 they were episodic and random manner (see Fig. 10-5). Uncommonly, cor-
significantly decreased approximately twofold to threefold in tisol intermediates (e.g., desoxycorticosterone and corticosterone)
adenomatous tissue compared with normal corticotrophic cells. are secreted (Reine etal, 1999; Behrend etal, 2004; Machida etal,
The GR mRNA levels did not differ between adenomatous and 2007; Davies etal, 2008; Frankot etal, 2012). Due to negative
normal corticotrophic cells (Teshima etal, 2009). The enzymes feedback by cortisol or its intermediates, which can possess glu-
11-HSD1 and 11-HSD2 are responsible for the conversion of cocorticoid activity, hypothalamic CRH and circulating ACTH
inactive cortisone to active cortisol and vice versa, respectively, concentrations are suppressed along with other POMC peptides
and help regulate glucocorticoid action. High expression of 11- (except -MSH) (Peterson et al, 1986a). With low systemic
HSD2 with low 11-HSD1 expression would lead to inactiva- ACTH concentrations, the contralateral adrenal cortex and the
tion of cortisol within tumor cells, which could, at least in part, normal cells in the involved adrenal gland atrophy (see Fig. 10-6).
Pathology 11-hydroxylase (CYP11B1) was evaluated in cortisol-secreting adre-

Cortical adenomas are partially or completely surrounded by a nocortical adenomas and carcinomas. The expression of ACTH-R
fibrous connective tissue capsule, well-demarcated, and usually single. was significantly lower in carcinomas than in normal adrenal glands;
Larger adenomas are yellow to red, distort the glands external sur- thus, upregulation of steroidogenic enzymes is not responsible for
face, and are partially or completely encapsulated. Adjacent cortical hypercortisolemia, but significant downregulation of the ACTH-R
tissue is compressed, and the medulla may be invaded. Small adeno- might be associated with malignancy (Galac etal, 2010a). Functional
mas are more yellow and can be difficult to distinguish from areas of mutations were not identified in genes for ACTH-R or PRKAR1A
hyperplasia. Histologically, cortical adenomas are composed of well- in tissue from 14 adenomas and 30 carcinomas. In comparison, 32%
differentiated cells resembling those of the normal zonae fasciculata or of tumors (four adenomas and 10 carcinomas) had missense muta-
reticularis. The tumor cells are arranged in broad trabeculae or nests tions of GNAS; 11 were in codon 201, one in codon 203, and two in
separated by small vascular spaces. The cells have abundant cytoplasm codon 227. Activating mutations would increase signaling from the
and are often vacuolated. Focal areas of hematopoiesis, calcification, receptor and, as a result, cortisol synthesis and secretion. Additional
or fat cell accumulation may be present (Capen, 2007). invitro assays are necessary to establish a causal relationship between
Adrenal carcinomas are typically variegated, yellow-red, and fri- the mutations and tumor pathogenesis and whether the mutations
able. They are often fixed in location due to invasion of surround- are activating (Kool etal, 2013).
ing tissue, including the caudal vena cava. They are composed of One case resembling human Carney complex, a familial human
highly pleomorphic secretory cells that are subdivided into small syndrome characterized by cardiac myxoma and extracardiac tumors
groups by fibrovascular stroma of variable thickness. Tumor cells associated with mutations in the PKA regulator gene PRKAR1A,
are usually large and polyhedral with prominent nucleoli and has been reported. A 9-year-old female Golden Retriever had a left
densely eosinophilic or vacuolated cytoplasm. Areas of hemor- atrial ossifying myxosarcoma, bilateral adrenocortical adenomas,
rhage are common. The contralateral adrenal cortex is atrophied, multiple areas of pituitary hyperplasia with expression of ACTH,
consisting primarily of the adrenal capsule and zona glomerulosa. and multiple pituitary Rathke cleft cysts. Genetic mutations were
Atrophy may also be present in the remnants of the compressed not detected in PRKAR1A (Adissu etal, 2010).
adrenal cortex around the functional tumor (Capen, 2007). The presence of vasopressin receptors on canine cortisol-secreting
Adenomas and carcinomas can be difficult to distinguish in some AT has been theorized, because dogs with ACTH-independent
cases. Thorough evaluation of morphologic features combined with hypercortisolism can secrete cortisol in response to lysine vasopres-
immunohistochemical assessment of the proliferation index may be sin (LVP) administration (van Wijk etal, 1994). Quantitative poly-
useful. In one study, morphologic criteria significantly associated merase chain reaction (PCR) analysis of expression of receptors for
with carcinomas included being more than 2 cm in diameter, periph- luteinizing hormone (LH) and gastric inhibitory polypeptide (GIP)
eral fibrosis, capsular invasion, a trabecular growth pattern, hemor- and the vasopressin receptors V1a, V1b, and V2 in 23 cortisol-secreting
rhage, and necrosis; hematopoiesis, fibrin thrombi, and cytoplasmic AT did not find evidence of overexpression of any of the receptors as
vacuolation were significantly associated with adenomas. A Ki-67 compared with normal adrenocortical tissue as a whole (i.e., all three
proliferation index was significantly higher in carcinomas. Mitotic adrenocortical zones were evaluated together). However, GIP and V2
index is low in adenomas and carcinomas (Labelle etal, 2004). receptors were present in the zona fasciculata of approximately 50%
of the tumors; neither receptor was present in the zona fasciculata of
Bilateral Tumors normal adrenal tissue. Thus, the presence of GIP and V2 receptors in
HAC caused by bilateral adenomas, carcinomas, or a combination the zona fasciculata of an AT may play a role in the pathogenesis of a
of adenoma and carcinoma can occur (Ford et al, 1993; Hoerauf cortisol-secreting AT (Galac etal, 2010b).
and Reusch, 1999; Anderson et al, 2001; Kyles et al, 2003; Stenske
et al, 2005; Adissu et al, 2010). Although in a study of 15 dogs with
Ectopic Adrenocorticotropic Hormone Syndrome
HAC caused by functioning ATs, three (20%) had bilateral tumors
(Hoerauf and Reusch, 1999), the authors experience is that the In humans, the ectopic ACTH syndrome comprises a varying group
incidence of bilateral ATs is far lower. Pheochromocytomas and ATs of tumors, including oat cell (small cell) carcinoma of the lung, thy-
may uncommonly occur simultaneously with one tumor per adrenal moma, pancreatic islet cell tumors, carcinoid tumors, medullary car-
gland (Von Dehn etal, 1995; Thuroczy etal, 1998; Hylands, 2005). cinoma of the thyroid, and pheochromocytoma, which synthesize
The presentation can be confusing, because ultrasonography may and secrete ACTH (Stewart, 2008). The tumors most commonly
reveal bilateral adrenomegaly, and endocrine testing suggests an AT. associated with ectopic ACTH syndrome arise from neuroendocrine
tumors. Because ACTH production within the tumors is not typically
Etiology sensitive to glucocorticoid-mediated negative feedback, high doses of
Little is known about the pathogenesis of canine cortisol-secreting dexamethasone do not typically effect cortisol concentrations (i.e.,
AT. In normal tissue, steroidogenesis is initiated by ACTH bind- the tumors are dexamethasone-resistant). In addition, ectopic CRH
ing to its receptor (ACTH-R) on adrenocortical cells. Proteins secretion with or without ACTH can occur rarely (Stewart, 2008).
involved in the second messenger system for the ACTH-R are pro- Ectopic ACTH syndrome has potentially been reported in three
tein kinase A (PKA) regulatory subunit 1 alpha (PRKAR1A) and the dogs (Churcher, 1999; Galac etal, 2005; Burgener etal, 2007).
protein encoded by the stimulatory G protein alpha subunit gene In one, ACTH was purportedly secreted from a primary hepatic
(GNAS). The acute ultimate response to the binding of ACTH is carcinoid (Churcher, 1999), but both examination of pituitary
mediated by StAR, which enhances cholesterol transport to the site function and morphology as well as proof of ectopic ACTH secre-
of steroidogenesis. Alterations in expression of or mutations within tion were lacking. Second, HAC was diagnosed in a 5-year-old
genes for StAR, ACTH-R, steroidogenic enzymes, PRKAR1A, intact male Dachshund that had clinical signs consistent with
and GNAS could play a role in tumor pathogenesis. Expression HAC, a positive ACTH stimulation test, an elevated endogenous
of the genes for ACTH-R, StAR, cholesterol side-chain cleavage ACTH (eACTH) concentration, and bilateral adrenomegaly on
enzyme (CYPP11A), 17-hydroxylase (CYP17), 3- hydroxys- ultrasound (Burgener et al, 2007). A low-dose dexamethasone
teroid dehydrogenase (HSD3B2), 21-hydroxylase (CYP21), and suppression test (LDDST) was consistent with PDH. However,
|
empty sella syndrome, a herniation of the subarachnoidal space

Simultaneous Pituitary-Dependent and Adrenal-
into the sella turcica with invisible or reduced size of the pitu-
Dependent Hyperadrenocorticism
itary gland, was diagnosed by magnetic resonance imaging (MRI).
At necropsy, the pituitary was mainly fluid-filled. Although no Rarely, dogs can have a functioning AT and a pituitary tumor (and
non-pituitary tumor was found on necropsy, the lack of pituitary bilateral adrenocortical hyperplasia) (Thuroczy et al, 1998; Greco
tumor tissue makes PDH unlikely. Given that partial suppression etal, 1999). Endocrine evaluation of such dogs is diagnostic for HAC
in response to dexamethasone was seen (which is not typical of if the pituitary tumor is secreting ACTH and/or the adrenal tumor
ectopic ACTH syndrome), the possibility of false-positive test is secreting cortisol. However, tests to distinguish between pituitary-
results for HAC must be considered. dependent and AT HAC provide confusing or contradictory results.
The most convincing report is of an 8-year-old intact male
German Shepherd (Galac et al, 2005). Cortisol secretion was
SIGNALMENT
not suppressed by high doses of dexamethasone, abdominal
ultrasound revealed bilateral adrenomegaly, and eACTH con-
Age
centrations were elevated; thus, dexamethasone-resistant PDH
was believed to exist. Hypophysectomy was performed, but the HAC is a disease of middle-age and older dogs. The vast majority
clinical signs did not abate nor was a tumor found on histologic ( 89%) of dogs with PDH and those with functioning ATs are
examination of the pituitary gland. Ten months after surgery, older than 6 years of age (Ling etal, 1979; Gallelli etal, 2010).
abdominal computed tomography (CT) revealed a mass in the More than 75% of dogs with PDH are older than 9 years of age,
area of the pancreas and liver nodules. Histologic examination and the mean age is 8.6 to 11.7 years (Reusch and Feldman, 1991;
of the mass, regional lymph nodes, and liver nodules allowed a Kipperman et al, 1992; Bertoy et al, 1995; Ortega et al, 1996;
diagnosis of metastatic neuroendocrine tumor. Although immu- Wood etal, 2007; Gallelli etal, 2010; Lien etal, 2010: Bellumori
nohistochemistry of the tumor was negative for ACTH, lack of etal, 2013). Dogs with HAC caused by functioning AT tend to be
staining does not rule out the possibility of ectopic ACTH pro- older than those with PDH. In one study, 92.5% of 41 dogs with
duction (Galac etal, 2005). ATs were 9 years of age or older (mean age 11.1 2.3 years and
11.4 2.1 years for dogs with adrenal carcinoma and adenoma,
Adrenocortical Nodular Hyperplasia and Food-Dependent respectively) compared to 77% of 44 dogs with PDH (mean age
Hyperadrenocorticism 10.4 3.2 years); however, no significant difference was detected
between the two groups (Reusch and Feldman, 1991).
Macronodular, ACTH-dependent hyperplasia of the adrenals occurs
in 10% to 40% of people with bilateral adrenocortical hyperplasia.
Gender
One or more nodules are present and can be quite large. Some nod-
ules may become autonomous from ACTH (Stewart, 2008). Mac- A gender predisposition has not been proven, but a female predis-
ronodular hyperplasia also exists in dogs (Greco etal, 1999). In a position may exist. In multiple studies female dogs accounted for
retrospective study of dogs with HAC and concurrent pituitary and 63% to 76% of dogs (Reusch and Feldman, 1991; Bertoy et al,
adrenal tumors, measurement of eACTH concentration was con- 1995; Ortega etal, 1996; Wood etal, 2007; Gallelli etal, 2010).
sistent with PDH in 11 dogs, with ATs in two, and was non-diag- However, no statistical comparisons were made to a control popu-
nostic in two. Four dogs had bilateral adrenal adenomas, potentially lation to determine if females were truly overrepresented. In one
from transformation of macronodular hyperplasia to adenomas. study, a significant difference was not detected between the sex dis-
The pathogenesis of macronodular hyperplasia in dogs is unclear, tribution of dogs with HAC and the general population (Ling etal,
but, as in humans, it may represent a variant of PDH. However, 1979); however, only 53% of dogs with HAC were female. In con-
why some dogs would develop diffuse adrenocortical hyperplasia trast, females are not the majority in all studies (Hess etal, 1998).
and a minority develop nodular hyperplasia is unknown.
An ACTH-independent bilateral nodular adrenocortical hyper-
Breed/Body Weight
plasia occurs rarely in humans. Most cases are due to aberrant
receptor expression within the adrenal cortex. Food-induced Overall, HAC occurs equally in purebred and mixed breed dogs
hypercortisolism due to enhanced adrenal responsiveness to (Bellumori etal, 2013). Although numerous breeds are commonly
GIP was the first type recognized, but aberrant expression of the mentioned to be at increased risk, a statistical predisposition has
vasopressin V1, -adrenergic, LH, serotonin, and angiotensin-1 been proven only for Poodles (likely Miniature Poodles only),
receptors with resultant adrenal responsiveness have now been Boxers, and Dachshunds (Ling etal, 1979). Various terrier breeds,
documented (Stewart, 2008). especially Boston Terriers, Beagles, and German Shepherd dogs are
Although not due to adrenocortical nodular changes, an ACTH- often mentioned in studies. PDH and ATs have been diagnosed in
independent, food-dependent HAC has been described in one dog virtually every breed (Tables 10-2 and 10-3) with PDH tending
(Galac etal, 2007). The diagnosis was made due to a combination of to occur more frequently in smaller dogs and ATs in larger dogs.
(1) low plasma eACTH concentration in the absence of an AT, (2) at Approximately 75% of dogs with PDH weigh less than 20 kg; in
least a doubling in the urine cortisol-to-creatinine ratio (UC:CR) on comparison, almost 50% of dogs with ATs, either adenoma or
two occasions in response to food, and (3) prevention of the meal- carcinoma, weigh more than 20 kg (Reusch and Feldman, 1991).
induced increase in cortisol concentration by octreotide, which is a
diagnostic criteria for food-dependent HAC in humans. Because the
HISTORY
dog of the case report had bilateral adrenomegaly on ultrasound, the
low eACTH concentration was the means by which the etiology was Most articles outlining the clinical signs of HAC are at least
determined to not be PDH. Potentially more cases of ACTH-inde- 10 years old. Because of heightened awareness of HAC in the
pendent HAC exist than are recognized because eACTH measure- past 20 years, diagnosis is now likely made earlier in the course
ment is not always performed in the diagnosis of HAC. of the disease when clinical signs are fewer and subtler (Behrend
TABLE 10-2 B
REED DISTRIBUTION OF TABLE 10-4 CLINICAL MANIFESTATIONS
DOGS DIAGNOSED WITH OF CANINE
PITUITARY-DEPENDENT HYPERADRENOCORTICISM*
HYPERADRENOCORTICISM
(TOTAL: 750 DOGS)* COMMON LESS COMMON UNCOMMON
Polyuria/polydipsia Lethargy Bruising
PERCENTAGE NUMBER BREED
Polyphagia Hyperpigmentation Thromboemboli
16% 119 Poodles (various breeds)
Panting Comedones Ligament rupture
11% 84 Dachshunds
Abdominal distention Pyoderma Facial nerve palsy
10% 76 Terriers (various breeds)
Endocrine alopecia Thin skin Calcinosis cutis
7% 54 Beagles
Hepatomegaly Poor hair regrowth Pseudomyotonia
6% 48 German Shepherd dogs
Muscle weakness Urine dribbling Testicular atrophy
5% 38 Labrador Retrievers
Muscle wasting Insulin-resistant Persistent anestrus
5% 36 Australian Shepherd diabetes mellitus
4% 30 Maltese Systemic hypertension
4% 28 Spaniel (various breeds)
Modified from Behrend EN, etal.: Diagnosis of spontaneous canine hyperadrenocorticism:
3% 22 Schnauzer 2012 ACVIM consensus statement (Small animal),J Vet Int Med 27:1292, 2013.
3% 22 Lhasa Apso *Categorization of frequency is based on identification at the time of initial presentation.
2% 19 Chihuahua
2% 18 Boston terrier
2% 15 Golden Retrievers etal, 2013). Accordingly, the current prevalence of clinical signs is
likely less than published and not known.
2% 14 Shih Tzu
2% 12 Boxer
Items of Importance Not in the History
16% 115 Other breeds (38 breeds)
Canine HAC is likely overdiagnosed due to the multitude of clini-
*Note: Data are observational; significant breed predisposition not assessed. cal signs and occurrence of false-positive results on screening tests.
The primary indication for pursuing a diagnosis of HAC is the
presence of one or more of the common clinical signs and physical
examination findings (Behrend etal, 2013). Conversely, presence
of clinical signs not associated with HAC is a reason to not pursue
TABLE 10-3 B
REED DISTRIBUTION OF DOGS testing. Vomiting, diarrhea, coughing, sneezing, pain, or bleed-
DIAGNOSED WITH FUNCTIONING ing is not caused by HAC. Poor appetite and seizures are uncom-
ADRENOCORTICAL ADENOMA mon and, if related to HAC, are due to the presence of a pituitary
OR CARCINOMA CAUSING macroadenoma.
HYPERADRENOCORTICISM
(TOTAL: 102 DOGS)* General Review
Adult-Onset Hyperadrenocorticism
PERCENTAGE BREED
The clinical signs can be subtle or dramatic but usually progress
15% Poodles (various breeds) slowly. Uncommonly, clinical signs may be intermittent with
12% German Shepherd dogs periods of remission (Peterson et al, 1982b). Not all dogs with
11% Dachshunds HAC develop the same signs. Common signs include polydipsia,
polyuria, polyphagia, abdominal enlargement, alopecia, panting,
10% Labrador Retrievers
and muscle weakness (Table 10-4). Cutaneous changes may be the
8% Terriers (various breeds) only clinical signs (Zur and White, 2011), so the presence of the
5% Cocker Spaniels common cutaneous manifestations of HAC, such as non-pruritic
4% Alaskan Malamute truncal alopecia and/or thin skin, without systemic signs warrants
screening for the disease. The duration of clinical signs and the
4% Boston terrier type of signs are similar between PDH and AT.
4% Shih Tzu Hyperadrenocorticism in Young Dogs. Rarely, HAC has been
3% Boxer diagnosed in dogs younger than 5 years of age (Figs. 10-7 and 10-8).
Growth retardation was noted along with the typical clinical signs.
3% Shetland Sheepdog
3% English Springer Spaniel
Polyuria and Polydipsia
3% Australian Shepherd
15% Other breeds (12 breeds) Polyuria and polydipsia are extremely common signs associated
with HAC. Polyuria may cause a loss of housebreaking or a need
*Note: Data are observational; significant breed predisposition not assessed. to urinate during the night. Polydipsia and polyuria previously
|
FIGURE 10-7 A 1-year-old dog with pituitary-dependent hyper-

adrenocorticism (PDH) (left) and a normal adult. Note the short
stature and immature hair coat in the young dog.
A B
C D
E
F
FIGURE 10-8 A, Mixed-breed 18-month-old dog with hyperadrenocorticism (HAC). B, Same dog (left) and a normal
littermate. C, Same dog as in A 5 months after initiation of mitotane therapy. D, A 6-month-old German Shepherd
dog with HAC. E, Same dog as in D after 4 years without therapy. F, Same dog as in D and E 4 months after initia-
tion of therapy with mitotane.
A B
FIGURE 10-9 A, Poodle with pituitary-dependent hyperadrenocorticism (PDH), illustrating the pot-bellied appear-
ance and diffuse alopecia sparing the head and distal extremities. B, A dog with PDH illustrating the pot-bellied
appearance. The dogs hair was clipped 1 year previously; note the lack of regrowth.
A B
FIGURE 10-10 A, Dog with hyperadrenocorticism (HAC). B, Same dog as in A on its side, demonstrating typical
pot-belly appearance.
has been documented in approximately 80% to 85% of dogs with the dog could have a pituitary macroadenoma compressing adjacent
HAC (Ling etal, 1979; Peterson, 1984). Owners often report the structures and elevating cerebrospinal fluid pressure.
water intake to be two to 10 times normal.
The cause of the polyuria remains obscure. In dogs with HAC
Abdominal Enlargement
either due to PDH (n = 9) or AT (n = 6), the sensitivity and thresh-
old of the osmoregulation of vasopressin secretion was abnormal in The potbellied or pendulous abdominal prole is a classic
most (Biewenga et al, 1991). Direct effects of glucocorticoids on clinical sign present in the majority of dogs with HAC (Figs.
renal responsiveness to vasopressin may also exist (Biewenga etal, 10-9 and 10-10). It is believed to be the cumulative result
1991) but are unproven. Although atrial natriuretic peptide con- of hepatomegaly filling out the cranial abdominal silhouette
centrations are increased in the serum of humans with HAC (Yam- caudal to the rib cage, decreased strength of the abdominal
aji etal, 1988) and could cause polyuria, it does not play a role in muscles, fat accumulation within the abdomen, and, at times,
canine HAC (Vollmar etal, 1991). Direct compression of the poste- an enlarged bladder due to polydipsia expanding the caudal
rior pituitary gland by an anterior pituitary tumor or compression of abdomen.
the hypothalamus or hypothalamic stalk can rarely cause concurrent Hepatomegaly is due to glycogen deposition (i.e., steroid hepa-
diabetes insipidus (Ferguson and Biery, 1988; Goossens etal, 1995). topathy). Muscle wasting is a direct result of protein catabolism
due to excess cortisol. The mechanism responsible for fat redistri-
bution is not understood.
Appetite
Polyphagia may be troublesome, because affected dogs may resort Muscle Weakness and Lethargy
to stealing food, eating garbage, begging continuously, and occa-
sionally aggressively attacking or protecting food. It is assumed to Dogs with HAC are usually capable of rising from a prone position
be a direct effect of glucocorticoids, which is a unique effect in dogs. and of going for short walks; however, exercise tolerance is often
Polyphagia does not occur with cortisol excess in humans or cats. reduced. Muscle weakness may be demonstrated by an inability to
Poor appetite can occur uncommonly in dogs with HAC. The climb stairs or to jump onto furniture or into a car. Owners may
most common reasons are the presence of a concurrent illness or believe the problem is age-related. Muscle weakness is at least partly
|
A B
FIGURE 10-11 Radiographs of fracture of the tibial crest (A) in an 18-month-old dog with hyperadrenocorticism
(HAC; see Fig. 10-10) with partially closed epiphyses. HAC delays epiphyseal closure in young dogs; note this dogs
opposite stifle demonstrates delayed closure but no fracture (B).
HAC: 80% had some form of alopecia; 57% had pyoderma; 43%
had hyperpigmentation; 25% were pruritic owing to seborrhea,
calcinosis cutis, demodicosis, or pyoderma; 12% had thin skin; 5%
had comedones; and 2% had calcinosis cutis (White etal, 1989). A
recent study, although small, documented similar incidences of the
common dermatologic signs (i.e., pyoderma, thin skin, hyperpig-
mentation, and comedones). Interestingly, although pruritus is not
expected in dogs with HAC due to the anti-inflammatory effects
of cortisol, it was a major clinical sign in four of 10 dogs (Zur and
White, 2011). Conversely, some dogs with HAC have no apparent
dermatologic signs (Peterson, 1984; Reusch and Feldman, 1991).
Alopecia and Pruritus

The hair loss associated with HAC is a common owner concern.
It is slowly progressive and may begin at points of wear (e.g., bony
FIGURE 10-12 Dog with ruptured gastrocnemius muscles, a condition that may prominences), eventually involving the flanks, perineum, and abdo-
have occurred secondary to concurrent hyperadrenocorticism (HAC). men. Atrophy of hair follicles and the pilosebaceous apparatus with
keratin accumulation in atrophic hair follicles is common; the fol-
licular atrophy disrupts attachment of the hair shaft to the follicle,
the result of muscle wasting caused by protein catabolism. Leth- causing hair loss. Alopecia can be mild to severe (Figs. 10-13 and
argy is probably an expression of muscle weakness and wasting. 10-14) with only the head and distal extremities retaining a coat.
Infrequently, affected dogs may not be capable of rising and
may have difculty standing for any length of time. A stress frac- Failure to Regrow Shaved Hair
ture across a tibial crest epiphysis, which had failed to close at a If a dog with HAC is shaved, hair regrowth is poor or nonexistent
normal age, occurred in a juvenile dog with HAC (Fig. 10-11). (see Figs. 10-9, B, and 10-15), and any new hair is typically abnor-
Atraumatic rupture of both gastrocnemius muscles (Fig. 10-12) mal (e.g., brittle, sparse, or ne) (see Fig. 10-15). In the authors
may have occurred in one dog secondary to spontaneous HAC; experience, poor hair regrowth after clipping is uncommonly due
unilateral rupture has occurred secondary to glucocorticoid to HAC; if it is, other clinical signs of HAC are present. If poor
administration and iatrogenic HAC (Rewerts etal, 1997). hair regrowth is the only clinical sign, it is more likely due to post
clipping alopecia, which is an idiopathic syndrome in which hair
can take up to 12 months to regrow and is normal in appearance
Cutaneous Markers
(Rhodes and Beale, 2002).
Cases seen by dermatologists may have a different constellation of
findings than those seen by others. Cutaneous manifestations can Thin Skin, Pyoderma, Seborrhea, and Demodicosis
occur without systemic signs (Zur and White, 2011). One report by Thin skin, poor healing (Fig. 10-16), and pyoderma can occur
dermatologists described cutaneous signs in 100% of 60 dogs with in dogs with canine HAC. Piloglandular and epidermal atrophy
A B
FIGURE 10-13 A, Dachshund with pituitary-dependent hyperadrenocorticism (PDH) showing severe, bilaterally
symmetric alopecia. B, Same dog as in A 20 months after beginning therapy with mitotane.
A B
FIGURE 10-14 A, A dog with bilaterally symmetric alopecia of the flanks and thighs. B, Labrador Retriever, which
had hyperadrenocorticism (HAC) caused by a functioning adrenal tumor, with alopecia and a poor hair coat second-
ary to HAC as well as a potbelly.
occur in 30% to 40% of dogs with HAC (White et al, 1989), been associated with naturally occurring HAC in approximately
which is likely due to the anti-proliferative effects of glucocorti- 10% of cases (White etal, 1989; Zur and White, 2011).
coids on fibroblasts, with inhibition of collagen and mucopolysac-
charide synthesis. Synthesis of collagen types I and III is decreased Bruising, Reduced Subcutaneous Fat, and Striae
with topical glucocorticoid therapy in people (Valencia and Kerdel, The fragility observed with thin skin is also present in the blood
2012) and likely with HAC in dogs. In some dogs, the subcutane- vessels. Excessive bruising can follow venipuncture (Fig. 10-17) or
ous blood vessels are easily visualized. In addition, keratin-plugged other minor trauma. Rarely, bruising occurs secondary to the pres-
follicles (comedones) can be found on the trunk, especially around ence of metal staples in a surgical scar from years before (Fig. 10-18,
the nipples and along the dorsal midline. Pyoderma is common, A and B). Atrophy of subcutaneous tissue may predispose to bruis-
likely due to multiple local cutaneous changes as well as immu- ing as well. Wounds heal more slowly, potentially with fragile, thin
nosuppression from excess cortisol, and may be poorly responsive scar tissue (see Fig. 10-18, C). Healing skin lesions may undergo
to therapy (Zur and White, 2011). Adult-onset demodicosis has dehiscence because of the limited amount of brous tissue.
|
FIGURE 10-15 Close-up of the dog in Fig. 10-14, B. The areas shown had been
shaved 8 months earlier prior to removal of small skin tumors. Note the failure of
the hair to grow back, as well as the obvious surgical scars, which are the result
of poor wound healing.
FIGURE 10-17 A dog with hyperadrenocorticism (HAC) that had two blood sam-
ples obtained from the jugular vein. The bruising was obvious 2 hours later.
appear to be predisposed. In one study, Rottweilers, Rottweiler/

Labrador retriever mixed breeds, Staffordshire Terriers, Boxers,
Boxer mixed breeds, Akitas, and Pomeranians were significantly
overrepresented, but the number of dogs in each breed was low
(Doerr etal, 2013).
Calcinosis cutis is uncommon in dogs with HAC (White
et al, 1989) but characteristic if it occurs. The pathophysiol-
A ogy is not known. On histopathology, calcinosis cutis is charac-
terized by dermal, diffuse or multinodular, dystrophic calcium
deposition. Subcutaneous involvement and osseous metaplasia
may occur. Fibrosis and inflammation, mainly with histiocytes
and lymphocytes, can be seen as well as other changes of HAC,
such as epidermal atrophy (Doerr etal, 2013). Abnormal col-
lagen fibrils due to the effects of glucocorticoids on collagen
synthesis may attract ion deposition (Doerr et al, 2013), and
secondary hyperparathyroidism may play a role (Ramsey etal,
2005). Affected dogs have firm, palpable erythematous pap-
ules to well-demarcated plaques that may feel mineralized. The
most common location is the dorsum, followed by the head and
inguinal area; other truncal locations may also be involved (Fig.
10-19), and the extremities are involved less frequently (Doerr
B etal, 2013). Calcinosis cutis does not always resolve with suc-
cessful treatment of HAC.
FIGURE 10-16 A, An 8-year-old mixed-breed dog that had been treated chroni-
cally with glucocorticoids. B, Open wounds on the ventral abdomen that were not
healing, likely due to the effects of chronic glucocorticoid therapy. Obesity
Owners of dogs with HAC usually comment on their pets
apparent weight gain. To the contrary, dogs with HAC do not
Calcinosis Cutis and Cutaneous Metaplastic Ossification usually gain a large amount of weight. Rather, most have fat
Although previously stated to be pathognomonic of spontaneous redistribution and a potbellied appearance, which can be mis-
or iatrogenic HAC, calcinosis cutis has also been reported as a taken for weight gain. In dogs and humans, truncal obesity
consequence of fungal infection, treatment of hypoparathyroid- appears to occur at the expense of muscle and fat wasting from
ism and renal failure, or as idiopathic. In general, large breed dogs the extremities and subcutaneous stores.
A B
C
FIGURE 10-18 A, Bruising in the area of an ovariohysterectomy performed 8 years earlier. B, Close-up of the
bruising shown in A caused by metal sutures and a decrease in subcutaneous fat that normally padded the
sutures. C, Thin, fragile, healed incision, typical of the poor healing in a dog with hyperadrenocorticism (HAC).
Respiratory Signs Pneumothorax secondary to PTE has been reported (Sobel and
Williams, 2009). The pathogenesis is described in more detail later
Panting (see Pulmonary Thromboembolism).
Panting is common in dogs with HAC; dyspnea is possible due
to thromboembolism (see later) but uncommon. Coughing is not
Reproductive Abnormalities
associated with HAC.
Several possible reasons exist for panting. First, as with other Owner concerns related to the reproductive tract in dogs with
muscles in the body, the respiratory muscles may be weak. Second, HAC are unusual, because most affected dogs are old, neutered,
the increased pressure placed on the diaphragm from abdominal or both. No information exists in the literature regarding repro-
fat accumulation and hepatomegaly can accentuate disturbances in ductive function specifically in dogs with HAC, nor sex hormone
ventilatory mechanics. Third, pulmonary interstitial and bronchial concentrations in female dogs with HAC or receiving exogenous
mineralization can be present, leading to decreased lung compliance glucocorticoids. Prednisone administration decreases basal tes-
(Berry etal, 1994; 2000; Schwarz etal, 2000). Even if present, miner- tosterone concentrations in dogs (Kemppainen et al, 1983).
alization may not always be visible on plain radiographs. Last, minor Although decreased testosterone would be expected to lead to
pulmonary thromboemboli may cause panting or tachypnea. Any or increased concentrations of LH from lack of negative feedback, in
all factors may be present in dogs with HAC. In one study, 33% of dogs with PDH, basal LH concentrations are not different from
dogs with PDH were hypoxemic, and no thromboemboli were pres- controls and, in fact, secretion was hyperresponsive to administra-
ent (Berry etal, 2000). Concurrent disease (e.g., collapsing trachea) tion of gonadotropin-releasing hormone (GnRH). Thus, hyper-
may exacerbate the respiratory issues of HAC. cortisolemia may affect LH secretion directly (Meij etal, 1997c).
Thromboembolism
Myotonia (Pseudomyotonia)
Thromboembolism is a recognized problem in dogs with HAC
(Keyes et al, 1993; Teshima et al, 2008; Sobel and Williams, Quite rarely, dogs with HAC develop a distinct myopathy char-
2009). Dogs with pulmonary thromboembolism (PTE) may have acterized by persistent, active muscle contraction after cessation of
chronic, mild signs or may develop acute, severe respiratory distress. voluntary effort (Braund et al, 1980; Swinney et al, 1998; Cisneros
|
FIGURE 10-20 An 11-year-old dog with hyperadrenocorticism (HAC) and myoto-

nia, resulting in extreme rigidity of the pelvic limbs and inability to walk.
PHYSICAL EXAMINATION
General Review
Common abnormalities include abdominal enlargement, pant-
ing, truncal obesity, bilaterally symmetric alopecia, hyperpig-
mentation, skin infections, comedones, and hepatomegaly (see
Table 10-4). Remarkable variation exists in the number and
severity of physical findings between patients.
Hyperpigmentation
B
Cutaneous hyperpigmentation may be diffuse or focal (see Fig.
FIGURE 10-19 A, A 10-year-old female spayed Labrador Retriever with calcino- 10-8, E). Histologically, increased numbers of melanocytes are
sis cutis. Note the multifocal to coalescing, raised masses on the lateral aspect found in the stratum corneum, basal epidermis, and dermal tis-
of the neck; the masses were palpably firm. Diffuse to patchy alopecia was pres- sues. The pathophysiology is not understood. Secretion of -MSH
ent in the affected areas. B, Radiograph showing dorsal midline (straight arrow) from the pituitary may contribute to hyperpigmentation in dogs
and preputial (curved white arrow) calcinosis cutis, as well as calcified femoral with PDH. However, as hyperpigmentation occurs as well in dogs
arteries (curved black arrows). (A, Photograph courtesy of Dr. Robert Kennis. In with ATs, pituitary secretion is not the only cause.
Rand J, editor: Clinical endocrinology of companion animals, Ames, IA, 2013,
Wiley-Blackwell, p. 47.) Hepatomegaly
An enlarged liver, a classic sign with canine HAC, contributes to
et al, 2011). Affected dogs develop a stilted gait, especially in the abdominal enlargement by filling out the cranial abdominal sil-
pelvic limbs, stiffness of the limbs, and enlarged muscles in the houette behind the rib cage. Hepatomegaly is easily palpated due
proximal limbs coincident with onset of other clinical signs of HAC to the weak abdominal muscles. If a dog thought to have HAC
(Cisneros etal, 2011). Inability to ambulate is possible (Fig. 10-20). does not have hepatomegaly or if the liver is small, another condi-
Myotonic, bizarre, high-frequency discharges are noted on electro- tion or a serious concurrent disease should be suspected.
myography (Braund etal, 1980). Clinical response to resolution of Grossly, the liver is typically large, pale, and friable. Histologic
HAC is not predictable (Swinney etal, 1998). changes in dogs with naturally occurring HAC or exposure to exog-
Myopathic changes in dogs with HAC-associated myoto- enous glucocorticoid are the same and were previously referred to
nia include fiber size variation, focal necrosis, internal nuclei, as vacuolar hepatopathy or steroid hepatopathy. The changes include
fiber splitting, subsarcolemmal aggregates, and fatty infiltration. increased hepatocyte size and centrilobular hepatocytic vacuola-
Type 2 muscle fibers are preferentially involved. Mitochondrial tion with a few, often single, large vacuoles that displace the cell
changes are the most prominent ultrastructural feature. Evidence nucleus to the periphery. Glycogen accumulation is concentrated
of demyelination suggests a chronic neuropathy may be present in periportal hepatocytes. Lipid deposits are not demonstrable
and underlie at least some of the muscular changes (Braund etal, with Sudan III stains. Hepatocellular necrosis, although present,
1980). However, histopathology may also be relatively unremark- is not a signicant feature (Badylak and Van Vleet, 1981).
able (Cisneros etal, 2011). The term vacuolar hepatopathy is now recognized as a misno-
mer; the hepatic changes are not specific for HAC or glucocorti-
coid exposure. Of 336 dogs with vacuolar hepatopathy, only 55%
Facial Paralysis
were classified as having been exposed to glucocorticoids (Sepesy
Anecdotally, dogs with HAC are believed to rarely develop uni- etal, 2006), and neoplasia and congenital or acquired hepatobili-
lateral or bilateral facial nerve paralysis. An association has never ary disease were common. The vacuolization was accompanied by
been proven. elevated alkaline phosphatase (ALP) activity as well; the enzyme
activity and vacuolar hepatopathy may be a marker of an illness- of polyphagia, typically resolve with time in dogs with SARDS
invoked physiologic stress. (Mattson etal, 1992; Stuckey etal, 2013); no study has performed
follow-up testing for HAC at 4 to 6 months after the initial diag-
Gonadal and Sex HormoneRelated Alterations nosis of SARDS. Thus, a link between SARDS and HAC is quite
unsubstantiated.
Due to low testosterone concentrations (see earlier), male dogs
with HAC could have bilaterally small, soft, spongy testicles, and
Blindness
decreased libido. In females, in theory, decreased LH could sup-
press normal ovarian function and lead to prolonged anestrus Blindness occurs rarely in dogs with PDH secondary to compres-
(Meij et al, 1997c). Although dogs with PDH have hyperpro- sion of the optic chiasm by a pituitary macroadenoma (Seruca
lactinemia (Meij etal, 1997a; 1997c) independent of excesses in et al, 2010). Blindness has also been reported in dogs with no
plasma cortisol, mammary development has not been reported in optic chiasm compression, possibly due to changes in ophthalmic
dogs with HAC. blood flow, interleukin-6, insulin, nitric oxide, triglycerides, and
In one case report, adrenal hypersecretion of androgens in adiponectin (Cabrera Blatter etal, 2012a; 2012b). However, the
a spayed female with HAC was hypothesized to have led to the proportion of blind dogs with HAC in the two studies by Cabrera
development of recurrent perianal adenomas. However, the mea- Blatter and colleagues is much higher than reported elsewhere
sured serum testosterone concentration was variable and did not (14% and 43%), and the possibility exists that many dogs had
correlate with development of the adenomas (Dow etal, 1988). SARDS and not HAC.
Thus, no documentation exists of an adrenal source of androgens
causing pathologic virilization in dogs (Johnson, 2013)
Acute Weakness Due to Non-Traumatic Rupture
of an Adrenal Mass
Ectopic Calcication
Non-traumatic rupture of an AT is rare. In five dogs in which
In addition to HAC causing calcinosis cutis, ectopic calcication this occurred, severe lethargy, weakness, and pale mucous
may also involve the tracheal rings and bronchial walls, the kid- membranes developed acutely. Abdominal pain was detected
neys, and (rarely) the major arteries and veins (see Fig. 10-19, B) on the physical examination. Each dog had acute intraabdomi-
(Berry etal, 2000; Schwarz etal, 2000). Because approximately nal or retroperitoneal hemorrhage, required immediate sup-
90% of dogs with HAC have elevated parathyroid hormone con- portive therapy, and had emergency exploratory abdominal
centrations, soft tissue calcification has been speculated to be due, surgery (Vandenbergh et al, 1992; Whittemore et al, 2001).
at least in part, to secondary hyperparathyroidism (Ramsey etal, Both adenocarcinomas and adenomas have ruptured. Although
2005). Ectopic calcication may be noted only histologically in this scenario is rare, it is one of the few situations (along with
some dogs. Calcic band keratopathy, a syndrome characterized PTE) in which a dog with HAC may develop an acute, life-
by a grey-white supercial corneal opacity horizontally oriented in threatening illness.
the interpalpebral opening, was reported in two dogs with HAC
(Ward etal, 1989).
Central Nervous System Signs
Bruisability Central nervous system (CNS) signs can occur in dogs with
PDH. Occasionally the CNS signs are present at the time of
Easy bruisability is common in people with HAC. It is not fre- diagnosis of PDH; alternatively, small tumors can grow after
quently observed in dogs, but it may be noted after venipuncture diagnosis, and CNS signs develop within weeks to years (Nelson
or trauma (see Figs. 10-17 and 10-18). Bruisability is likely due etal, 1989; Bertoy etal, 1996). Due to boney confines, pituitary
to cortisol-induced inhibition of collagen synthesis, leading to masses expand dorsally and may compress or invade the hypo-
weaker blood vessel walls. thalamus and other suprasellar structures, may invaginate the
pituitary stalk that connects the pituitary with the hypothalamus,
or may dilate the infundibular recess and third ventricle. In addi-
Sudden Acquired Retinal Degeneration Syndrome
tion, the second, third, and fourth cranial nerves may be affected
Sudden acquired retinal degeneration syndrome (SARDS) is an (Capen, 2007).
idiopathic retinal disorder that produces sudden, permanent When neurologic signs are rst recognized in dogs with PDH,
blindness in adult dogs. The syndrome is characterized by non- they can be nonspecific and subtle. Common initial signs include
inflammatory degeneration and loss of retinal photoreceptors. being dull, listlessness, and inappetence; they may progress to
An association has been suggested between SARDS and HAC anorexia, restlessness, loss of interest in normal household activi-
because dogs with SARDS can have clinical signs suggestive of ties, delayed response to stimuli, disorientation, and stupor. Other
HAC (e.g., polyuria, polydipsia, polyphagia and weight gain) CNS signs reported in dogs with macrotumors include circling,
(van der Woerdt et al, 1991; Mattson et al, 1992; Montgomery et al, pacing, head pressing, ataxia, behavioral alterations (i.e., aggres-
2008; Stuckey et al, 2013). However, not all dogs with SARDS sion), blindness, adipsia, and seizures (Fig. 10-21 and Box 10-1;
have signs consistent with HAC; indeed in one study only 33% Nelson etal, 1989; Kipperman etal, 1992). A caveat exists, how-
of dogs with SARDS had systemic signs (Montgomery et al, ever, that neurologic signs can occur for other reasons in dogs
2008). Dogs with SARDS have had positive tests for HAC, but with PDH (Wood etal, 2007). Thus, those reported in dogs with
in others, negative or conflicting results were obtained (van der PDH may not have been due to the pituitary tumor itself. With
Woerdt et al, 1991; Mattson et al, 1992; Stuckey et al, 2013). The severe hypothalamic compression, dysfunction of the autonomic
chance of a false-positive test result on a screening test for HAC nervous system develops rarely; clinical signs include adipsia, loss
due to the stress of acute blindness must be considered. Further- of temperature regulation, erratic heart rate, and stupor. These are
more, the clinical signs suggestive of HAC, with the exception considered terminal signs.
|
Clinical signs:
pituitary macro tumor syndrome BOX 10-1 C
linical Signs Caused by an Enlarging Pituitary
90
Tumor in Dogs with Hyperadrenocorticism
80 Dullness, listlessness
70 Inappetence (poor appetite)/anorexia (no appetite)
Restlessness
60
Loss of interest in normal activities
Percent
50 Delayed response to various stimuli

Disorientation/aimless pacing
40
Altered mentation
30 Obtundation
20 Stupor
Ataxia
10 Circling
0 Head pressing
Dull listless Inappetence/ Disorientation Aimless Behavior changes
A anorexia wandering/
Blindness
pacing/
blind?* Seizures
Clinical signs: Coma
pituitary macro tumor syndrome Adipsia
45
Loss of temperature regulation
40
35
neurologic signs. In dogs with PDH, 71% of 84 dogs without
30
neurologic abnormalities and 66% of 73 dogs with neurologic
Percent
25 abnormalities had a pituitary macrotumor (Wood etal, 2007).

20 The diagnosis of a macroadenoma depends on imaging via CT
15 or MRI. The possibility that the CNS abnormalities are an adverse
10 effect of mitotane, if that is being administered, or due to a con-
5 current illness must be eliminated.
0
Difficulty Ataxia Head Circling Incon- Seizures ROUTINE BLOOD AND URINE EVALUATION
B laying down pressing tinence
FIGURE 10-21Bar graphs (A and B) illustrating the most common clinical General Approach
signs observed in dogs with pituitary macroadenoma syndrome causing central
nervous system (CNS) signs (note the difference in the vertical scale of the two Any dog suspected of having HAC should be thoroughly evalu-
graphs). *Note that it can be difficult in some cases to determine if a dog is truly ated before specic endocrine testing is done. Each dog should
blind or severely disoriented. have a complete blood count (CBC), urinalysis with culture,
and a complete serum chemistry prole performed. In addition,
abdominal ultrasonography (preferred over radiography) should
Predicting which pituitary tumor will grow is impossible. be considered. The initial results not only help ensure the correct
Although one study suggested macroadenomas (i.e., tumor >10 diagnosis is being pursued; they also might identify concomitant
mm in height) were more likely in dogs weighing more than 20 kg medical problems.
(Duesberg etal, 1995), other studies found no relationship with Certain clinicopathologic changes are consistent with a
weight (Nelson etal, 1989; Bertoy etal, 1995; Wood etal, 2007). diagnosis of HAC (Table 10-5), but none is pathognomonic.
In 21 dogs with PDH that did not have CNS signs at the time of Laboratory test results must always be interpreted within the
diagnosis of HAC, 11 (52%) had a visible masses on MRI that context of the history and physical examination. An absence of
ranged from 4 to 12 mm in height (Bertoy etal, 1995). Thirteen common clinical signs should strongly decrease the suspicion
of the 21 dogs with PDH were followed over 1 year; five of the of HAC, and perhaps even stop pursuit of such a diagnosis.
13 had no mass visible originally, whereas eight dogs did. Over If consistent history and clinical signs are present, the greater
the year, six of the 13 dogs (46%) had tumor growth; two of the the number of suggestive clinicopathologic abnormalities docu-
six did not have a visible mass on the initial MRI. In four dogs, a mented, the stronger the suspicion of HAC. Failure to identify
tumor was initially seen, and it increased in size over the year; two clinicopathologic abnormalities should not, by itself, rule out
of the four dogs developed a macroadenoma with tumor height of HAC (Behrend etal, 2013).
11 and 14 mm and had CNS signs (Bertoy etal, 1996).
Predicting which dogs will develop neurological signs is also Complete Blood Count
impossible. Dogs can have neurological signs with tumors less
than 10 mm diameter; conversely, dogs with a macroadenoma Neutrophilia and monocytosis are common due to steroid-enhanced
might not have detectable neurological abnormalities (Nelson capillary demargination of these cells and prevention of normal cellu-
etal, 1989; Kipperman etal, 1992; Wood etal, 2007). No appar- lar egress from the circulation. Lymphopenia is most likely the result
ent relationship was detected in one study between the presence of steroid-induced lympholysis, and eosinopenia results from bone
of a pituitary tumor regardless of size and the development of marrow sequestration of eosinophils. The constellation of changes
TABLE 10-5 H
EMATOLOGIC, SERUM documented the presence of an elevated ALP activity in greater
BIOCHEMICAL, URINE, than 80% to 90% of dogs with HAC (Ling etal, 1979; Teske etal,
AND RADIOGRAPHIC 1989). Previously, approximately 15% of board-certified internists
ABNORMALITIES THAT OCCUR and dermatologists would not pursue a diagnosis of HAC if ALP
WITH HYPERADRENOCORTICISM activity was in the reference range (Behrend etal, 2002); however,
given that dogs with HAC are likely currently diagnosed earlier in
TEST ABNORMALITY the course of disease, the percentage of dogs with HAC with an
increased ALP activity may be lower. Thus, using an ALP activity
Complete blood count Mature leukocytosis within the reference range as a means to rule out HAC may not be
(CBC) Neutrophilia a wise practice.
Lymphopenia
Eosinopenia Alanine Aminotransferase
Erythrocytosis; mild Alanine aminotransferase (ALT) activity is commonly increased
Serum chemistries Increased alkaline phosphatase in HAC, but the elevation is usually mild (i.e., < 400 IU/L).
(ALP; sometimes extremely elevated) Elevations in serum ALP activity are relatively greater than that
Increased alanine aminotransferase (ALT) of ALT. Increases in ALT are not believed to be due to increased
(usually mild) gene expression (Hadley et al, 1990) but secondary to damage
Hypercholesterolemia caused by swollen hepatocytes, glycogen accumulation, or inter-
Hypertriglyceridemia ference with hepatic blood flow.
Hyperglycemia
Increased bile acids Cholesterol and Triglycerides
Decreased blood urea nitrogen (BUN) Glucocorticoid stimulation of lipolysis causes an increase in blood
Urinalysis Urine specific gravity less than 1.015, lipid and cholesterol concentrations. Ninety percent of dogs with
often less than 1.008 HAC have hypercholesterolemia. Approximately 10% of dogs
Proteinuria with HAC have serum cholesterol concentrations less than 250
Radiography/ultra Hepatomegaly
mg/dL; 15% have concentrations of 250 to 300 mg/dL; and
sonography Excellent abdominal contrast
75% have concentrations greater than 300 mg/dL (Fig. 10-22;
Osteoporosis
Ortega et al, 1995). Hypertriglyceridemia is also common (see
Calcinosis cutis/dystrophic calcification
Fig. 10-22). Lipid distribution within particles can also be altered
Adrenal calcification (usually adrenal tumor)
(e.g., the amount of cholesterol in verylow-density, low-density,
Pulmonary thromboembolism (PTE) (rare)
and high-density lipoprotein fractions) (Jerico etal, 2009).
Calcified trachea and main stem bronchi Blood Glucose and Serum Insulin
Pulmonary metastasis of adrenal carcinoma
Glucocorticoids antagonize the effects of insulin, leading to
Blood pressure Hypertension increased hepatic gluconeogenesis and decreased peripheral glucose
Thyroid testing Low thyroxine (T4) concentrations utilization. Thus, dogs with HAC can have mild hyperglycemia
Triiodothyronine (T3) concentrations (Peterson etal, 1984a; 1986b; Elliott etal, 1997). Insulin concen-
trations can be elevated (Wolfsheimer and Peterson, 1991; Mont-
gomery etal, 1996; Cho etal, 2014). Binding of erythrocyte insulin
in the white blood cell differential (i.e., overall leukocytosis with receptors is decreased in dogs with HAC, but it may be the cause
neutrophilia, monocytosis, eosinopenia, and lymphopenia) is called or effect of hyperinsulinemia (Wolfsheimer and Peterson, 1991). A
a stress leukogram and is common in dogs with HAC. A mild small percentage of dogs with HAC have overt diabetes mellitus.
polycythemia can also occur. Approximately 75% to 80% of dogs
with HAC have an increased platelet count (Pace etal, 2013; Rose Blood Urea Nitrogen
etal, 2013). The signicance of the thrombocytosis is unknown. The polyuria of HAC leads to continual urinary loss of blood urea
nitrogen (BUN). Thus, BUN can be below the reference range
(Behrend etal, 2013).
Serum Biochemical Profile
Alkaline Phosphatase Phosphate
ALPs are a group of enzymes that catalyze the hydrolysis of phosphate Hypophosphatemia had been reported to occur in approximately
esters. Their main source is the liver, with bone ALP contributing one-third of dogs with HAC (Peterson, 1984), potentially from a
smaller amounts to the circulation; both forms have serum half-lives glucocorticoid-induced increase in urinary phosphate excretion.
of approximately 3 days. Intestinal, placental, and renal ALPs are not More recently, however, hyperphosphatemia was noted in most
detectable in serum, because their half-lives are only minutes. dogs with HAC in one study (Ramsey etal, 2005). The reason for
A uniquely canine corticosteroid-induced alkaline phospha- the difference is not apparent. The finding of hyperphosphatemia
tase (CIALP) also can be measured in serum. The source is the was unexpected and was possibly an artifactual elevation due to
bile canalicular membrane of hepatocytes (Sanecki et al, 1987). lipemia (Ramsey etal, 2005).
Exposure to exogenous and endogenous glucocorticoids increases
synthesis of CIALP as well as other enzymes in the liver (liver ALP Bile Acids
isoenzymes), kidneys, and intestines (Sanecki etal, 1987; Solter Pre- and post-prandial bile acid concentrations may be mildly
etal, 1993; Wiedmeyer etal, 2002a; 2002b). increased in up to 30% of dogs with HAC (Reusch, 2005). Param-
Increased ALP activity is the most common routine abnormality eters of liver function such as bile acid concentration or bromo-
on a serum biochemistry profile in dogs with HAC. Older literature sulfophthalein (BSP) retention have been inconsistently affected
|
400
Normal values
350
Untreated PDH
Serum lipid concentrations (mg/dl)
300 Poorly controlled PDH
250 Well controlled PDH
200
150
100 FIGURE 10-22Serum cholesterol, triglyceride, and cholesterol

content in very-low density lipoprotein (VLDL), low-density lipopro-
50 tein (LDL), and high-density lipoprotein (HDL) particles in normal
dogs, dogs with untreated hyperadrenocorticism (HAC) and poorly
0 controlled and well-controlled treated dogs with naturally occur-
Cholesterol Triglycerides VLDL LDL HDL ring HAC.
by glucocorticoid administration (Badylak and Van Vleet, 1981; was 0.70 (range, 0.03 to 4.2) in one study (Hurley and Vaden,
DeNovo and Prasee, 1983; Solter etal, 1994). Any change in liver 1998) and 1.66 in another (Smets etal, 2012). When comparing
function, however, is not considered to be clinically important. dogs with PDH and AT, the mean UPCR were 1.47 1.69 and
2.74 2.8, respectively (Ortega etal, 1996). The UPCR in dogs
Electrolytes with ATs was significantly higher than that for dogs with PDH.
Although of little diagnostic or clinical signicance, mild hyper- Microalbuminuria (urine albumin-to-creatinine ratio 0.03 to
natremia, hypochloremia, and hypokalemia can be seen in some 0.3) and albuminuria (urine albumin-to-creatinine ratio > 0.3)
dogs with HAC (Ling etal, 1979). were present in 38.6% and 48.5%, respectively, of dogs with
HAC. Interestingly, the incidence of microalbuminuria was signif-
Amylase and Lipase icantly higher in dogs with PDH versus ATs (52.5% versus 20%),
Pancreatitis is uncommon in dogs with HAC. Although a link whereas the incidence of albuminuria was significantly lower in
between glucocorticoids and pancreatitis has previously been pos- dogs with PDH versus ATs (32.5% versus 70%) (Lien etal, 2010).
tulated, the concerns have largely been dismissed (see Chapter 14). The etiology of the proteinuria is unclear. The underlying glo-
merular lesion is typically glomerulosclerosis (Ortega etal, 1996;
Urinalysis Waters etal, 1997). In one study, the ACTH-stimulated cortisol
concentration correlated with the UPCR (Ortega et al, 1996).
Concentration Hypertension is common in dogs with HAC and could contrib-
The most frequent urinalysis abnormality in dogs with HAC is ute. However, conflicting results have been obtained with regard
dilute urine (specic gravity < 1.020). A large percentage of dogs to correlation between systemic blood pressure and degree of pro-
with HAC have a specic gravity in a randomly obtained urine teinuria (Ortega et al, 1996; Lien et al, 2010). Glucocorticoids
sample less than 1.015 (Smets etal, 2012). Owners of any dog sus- may induce glomerular hypertension (Ortega etal, 1996).
pected of having polyuria/polydipsia should obtain a urine sample Treatment of HAC typically improves the proteinuria, but it does
by clean-catch prior to bringing their pet to the hospital. Hospital- not resolve in 20% to 40% (Ortega etal, 1996; Hurley and Vaden,
ization can alter drinking behavior, and a dog polyuric and poly- 1998; Smets etal, 2012). After treatment and adequate cortisol sup-
dipsic at home may drink less when hospitalized; dogs with HAC pression, the UPCR in five dogs with PDH remained high (1.2 to
can concentrate their urine to some degree if water-deprived. It 6.5). In dogs in which the UPCR normalized, it required more than
should also be noted that a single urine sample with a low specific 4 to 12 weeks of control of the HAC (Hurley and Vaden, 1998).
gravity does not by itself prove the presence of polyuria/polydipsia. For 16 dogs with well-controlled PDH or four whose AT had been
removed, the mean UPCR was 0.64 0.98 and 1.1 1.32.
Glucose
By itself, HAC should not cause glucosuria. The presence of glu- Urinary Tract Infection
cose in the urine of a dog with HAC signifies the presence of In two studies, approximately half the dogs with HAC had a
another problem, most likely diabetes mellitus. urinary tract infection (UTI) at the time of initial examina-
tion. However, less than 5% had clinical signs of infection,
Proteinuria and approximately 18% had pyuria and bacteriuria noted on
Proteinuria occurs in more than half of dogs with HAC ( Ortega et urine sediment exam (Ling etal, 1979; Forrester etal, 1999).
al, 1996; Hurley and Vaden, 1998; Lien etal, 2010; Smets etal, Whether the infection was in the lower or upper urinary tract
2012); the exact percentage varies between studies and is not clearly (i.e., pyelonephritis) was not determined. Likely, increased uri-
stated in all of them. The proteinuria is typically mild to moderate nary cortisol concentration suppresses inflammation and thus
(i.e., urine protein-to-creatinine ratio [UPCR] < 5). Hypoalbu- clinical signs. Therefore, a urine culture should be considered in
minemia does not occur secondary to proteinuria due to HAC; the initial work-up of dogs with HAC. The bacteria isolated are
thus, if hypoalbuminemia is present, another cause for proteinuria common, and the sensitivities are typical of any UTI (Forrester
should be sought. In untreated dogs with HAC, median UPCR etal, 1999). HAC may also cause persistent UTI or reinfection
(Seguin etal, 2003). The high incidence of UTI could be due to initiated if needed. If systolic blood pressure is more than180
immunosuppression due to glucocorticoid excess. Also, dilute mm Hg, which means the risk of target organ damage is consid-
urine increases susceptibility to UTI (Lulich and Osborne, ered to be high, antihypertensive therapy should be considered;
1994). Whether dogs with HAC have a higher incidence of once the HAC is controlled, the need for anti-hypertension
pyelonephritis is unknown. medications should be reevaluated.
COMPLICATIONS ASSOCIATED Hypothyroidism

WITH HYPERADRENOCORTICISM
Clinical signs and routine laboratory changes associated with hypo-
Urinary Crystals and Calculi thyroidism and HAC can overlap (e.g., lethargy, hypercholesterol-
emia, and bilaterally symmetric, non-pruritic alopecia). (It should
Of 20 dogs with both HAC and urolithiasis, 16 had calcium- be noted that polyuria/polydipsia is not a sign of hypothyroid-
containing uroliths (13 with calcium oxalate and one each with ism.) Determining which disease is present can be difficult because
calcium apatite, mixed calcium hydrogen phosphate, and dihy- hypercortisolemia causes secondary hypothyroidism and may also
drate carbonate-apatite struvite), and four had struvite calculi. alter thyroid hormone binding to plasma proteins, enhance the
Dogs with HAC and urolithiasis were 10 times more likely to metabolism of thyroid hormone, or decrease peripheral deiodin-
have calcium-containing stones than breed-matched controls with ation of thyroxine (T4) to triiodothyronine (T3) (Ferguson and
urolithiasis but not HAC (Hess etal, 1998). In humans, gluco- Peterson, 1992). Approximately 40% to 60% of dogs with HAC
corticoids increase urinary calcium excretion, which in turn may have decreased basal serum T4 and/or T3 concentrations, and
increase the risk of development of calcium-containing uroliths. 24% have decreased free T4 concentrations (Peterson et al, 1984b;
The incidence of urinary calculi in dogs with HAC is unknown Ferguson and Peterson, 1992). Given that secondary hypothyroid-
but seems to be quite low. ism typically resolves with treatment of HAC (Ferguson and Peterson,
1992) and that concurrent spontaneous hypothyroidism and HAC
occurs rarely (Blois etal, 2011), if a patient is suspected to have both
Hypertension
hypothyroidism and HAC and if HAC is confirmed, it should be
Moderate, sustained hypertension occurs in more than 90% of treated and thyroid replacement therapy should be postponed. Once
humans with HAC. Multiple factors have been implicated in its the HAC is controlled, thyroid function should be reassessed.
development, including excessive secretion of renin (the protein
that acts to release angiotensin I), activation of the renin-angio- Diabetes Mellitus
tensin system via alternative stimulators, enhanced vascular sen-
sitivity to pressors (e.g., catecholamines and adrenergic agonists), Diabetes mellitus and HAC can occur concurrently. Either can be
reduction of vasodilator prostaglandins, and increased secretion of diagnosed first, with the other disease following at variable lengths
nonzona glomerulosa mineralocorticoids (e.g., deoxycorticoste- of time. How often they occur concurrently is not clear but is
rone) (Yamaji etal, 1988). likely not often. Diagnosis of HAC in a diabetic can be exceed-
The reported incidence of hypertension in dogs with HAC is ingly difficult (see later) clouding the issue; uncontrolled diabetes
31% to 86%. Comparison between studies is difficult because the mellitus can cause false-positive results on screening tests for HAC
methods of blood pressure measurement are not the same and the and give the incorrect impression of a high rate of concurrence.
definition of hypertension varies slightly. Normal blood pressure
can also vary between breeds (Bodey and Michell, 1996). The Gallbladder Mucocele
degree of hypertension is often mild to moderate, but reported
mean systolic blood pressure ranges from approximately 160 mm An association between HAC and gallbladder mucoceles has
Hg to 202 mm Hg (Ortega etal, 1996; Goy-Thollot etal, 2002; been postulated, but remains to be proven. In one study, 23% of
Lien et al, 2010; Smets et al, 2012; Arenas et al, 2014). In one 30 dogs with mucocele were reported to have HAC (Pike etal,
study, mean blood pressure was higher in dogs with ATs (164.1 2004). Similarly, in 78 dogs with gallbladder mucocele, 21% had
36.7 mm Hg) versus dogs with PDH (142.2 24.9) (Lien etal, HAC, and the odds of a mucocele in dogs with HAC were 29
2010), but no difference was found in another (Ortega etal, 1996). times that of age- and breed-matched dogs without HAC (Mesich
The etiology of the hypertension is unknown and likely multifac- etal, 2009). However, how the diagnosis of HAC was made was
torial. Aldosterone concentrations are decreased in dogs with PDH not described in the former study, and the diagnosis could not be
(Golden and Lothrop, 1988; Goy-Thollot etal, 2002). Hypercorti- confirmed by the authors in either study given the retrospective
solemia could contribute to hypertension because pressor sensitiv- nature of the studies. In a third study, only two of 58 dogs with
ity to norepinephrine infusion is increased in dogs with iatrogenic a mucocele had HAC (Kutsunai, 2014). Because hyperlipidemia
HAC (Martinez etal, 2005). Hypertension typically improves with may be a risk factor for mucocele formation (Kutsunai, 2014)
control of HAC but does not resolve in all dogs (Ortega etal, 1996; and the majority of dogs with HAC are hyperlipidemic, the pos-
Goy-Thollot etal, 2002; Smets etal, 2012), potentially suggesting sibility exists that hypercortisolemia does not contribute directly
that HAC causes chronic, irreversible changes in some patients. to mucocele formation. In six dogs treated with hydrocortisone
Hypertension raises concern because of its sequelae such as (8 mg/kg every 12 hours) for 3 months, all of them developed
left ventricular hypertrophy and renal damage and potential gallbladder sludge by day 56, but so had three of six control
to exacerbate congestive heart failure if present due to cardiac dogs; no significant differences were seen between groups at
disease. Blood pressure should be measured in dogs diagnosed any sampling time. Solutes associated with gallbladder sludge in
with HAC especially because severe hypertension may occur. If humans (i.e., bilirubin, cholesterol, and calcium) were decreased
the hypertension is mild (e.g., < 180 mm Hg systolic), therapy by hydrocortisone administration (Kook etal, 2011). However,
for HAC can be initiated and the blood pressure reevaluated the study by Kook and colleagues was small, and HAC could
after control is obtained; antihypertensive therapy can then be lead to mucocele formation by other mechanisms (e.g., changes
|
in gallbladder motility or in glycoproteins, such as mucin) (Kook complexes, may be signicantly increased in dogs with HAC,
etal, 2011; Mesich etal, 2009). and inhibition of brinolytic activity is not associated with HAC
(Jacoby etal, 2001; Pace etal, 2013). Changes in thromboelastog-
raphy consistent with hypercoagulability can also occur in dogs
Pulmonary Thromboembolism
with HAC (Pace etal, 2013; Park et al, 2013; Rose et al, 2013).
PTE is a complication of hypercoagulability, blood stasis, and However, not all dogs with HAC have changes consistent with
damage to the endothelial lining of blood vessels (LaRue and hypercoagulability; for those that do, no specific, consistent pat-
Murtaugh, 1990) and ranges in importance from incidental and tern can be identified. Furthermore, evidence of hypercoagulabil-
clinically irrelevant thromboembolism to massive embolism with ity has not been shown to have a clinical correlation with PTE
sudden death. Hypercoagulability leads to thrombi formation in (i.e., many dogs have at least one marker of hypercoagulability,
the leg, pelvic, and arm veins of people with proximal extension but PTE secondary to HAC is considered rare).
as clots propagate. As thrombi form in the deep veins, they may Severe PTE is one of the few complications of HAC that can
dislodge and embolize to the pulmonary arteries. Pulmonary arte- be fatal. Occurrence of PTE should be considered in all dogs with
rial obstruction and platelet release of vasoactive agents, such as HAC that acutely develop tachypnea, orthopnea, and/or dyspnea.
serotonin, worsen pulmonary resistance. The resulting increase in Anecdotally, PTE is believed by some to be more common after
alveolar dead space and redistribution of blood flow creates areas adrenalectomy or after initiation of medical therapy for HAC.
with ventilation to perfusion mismatch, impairs gas exchange, and Thoracic radiography is an important component of the evaluation
stimulates alveolar hyperventilation. Reflex bronchoconstriction of any dyspneic animal. Radiographs of dogs with PTE may reveal
augments airway resistance. Lung edema (if present) decreases pleural effusion, loss of the pulmonary artery, alveolar inltrates,
pulmonary compliance. As right ventricular afterload increases, cardiomegaly, hyperlucent lung elds, enlargement of the main
right ventricular wall tension rises, possibly leading to right ven- pulmonary artery, or no abnormalities (Johnson et al, 1999).
tricular dilation, dysfunction, and ischemia (Goldhaber, 1998). Alternatively, increased diameter and blunting of the pulmonary
PTE is a potential complication of HAC (Keyes et al, 1993; arteries, lack of perfusion of the obstructed pulmonary vascula-
Teshima etal, 2008; Sobel and Williams, 2009), as well as several ture, and overperfusion of the unobstructed pulmonary vascula-
other disorders (Box 10-2), and is due, at least in part, to HAC- ture may be seen (Fig. 10-23). Normal thoracic radiographs in a
induced hypercoagulability. Humans with HAC are four times dyspneic patient that lacks large airway obstruction may be con-
more likely to suffer thromboembolic complications than the gen- sistent with PTE. Further discussion of PTE is beyond the scope
eral population (Meaney etal, 1997). Patients who undergo surgery of this chapter.
for HAC are specically predisposed to thrombosis (Reitmeyer etal,
2002). Other factors present in dogs with HAC that may predispose SPECIFIC EVALUATION OF THE
patients for PTE are obesity, hypertension, increased hematocrit PITUITARY-ADRENOCORTICAL AXIS
(resulting in vascular stasis), and prolonged periods of recumbency.
Although overall it appears that dogs with naturally occurring A suspicion of HAC should be established from the history,
HAC have hypercoagulable tendencies, study results have been physical examination ndings, results of routine laboratory tests
inconsistent. No evidence of hypercoagulability was found in (CBC, serum biochemistry prole, and urinalysis), radiographs,
one study, but it included only nine dogs with untreated HAC and/or ultrasonography. Confirmation of a diagnosis of HAC
and may have been underpowered (Klose etal, 2011). Levels of
procoagulation factors II, V, VII, IX, X, XII, and brinogen are
signicantly increased in dogs with HAC (Feldman etal, 1986;
Jacoby etal, 2001). Antithrombin, an anti-thrombotic agent, was
signicantly decreased in one study, which could allow clot forma-
tion (Jacoby etal, 2001); however, other studies did not find the
same (Feldman etal, 1986; Pace etal, 2013; Park etal, 2013). A
marker of subclinical thrombosis, thrombin-antithrombin (TAT)
BOX 10-2 P
rimary Clinical Disorders in 29 Dogs
with Pulmonary Thromboembolism*
Immune mediated hemolytic anemia

Neoplasia
Systemic bacterial disease
Sepsis
Pneumonia
Pyothorax
Endocarditis
Hyperadrenocorticism (HAC)
Amyloidosis (protein-losing nephropathy)
Cardiomyopathy
Megaesophagus
FIGURE 10-23 Dorsoventral thoracic radiograph of a dog with pulmonary throm-
*Modified from Johnson LR, etal.: Pulmonary thromboembolism in 29 dogs: boembolism (PTE) that resulted in a focal area of density, which is outlined by
1985-1995, J Vet Intern Med 13:338, 1999. the arrows.
must be done with specific endocrine tests. The evaluation for can predict the size of a pituitary tumor. In order to determine if a
HAC proceeds through two basic steps of screening and differ- macroadenoma is present, imaging must be performed.
entiating. Screening tests (e.g., LDDST, ACTH stimulation test, It must be emphasized that the decision to treat a dog for HAC
and UC:CR measurement) conrm or rule out the existence of should never be based solely on laboratory results. If a dog has no
HAC. If a diagnosis of HAC is confirmed, the second step is to clinical signs, treatment is not recommended (see later).
perform a biochemical differentiating test or imaging to distin-
guish between PDH and AT.
Sensitivity and Specicity
The mainstay of diagnostic procedures is measurement of
plasma, serum, or urine cortisol concentrations. Assays for cor- In order to understand how good a test is, comprehension of the
tisol include radioimmunoassay (RIA), enzyme-linked immuno- statistical terms sensitivity and specificity is helpful. Sensitivity is
sorbent assay (ELISA), and chemiluminescence. To the authors the percentage of individuals with the disease who are correctly
knowledge, data regarding in-house cortisol measurements have identified by the test. It reflects the false-negative rate. For exam-
not been reported in the peer-reviewed literature. ple, if the LDDST is 95% sensitive for diagnosing HAC, of all
For measurement of cortisol in blood, serum or plasma can be dogs with the disease, 95% have abnormal LDDST results con-
used. The samples should be centrifuged within 2 hours of collec- sistent with HAC, and the other 5% do not (i.e., the test is false
tion. Cortisol concentrations in plasma are stable, and cooling of negative in 5% and the diagnosis would be missed). Specificity
the sample is not necessary; serum, however, should be shipped is the percentage of individuals without the disease who have a
cold (Reimers etal, 1991; Behrend etal, 1998). However, to best negative result. It reflects the false-positive rate. For example, if
ensure adequate sample integrity, after centrifugation, samples the ACTH stimulation test has a specificity of 86% for diagnosing
should either be refrigerated for up to 24 hours or frozen for lon- HAC, of all dogs with a negative ACTH stimulation test result,
ger at 20 C. Urine can be stored at 4 C for up to 4 days or 86% do not have the disease, and 14% have a false-positive result.
at 20 C for more than 5 days. Samples should be sent to the Sensitivity and specicity are never 100% for any test. Therefore,
laboratory overnight; sample type will not matter, and no special more than one screening test may be necessary for the diagnosis of
packaging is needed (Behrend etal, 2013). HAC, especially in dogs without classic clinical signs of the disease
The extent to which lipemia and hemolysis interfere with assay or in those with known non-adrenal disease (e.g., diabetes mel-
performance is assay-dependent. Exogenous glucocorticoids can litus). If a test is negative but suspicion for HAC remains, another
interfere with measurement of cortisol in two ways. First, cer- test should be performed. If more than one test is negative, the
tain synthetic glucocorticoids (e.g., hydrocortisone, prednisone, possibility that the patient does not have HAC must be consid-
prednisolone, and methylprednisolone) can cross-react in cortisol ered. Alternatively, the patient may have mild HAC and the tests
assays, falsely elevating the apparent cortisol concentration. The have not yet become positive. It may be worthwhile to retest in 3
degree of cross-reactivity is assay-dependent. To avoid cross-reac- to 6 months if clinical signs progress.
tivity, no synthetic glucocorticoid that cross-reacts should be given
for at least 12 hours before a sample is drawn for measurement of
Special Considerations
cortisol; a 24-hour withdrawal can be observed for greater assur-
ance that the synthetic glucocorticoid has been cleared. Second, Phenobarbital Administration
exogenous glucocorticoids can exert negative feedback on the Side effects of phenobarbital include polydipsia, polyuria, and
hypothalamic-pituitary-adrenal axis and cause adrenocortical atro- polyphagia. In addition, phenobarbital administration can cause
phy, suppressing cortisol concentrations. The amount of time nec- increases in serum ALP activity (Foster et al, 2000b; Muller
essary for recovery of the hypothalamic-pituitary-adrenal axis after et al, 2000b). Thus, suspicion of HAC can arise in dogs receiv-
discontinuation of exogenous glucocorticoid therapy is unpredict- ing phenobarbital therapy. Unfortunately, confirmation of HAC
able and variable depending on patient factors, the dose and form in phenobarbital-treated dogs is challenging. Although no effect
of glucocorticoid, and the duration of therapy (see Chapter 14). of phenobarbital on LDDST results overall has been docu-
In the following section, reference ranges will not be provided. mented, occasional phenobarbital-treated dogs may not show
Each laboratory must establish its own. Measured concentrations suppression (Chauvet et al, 1995; Foster et al, 2000a; Muller et
can vary between methods and even between laboratories using al, 2000b). No effect on the ACTH stimulation test was docu-
the same method (Behrend etal, 2013). mented overall or individually in healthy dogs treated with phe-
nobarbital for 8 weeks (n = 12) (Dyer etal, 1994) or 29 weeks (n
= 12) (Muller etal, 2000a), or in epileptic dogs treated for 1 year
SCREENING TESTS: CONFIRMING A DIAGNOSIS
(n = 5) (Chauvet etal, 1995) or more than 2 years (n = 5) (Dyer
OF HYPERADRENOCORTICISM
etal, 1994). Thus, if a dog on phenobarbital is suspected to have
Screening tests for spontaneous HAC aid in distinguishing dogs with HAC, consideration should be given to switching to another anti-
HAC from dogs that do not have HAC. Diagnosis of HAC depends convulsant. If clinical and laboratory abnormalities persist, sub-
on demonstration of either 1) increased cortisol production, or 2) stantiating the suspicion of HAC, testing may then be performed.
decreased sensitivity of the hypothalamic-pituitary-adrenal axis to If discontinuation of phenobarbital is impossible, LDDST results
negative glucocorticoid feedback. Routinely used screening tests should be interpreted cautiously (Behrend etal, 2013). An ACTH
include the ACTH stimulation test, LDDST, and the UC:CR. No stimulation test may be better in dogs on phenobarbital, but the
test has 100% diagnostic accuracy, and all can have false-positive lower sensitivity of the test (see later) must be considered.
results (i.e., a dog that does not have HAC has a test consistent
with the diagnosis) and false-negative results (i.e., a dog with HAC Dogs with Known Disease, Especially Diabetes Mellitus
has normal test results). In some cases, more than one test must be Suspicion of HAC can arise in dogs known to have a non-adre-
done to fully rule in or rule out a diagnosis of HAC. Positive and nal illness (NAI) (e.g., diabetes mellitus). Many illnesses affect
negative predictive values are dependent upon disease prevalence. results of HAC screening tests (Chastain et al, 1986; Kaplan et
In a population appropriately screened so that disease prevalence al, 1995; Gieger et al, 2003; Boozer et al, 2006). The likelihood
is high, diagnostic tests will be more accurate. No biochemical test of a false-positive result on a screening test can increase with the
|
severity of the non-adrenal disease (Kaplan et al, 1995). Some the effect of NAI on the results of screening tests should be kept
dogs with NAI can have positive test results on both the LDDST in mind and results interpreted cautiously.
and ACTH stimulation test and still not have HAC (Chastain
etal, 1986). The UC:CR measured on a single urine sample is the Urine Cortisol-to-Creatinine Ratio
least specific test when NAI is present (Kaplan etal, 1995; Gieger
etal, 2003). The UC:CR can be used to screen for HAC as an assessment of
Ideally, testing for HAC should be avoided if serious NAI exists. adrenocortical reserve. The advantages are that the test is safe and
Testing for HAC is not mandatory at the time suspicion arises. easy, has a high sensitivity, and is relatively inexpensive. Measure-
Postponing testing until concurrent illnesses are resolved or con- ment of the UC:CR can also be combined with dexamethasone
trolled is recommended, but the severity of the concurrent illness suppression testing, providing a differentiation test as well (see
must be considered. In addition, some diseases cannot be resolved later). The main disadvantage is that the specificity can be quite
(e.g., diabetes mellitus). At the least, the non-adrenal disease low, depending on the laboratory performing the testing. The
should be controlled as best as possible before testing for HAC. UC:CR without dexamethasone suppression can never differenti-
The degree of suspicion for HAC must be considered. Cer- ate between PDH and AT.
tain diseases can have similar clinical signs. For example, diabetic
patients will have polyuria/polydipsia and polyphagia, hepato- Protocol
megaly, and increased serum ALP activity. A strong suspicion for A single, midstream free-catch urine sample is used. The urine
HAC in a diabetic should be built on the presence of clinical signs should be centrifuged and at least 1.0 mL of supernatant submit-
that are typical of HAC but not diabetes mellitus (e.g., bilater- ted. To avoid the influence of stress, urine for a UC:CR should
ally symmetrical alopecia or calcinosis cutis). If solid suggestion be collected at home at least 2 days after a visit to a veterinary
of HAC exists, diagnostic testing can be pursued earlier. However, clinic (Fig. 10-24) (van Vonderen etal, 1998). Although a UC:CR
30,0 30,0
Urinary C/C ratio (106)

20,0 20,0
10,0 10,0
0,0 0,0
1 2 3 4 1 2 3
A Days B Days
30,0 Hospitalization
20,0
10,0
0,0
1 2 3 4
C Days
FIGURE 10-24 A, Urine cortisol-to-creatinine ratio (UC:CR) measured in 19 healthy pet dogs before and after a visit to
a veterinary practice for yearly vaccination. The arrow indicates the time of the visit to the veterinary practice. The line
indicates the upper reference limit of the assay. B, UC:CR measured in 12 pet dogs before and after a visit to a referral
clinic for orthopedic examination. The arrow indicates the time of the visit to the referral clinic. The increase in the
UC:CR on day 3 in one dog was most probably caused by an additional visit to a veterinary hospital. The line indicates
the upper reference limit of the assay. C, UC:CR measured in nine healthy pet dogs before, during, and after a 1-day
hospitalization at a referral clinic. The line indicates the upper reference limit of the assay. (From van Vonderen IK,
etal.: Influence of veterinary care on the urinary corticoid-to-creatinine ratio in dogs, J Vet Intern Med 12:431, 1998.)
sample can be collected at any time of day (Zeugswetter et al, Consequently, with assays currently available commercially, in the
2010), morning urine may be preferred, because it usually United States and Canada, a UC:CR is a good way to rule out the
represents several hours of urine production. diagnosis of HAC but not to rule it in. With a sensitivity of more
than 90%, it would be very unlikely that patients with a normal ratio
Interpretation would have HAC. However, because one study found the sensitiv-
Urine cortisol excretion increases as a reflection of augmented ity of the UC:CR to be 75% (Kaplan etal, 1995), any dog with a
adrenal secretion, adjusting for fluctuations in blood concentra- normal UC:CR for which there is a high suspicion of HAC should
tions. Because creatinine excretion is relatively constant and kid- be further evaluated by an LDDST or ACTH stimulation test. Due
ney function is stable, dividing the urine cortisol concentration by to the low specificity, an elevated UC:CR is not diagnostic for HAC.
the creatinine concentration negates the effect of urine volume in As a result, in patients with an elevated UC:CR, a diagnosis of HAC
interpreting urine cortisol concentration. must always be confirmed with a LDDST or ACTH stimulation test.
Statistics
Adrenocorticotropic Hormone Stimulation Test
In one study of dogs with physical and biochemical changes con-
sistent with HAC, the sensitivity of finding two basal UC:CRs The ACTH stimulation test assesses adrenocortical reserve. It is
above the cutoff level was 99%, and the specificity was 77% (Rijn- the gold standard for diagnosis of iatrogenic HAC, and it is the
berk etal, 1988a). In some dogs, considerable day-to-day varia- only test recommended for monitoring response to therapy for
tion exists in the UC:CR. In mild cases, a UC:CR may be just HAC. With regard to its use as a screening test for HAC, the
within the reference range 1 day and increased another day. advantages are that the test is safe, simple, and not time-consum-
The assay used by Rijnberk and colleagues was proprietary ing (lasting only 1 or 2 hours). The main disadvantage is a lower
and not available for use in the United States. In other studies, sensitivity than the LDDST, especially for dogs with an AT (see
when a single, random urine sample was collected in veterinary later). In addition, the ACTH stimulation test can never differen-
hospitals, the reported sensitivity and specificity of the UC:CR tiate between PDH and AT. Although in one study the responses
for diagnosis of HAC ranges from 75% to 100% (Stolp et al, in dogs with adrenal carcinoma were higher than dogs with an
1983; Smiley and Peterson, 1993; Kaplan et al, 1995; Jensen adrenal adenoma (Peterson etal, 1982b), no consistent difference
et al, 1997) and 20% to 25%, respectively (Stolp et al, 1983; was noted in another (Feldman, 1983b).
Feldman and Mack, 1992; Smiley and Peterson, 1993; Kaplan
et al, 1995; Fig. 10-25). Whether the assay used (Rijnberk etal, Protocol
1988a) or the collection of samples at home, or both, accounts The test can begin at any time of day and without patient prepa-
for the higher specificity is unknown. Which assay is used can ration. Numerous protocols have been published in healthy
significantly affect results of UC:CR measurement (Kolevska dogs and dogs with HAC. Synthetic polypeptides containing
and Svoboda, 2000). the biologically-active first 24 amino acids of ACTH are avail-
able (e.g., cosyntropin [Cortrosyn] or tetracosactide acetate
[Synacthen]). Although in healthy dogs, doses as low as 0.5 g/kg
432 maximally stimulate cortisol secretion (Martin etal, 2007), only
291 524 doses tested in dogs with HAC can be endorsed.
244
240 The currently recommended protocol is to administer 5 g/kg
Urine cortisol-to-creatinine ratio
200 cosyntropin or tetracosactrin intravenously with a maximum of

250 g per dog; samples for cortisol measurement should be drawn
160 before and 1 hour after administration (Kerl et al, 1999; Frank et al,
2000). Although cosyntropin can be administered intramuscularly
120 in normal dogs with the same effect (Behrend etal, 2006), the intra-
venous (IV) route is preferred to avoid issues with drug absorption.
Recently, a generic form, cosyntropin injection, was introduced for
80
IV use only. No differences in cortisol concentrations were found in
response to 250 g Cortrosyn intramuscularly (IM) or cosyntropin
40 injection IV in 18 healthy dogs (Cohen and Feldman, 2012). The
study, however, included only healthy dogs, and the dose used (250
0 g/dog) is higher than needed for the vast majority of dogs.
Apparently HAC Suspect HAC Non-adrenal Using a dose of 5 g/kg allows multiple uses of a single vial
healthy (25) (21) disease of cosyntropin. Cortrosyn can be reconstituted and frozen in
(31) (28) aliquots at 20o C in plastic syringes for 6 months (Frank and
FIGURE 10-25 Box plots of urine cortisol-to-creatinine ratios (UC:CRs) found in Oliver, 1998). Because the effect of thawing and refreezing has
apparently healthy dogs, dogs with hyperadrenocorticism (HAC), dogs in which not been investigated, the author recommends freezing in 50 g
HAC was initially suspected but that did not have the disease (suspect HAC), aliquots, thawing only those needed for a test. Whether Synacthen
and dogs with a variety of severe, non-adrenal diseases. The number of dogs in or cosyntropin injection can be frozen has not been investigated.
each group is shown in parentheses. The box represents the interquartile range In some countries, compounded ACTH preparations are avail-
from the 25th to 75th percentiles (the middle half of the data). The horizontal able. In healthy dogs, after administration of four compounded
bar through the box is the median. The upper whisker shows the 10th percentile products (2.2 U/kg IM), cortisol concentrations at 60 min were
and the lower whisker the 90th. Outlying data points are represented by the similar to each other as well as to concentrations after Cortrosyn
circles (exact value is given). (From Smiley LE, Peterson ME: Evaluation of a (5 g/kg IV). However, at later times cortisol concentrations varied
urine cortisol:creatinine ratio as a screening test for hyperadrenocorticism in considerably. Thus, if using compounded forms (2.2 U/kg IM), sam-
dogs, J Vet Intern Med 7:163, 1993.) ples should be collected before and at 1 and 2 hours after injection
|
(Kemppainen et al, 2005). Certain caveats exist. First, dogs with with HAC in the peer-reviewed literature, its use cannot be recom-
HAC were not included in the study. Second, a single vial of ACTH mended because the correct protocol in diseased dogs is unknown.
from each compounding pharmacy was used. Whether gels obtained
from any compounding pharmacy or even a different vial from the Interpretation
same compounding pharmacy would perform similarly is unknown. The absolute values for the pre- and post-ACTH cortisol concen-
A tetracosactrin depot product, (Synacthen depot), designed trations must be assessed. Evaluation of ratios or relative changes
for protracted tetracosactrin release, has been evaluated in healthy is not recommended. Some laboratories include a borderline
dogs. Peak cortisol response occurred at 120 to 180 minutes after range for results of the post-ACTH cortisol concentration; if a
administration (250 g/dog IM or 5 g/kg IM). In comparison, dogs results falls within the range, HAC, unfortunately, cannot
the peak response to a non-depot cosyntropin occurred earlier be ruled in or ruled out.
(i.e., at 60 to 90 minutes) and was significantly higher (Ginel etal, Dogs with PDH have bilateral adrenocortical hyperplasia with
2012). Because the depot form has not been evaluated in dogs an increased capacity to synthesize and secrete excessive amounts of
cortisol. Dogs with functioning ATs have a similar abnormal capac-
ity to synthesize and secrete excess cortisol. Therefore, dogs with
either PDH or AT have the potential for an exaggerated response to
ACTH stimulation (Fig. 10-26). In dogs with iatrogenic HAC, the
Plasma or serum cortisol concentration
adrenal cortex is suppressed by exogenous glucocorticoid adminis-

tration (see Chapter 14). Accordingly, endogenous cortisol concen-
trations are below the reference range, which is usually below the
ism sensitivity of the assay (Fig. 10-27). Iatrogenic HAC is diagnosed
rtic
o co on the basis of suppressed cortisol concentrations, the presence of
en
a dr clinical signs of HAC, and a history of exogenous glucocorticoid
er therapy by any route, including topical.
yp
u sh
neo Test Statistics
nta
po lth y The sensitivity of the ACTH stimulation test for canine HAC in
S Hea
general ranges from 57% to 95%. For dogs with HAC due to an
AT, sensitivity is 57% to 63%; for dogs with PDH it is 80% to
Iatrogenic hyperadrenocorticism 83%. Specificity ranges from 59% to 93% (Reusch and Feldman,
1991; Kaplan etal, 1995; van Liew, etal, 1997; Gieger et al, 2003;
Baseline Post stimulation
cortisol cortisol Behrend et al, 2005; Monroe et al, 2012).
Time
Influence of Drugs
FIGURE 10-26 Idealized plasma or serum cortisol concentrations measured be- Glucocorticoids of any form (see Chapter 14), progestagens
fore and after administration of synthetic adrenocorticotropic hormone (ACTH) (Selman et al, 1997), and ketoconazole (Willard et al, 1986)
in healthy dogs, dogs with spontaneous hyperadrenocorticism (HAC), and those suppress cortisol secretion. Phenobarbital has no known effect
with iatrogenic HAC. The gray area denotes the reference range. on the ACTH stimulation test.
ACTH stimulation test
Post-ACTH cortisol Post-ACTH cortisol Post-ACTH

below the within reference range cortisol above
reference range reference range
Addisons HAC Addisons HAC Addisons HAC

suspect suspect suspect suspect suspect suspect
Addisons 1. Exogenous glucocorticoid therapy Addisons Not consistent Addisons Consistent

(post-ACTH usually 2. Other medication ruled out with HAC ruled out with HAC
nondetectable) 3. Inactive ACTH
4. Inappropriate sampling
5. Wrong ACTH dose
6. AT (rare reason for result)
7. Spontaneous hypoadrenocorticism
FIGURE 10-27 Algorithm for interpretation of adrenocorticotropic hormone (ACTH) stimulation test results for di-
agnosis of (screening for) hyperadrenocorticism (HAC). (In Rand J, editor: Clinical endocrinology of companion
animals, Ames, IA, 2013, Wiley-Blackwell, p. 51.)
Results below the Reference Range is one of the two characteristics of HAC diagnosis. Additionally,
Occasionally in dogs being screened for HAC, a less than normal dexamethasone may be metabolized quicker in dogs with HAC
ACTH response occurs. The most likely possibility is that the dog than in healthy dogs (Kemppainen and Peterson, 1993). Two large
has received exogenous glucocorticoids, including topical. If glu- advantages of the LDDST are that the sensitivity for diagnosis of
cocorticoid therapy has been carefully ruled out, other possibilities HAC is high, and the test differentiates between PDH and AT in
exist (see Fig. 10-27): approximately 40% of dogs with HAC. It is considered safe even
1. The patient has received progestagens or ketoconazole or any though a single report exists of a dog that had a fatal anaphylactic
medication that suppresses cortisol secretion. reaction to dexamethasone (Schaer et al, 2005). The test is also
2. The ACTH used was inactive (e.g., the vial has expired, previ- relatively inexpensive. The disadvantages are that it has a lower
ously reconstituted cosyntropin was not stored correctly, or an specificity and it requires 8 hours to complete.
ineffective compounded formulation was used).
3.
The post-ACTH sample was collected at an inappropriate Protocol
time. With compounded forms, the peak response can occur To perform an LDDST, dexamethasone or dexamethasone
at 1 or 2 hours post-ACTH, even though most compounding sodium phosphate can be used as long as calculations are based on
pharmacies recommend only a 2-hour sample. If only a 2-hour the concentration of the active ingredient. Dexamethasone (0.01
post-ACTH sample is collected, the diagnostic cortisol con- to 0.015 mg/kg) is administered intravenously, and blood should
centration may be missed (Kemppainen etal, 2005). be drawn before and at 4 and 8 hours after injection (Behrend
4. The dose of ACTH was miscalculated and was too low. etal, 2013). Dexamethasone should be diluted in sterile saline, if
5. Infrequently, a subnormal ACTH response is seen in dogs necessary, for small dogs for accurate dosing. If part or all of the
with ATs. The most likely explanation in such cases is that dexamethasone is given out of the vein, the test should be stopped,
the AT is secreting either a progestin (Norman etal, 1999), or and a period of at least 48 hours should elapse before reinjection.
a cortisol intermediate, such as corticosterone (Behrend etal,
2004; Frankot etal, 2012). Progestins and some cortisol inter- Interpretation
mediates bind the glucocorticoid receptor, so they can cause Lack of suppression on an LDDST is consistent with a diagnosis of
the clinical signs of HAC and exert negative feedback on the HAC. Normally, dexamethasone feeds back onto the pituitary turn-
pituitary, decreasing ACTH secretion. As a result, normal ad- ing off ACTH secretion for up to 24 to 48 hours (Toutain etal, 1983).
renocortical tissue atrophies and endogenous cortisol concen- When systemic ACTH concentration falls, the secretory stimulus to
trations are below the reference range. the adrenal cortex diminishes, and cortisol release decreases. Thus,
6. The patient has spontaneous hypoadrenocorticism. This would in normal dogs, plasma cortisol concentration 4 and 8 hours after
be unlikely because the clinical signs, for the most part, are not dexamethasone is below the laboratory cutoff (e.g., < 1 to 1.5 g/dL
similar to those of HAC. [30 to 45 nmol/L]). Conversely, a diagnosis of HAC is supported by
an 8-hour post-dexamethasone plasma cortisol concentration above
the laboratory cutoff (Fig. 10-28). With PDH, the pituitary tumor
Low-Dose Dexamethasone Suppression Test
is relatively resistant to feedback. Thus, some ACTH secretion per-
The LDDST demonstrates decreased hypothalamic-pituitary- sists despite the dexamethasone injection and, in turn, cortisol release
adrenal axis sensitivity to negative glucocorticoid feedback, which continues. For patients with an AT, endogenous ACTH (eACTH)
LDDST
8-hr sample lab cut-off* 8 hr sample lab cut-off*
Not consistent with HAC Consistent with HAC
4 hr lab cut-off* 4 hr lab cut-off 4 hr sample lab cut-off*

AND/OR
4 and/or 8 hr sample 50% baseline?
Rule out HAC Suspicious for but Yes No

not diagnostic
of PDH; further
FIGURE 10-28 Algorithm for interpretation of low-dose testing suggested
Consistent PDH or AT
dexamethasone suppression test (LDDST) results for di- with PDH
agnosis of (screening for) hyperadrenocorticism (HAC).
(Modified from Rand J, editor: Clinical endocrinology of
companion animals, Ames, IA, 2013, Wiley-Blackwell, Options:
* Check with own lab for value; usually
eACTH
p. 50.) AT, Adrenocortical tumor; eACTH, endogenous approximately 1 to 1.5 mg/dL (30 to 45 nmol/L)
HDDST
ACTH; HDDST, high-dose dexamethasone suppression Imaging
test; PDH, pituitary-dependent hyperadrenocorticism.
|
is already suppressed due to continuous, autonomous cortisol secre-

Tests Not Recommended as Screening Tests
tion from the tumor. Dexamethasone has no further effect on the
pituitary, and adrenal cortisol secretion continues. Resting (Baseline) Cortisol Concentrations
Cortisol is secreted episodically; thus, values change throughout
Statistics the day. Although mean daily cortisol concentration is increased
The reported sensitivity and specificity of the LDDST ranges from in dogs with HAC, an individual, random measurement can be
85% to 100% and from 44% to 73%, respectively (Feldman, within the reference range. Conversely, dogs without HAC can
1983a; Chastain et al, 1986; Rijnberk et al, 1988a; Reusch and Feld- have elevated baseline cortisol concentrations (Chastain et al,
man, 1991; Kaplan et al, 1995; Feldman et al, 1996; van Liew et al 1986; Church etal, 1994).
1997; Mueller et al, 2006). By combining previous reports, it was
determined that 640 tests were positive in 673 dogs for an overall Serum CorticosteroidInduced Alkaline Phosphatase Activity
sensitivity of 95.1% (Behrend and Kemppainen, 2001). In general, As with total ALP activity, CIALP activity is elevated in most
the more severe the NAI present, the more likely a false-positive dogs with HAC or in dogs that have received exogenous glu-
test result (i.e., the lower the specificity) (Kaplan etal, 1995). Stress cocorticoids. Unfortunately, the specificity of CIALP activity
during a test may also potentially affect results (May etal, 2004). measurement for the diagnosis of HAC is low (Fig. 10-29). In
general, CIALP appears in a large number of samples when
Inverse Pattern ALP is high for any reason (Eckersall etal, 1986) and can have
An inverse pattern, in which the cortisol concentration 8 hours CIALP accounting for at least 50% of the total (Eckersall et al,
after dexamethasone was within the reference range (i.e., sup- 1986; Kidney and Jackson, 1988; Wilson and Feldman, 1992;
pressed) but the cortisol concentration 4 hours post-dexametha- Solter etal, 1993). More importantly, dogs likely to be screened
sone was increased, was described in five dogs with PDH (Mueller for HAC (e.g., those with diabetes mellitus or hypothyroidism
etal, 2006). Thus, although the inverse pattern is not diagnostic or those given exogenous glucocorticoids or phenobarbital)
for HAC, it is highly suspicious. If the inverse pattern is obtained can have elevated ALP levels with greater than 50% CIALP
in a dog screened for HAC, further testing should be pursued. activity (Kidney and Jackson, 1988; Teske et al, 1989; Wil-
son and Feldman, 1992). Conversely, some dogs with HAC
Influence of Drugs have little to no CIALP elevation (Kidney and Jackson, 1988;
Dexamethasone is metabolized primarily by cytochrome P450 3A4. Teske et al, 1989). Overall, the sensitivity of elevated CIALP
Agents that increase the enzymes activity (e.g., carbamazepine, phe- activity for glucocorticoid exposure (i.e., HAC or glucocorti-
nytoin, rifampicin, and barbiturates) accelerate dexamethasone clear- coid therapy) is approximately 95%, but the specificity may
ance and could cause false-positive results on an LDDST. In veterinary be as low as 18% (Teske et al, 1989; Wilson and Feldman,
medicine, only phenobarbital has been studied. Although no overall 1992).
effect of phenobarbital on LDDST results has been found, occasional
phenobarbital-treated dogs may not show suppression (Chauvet etal, Abdominal Ultrasonography
1995; Foster et al, 2000a; Muller et al, 2000a). Although dogs with HAC have adrenal gland measurements
significantly greater than those of normal dogs (Barthez et al,
Combined Dexamethasone Suppression/ 1995; Widmer and Guptill, 1995; Grooters et al, 1996; Hoerauf
Adrenocorticotropic Hormone Stimulation Test and Reusch, 1999; Choi et al, 2011), an overlap in the range
of measurements occurs between dogs with HAC and normal
The test combines a screening test (ACTH stimulation test) and dogs. Thickness (i.e., the dorsoventral dimension) has been sug-
a differentiating test (high-dose dexamethasone suppression test gested to be a better assessment of enlargement (Grooters etal,
[HDDST]) with the aim of diagnosing and differentiating in one test. 1994; 1995; 1996) , but overlap still exists between normal
To perform the test, dexamethasone (0.1 mg/kg IV) is administered dogs and dogs with PDH (Grooters etal, 1996). In addition,
with a blood sample taken before and 2 to 6 hours later (Zerbe, 2000). the finding of an AT is not synonymous with HAC. Ultraso-
Immediately after the second blood sample an ACTH stimulation test nography cannot distinguish a functional AT from a nonfunc-
is performed. The arms of the test are interpreted as for the individual tional tumor, a pheochromocytoma, a metastatic lesion, or a
tests (i.e., HDDST and ACTH stimulation test) and with the same granuloma.
reference ranges. Test sensitivity has been estimated at 76% (Feldman,
1985), 86% (Feldman, 1986), and 93% (Zerbe, 2000). The author
DIFFERENTIATING PITUITARY-DEPENDENT
of the former two studies, therefore, concluded that due to the lower
HYPERADRENOCORTICISM AND
sensitivity, the test was not helpful and could not be advocated.
ADRENOCORTICAL TUMOR
Part of the confusion may result in how the test is interpreted. If
the test is evaluated as a whole (i.e., a diagnosis of HAC is made if Differentiating tests should only be done after a screening test has
a dog does not suppress in response to dexamethasone and has an confirmed the presence of HAC; differentiating tests cannot be
elevated response to ACTH), then the sensitivity is relatively low. interpreted if the diagnosis of HAC is in question. It is important
However, if the diagnosis is made on the basis of the ACTH stimula- to differentiate PDH and AT because treatment and prognosis
tion portion alone, the sensitivity would be the same as performing differ. No clinical or routine biochemical features exist that aid
an ACTH stimulation test without previous dexamethasone injec- in distinguishing dogs with functioning adrenal adenomas from
tion (as long as the ACTH is given within 8 hours of the dexametha- those with adrenal carcinomas. Laboratory test options for dif-
sone [Kemppainen and Sartin, 1984b]). Thus, the combined test ferentiating include the HDDST and measurement of eACTH
is subject to all of the caveats as the ACTH stimulation test alone. concentration. In some cases, the LDDST may provide the differ-
The dexamethasone suppression portion can then be viewed as a entiation as well as the diagnosis. Imaging can also be performed
standalone differentiation test. However, the HDDST is not perfect to distinguish PDH and AT. As with the screening tests, no test is
either, and differentiation is not always achieved (see later section). 100% accurate.
100
10,000 11,988
90
4,560
3,060
2,578 2,334 80
1,683
1000
756 70
Percentage CIALP of total ALP

634
60
Total CIALP (IU/L)
100
69 50
40
10
6
30
1 20
10
0.1 0.1
0.1 0.1
Spontaneous Exogenous Liver Diabetes Spontaneous Exogenous Liver Diabetes
A hyperadreno- glucocorticoid disease mellitus B hyperadreno- glucocorticoid disease mellitus
corticism therapy corticism therapy
FIGURE 10-29 A, Mean and range of serum corticosteroid-induced alkaline phosphatase (CIALP) activity in dogs
with naturally occurring hyperadrenocorticism (HAC), chronically treated with glucocorticoids, with liver disease,
and with diabetes mellitus. B, The percentage of total serum alkaline phosphatase (ALP) activity accounted for by
the CIALP fraction in the same four groups described in A. These graphs show that CIALP is a sensitive indicator of
HAC (dogs with the disease usually have an elevated activity), but it is not a specific test (dogs with other condi-
tions also can have a markedly elevated CIALP activity).
Suppression 86/109 (79%)

111/178 (62%) had suppressed
110/111 = PDH on LDDS
FIGURE 10-30 A, Of 178 dogs with naturally occurring hyper-
adrenocorticism (HAC) that were tested with both the low-dose
and high-dose dexamethasone suppression tests (LDDST and
HDDST), 111 dogs suppressed using one of the criteria defined
in the text. Of the 111 dogs, 110 had pituitary-dependent hy-
No suppression
peradrenocorticism (PDH). Twenty-nine of 30 dogs (97%) with
67/178 (38%)
adrenal tumors did not suppress using any of the criteria, and 29/30 (97%) = ATH 22/109 (21%)
38 of the 148 dogs with PDH (26%) did not suppress. B, Of 38/148 (26%) = PDH Did not suppress
the 109 dogs that suppressed on the HDDST, 86 (79%) had on LDDS
already shown suppression on the LDDST. A B
Suppression Tests of baseline, either PDH or AT is possible. Approximately 60%

of dogs with HAC can be determined to have PDH using an
Low-Dose Dexamethasone Suppression Test LDDST (Fig. 10-30). However, if the baseline cortisol is already
If the 8-hour post-dexamethasone concentration is greater than less than the laboratory cutoff, these guidelines do not apply
the laboratory cutoff (e.g., > 1 to 1.5 g/dL [30 to 45 nmol/L]), (Norman etal, 1999). In rare cases, dogs with an AT may meet
results are consistent with HAC (see earlier; see Fig. 10-28). one of these criteria for diagnosing PDH (Norman etal, 1999).
If, additionally, the 4-hour post-dexamethasone concentration
is below the laboratory cutoff or if one or both post-dexametha- High-Dose Dexamethasone Suppression Test
sone concentrations is less than 50% of baseline, PDH is present Many of the advantages and disadvantages of the LDDST apply
(Feldman etal, 1996). If both post-dexamethasone concentra- to the HDDST. One disadvantage of the HDDST is that it can
tions are above the laboratory cutoff and neither is less than 50% never confirm the presence of an AT. If a dog does not suppress
|
HDDST normally under feedback control. Complete loss of feedback regula-

tion in an anterior pituitary tumor is also possible.
Comparison of the Low-Dose and High-Dose Dexamethasone

Suppression Test as Differentiating Tests
8-hr sample lab cut-off* 8 hr sample lab cut-off*
The largest study evaluating both suppression tests included
181 dogs with PDH and 35 with AT (Feldman et al, 1996).
Consistent with PDH Consistent with PDH or AT
Some dogs with a mitotane-responsive AT may have been
included in the PDH group. Approximately 75% of dogs with
PDH met at least one criterion for suppression on either the
4 hr sample lab cut-off*
LDDST or HDDST. Of dogs with PDH, 12% did not sup-
AND/OR press on an LDDST but did on the HDDST. Dexamethasone
4 and/or 8 hr sample 50% baseline resistance (i.e., no criteria were met on the LDDST) occurred
in all dogs with ATs and the remainder of the dogs with PDH.
Yes No
However, two dogs with AT did meet the criteria for suppres-
sion on the HDDST. The criteria proposed in this study still
Consistent PDH or AT are well accepted, although no follow-up studies have been
Different from LDDST with PDH performed for confirmation. In 41 dogs with ATs in another
study, 28 LDDST and 30 HDDST were performed (Reusch
* Check with own lab for eACTH and Feldman, 1991). No suppression was seen on any test.
value; usually approximately Imaging
1 to 1.5 g/dL (30 to 45 nmol/L) Dexamethasone Suppression with Urine Cortisol-to-Creatinine Ratio
FIGURE 10-31 Algorithm for interpretation of high-dose dexamethasone sup- Decreased blood cortisol concentration after dexamethasone
pression test (HDDST) results for differentiating between pituitary- and adrenal- administration is reflected in a decreased UC:CR. The advantage
dependent diseases. An HDDST should only be performed after a screening test of combining dexamethasone suppression with a UC:CR is that
has confirmed the presence of HAC. AT, Adrenocortical tumor; eACTH, endogenous potentially screening and differentiating can be done with a single
adrenocorticotropic hormone; LDDST, low-dose dexamethasone suppression test that is safe and easy to perform.
test; PDH, pituitary-dependent hyperadrenocorticism. (In Rand J, editor: Clinical Protocol. For the test, after collection of a morning urine sam-
endocrinology of companion animals, Ames IA, 2013, Wiley-Blackwell, p. 50.) ple on 2 consecutive days at home, three doses of dexamethasone
should be administered (0.1 mg/kg by mouth at 6- to 8-hour
intervals), and a third urine sample is collected the next morning.
on the HDDST, there is approximately a fifty-fifty chance that it Interpretation. The combination of dexamethasone suppres-
has PDH or AT, and another differentiation test must be done. In sion and UC:CR has been validated only using a proprietary as-
addition, if a diagnosis was made with the LDDST but a differen- say (see Urine Cortisol-to-Creatinine Ratio). Using this assay, a
tiation was not achieved, the HDDST is not likely to be able to decrease in the third UC:CR to less than 50% of the mean basal
differentiate either (Feldman etal, 1996), and another differentia- values is consistent with PDH (Galac etal, 1997). Lack of sup-
tion test should be pursued (see Fig. 10-30). pression does not confirm AT.
Protocol. The HDDST is performed similarly to the LDDST Statistics. In 160 dogs with HAC (49 with ATs and 111 with
with respect to the timing of samples, but the dose used is tenfold PDH), suppression to less than 50% of the basal UC:CR occurred
higher (i.e., 0.1 mg/kg dexamethasone). The free alcohol form of in 72% of dogs with PDH (Galac et al, 2009). The remaining
dexamethasone should be avoided (Behrend etal, 2013). If any dogs with PDH were dexamethasone-resistant. In dogs with ATs,
of the dexamethasone is given out of the vein, the test should be the maximum suppression was 44%.
stopped and started again after at least 72 hours.
Interpretation. Even though the ability of cortisol to suppress Discordant Test Results
ACTH secretion in dogs with PDH is abnormal, a large dose of Discordance between results of suppression tests and other dif-
dexamethasone may overcome the resistance to feedback. For dogs ferentiating tests may occur. Changes in dexamethasone metabo-
with an AT, a high dose of dexamethasone will have little to no effect lism may also influence results of suppression tests (Behrend etal,
on cortisol secretion, as for the low dose. Therefore, suppression to 2013) (see the next section).
either below the laboratory cutoff or to less than 50% of baseline
at either 4 or 8 hours post-dexamethasone is consistent with PDH Endogenous Adrenocorticotropic Hormone Measurement
(Fig. 10-31) (Feldman etal, 1996). Rarely dogs with an AT can
have suppression to the borderline of the cutoff between PDH and The advantages of measuring eACTH include the requirement
AT (Feldman etal, 1996). Therefore, when baseline values are close of a single sample, and the test can definitively diagnose an AT.
to the laboratory cutoff for a suppressed value or when suppression Measurement of eACTH is the most accurate standalone bio-
is just at 50%, the results are suspect and warrant confirmation. chemical test for differentiating PDH from AT. On the other
Statistics.In approximately 75% of dogs with PDH, cortisol hand, eACTH is labile, and specific, strict guidelines for han-
concentrations meet the criteria for suppression on a HDDST. The dling must be followed. Second, a grey zone exists in the results;
remaining dogs with PDH do not demonstrate suppression even af- if a measured concentration falls in the grey zone, a differen-
ter receiving higher dexamethasone dosages (Feldman etal, 1996). In tiation cannot be made. For example, at the Auburn Univer-
dogs with PDH that do not suppress, a large pituitary tumor is more sity Endocrine Diagnostic Service an eACTH concentration
likely (Kooistra etal, 1997b; Bosje etal, 2002). Additionally, lack of less than 10 pg/mL is consistent with an AT, whereas more than
response may be due to the pituitary tumor having arisen from the 15 pg/mL is consistent with PDH. The area between is a grey
intermediate lobe of the pituitary as compared with the anterior lobe zone. Although other laboratories may have different cutoffs,
(Peterson etal, 1986a; peterson, 1987). The intermediate lobe is not a grey zone will exist. Concentrations of eACTH do not differ
between healthy dogs and those with PDH, so measurement is

400
not useful to screen for HAC (Hanson etal, 2006).
300
RIA and chemiluminescent assays have been validated for
eACTH measurement (Kemmpainen et al, 1994; Scott-Moncrieff
200 et al, 2003; Rodriguez Pineiro et al, 2009; Zeugswetter et al,
2011). Measured concentrations are lower using chemilumines-
cent technology compared to RIA (Rodriguez Pineiro etal, 2009).
130
Protocol
120
Blood should be collected into chilled, silicon-coated glass or plastic
Plasma eACTH (pg/mL)
110 tubes containing ethylenediaminetetraacetic acid (EDTA), centri-

100
fuged within 15 minutes (ideally in a cooled centrifuge), and the
plasma transferred to plastic tubes and frozen immediately (Behrend
90 etal, 2013). Samples must stay frozen until analysis; if a courier is
80 used for quick transport to a reference laboratory, ice may be suffi-
cient. If samples are shipped, they should be sent overnight packed
70 in dry ice. Plasma proteases degrade eACTH rapidly if samples are
60 not cooled appropriately. Addition of the protease inhibitor apro-
tinin (Trasylol) prevents eACTH degradation (Kemppainen etal,
50 1994). With the Immulite assay, aprotinin introduces an artifactual
40 decrease (Scott-Moncrieff etal, 2003) and is not recommended.
30
No clear evidence exists that the specific time of sample col-
lection affects the results or discriminatory power of the test. In
20 healthy dogs, eACTH concentrations did not return to baseline
10 until 24 hours after performance of an ACTH stimulation test
and 12 hours after an LDDST (Bugbee etal, 2013).
Clinically Dogs with Dogs with
healthy pituitary-dependent adrenocortical tumor Interpretation
dogs hyperadrenocorticism In dogs with PDH, eACTH concentration is normal to elevated
FIGURE 10-32 Endogenous plasma adrenocorticotropic hormone (eACTH) concen- due to secretion from the pituitary tumor. In dogs with an AT, the
trations from clinically healthy dogs, dogs with pituitary-dependent hyperadre- autonomous tumoral secretion of cortisol turns off ACTH secre-
nocorticism (PDH) and dogs with cortisol-secreting adrenocortical carcinomas tion; eACTH concentration should be below normal (Fig. 10-32).
or adenomas. Each box represents the interquartile range from the 25th to 75th
percentiles (the middle half of the data). The horizontal bar through the box is the Statistics
median. The upper whisker indicates the 10th percentile, and the lower whisker The accuracy for differentiating PDH from AT depends upon the
indicates the 90th percentile. Outlying data points are represented by the circles. analytical sensitivity and working range of the assay (Table 10-6).
The most common problem with the eACTH assay is a poor work-
ing range at the lower end; some dogs with PDH have eACTH
concentrations at or below what the assay can measure accurately,
TABLE 10-6 R
ESULTS OF ENDOGENOUS ADRENOCORTICOTROPIC HORMONE ASSAYS FOR DOGS
WITH HYPERADRENOCORTICISM*
PITUITARY-DEPENDENT
STUDY ASSAY HYPERADRENOCORTICISM ADRENOCORTICAL TUMOR NUMBER INCORRECT
Zeugswetter etal, 2011 Immulite 1000 49 dogs 10 dogs 9/59
Rodriguez Pineiro etal, 2009 Immulite 2000 91 dogs 18 dogs 0/109
(6 to 1250 pg/mL) (< 5 pg/mL)
Castillo etal, 2009 Nichols IRMA 5 dogs NA NA
9 to 30 pmol/L
Scott-Moncrieff etal, 2003 Immulite ACTH IRMA 11 dogs 4 dogs
(Allegro) < 5 to 50 pg/mL < 10 pg/mL 4/15 (Immulite)
9 to 99 pg/mL < 10 pg/mL 3/15 (IRMA)
Gould etal, 2001 Nichols IRMA 21 dogs 5 dogs 2/28
28 to 1132 pg/mL < 5 pg/mL
1 dog 1 dog
< 5 pg/mL 76 pg/mL
From Behrend etal.: Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (Small animal),J Vet Int Med 27:1292, 2013.
ACTH, Adrenocorticotropic hormone; IRMA, immunoradiometric assay.
*Last 10 years with currently available assays only.
|
particularly with the Immulite 1000 analyzer. The largest study of to CRH and lysine vasopressin (LVP) were assessed in healthy dogs
eACTH in dogs with HAC used a two-site solid-phase chemilumi- and dogs with PDH or AT (van Wijk etal, 1994). Dogs with PDH
nescent immunometric assay (Immulite ACTH kit and Immulite had a greater response to vasopressin than to CRH, and AT cells
2000 analyzer) and showed excellent discrimination between PDH acquired sensitivity to LVP independent of ACTH. In another study,
and AT (Rodriguez Pineiro etal, 2009). No dogs with PDH had the response to desmopressin, a synthetic form of vasopressin, was
undetectable eACTH concentrations, which was likely due to the evaluated (Zeugswetter et al, 2008). Desmopressin was injected (4
analytical sensitivity (5 pg/mL); however, the range of eACTH con- g IV) with samples collected before and after 30, 60, and 90 min-
centrations for dogs with PDH was 6 to 1250 pg/mL, with many utes. Desmopressin significantly stimulated cortisol secretion in dogs
dogs falling close to the lower end of the range. Thus, less sensitive with PDH but not in dogs with ATs or other diseases. Using a cut-
assay systems (e.g., Immulite 1000) would likely have poorer dis- off value of a 10% increase over baseline, it was possible to exclude
crimination. Intra-assay and inter-assay variability (increased at lower the presence of an AT in 75% of patients (Zeugswetter etal, 2008).
eACTH concentrations), pulsatile ACTH secretion, and inappropri- However, because only seven dogs with ATs were included, further
ate sample handling allowing ACTH degradation increase the likeli- study is needed for verification. In addition, the test does not appear
hood of a falsely low value in dogs with PDH (Behrend etal, 2013). to provide much benefit over other biochemical differentiating tests.
When study results were combined, 240 (82%) of 292 tests in
245 dogs were diagnostic for PDH or AT. With repeat testing DIAGNOSTIC IMAGING
when the initial result was in the grey zone, 235 out of 245 dogs
(96%) had a definitive differentiation (Behrend and Kemppainen, Radiography
2001). Unfortunately there is no way to predict when a blood
concentration will be in the diagnostic range. Screening
Diagnosis of HAC cannot be done solely with imaging and must
Discordant Test Results rely on hormone tests. Moreover, finding normal-sized adrenal
Discordance between eACTH concentration and results of other glands does not rule out HAC (Behrend etal, 2013).
differentiating tests sometimes occurs. Episodic eACTH secre- Bronchial mineralization can be seen on thoracic radiographs
tion, poor assay sensitivity, and sample degradation are potential and is consistent with a diagnosis of HAC. Changes consistent with
explanations. Stress and the presence of multiple adrenal disorders PTE may be seen (see earlier section). If an AT is present, three-view
(e.g., PDH with pheochromocytoma or a cortisol-secreting AT thoracic radiographs should be taken for assessment; pulmonary
with PDH) may also influence ACTH concentrations (Behrend metastases uncommonly occur with ATs (Anderson et al, 2001;
etal, 2013). Ectopic ACTH secretion and food-stimulated cortisol Kyles etal, 2003; Schwartz etal, 2008; Arenas etal, 2014).
secretion could also cause discordance (Galac etal, 2007; 2009). Changes associated with HAC that may be seen on abdominal
radiographs include hepatomegaly, a pendulous abdomen, and dys-
trophic mineralization of structures, such as the renal pelvis, liver,
Corticotropin-Releasing Hormone and Vasopressin
gastric mucosa, and abdominal aorta (Penninck et al, 1988; Berry
Response Testing
et al, 1994; Schwarz etal, 2000). Hepatomegaly is quite common
Pituitary corticotropes respond to CRH and vasopressin. Accord- (Penninck etal, 1988); conversely, finding a small liver makes HAC
ingly, CRH and vasopressin stimulation tests have been evaluated as unlikely (Schwarz et al, 2000). Good contrast, due to abdominal
a differentiating test for HAC. Plasma ACTH and cortisol responses (primarily omental) fat deposition, is usually observed (Fig. 10-33).
B
FIGURE 10-33Lateral (A) and ventrodorsal (B) abdominal radiographs of a dog with a functioning adrenal tumor
causing hyperadrenocorticism (HAC). Note the calcified adrenal tumor (arrows), hepatomegaly, and excellent con-
trast due to fat mobilization.
Left adrenal - 5 mm Right adrenal - 6 mm
A B
FIGURE 10-34 A, The left adrenal gland is located craniomedial to the left kidney and ventrolateral to the aorta
between the caudal mesenteric and renal arteries. The typical shape is that of a peanut or dumbbell. The cursors
are measuring the thickness of the caudal pole. B, The right adrenal gland has a variable shape including that
of a comma or boomerang. Because of the shape, it is difficult to image the entire gland in one plane. The
extremities of the gland are often not symmetrical. The cursors are measuring the thickness of the caudal pole.
The images were obtained in the sagittal plane with the dog in dorsal recumbency. The normal size of the adrenal
glands is highly variable between dogs for both width and length. The most commonly cited value for the upper
limit of normal is 7.4 mm in the dorsoventral dimension. (Images courtesy of Dr. Robert Cole.)
Osteopenia occurs with HAC from hypercalciuria, suppressed intes- fundus or intestines, large body size, obesity, abdominal lymph-
tinal calcium absorption, and direct effects of cortisol on bone, but it adenopathy or masses, renal mineralization, or liver disease can
is usually mild and clinically unimportant. Uncommonly, calcinosis prevent or complicate evaluation. Body size affects the ability to
cutis may be noted (see Fig. 10-19). examine the right adrenal gland more than the left.
All thoracic and abdominal radiographic findings are not spe- In healthy dogs, the left adrenal gland has a peanut or dumb-
cific for HAC, and osteopenia can be easily misdiagnosed in any bell shape when imaged in a sagittal plane, and the right adrenal
obese animal due to radiographic artifact (Schwarz etal, 2000). gland has a V or comma shape when imaged in a mediolateral plane
Therefore, these radiographic findings may increase the suspicion (Fig. 10-34). The contour of the glands should be smooth, and the
for HAC but would not aid in confirmation or differentiation. parenchyma should be homogeneous and less echogenic than the
Abdominal radiography can be helpful in differentiation if an adjacent renal cortex (Voorhout, 1990; Grooters et al, 1995; 1996).
adrenal mass is found (see the following section). Because the adrenal glands long axis is often misaligned with either
the medial or dorsal plane of the body, cross-sectional images may
Differentiation lead to oblique views and miscalculation of glandular dimensions.
Besides identifying nonspecific changes consistent with HAC, In dogs with PDH, bilateral adrenal enlargement may be found
abdominal radiographs may be helpful for differentiation. In a (Fig. 10-35). The adrenal margins appear more rounded, and the
compilation of 94 ATs in 88 dogs (six dogs had bilateral adenomas glands subjectively may appear thicker, giving them a plump
or carcinomas), 50 ATs (53.1%) were detected due to calcification appearance compared with adrenal glands of normal dogs (Groot-
within the tumor (40) and/or visualization of a mass (17) (Behrend ers etal, 1996). Adrenal gland thickness (i.e., maximum dorsoventral
and Kemppainen, 2001). Tumors less than 20 mm in diameter are dimension of the adrenal gland in a sagittal plane) is the most infor-
not likely to be visualized (Voorhout etal, 1990). Both adenomas mative parameter for ultrasonographic assessment of the size of canine
and carcinomas can contain mineral densities or appear as a mass adrenal glands (Grooters etal, 1995; Barberet etal, 2010). The most
cranial to the kidney. Although diffuse, ill-defined mineralization accepted and commonly used measurement is a single cutoff value of
usually is associated with adrenal neoplasia discrete, well-marginated 7.4 mm for normal maximum diameter of the larger of the cranial
mineralization develops in clinically normal dogs and may be a or the caudal pole in either a sagittal or transverse plane regardless of
dystrophic change (Widmer and Guptill, 1995). Mineralization body weight. In studies, measurements greater than the cutoff had a
also rarely occurs in the adrenals of dogs with PDH (Grooters sensitivity of 77% and a specificity of 80% for the diagnosis of PDH
etal, 1996). In dogs with bilateral tumors, only one may be visu- (Widmer and Guptill, 1995; Barthez etal, 1995), but breed and dog
alized (Penninck et al, 1988; Reusch and Feldman, 1991; Ford et size was not taken into account. Body size may affect reference ranges
al, 1993). Consequently, finding one tumor does not rule out the (Barthez et al, 1995; Grooters et al, 1995; 1996; Douglass et al, 1997;
presence of bilateral disease, but bilateral tumors are rare. Choi etal, 2011). The adrenal glands of dogs with PDH are often
homogeneous and hypoechoic compared with adjacent renal cortices
(Gould etal, 2001). Alternatively, variably sized focal areas of increased
echogenicity may be seen. The areas represent either bilateral nodular
Ultrasonography has more application as a differentiating tool cortical hyperplasia, an uncommon form of HAC (see Adrenocortical
than radiography because both adrenal glands are routinely visual- Nodular Hyperplasia and Food-Dependent Hyperadrenocorticism),
ized by experienced ultrasonographers. Small or non-calcified ATs or calcification of adrenal tissue (Grooters etal, 1996).
can be detected, and bilateral adrenal enlargement can be docu- Asymmetry of shape within a single gland or of size between glands
mented in dogs with PDH. However, presence of gas in the gastric should not be interpreted as a tumor. Normal shape can vary (Fig. 10-36).
|
1
1
Right adrenal - 8 mm
A Left adrenal - 9 mm B
FIGURE 10-35 Bilateral adrenomegaly in a small breed dog with pituitary-dependent hyperadrenocorticism (PDH).
The left adrenal gland (A) measures 9 mm and the right adrenal gland (B) measures 8 mm in dorsoventral di-
mensions. Both adrenal glands, although enlarged, maintain a typical shape. Both adrenal glands are slightly
hypoechoic compared with normal; decreased echogenicity is often seen in patients with PDH. The images were
obtained in the sagittal plane with the dog in dorsal recumbency. (Images courtesy of Dr. Robert Cole.)
2
0
3
1
4
A Left adrenal B 2
2 Right adrenal - 6 mm
4
1
2
5
C D
7
FIGURE 10-36 Adrenal glands are often described as peanut- or dumbbell-shaped (i.e., centrally narrowed), as
shown in A. However, adrenal glands shapes are variable. Larger breed dogs often have adrenal glands that are
more linear in shape without the central narrowing as shown in B and C. The right adrenal gland often has a boo-
merang or comma shape giving the cranial pole a widened appearance (D). The images were obtained in the
sagittal plane with the dog in dorsal recumbency. (Images courtesy of Dr. Robert Cole.)
In some dogs, the cranial pole of the left adrenal is nearly twice as but an AT is not always seen. In studies compiling 71 dogs, 68
wide as the other regions. In the V-shaped right gland, the two sides of 79 (86%) tumors were found (eight had bilateral tumors)
may have different lengths (Grooters etal, 1995). The length of the (Behrend and Kemppainen, 2001). When the tumor was
two glands is typically not the same, and either the right or left gland missed, the affected adrenal gland appeared normal or was not
may be the longer (Douglass etal, 1997). In dogs with PDH, mild visualized (Kantrowitz et al, 1986; Reusch and Feldman, 1991;
asymmetry between the two glands may also occur (Benchekroun, Ford et al, 1993). The ultrasonographic appearance of an AT
2010; Rodriguez Pineiro et al, 2011). varies (Figs. 10-37 and 10-38). Moderate asymmetry, contralat-
Ultrasonography defines location, size, and organ involve- eral adrenocortical atrophy (adrenal width < 4 to 5 mm), and
ment of adrenal masses more precisely than radiography alone, destruction of normal tissue architecture are consistent with a
Right adrenal - 3.2 mm

Left adrenal nodule - 1.2 cm
R kidney
x
+ . . ... . . . +
x
A B
FIGURE 10-37 A, There is a hyperechoic, well-defined nodule in the cranial pole of the left adrenal gland. B, The
contralateral gland is atrophied (3.2 mm), suggesting the nodule in the left adrenal is secreting cortisol. Most
adrenal adenocarcinomas are larger and have a more variable echogenicity than what is displayed here. The im-
ages were obtained in the sagittal plane with the dog in dorsal recumbency. (Images courtesy of Dr. Robert Cole.)
Left adrenal Right adrenal
+
+
0.3 cm
A B
FIGURE 10-38 A, The left adrenal gland is small, measuring 3 mm. B, There is a large (2.2 cm diameter) mass in the
area of the right adrenal gland. The mass has ill-defined borders, mixed echogenicity, and an abnormal shape; all
changes are suggestive of malignancy. With most functional tumors, the contralateral adrenal gland will be smaller
than normal, as in A. It is possible, however, for the contralateral adrenal gland to be within normal size limits. Most
adrenal masses start as a small round to oval lesion, typically at one pole of the gland. As the mass continues to
grow, the adrenal gland loses its normal shape and often takes a spherical/rounded shape with a variable echogenic
appearance. It is very important to evaluate for local extension into the adjacent kidney or nearby vessels. The im-
ages were obtained in the sagittal plane with the dog in dorsal recumbency. (Images courtesy of Dr. Robert Cole.)
|
cortisol-secreting AT. The tumor may be hypoechoic, isoechoic, Computed Tomography and Magnetic Resonance Imaging
or hyperechoic compared to the renal cortex or have mixed
echogenicity. Mineralization can be visualized as a hyperechoic Pituitary
area with acoustic shadowing (Kantrowitz et al, 1986; Voor- Pituitary imaging provides valuable information regarding treat-
hout et al, 1990; Besso et al, 1997; Hoerauf and Reusch, 1999). ment options and prognosis. With standard CT, pituitary tumors,
Areas of necrosis or hemorrhage can be anechoic, hypoechoic, if seen, are typically located in the sella turcica (Fig. 10-39)
or isoechoic. The adrenal gland may also simply appear enlarged and extend dorsally and laterally along the base of the brain
(Ford et al, 1993). Distinguishing macronodular hyperplasia (Fig. 10-40). Of eight pituitary tumors, five were isodense on
from an AT can be difficult with ultrasonography. A bilateral non-contrast scans, and the remainder were hyperdense. Bilat-
AT can be mistaken for bilateral adrenal hyperplasia, falsely pro- erally symmetric hydrocephalus, a mass effect, peritumoral
viding a diagnosis of PDH. edema, and mineralization may also be seen (Turrel et al, 1986;
Differentiation between an adrenal adenoma and carcinoma is Nelson et al, 1989). Most tumors have minimal to marked con-
unlikely with ultrasound because they can have a similar appear- trast enhancement and well-defined margins (Turrel etal, 1986;
ance. Neither echogenicity nor the presence of mineralization Voorhout et al, 1990). Contrast enhancement can be homog-
can be used. An adrenal gland width more than 4 cm correlates enous or heterogenous; an area of hypoattenuation may also be
highly with malignancy. Lesions suggestive of metastasis may seen (Turrel et al, 1986). Small pituitary tumors may not be
be found, especially in the liver (Reusch and Feldman, 1991). visualized with or without contrast, so absence of a visualized
Evidence of invasion into the vena cava is suggestive of a carci- mass does not rule out PDH. It is likely, however, that a tumor
noma. Indication of invasion, however, can be missed (Besso et al, would be seen in all cases where a pituitary mass is causing neu-
1997; Voorhout et al, 1990). In one study of 34 dogs with 36 rological signs. In cases where neurological signs had developed,
ATs, abdominal ultrasound was 100% sensitive and 96% spe- a mass was found (Nelson etal, 1989). In dogs with PDH with
cific for identifying the presence of a tumor thrombus within small pituitary lesions, contrast-enhanced CT may reveal a non-
the caudal vena cava. However, when all forms of vascular inva- enlarged pituitary (Bertoy et al, 1995; Kooistra et al, 1997b; van
sion were evaluated, including patients with vascular wall inva- der Vlugt-Meijer et al, 2004; Auriemma et al, 2009; Rodriguez
sion without a concurrent thrombus, sensitivity and specificity Pineiro et al, 2011).
were 76% and 96%, respectively (Davis et al, 2012). With a A variation of CT, dynamic contrast-enhanced CT, takes advantage
cortisol-secreting AT, atrophy of the contralateral gland may not of the difference in pituitary blood supply. Blood supply to the poste-
always be detectable by ultrasound. No significant difference rior pituitary is direct (arterial), whereas that of the anterior pituitary
exists between dimensions of normal adrenals and adrenals con- is mainly indirect via the pituitary portal system. In normal canine
tralateral to an AT, and the normal two-layer appearance depict- pituitaries, after IV administration of contrast medium, the poste-
ing the medulla and cortex may be seen in atrophied glands rior pituitary is identified first as an early intense enhancement of
(Hoerauf and Reusch, 1999). the central part of the gland. In later images, the anterior pituitary is
Lateral ventricles
Cranium
Temporal muscle
Cranium
Thalamus
Cribiform Cerebellum
Third plate
ventricle
Nasal
turbinates Spinal
cord
Masseter
muscle
Hypothalamus
Sella turcica
A Sella B Brainstem
turcica Trachea Trachea
FIGURE 10-39 Orientation of the (A) transverse and (B) midline sagittal sections on brain scans. (From Bertoy EH,
etal.: Magnetic resonance imaging of the brain in dogs with recently diagnosed but untreated pituitary-dependent
hyperadrenocorticism, J Am Vet Med Assoc 206:651, 1995.)
visualized as a peripheral rim enhancement with a hypodense center followed for 1 year, six dogs (46%) had tumor growth. Of 13
(Love etal, 2000; van der Vlugt-Meijer etal, 2003). The initial phase with masses visible on MRI, four (36%) developed neurologi-
has been termed the pituitary flush. The size of the pituitary relative to cal signs within 1 year (Bertoy etal, 1995; 1996). Accordingly,
the brain (the P/B ratio) can also be assessed (Kooistra etal, 1997b). CT or MRI should be considered in all dogs with PDH at the
In dogs with PDH, small tumors can be visualized as an increase in time of diagnosis. If no mass is seen, the dog should be treated
P/B ratio or displacement or disruption of the pituitary flush, but the medically with no follow-up imaging required. If a mass 3 to 7
results may still be normal; thus, the sensitivity is not 100% (van der mm in diameter is seen, medical treatment of the HAC should
Vlugt-Meijer etal, 2004). If hypophysectomy is being considered, the be administered and imaging should be repeated in 12 to 18
greater sensitivity of dynamic CT for detecting a pituitary mass of any months. If the mass is more than 8 mm in diameter, radiation
size may be helpful to ensure the correct treatment is being provided. therapy should be pursued. Medical therapy can be added if clin-
In other cases, dynamic CT may not be warranted. ical signs of HAC are still present after 3 to 6 months or if they
Treatment for a pituitary macroadenoma (i.e., an adenoma recur (Feldman and Nelson, 2004). No benefit has been shown
> 10 mm diameter) requires radiation therapy for local tumor for irradiation of tumors smaller than 8 mm.
control. Survival post-radiation depends on tumor size and the MRI has been utilized not as a differentiation test but to assess
presence of neurological signs before treatment; the smaller the the size of a pituitary mass in known cases of PDH (Fig. 10-41).
tumor and the milder the neurological signs (or absent), the bet- Using a 1.5-Tesla magnet for MRI, assessment of signal intensity
ter the response to therapy and the longer the survival (Goossens on a T1-weighted image, as well as displacement of the pos-
et al, 1998; Theon and Feldman, 1998). In dogs with PDH terior pituitary lobe, can be helpful in the diagnosis of PDH
A B
FIGURE 10-40Pre- (A) and post- (B) contrast, transverse, 5-mm thick computed tomography (CT) images of the
brain at the level of the pituitary fossa. Pre-contrast, mild hyperattenuation in the ventral calvarium dorsal to the
pituitary fossa can be seen (black arrow); post-contrast, a ring enhancement of this area is visualized (black
arrow). (Images courtesy of Dr. John Hathcock.)
A B
FIGURE 10-41 Post-contrast sagittal (A) and transverse (B) 5-mm thick magnetic resonance imaging (MRI) im-
ages at the level of the pituitary fossa. There is a large non-homogenous, markedly contrast-enhancing mass pres-
ent in the ventral calvarium arising from the pituitary fossa. (Images courtesy of Dr. John Hathcock.)
|
(Taoda et al, 2011). However, low-field MRI (0.2-Tesla mag- Abdomen

net) provides comparable information as dynamic CT on the Abdominal CT is a sensitive way of assessing adrenal gland
presence of pituitary adenomas (Auriemma etal, 2009). In two structure (Fig. 10-43). Hyperplastic glands may appear slightly
studies of dogs with PDH that were showing neurologic signs rounded in comparison to the normal adrenal glands, mineraliza-
not due to direct mitotane toxicity, a pituitary mass was seen in tion not apparent on radiography may be found, and hypoplasia
all. Typically masses causing neurological signs are more than 10 of a gland contralateral to an AT can be seen (Bailey, 1986; Emms
mm in diameter, but a Dachshund with a 5-mm mass had neu- etal, 1986). However, enlargement is not always apparent in dogs
rological signs. Most tumors are contrast-enhancing (Duesberg with PDH (Emms et al, 1986). Unilateral nodular hyperplasia
et al, 1995; Bertoy et al, 1996). cannot be distinguished from an AT. Poor demarcation, irregular
Although in one study the size of the pituitary tumor corre- contrast enhancement, and a non-homogenous texture have been
lated with resistance to suppression by dexamethasone (Koo- suggested to be evidence of malignancy (Voorhout etal, 1990).
istra etal, 1997b), commercially available biochemical testing Contrast enhancement varies (Bailey, 1986; Emms etal, 1986).
cannot reliably differentiate tumor size (Fig. 10-42) (Kipper- Although CT can be quite accurate for determining vascular
man et al, 1992; Bertoy et al, 1995; Duesberg et al, 1995; invasion (Rodriguez Pineiro etal, 2011; Figs. 10-44 and 10-45),
Wood et al, 2007). The absence of neurological abnormali- enlarged adrenal glands may adhere to or compress the vena cava
ties does not exclude the presence of a pituitary macrotumor suggesting invasion when it is not present (Emms et al, 1986;
(Kipperman et al, 1992; Kooistra et al, 1997b). Measurement Voorhout etal, 1990).
of POMC and a precursor to ACTH, pro-ACTH, may be
helpful (Bosje etal, 2002; Granger etal, 2005) if the assays TREATMENTGENERAL APPROACH
become commercially available.
In humans, an empty sella is a herniation of the subarach- Treatment options and protocols and prognosis vary depending
noidal space into the sella turcica with invisible or reduced on the form of HAC present. Therefore, differentiation between
size of the pituitary gland; the empty sella syndrome may or PDH and AT should be obtained before choosing a therapy. For
may not be associated with endocrine disturbances (Konar PDH, the medical options are mainly trilostane and mitotane. In
etal, 2008). The MRI scans of 377 dogs were reviewed, and a Europe and limited centers within the United States, hypophysec-
partial or total empty sella was found in 11 (3.6%). Only one tomy (i.e., complete pituitary removal) is available. For ATs, the
dog had a supposed endocrinopathy. The dog had elevations treatment of choice is adrenalectomy. Surgery is not always pos-
in serum ALP activity and cholesterol concentration, increased sible, however, for numerous reasons. The main medical options
eACTH concentration, and bilaterally enlarged adrenal glands. are as for PDH. The protocol for mitotane use, however, may be
Although an LDDST was supportive of PDH per the authors, different when treating AT (see TreatmentMedical Manage-
the remnants of the pituitary gland found at post mortem were ment Using Mitotane). Overall, therapy should be selected on the
histologically normal (Konar et al, 2008). Thus, the diagno- basis of the form of HAC as well as the veterinarians experience.
sis of HAC is questionable, and no evidence exists for a link Excellent rapport between veterinarian and owner is impera-
between empty sella and endocrinopathies in general or HAC tive during the long-term management of HAC. The surgical and
in particular in dogs. medical options should be discussed in detail, including what is
No visible mass
Visible mass No mass Mass No mass Mass
12 300
70 10 10
9 9
60 10 250
Plasma [cortisol] g/dL
Plasma [ACTH] pg/mL

8 8
50
Cortisol (g/dL)
7 7 8 200
40 6 6
5 5 6 150
30 4 4
4 100
20 3 3
2 2 2 50
10
1 1
0 0 0 0 0
post-ACTH 4 hours post 8 hours post 8 hour high dose Basal
A low dose dex. low dose dex. B dexamethasone sample
FIGURE 10-42 A, Plasma cortisol concentrations 1 hour after intramuscular (IM) administration of 0.25 mg of syn-
thetic adrenocorticotropic hormone (ACTH) and 4 and 8 hours after intravenous (IV) administration of 0.01 mg/kg
of dexamethasone in dogs with pituitary-dependent hyperadrenocorticism (PDH). Triangles denote dogs without a
visible pituitary mass on magnetic resonance imaging (MRI) scan; circles denote dogs with a visible pituitary mass
on MRI scan. Shaded areas indicate reference ranges. B, Plasma cortisol concentrations 8 hours after IV adminis-
tration of 0.1 mg/kg of dexamethasone (left), and basal plasma endogenous ACTH (eACTH) concentrations (right).
Black diamonds and black circles denote dogs with values less than 50% of baseline cortisol concentrations after
dexamethasone administration; open diamonds and open circles denote dogs with values greater than 50% of
baseline cortisol concentrations after dexamethasone administration. (From Bertoy EH, etal.: Magnetic resonance
imaging of the brain in dogs with recently diagnosed but untreated pituitary-dependent hyperadrenocorticism, J
Am Vet Med Assoc 206:651, 1995.)
A B
C D
FIGURE 10-43 Series of post-contrast, transverse, 5-mm thick, computed tomography (CT) images demonstrating
normal right and left adrenal glands and their relation to the caudal vena cava and right and left kidneys. The
sequential scans (A through D) move progressively from cranial to caudal, showing the right adrenal (short white
arrow) and right kidney (curved white arrow) first; the left adrenal (short open arrow) and left kidney (curved open
arrow) are more caudal. Note also the round, caudal vena cava (long white arrow). Vertebrae can be seen at the
top. (Images courtesy of Dr. John Hathcock.)
FIGURE 10-44Post-contrast, transverse, 3-mm thick computed tomography

(CT) image at the level of the cranial pole of left kidney. The left adrenal gland is FIGURE 10-45Post-contrast, transverse, 5-mm thick computed tomography
enlarged and irregularly shaped with non-homogeneous, mild contrast enhance- (CT) image at the level of the right kidney (curved white arrow). The right adrenal
ment (short open arrow). The right adrenal gland is not visualized. The neoplastic gland (short white arrow) is markedly enlarged and non-homogeneously, mildly
mass extends into the lumen of the caudal vena cava (long white arrow). The contrast-enhancing. Invasion of the mass into the caudal vena cava is seen as a
right (curved white arrow) and left (curved open arrow) kidneys can be seen. filling defect with a ring of contrast enhancement at the periphery of the caudal
(Images courtesy of Dr. John Hathcock.) vena cava (long white arrow). The cranial pole of the left kidney can be seen
(curved open arrow); the left adrenal gland is not visualized. (Image courtesy of
Dr. John Hathcock.)
|
expected of the owner. Owners should understand the advantages complications are common, and the reported mortality is variable
and disadvantages of all therapies, including the fact that medical but can exceed 25%. Thus, adrenalectomy should be undertaken
therapy will not cure the disease and therapy will be lifelong. In only by experienced surgeons in a hospital with a well-equipped
dogs with PDH, neither mitotane nor trilostane affect the pitu- intensive care unit (ICU) and 24-hour observation and care.
itary tumor; therefore excessive ACTH secretion continues or Veterinarians should be realistic when recommending adrenal-
becomes exaggerated (Nelson etal, 1985; Mantis et al, 2003; Witt ectomy. Medical treatment offers a viable alternative, especially
and Neiger, 2004). Failure to continue therapy usually results in for aged dogs or dogs at increased risk for anesthetic, surgical, or
regrowth of the adrenal cortices and return of clinical signs. postsurgical problems and for dogs with documented metastatic
disease or extensive major vein thrombosis. Dogs with tumors
that are large (diameter > 5 cm), that have infiltrated the kidney
To Treat or Not To Treat
or body wall, or that have extensive caudal vena caval invasion
An urban legend exists that survival is the same whether or not a (especially thrombi that extend beyond the hepatic hilus) have
dog with HAC is treated. That statement has never been scientifi- a high probability of serious postoperative complications and a
cally evaluated. It may be true for some dogs, but likely not all. poor outcome. Similarly, so do dogs with metastatic lesions (typ-
Importantly, treatment typically greatly improves quality of life ically in the liver and uncommonly in the lungs), with low anti-
for both the owner and dog. thrombin III concentrations, that are debilitated, or that have
On the other hand, not all dogs with positive tests for HAC need advanced clinical manifestations of HAC. In general, the prob-
to be treated, and the decision should be made on a case-by-case ability of a successful outcome is lower, and the likelihood of
basis. In deciding when to treat, consideration should be given to perioperative complications is greater the larger the AT. Removal
the dog, quality of life, the owner, and clinical signs. None of the of an AT with a diameter of more than 5 cm can be difficult
drugs are cheap, and neither mitotane nor trilostane are benign; even when surgery is performed by an experienced surgeon. The
therefore, treatment is not to be taken lightly. If the only clini- larger the adrenal mass, the greater the probability it is a carci-
cal sign is a benign clinicopathologic finding (e.g., elevated serum noma and that metastasis has occurred, regardless of findings
ALP activity) treatment is not warranted (neither is testing). If the during the preoperative evaluation.
issue is only cosmetic (e.g., poor hair) or very mild (e.g., slight Several studies have evaluated prognostic factors for short-
increase in thirst and urination), a frank discussion should be had term survival after adrenalectomy (Schwartz et al, 2008; Lang
with the owner of the risks and benefits. In making the decision, et al, 2011; Massari et al, 2011; Barrera et al, 2013). All dogs
further questioning of the owner on issues that might relate to undergoing adrenalectomy were included regardless of tumor
clinical signs (e.g., the dog has stopped jumping on furniturea type (i.e., ATs and pheochromocytomas), although 76% of 240
sign of possible muscle weakness) can be helpful, as well as seek- tumors were histologically classified as adrenocortical adeno-
ing evidence of clinical signs that the owner might not note (e.g., mas or carcinomas. The definition of short-term survival varied
serial evaluation of urine samples collected at home for consistent between studies, ranging from 6 to 14 days (i.e., dogs lived at
suggestion of polyuria/polydipsia). It is also important to test for least 6 to 14 days after adrenalectomy). Preoperative variables sig-
proteinuria by measurement of a UPCR and for hypertension by nificantly associated with shorter survival times included size of
measurement of blood pressure. Both can damage the body; so the AT, presence and extent of vena caval invasion, concurrent
if either or both are present and due to HAC, treatment may be azotemia, and presence of acute adrenal hemorrhage (Schwartz
more imperative. On the other hand, clinical signs may be rec- etal, 2008; Lang etal, 2011; Barrera etal, 2013). Intraoperative
ognized in retrospect; for example, an owner attributes decreased variables associated with shorter survival times included hemor-
playing to old age, but when HAC is treated, the activity increases. rhage requiring a blood transfusion and concurrent nephrectomy
Treatment of HAC can unmask diseases that may be inappar- (Schwartz etal, 2008; Barrera etal, 2013). Postoperative variables
ent due to the anti-inflammatory effects of hypercortisolemia. associated with shorter survival times included development of
For example, clinical signs of atopy or degenerative joint dis- pancreatitis, PTE, acute renal failure, disseminated intravascular
ease may develop with treatment of HAC as cortisol concentra- coagulation, hypotension, and hypoxemia (Schwartz etal, 2008;
tions decrease. Barrera etal, 2013). In one study, extensive vena caval invasion
was the most significant risk factor for poor short-term survival
(Barrera etal, 2013).
Therapy Without Dening the Underlying Cause
Imaging provides valuable information about tumor size. In
At times, clear differentiation between PDH and AT is not possible general, a small AT is arbitrarily dened as being 4 cm or less
due to such issues as owner nancial constraints or inconclusive in maximum diameter and a large tumor is arbitrarily dened
or conflicting results on differentiating tests. In such a situation, as 5 cm or more in maximum diameter. Small tumors are more
given that the vast majority of dogs have PDH, therapy can be likely to be adenomas, well-encapsulated, and somewhat easier to
initiated accordingly. However, the owners should understand remove surgically than large tumors, which are usually carcino-
that an accurate prognosis cannot be given and that attempting mas, not well-encapsulated, and can be difcult to excise surgi-
to differentiate between the forms once therapy is started is quite cally. However, adrenocortical carcinomas also may be small.
difficult, if not impossible. Histologic evaluation of any tumor is imperative in order to deter-
mine appropriate postoperative and long-term care.
TREATMENTSURGERY Preoperative Evaluation and Management
Cortisol-secreting AT are challenging to manage following
Adrenalectomy
adrenalectomy, in part, because of concurrent immunosuppres-
Overview and Selection of Cases sion, impaired wound healing, systemic hypertension, and a
Adrenalectomy is the treatment of choice for a cortisol-secreting hypercoagulative state; frequent tumoral infiltration into sur-
AT. It is technically difficult, serious intra- and postoperative rounding blood vessels and soft tissues; potential postoperative
development of pancreatitis (especially with a right-sided significantly increase the risk for intra- or postoperative complica-
adrenal mass); and existence of hypoadrenocorticism follow- tions. Adrenal tumors typically metastasize to the liver or lungs,
ing removal of the mass. The most worrisome complication of or both. Approximately 10% of dogs with HAC caused by an AT
adrenalectomy is thromboembolism, which typically develops have obvious metastases at the time of initial examination.
during or within 24 hours of surgery and carries a high mortal- Abdominal ultrasound is a good screening test for identifica-
ity rate (see Postoperative Complications and Survival). Several tion of metastases and vascular invasion (Davis et al, 2012).
steps may help minimize this complication. Medical control If metastasis is suspected, an ultrasound-guided biopsy of
of the HAC prior to surgery for 3 to 4 weeks can reverse the the lesions can be performed for conrmation. However, CT
metabolic derangements and minimize many of the complica- may be preferred, because significant and critical differences
tions associated with surgical removal of a cortisol-secreting AT. between findings on ultrasound versus CT regarding size of the
Because the treatment is expected to be short-term, trilostane tumor and presence and severity of vascular invasion and infil-
may be preferred (Vetoryl, Dechra Veterinary Products; 1 mg/ tration of surrounding soft tissues may occur. CT scans are a
kg every 12 hours initially). An ACTH stimulation test should non-invasive and effective method for evaluating the size and
be performed and serum electrolytes should be measured prior shape of the adrenal glands and the presence and severity of
to and 10 to 14 days after initiating treatment (see Treatment invasion of the tumor into blood vessels, surrounding organs,
Medical Management with Trilostane). The goals of therapy are and body wall. CT may also be used to identify metastatic disease
improvement in clinical signs and a post-ACTH serum cortisol (Voorhout et al, 1990; Widmer and Guptill, 1995; Hill and
concentration between 2 and 6 g/dL (55 to 170 nmol/L). The Scott-Moncrieff, 2001).
dosage of trilostane is adjusted as needed. Serum electrolytes In addition to routine blood and urine tests, systemic blood
are monitored for changes consistent with hypoaldosteronism. pressure should be measured and hypertension treated accord-
Adrenalectomy should be performed once the hypercortisolemia ingly. Cross-matching should be performed in anticipation of a
is controlled but no later than 30 days after initiating medical blood transfusion during or after surgery. Assessment of a UPCR
treatment, regardless of the state of control of the disease. and serum antithrombin III concentrations is also recommended.
On the day prior to surgery, thoracic radiographs should be If the UPCR is signicantly increased, the antithrombin III
performed to ensure that metastatic disease is not present (Fig. concentration signicantly decreased, or both, the dog may be
10-46) and an abdominal ultrasoundor better yet CT or MRI, at greater risk for thromboembolism than the typical dog with
if availableshould be done to assess the size of the adrenal HAC (Ortega etal, 1995; Jacoby etal, 2001).
mass; presence of metastatic disease or invasion of the mass into
the phrenicoabdominal vein, caudal vena cava, or surrounding Surgical Approaches
tissues; and evidence of hemorrhage within the tumor or retro- The recommended surgical approach is either paracostal (flank), or
peritoneal space. Surgery may not be indicated if unexpected ventral midline. In dogs, the ventral midline laparotomy is most
or previously unrecognized complications are identified, which commonly used; compared to other approaches, it provides the best
B
FIGURE 10-46Lateral (A) and dorsoventral (B) thoracic radiographs from a dog with hyperadrenocorticism (HAC)
caused by an adrenocortical tumor (AT) that has metastasized to the lungs.
|
opportunity for visualization of both adrenal glands as well as other it avoids the risk of abdominal herniation through a ventral midline
abdominal structures for evidence of metastasis and provides better incision in dogs with poor wound healing (see Fig. 10-47). It is best
exposure of the vena cava if vascular occlusion is required during suited for unilateral, uncomplicated adrenal masses.
resection (Adin and Nelson, 2012). On the other hand, exposure of
the dorsal retroperitoneal space can be challenging in deep-chested Laparoscopy
dogs and postoperative pancreatitis is a concern, especially with Laparoscopic adrenalectomy can be done in dogs with non-inva-
right-sided adrenal tumors (Fig. 10-47). For dogs with large masses sive adrenal masses. Advantages of minimally invasive laparoscopic
and for tumors that are difcult to visualize, are invading vascular adrenalectomy include better visualization of abdominal organs
structures (most commonly the vena cava), or are infiltrating the and the adrenal mass, limited manipulation of other abdominal
kidney or abdominal wall, exposure can be improved by adding a organs, decreased surgical wound complications, improved post-
flank (paracostal) incision to the ventral midline approach. Theo- operative comfort, faster recovery period, and a shorter hospital
retically, the flank approach has the advantage of improved expo- stay (Jimnez Pelez etal, 2008; Naan etal, 2013). Dogs are placed
sure to the dorsal abdomen, including the vena cava and aorta, and in a sternal or oblique lateral position, and three or four ports for
Second lumbar vertebra

Sublumbar muscles
Skin
Epaxial muscles
Fat Fat
Left Right
kidney kidney
Spleen Liver
Pancreas
Vena
Descending
Left cava
colon
adrenal Right
Obliquus Peritoneum
Transversus M. gland adrenal
externus M. Aorta gland Descending
Obliquus
Cisterna duodenum
internus M.
A chyli
B
FIGURE 10-47 A, Anatomic diagram showing the location of the canine adrenal glands and the surgical approach
(dashed lines) via paracostal incisions to each gland. B, Photograph of a dog with hyperadrenocorticism (HAC)
caused by an adrenal tumor that was removed via the paracostal approach. (A, From Johnston D: Adrenalectomy
via retroperitoneal approach in dogs, J Am Vet Med Assoc 170:1093, 1977.)
the camera, operative instruments, and a retractor are inserted into is noticeably less, most dogs are ambulatory a few hours post-
the abdominal cavity (Fig. 10-48). The abdominal viscera, includ- anesthesia, and many are discharged the next day. Postoperative
ing the pancreas, should move ventrally due to gravity, creating pancreatitis and PTE are very uncommon, especially if dogs are
a working space for access to the adrenal mass while minimizing treated with trilostane for 3 to 4 weeks prior to surgery.
manipulation of other viscera (Fig. 10-49). Adrenal masses with See Small Animal Surgery by Fossum (2012) and Veterinary
a diameter up to 5 cm can be removed. In a preliminary evalua- Surgery: Small Animal by Tobias and Johnston (2012) for more
tion, Mayhew and other soft tissue surgeons at the University of detailed information on the surgical techniques for adrenalectomy.
California, Davis (UC Davis) compared the perioperative mor-
bidity and mortality in 23 dogs undergoing laparoscopic adrenal- Intra- and Postoperative Management
ectomy to that of 25 dogs that underwent adrenalectomy using Autonomous cortisol secretion from an AT suppresses pituitary
a ventral midline laparotomy. The ATs were similarly sized and ACTH release via negative feedback, resulting in signicant atro-
non-invasive. Perioperative death did not occur in the laparoscopy phy of normal cortisol-secreting cells in the contralateral adrenal
group, but two dogs in the laparotomy group died. Surgery time gland. Therefore, acute hypocortisolism is expected after surgery.
and postoperative hospitalization time were significantly shorter in Suppression of eACTH by the tumor may also cause some atro-
the laparoscopy group. In the UC Davis experience, with laparos- phy of aldosterone-secreting cells.
copy, recovery from surgery is quicker, postoperative discomfort Glucocorticoid therapy is not indicated before adrenalectomy,
because it may worsen hypertension, cause overhydration, and
increase the risk of thromboembolic episodes. Beginning with
anesthesia, IV uids should be administered at a surgical main-
tenance rate. In order to preemptively address the acute hypo-
cortisolism that will occur, once the tumor is identied by the
4 surgeon, dexamethasone (0.05 to 0.1 mg/kg) should be placed
in the IV infusion bottle and given over 6 hours. A taper-
ing dexamethasone dose (e.g., decreasing the dose by 0.02 mg/
kg/24 hours but going no lower than 0.02 mg/kg) should con-
tinue to be administered IV at 12-hour intervals until the dog
can safely be given oral medication without the danger of vom-
3 iting (typically 24 to 48 hours postoperatively). At that point,
2 1 the glucocorticoid supplement should be switched to oral
prednisone (0.25 to 0.5 mg/kg b.i.d. [bis in die; twice a day]).
Once the dog is eating and drinking on its own, the frequency
of prednisone administration should be decreased to once a day
and given in the morning. The dosage is then gradually reduced
in small increments at 2 to 4 week intervals during the ensuing
3 to 6 months, as long as the dog maintains an appetite and does not
FIGURE 10-48 Schematic of portal placement in a dog undergoing laparoscopic develop lethargy or vomiting, until the dosage is extremely low. If a
adrenalectomy. The dog is placed in oblique lateral recumbency and four portals unilateral adrenalectomy has been performed, prednisone supple-
are placed for the camera (1), operative instruments (2 and 3), and a retractor mentation can eventually be discontinued once the contralateral
(4). (Illustration by Tim Vojt; from Adin CA. Nelson RW: Adrenal glands. In Tobias normal adrenocortical tissue becomes functional. ACTH stimula-
KM, Johnston SA, editors: Veterinary surgery: small animal, St Louis, 2012, Else- tion tests can be used to guide prednisone therapy; if the dog has a
vier Saunders, p. 2040.) normal ACTH stimulation test result, prednisone administration
A B
FIGURE 10-49 A, A cortisol-secreting adrenal mass (left) and laparoscopic images of the kidney (right) in a dog
shortly after placement of the ports and insertion of the camera. The dogs head is to the left. B, Adrenal mass in A
after dissection of the mass from surrounding structures and just prior to removal. (Images courtesy of Phil Mayhew.)
|
is no longer needed. An ACTH stimulation test can also be used have frequent, short walks (every 2 to 3 hours) to promote blood
to confirm a glucocorticoid deficiency and the need to increase the flow and minimize clot formation.
prednisone dosage if a dog becomes listless, anorectic, or ill dur- Postoperative complications following adrenalectomy are com-
ing the tapering process. Lifelong prednisone at a dosage of 0.1 to mon with reported rates as high as 50%. Two recent retrospective
0.2 mg/kg administered once or twice daily is required for dogs studies reported postoperative complication rates of 30% and
that had a bilateral adrenalectomy. 35% for 60 and 41 dogs, respectively (Schwartz etal, 2008; Lang
Alternatively, rather than assuming that glucocorticoid supple- et al, 2011). Postoperative complications include pancreatitis,
mentation is needed, an ACTH stimulation test may be com- PTE, acute renal failure, septic peritonitis, hypoadrenocorticism,
pleted 6 to 8 hours after surgery to assess the success of surgery hypotension, cardiac arrhythmias, and cardiac arrest (Schwartz
and the need for glucocorticoid therapy. If results are low (pre- etal, 2008; Lang etal, 2011; Barrera etal, 2013).
ACTH and post-ACTH serum cortisol concentrations < 1 g/ In four recent studies, the reported postoperative mortal-
dL [30 nmol/L]), the surgery was likely a success, and this pro- ity was 22% for 41 dogs with an adrenal tumor (Schwartz
vides proof that glucocorticoid therapy is necessary; however, etal, 2008), 13% for 47 dogs with an AT (Lang etal, 2011),
nonfunctional metastases are still a possibility. If the results are 15% for 52 dogs with an adrenal tumor (Massari etal, 2011),
similar to those obtained prior to surgery, then remnant func- and 25.5% for 86 dogs with an adrenal tumor (Barrera etal,
tional tumor tissue is still present and exogenous glucocorticoids 2013). In total, post-adrenalectomy mortality was reported in
are not necessary. 45 of 226 dogs (20%).
Serum electrolyte concentrations should be closely moni- It is difficult to assess the severity of compromised wound heal-
tored postoperatively. Development of mild hyponatremia and ing in a dog with HAC. Thus, stitches should not be removed
hyperkalemia is common within 72 hours of surgery and usu- until regrowth of hair in the region of the incision is evidentno
ally resolves in 1 to 2 days as exogenous glucocorticoid doses matter which surgical approach was used.
are reduced and the dog begins to eat. Because short-term min- Median survival time for the dogs that survived the postopera-
eralocorticoid therapy is rather benign and because it is not tive period and were discharged from the hospital was 690 days,
possible to determine which dogs will have transient problems 492 days, 953 days, and 48 months (Schwartz etal, 2008; Lang
and which will have serious mineralocorticoid decits, treat- etal, 2011; Massari etal, 2011; Barrera etal, 2013). Long-term
ment is recommended if these abnormalities become worri- survival time was significantly shorter in dogs with adrenal ade-
some (i.e., serum sodium < 135 mEq/L or serum potassium > nocarcinomas, adrenal tumors with a diameter of 5 cm or more,
6.5 mEq/L) or if they persist longer than 72 hours. An injec- metastases, and vena cava thrombosis (Massari etal, 2011). Sur-
tion of desoxycorticosterone pivalate (DOCP; Percorten-V, vival time was also significantly shorter when adrenalectomy was
Novartis Pharmaceuticals) is recommended with measurement combined with additional abdominal surgical intervention.
of serum electrolytes performed 14 and 25 days after the injec-
tion (see Chapter 12). If a unilateral adrenalectomy was done, Hypophysectomy
the dog is healthy, and serum electrolytes are normal on day
25, the dog should be reevaluated 7 days later. If serum elec- For several decades, selective pituitary microsurgery using the
trolytes are still normal, additional DOCP treatment is not transsphenoidal approach has been considered the treatment of
needed. In the authors experience, a second dose has never choice for pituitary tumors causing HAC in humans (Melby,
been needed. If bilateral adrenalectomy is performed, DOCP 1988; Rees et al, 2002). Initial studies in veterinary medicine
therapy will be lifelong. developing the microsurgical technique, identifying postopera-
Alternatively, fludrocortisone acetate (0.02 mg/kg; see Chap- tive complications and assessing postoperative pituitary func-
ter 12) can be used in place of DOCP. Oral mineralocorticoids tion, or lack thereof, were done in healthy dogs approximately
can be given twice daily. If a unilateral adrenalectomy was per- 25 years ago (Lantz etal, 1988; Niebauer and Evans, 1988; Nie-
formed, fludrocortisone administration can usually be tapered and bauer et al, 1990). Since then, Meij and colleagues at Utrecht
discontinued within 1 to 2 weeks. Serum electrolyte concentra- University, the Netherlands, have published several articles
tions can be measured during tapering and a few days after dis- detailing their experiences with transsphenoidal hypophysec-
continuation to ensure that they are within reference ranges. If tomy in dogs with PDH, beginning with a detailed description
hyperkalemia or hyponatremia are present, the fludrocortisone of their microsurgical technique and assessment of pituitary
dose should be increased or reinitiated, and tapering over 10 to function after transsphenoidal hypophysectomy in healthy Bea-
14 days should be attempted again. gle dogs (Meij etal, 1997a; 1997b) and followed by short-term
( 3 years) results of transsphenoidal hypophysectomy in 52
Postoperative Complications and Survival dogs with PDH (Meij etal, 1998).
The most worrisome complication following removal of a cortisol- In 2005, the Utrecht group reported on the long-term results
secreting AT is thromboembolism, which typically occurs during of transsphenoidal hypophysectomy in 150 dogs with PDH
or within 24 hours of surgery and carries a high mortality rate. (Hanson etal, 2005). Preoperatively, the pituitary glands, as mea-
Several steps can help minimize this complication (see earlier). sured by contrast-enhanced CT or MRI images, ranged in height
The first is to be realistic about case selection for adrenalectomy from 2.1 to 15 mm (median, 5.1 mm), in width from 3.3 to 17
(see Overview and Selection of Cases). With proper case selection mm (median, 6.1 mm), and in length from 2 to 18 mm (median,
and management, anticoagulation therapy is no longer recom- 5.0 mm). The pituitary glands were not enlarged in 74 dogs, with
mended unless PTE develops. Anesthetic drugs and pain medi- a pituitary-to-brain ratio ranging from 0.15 to 0.31 and were
cations should be administered at dosages that allow a dog to be enlarged in 76 dogs with pituitary-to-brain ratios ranging from
ambulatory within 4 hours of surgery. Anesthesia time should be 0.32 to 0.76.
as short as possible; additional procedures while the dog is under Postoperative complications included central diabetes insipidus
anesthesia should not be done. If available, laparoscopic adre- (CDI), hypernatremia, keratoconjunctivitis sicca (KCS), and sec-
nalectomy should be performed whenever possible. Dogs should ondary hypothyroidism (Meij et al, 1998; Hanson et al, 2005).
Postoperative hormonal replacement therapy included synthetic to the effects of mitotane, aldosterone secretion can be decreased
vasopressin (DDAVP), glucocorticoids, and levothyroxine. Postop- by mitotane (Golden and Lothrop, 1988; Goy-Thollot etal, 2002;
erative CDI was transient in 78% of 127 dogs; DDAVP was discon- Reid et al, 2014) and complete adrenocortical insufficiency can
tinued 2 weeks after surgery in 47% and eventually discontinued in occur in 6% to 10% of dogs receiving mitotane (Kintzer and
an additional 31% a median of 133 days (range, 28 to 1329 days) Peterson, 1991). Aldosterone deficiency can be life-threatening.
post-surgery (Hanson et al, 2005). CDI was present until death Interestingly, normal dogs appear relatively resistant to the
or until latest follow-up in 22% of the dogs. In another study, the adrenocorticolytic effects of mitotane. Four healthy dogs received
incidence of postoperative permanent CDI in dogs undergoing 50 mg/kg of mitotane 5 days per week. Two of the four died after
transsphenoidal surgery for PDH was strongly influenced by the 20 and 21 months of therapy, respectively. The third dog was eutha-
size of the pituitary tumor; the larger the tumor, the more likely for nized after 21 months of therapy, and the fourth dog was alive after
postoperative CDI to be permanent (Teshima etal, 2011). 38 months of receiving the drug (Nelson and Woodard, 1949). An
Blepharospasm and KCS developed postoperatively in 31% of additional 10 dogs were treated at a dosage of 50 mg/kg/day. One
150 dogs, occurred more frequently in the left eye, and required dog died after 124 consecutive days of treatment, and a second died
treatment for a median of 58 (right eye) and 70 days (left eye) after 147 days. The remaining eight dogs were clinically healthy at
(Hanson etal, 2005). Low tear production remained until death the time of euthanasia, after 36 to 150 consecutive days of drug
in approximately 7% of affected dogs. The KCS is believed to therapy. The dogs, however, had biochemical evidence of decreased
result from direct (trauma) or indirect (ischemia) neuropraxia of adrenocortical reserve after 3 to 10 days of therapy (Kirk etal, 1974).
the major petrosal nerves during surgery (Meij etal, 1997a). Therapy of HAC with mitotane occurs in two phases: induc-
Twelve of the 150 dogs died within 4 weeks of surgery. One hun- tion (loading) and maintenance. Before initiation of therapy, the
dred twenty seven (92%) of 138 dogs that were alive after 4 weeks dogs attitude, activity, daily water intake, and appetite should be
experienced remission within 8 weeks of surgery; remission was carefully observed. Awareness of these factors aids in assessment of
defined as resolution of clinical signs of HAC and UC:CR values in treatment success or failure and in recognition of adverse reactions
the reference range. Nine dogs had residual disease, one dog had sus- or the development of new problems, such as those associated
pected ectopic ACTH production, and one dog was lost to follow-up. with a growing pituitary tumor. The presence of a decreased appe-
HAC remained in remission in 95 of 127 dogs (75%). In 32 of 127 tite at any time is a contraindication to administration of mitotane
dogs (25%), signs of HAC and increased UC:CR values recurred at 6 without further assessment.
weeks to 56 months (median, 18.3 months) after surgery. The 1-year, Loading is typically done with the patient at home. The load-
2-year, 3-year, and 4-year estimated survival rate was approximately ing phase can be long (see later). In addition, eating and drinking
84%, 76%, 72%, and 68%, respectively. The 1-year, 2-year, 3-year, behavior are important to judgment of efficacy, and both can be
and 4-year estimated relapse-free fraction was approximately 88%, diminished by hospitalization.
75%, 66%, and 59%, respectively. Survival and disease-free fractions
of dogs with enlarged pituitaries (pituitary-to-brain ratios > 0.31)
Pituitary-Dependent Hyperadrenocorticism
were significantly lower than in dogs with non-enlarged pituitaries.
Based on the experiences at Utrecht University, microsurgical Loading Phase
transsphenoidal hypophysectomy is an effective long-term treat- General Protocol. Before dispensing the medication, the owner
ment of PDH in dogs. Early diagnosis of a corticotroph adenoma should receive thorough instructions on what should be moni-
is important. Transsphenoidal hypophysectomy is most effective tored and when the drug should be discontinued. For treatment
in dogs with non-enlarged or moderately enlarged pituitaries. Size of PDH, a starting dose of 40 to 50 mg/kg divided twice daily
of the pituitary tumor has a direct impact on survival, disease- (i.e., 20 to 25 mg/kg b.i.d.) by mouth should be used (Kintzer
free fractions, and incidence of permanent CDI in dogs. Unfortu- and Peterson, 1991). Mitotane should always be given with food,
nately, the number of sites currently offering hypophysectomy as because this increases the bioavailability of intact tablets (Watson
a treatment option for PDH is very limited in the United States. et al, 1987). In smaller dogs, division may be impossible due to
a 500-mg pill size, and the drug can be given in one dose. Dos-
es higher than 50 mg/kg/day increase the risk of complete corti-
TREATMENTMEDICAL MANAGEMENT
sol deficiency (Kintzer and Peterson, 1991). Loading should end
USING MITOTANE
when appetite decreases, vomiting or diarrhea occurs, the patient
Mitotane (o,p-DDD [Lysodren]) was the mainstay of medical becomes listless, water intake drops to less than 60 mL/kg/day
therapy of canine HAC for many years. A chlorinated hydrocar- (1 cup = 240 mL and 1 oz = 30 mL) or for a maximum of 8 days
bon, mitotane is adrenocorticolytic, causing selective necrosis of (Fig. 10-50). Feeding twice daily during loading allows better as-
the zona fasciculata and zona reticularis, which are the adreno- sessment of appetite. Appetite changes can be subtle, including eat-
cortical zones that secrete cortisol and sex hormones. Mitotane ing slower than usual. In order to closely monitor the patient, best
covalently binds to adrenal proteins following its metabolism judge the endpoint, and impress on an owner the seriousness of
in adrenocortical tissue to a reactive acyl chloride intermediate overdosing, daily calls to the owner may be helpful. When signs sug-
(Cai etal, 1995). The toxin is fairly specific for the adrenal glands gest loading is complete or at the end of 8 days if no changes have
(Kirk et al, 1974). However, in normal dogs, mitotane caused occurred, adrenal reserve is assessed by ACTH stimulation testing.
fatty degeneration and centrolobular atrophy of the liver, and hep- When performing ACTH stimulation tests for monitoring, a dose
atotoxicity secondary to mitotane therapy for HAC has occurred of 1 g/kg cosyntropin can be used (Aldridge etal, 2014). If the
(Webb and Twedt, 2006). signs of HAC have not changed, daily therapy can continue until
The advantages of using mitotane are a high efficacy, especially the results of the ACTH stimulation test are known; otherwise, mi-
for PDH, and the ability to monitor therapy objectively by use totane should be discontinued while awaiting the laboratory report.
of an ACTH stimulation test. Disadvantages are a relatively high Coadministration of glucocorticoids to ease loading or avoid
rate of adverse effects and the adrenocorticolytic effects may not signs of glucocorticoid deficiency if hypocortisolemia occurs is
be reversible. Although the zona glomerulosa is relatively resistant controversial. A concern is that coadministration of glucocorticoids
|
Mitotane
40 to 50 mg/kg divided b.i.d.
Decreased appetite, vomiting,

diarrhea, or listlessness
OR
Water intake 60 mL/kg
OR
Maximum of 8 days
Response below ideal Response ideal Response above ideal
No further mitotane
Retest in 2 wks Begin maintenance Continue loading 3 to 7 days
If cortisol non-detectable, 50 mg/kg/wk divided OR until clinical signs develop
that loading complete
measure Na/K
(see above);
Repeat ACTH stim at that time
Response below ideal Response ideal
If cortisol non-
detectable,
measure Na/K
FIGURE 10-50 Algorithm for induction therapy using mitotane for pituitary-dependent hyperadrenocorticism (PDH).
The ideal range for basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration is approximately
1 to 5 g/dL (30 to 150 nmol/L) pre- and post-ACTH; readers should check with their laboratory for their recommend-
ed range. (In Rand J, editor: Clinical endocrinology of companion animals, Ames, IA, 2013, Wiley-Blackwell, p. 55.)
will obscure the endpoint leading to continued therapy and pos- 7 days depending on how close the concentrations are to the ideal
sible overdose; however, some authors do not believe that to be the or until clinical signs occur that suggest loading has been com-
case (Kintzer and Peterson, 1991). Prednisone can be dispensed pleted. Evaluation of the UC:CR is not a reliable monitoring tool
(0.2 mg/kg) for an owner to give if moderate to severe vomiting (Angles etal, 1997; Guptill etal, 1997; Randolph etal, 1998).
and/or diarrhea occur. However, once prednisone is administered, The mean time required to achieve adequate control is 11 days,
an ACTH stimulation test should not be done for at least 12 hours but up to 2 months is possible (Kintzer and Peterson, 1991). In
due to cross reactivity of prednisone in cortisol assays. general, smaller dogs (< 12.5 kg) and those receiving phenobar-
The duration of loading cannot be predicted by severity of dis- bital may require greater than average induction times. Approxi-
ease or pretreatment cortisol concentrations (Kintzer and Peterson, mately 33% of dogs will have a serum cortisol concentration less
1991). The success of mitotane therapy is judged mainly by perfor- than ideal (e.g., post-ACTH cortisol concentration < 1 g/dL
mance of ACTH stimulation tests with the goal of the induction [30 nmol/L]) after induction; mitotane therapy should be discon-
phase being serum cortisol concentrations pre- and post-ACTH tinued and an ACTH stimulation test performed after 2 weeks
stimulation in the lower part of the normal resting range (e.g., to assess adrenal function. Prednisone should be administered at
cortisol concentration of 1 to 5 g/dL [30 to 150 nmol/L] pre- physiological doses (0.2 mg/kg) during that time, but none should
and post-ACTH). Clinical signs should be taken into account as be given in the 12 to 24 hours before performing an ACTH stim-
well; for example, a post-ACTH cortisol concentration of approxi- ulation test. In most dogs, serum cortisol concentrations will rise
mately 5 to 8 g/dL (150 to 220 nmol/L) is acceptable if the clini- into the ideal range within 2 to 6 weeks, but up to 18 months may
cal signs have resolved and the dog is doing well. Dogs with PDH be needed (Kintzer and Peterson, 1991). When documentation of
that continue to have responses to ACTH in the range for normal recovery of cortisol secretion occurs and the concentrations are in
dogs (e.g., post-ACTH cortisol concentration of 8 to 20 g/dL the ideal range, maintenance therapy can be initiated. If the cor-
[220 to 560 nmol/L]) tend to have ongoing clinical signs. If pre- tisol concentrations are much greater than ideal when recovery is
and post-ACTH cortisol concentrations are within the ideal range, first recognized, loading will have to be performed again.
maintenance therapy should begin. If cortisol concentrations are Adverse Effects. Adverse effects are generally gastrointestinal or
above the desired range, loading should continue for another 3 to neurological and include weakness, vomiting, anorexia, diarrhea,
and/or ataxia. One or more adverse effects occur in approximately (range, 0.7 to 2.2), usually within the first 3 weeks of therapy. In
25% of dogs with PDH during loading (Kintzer and Peterson, the other three dogs, the insulin requirement did not change de-
1991). They develop as serum cortisol concentration falls rapidly spite control of the HAC (Peterson etal, 1981); another cause of
and typically resolve quickly with appropriate therapy. If adverse insulin resistance was suspected.
effects occur, mitotane administration should be discontinued and To try to slow the return to insulin sensitivity and avoid hypogly-
prednisone administered (0.2 mg/kg) until the dog can be exam- cemia, the recommended induction dose for dogs with concurrent
ined, an ACTH stimulation test performed, and serum electro- HAC and diabetes mellitus is 25 mg/kg once daily. Furthermore,
lytes measured to assess possible aldosterone deficiency. Most dogs although administration of prednisone during induction therapy
show a clinical response to glucocorticoid administration within 2 for PDH is discouraged in general by some authors because it
to 3 hours. Persistence of apparent adverse effects may signify the may obscure recognition of having achieved the endpoint of
presence of another medical problem. loading, prednisone (0.4 mg/kg once daily) should be given to
Gastrointestinal signs can be difficult to interpret because diabetics receiving induction phase mitotane to help avoid hypo-
they could be due to direct drug toxicity, hypocortisolemia, or glycemia. Even with these precautions, diabetic patients should
another problem (Fig. 10-51). It is the authors impression that be monitored more closely than usual during induction. Because
during loading, dogs may develop a relative cortisol deficiency. uncontrolled diabetes mellitus causes polyuria/polydipsia and
Because they have been hypercortisolemic for a prolonged polyphagia, decreases in water drinking, appetite, and urine pro-
period, a sudden decrease in cortisol concentrations may cause duction may not occur even if the HAC is controlled. If a dog
signs of hypocortisolemia, even if the cortisol concentrations is receiving insulin when mitotane therapy is initiated, the first
are within or slightly above the ideal range. It is further the recheck ACTH stimulation test should occur as usual (day 8 of
authors impression that treatment with prednisone for 2 to loading), and the diabetic control should be checked as well.
4 days suffices; the clinical signs abate and do not return after
the prednisone is discontinued. If they do, another cause Maintenance Therapy
should be sought. General.Maintenance therapy will be necessary for the re-
Resistance to Mitotane. If a dog does not respond to the in- mainder of the dogs life, although the dose and frequency varies
duction protocol after 21 days, the following factors that could between patients and can vary in an individual patient over time
contribute to mitotane resistance should be considered: (Fig. 10-52). In the absence of maintenance therapy, adrenal gland
1.
The patient may have an AT, which is more resistant to hyperplasia recurs in response to continued ACTH secretion. The
mitotane. maintenance phase uses a much lower mitotane dose of 50 mg/
2. The patient may be inherently resistant to mitotane; some dogs kg/week by mouth (Kintzer and Peterson, 1991) divided into as
with PDH have required up to 60 days of daily therapy or many days of treatment each week as is logical and convenient
doses of 100 to 150 mg/kg/day. Smaller dogs may require high- (e.g., if a dog is scheduled to receive one tablet weekly, one-quar-
er doses (Kintzer and Peterson, 1991). ter tablet can be given 4 days per week). Because approximately
3. The induction dose is too low. Dogs receiving less than 40 mg/ 60% of dogs with PDH on maintenance mitotane therapy, es-
kg/day are less likely to be adequately controlled after 10 days. pecially those receiving less than 50 mg/kg/week, relapse within
4. The drug is not being absorbed well. Ensure the medication is 12 months of starting therapy (Kintzer and Peterson, 1991), an
being given with food, preferably a fatty meal. ACTH stimulation test should be performed 1, 3, and 6 months
5. The diagnosis may be incorrect or the patient has iatrogenic after initiating maintenance therapy and approximately every 3
HAC. months thereafter to ensure continued control. If the pre- and
6. The drug may not be potent; replacing the owners supply post-ACTH serum cortisol concentrations are in the ideal range,
should be considered. therapy can remain as is. If the post-ACTH cortisol concentration
7. The dog is receiving another drug that is interfering with the is mildly elevated (e.g., 5 to 9 g/dL [150 to 250 nmol/L]), the
actions of mitotane. In one study, the two dogs that required maintenance dose should be increased 25% and the dog retested
the highest weekly maintenance dosages of mitotane (330 and after 1 month to determine if adequate control has been achieved.
318 mg/kg) were both receiving anticonvulsant drugs (Kintzer If so, maintenance therapy should continue at the new dose. If
and Peterson, 1991). serum cortisol concentrations are still above ideal, reinstitution of
8. The owner may not be giving the medication as directed. induction therapy should be considered. If the post-ACTH corti-
Diabetic Patients.Special consideration should be given to sol concentration is moderately to greatly increased (e.g., > 9 g/
patients with concomitant HAC and diabetes mellitus, although dL [250 nmol/L]), loading therapy should be reinstituted. If in-
the combination is uncommon. Therapy for the diabetes mellitus duction therapy is reinitiated, the decision to end loading should
should begin immediately upon diagnosis. If the two diseases are be based on the same clinical signs as during the initial loading or
diagnosed simultaneously, a low dose of insulin should be initi- it should be continued for a maximum of 7 days. Once serum cor-
ated to prevent ketoacidosis (see Chapter 6). Attempts to control tisol concentrations are again within the ideal range, maintenance
the diabetes mellitus are not recommended until the HAC is in therapy should be reinstituted at a 50% higher mitotane dosage.
remission because the insulin dose will diminish once cortisol In 184 dogs with PDH treated with mitotane for a mean of
concentrations decrease. Similarly, if a long-term diabetic has 2 years, the final maintenance dosage required ranged from 27 to
insulin resistance secondary to HAC and requires large doses of 330 mg/kg/week, with the two highest doses required by dogs also
insulin for adequate glycemic control, treatment with mitotane receiving phenobarbital. Median survival time was 1.7 years (range,
usually removes the insulin resistance and can lead to a rapid de- 10 days to 8.2 years) with the response judged as excellent in 83%,
crease in insulin requirement. Consequently, insulin overdosage fair in 16%, and poor in 0.6% (Kintzer and Peterson, 1991).
and hypoglycemia may occur if the insulin dose is not decreased. Adverse Effects. Approximately 33% of dogs on maintenance
In eight out of 11 dogs with concurrent PDH and diabetes melli- therapy develop adverse effects including anorexia, vomiting,
tus that were treated with mitotane, the mean insulin requirement weakness, diarrhea, and/or ataxia, typically shortly after initiation
decreased from 4.6 U/kg/day (range, 3.3 to 6.6) to 1.7 U/kg/day of a maintenance dosage or during periods of relapse when daily
|
Gastrointestinal signs
(i.e., decreased appetite, anorexia,
vomiting, and/or diarrhea)
Consider:
1. Hypocortisolism
2. Direct mitotane side effects
3. Unrelated to mitotane
Discontinue mitotane
until evaluation ASAP
History, PE
CBC/Profile/UA
Imaging (if needed)
Problem identified Problem not identified
Address problem; ACTH stimulation

continue to treat HAC test
PDH AT
Cortisol Cortisol Induction Maintenance

nondetectable detectable
Continue mitotane.
Relative cortisol deficiency? Reassess history, PE,
Follow Figs.
Try increasing prednisone CBC/Profile/UA
10-50 or 10-52
(0.4 mg/kg/d) Imaging
Induction Maintenance
Signs do not resolve Problem not identified
Continue loading. Reassess history, PE,

Relative cortisol deficiency? Drug intolerance; Drug intolerance;
CBC/Profile/UA give lower doses give lower doses
Try prednisone 0.2 mg/kg/d
and wean off slowly Imaging more frequently more frequently
Signs do not resolve Problem not identified Signs do not resolve Signs do not resolve
Drug intolerance; Drug intolerance; Decrease dose in Decrease dose in

give lower doses give lower doses 10%-25% increments 10%-25% increments
more frequently more frequently until find max tolerable dose until find max tolerable dose
FIGURE 10-51 Algorithm for approach to gastrointestinal signs in a patient receiving mitotane. ACTH, Adreno-
corticotropic hormone; AT, adrenocortical tumor; CBC, complete blood count; HAC, hyperadrenocorticism; PDH,
pituitary-dependent hyperadrenocorticism; PE, physical examination; profile, complete serum biochemical profile;
UA, urinalysis.
Scheduled routine recheck or if clinical signs of hyperadrenocorticism develop
No further mitotane
Repeat ACTH stim Continue therapy as is
in 2 to 3 wks
If cortisol non-detectable, Post-ACTH Post-ACTH moderately
measure Na/K mildly elevated or severely elevated
(approximately 6-9 g/dL) (>approximately 9 g/dL)
Response below ideal Response ideal

Increase mitotane Reinitiate loading therapy
dose 25% and repeat for 5 to 7 days and
ACTH stimulation test follow induction protocol
If cortisol non- Reinitiate maintenance in 4 wks including ACTH stim
detectable, therapy 25% lower dose
measure Na/K
When control achieved

as judged by ACTH stim,
reinstitute maintenance therapy
at a 50% higher dose
FIGURE 10-52 Algorithm for maintenance therapy using mitotane for pituitary-dependent hyperadrenocorticism
(PDH). Ideal range for basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration is approxi-
mately 1 to 5 g/dL (30 to 150 nmol/L) pre- and post-ACTH. (In Rand J, editor: Clinical endocrinology of compan-
ion animals, Ames, IA, 2013, Wiley-Blackwell, p. 56.) AT, Adrenocortical tumor; CBC, complete blood count; PDH,
pituitary-dependent hyperadrenocorticism; PE, physical examination; UA, urinalysis.
therapy is reinstituted. If these develop, mitotane therapy should of partial aldosterone deficiency is unclear. However, if a dog
be discontinued, prednisone administered (0.2 mg/kg), an ACTH receiving mitotane is lethargic, weak, or hypotensive and cortisol
stimulation test performed, and serum electrolyte concentrations deficiency or other disease is not present to explain the clinical
measured. Presence of glucocorticoid deficiency with or without signs, basal and ACTH-stimulated aldosterone concentrations
mineralocorticoid deficiency can be documented and differenti- should be measured. Aldosterone concentrations are best measured
ated from direct drug toxicity. If the clinical signs are due to a hy- before and 30 minutes after ACTH if using cosyntropin for the
poadrenal state, they should resolve quickly with prednisone ad- ACTH stimulation test (Reid et al, 2014). If mineralocorticoid
ministration. If the signs do not abate, presence of a non-adrenal deficiency is present, the patient needs to be treated accordingly.
illness should be suspected. Mitotane dose reduction may be nec- Neurological signs in a dog receiving mitotane (e.g., disorienta-
essary for dogs that develop adverse reactions or an alternate dos- tion, dullness, or inappetence) may be due to direct drug toxicity
ing scheme can be used (e.g., divide the dose into smaller amounts or presence of a pituitary macroadenoma. If due to direct drug
to be given more frequently during the course of the week). toxicity, signs occur the day the medication is given and usually
If glucocorticoid deficiency is documented (e.g., pre- and post- resolve within a few hours. Imaging (i.e., CT or MRI) is required
ACTH serum cortisol concentration < 1.0 g/dL [30 nmol/L]), to confirm the presence of a large tumor. Of 173 dogs with PDH
mitotane therapy should be discontinued and physiological pred- for which a cause of death or euthanasia was known, 6% devel-
nisone replacement therapy (0.2 mg/kg) continued until serum oped a pituitary macroadenoma at 55 days to 5.6 years after initia-
cortisol concentrations pre- and post-ACTH rise into the ideal tion of mitotane therapy with a median of 9.7 months (Kintzer
range, which usually requires 2 to 6 weeks but can take months. and Peterson, 1991).
Decreased aldosterone secretion was previously thought to be Time Sequence for Improvement in Signs and Biochemical
uncommon and to occur only in dogs with cortisol deficiency. Abnormalities. If therapy is successful, the majority of clinical signs
However, decreased aldosterone secretory reserve occurs in 79% of and complications of HAC resolve over time. Polyuria, polydipsia,
dogs with PDH treated with mitotane regardless of level of control and polyphagia should resolve when cortisol secretion is adequately
of PDH and cannot be predicted by measurement of electrolyte controlled or shortly thereafter. Resolution of some clinical signs
concentrations (Reid etal, 2014). Although the zona glomerulosa (e.g., muscle weakness, skin manifestations, non-healing wounds,
is relatively resistant to the effects of mitotane, complete mineralo- and/or anestrus) may take 3 to 6 months or longer; calcinosis cutis
corticoid deficiency is seen in approximately 6% of dogs anywhere may never fully clear. Dogs with cutaneous signs can have a period
from 1 month to years after initiation of maintenance therapy and of severe seborrhea and a poor hair coat or worsening alopecia and
is often permanent (Kintzer and Peterson, 1991). The significance pruritus, which may last 1 or 2 months, before a healthy hair coat
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A B
C
FIGURE 10-53 A Papillon with pituitary-dependent hyperadrenocorticism (PDH) (A) before therapy and 6 weeks
after initiation of mitotane therapy (B), which resulted in the appearance of a new, puppy-like hair coat. C, The
same dog 10 weeks later, with a good, adult coat.
returns. Some dogs go through a phase of puppy hair coat before HAC. Resolution of the HAC (due to mitotane or other therapy)
the normal adult coat returns (Fig. 10-53). A few dogs have dra- may allow such problems (e.g., arthritis, atopy, and flea hyper-
matic changes in coat color after successful therapy (Fig. 10-54). sensitivity) to become clinically obvious. Potentially, therapy with
Liver enzyme activities may not normalize or improve. glucocorticoids may be indicated for treatment. Mitotane and glu-
Serum cholesterol concentration may take months to decrease cocorticoids can be administered concomitantly. The patient will
In humans, mitotane can increase serum lipid concentrations likely do better overall if the HAC is in remission, and a controlled
(Maher et al, 1992). Improvement in blood pressure can be dose of glucocorticoid is given as needed.
detected within 3 to 6 months. Because hypertension may exist
independent of the HAC, it does not dissipate in all treated Planned Medical Adrenalectomy
dogs. Urine protein loss usually improves within 4 to 6 months An alternative protocol for treating PDH is aimed at non-selective
of initiation of therapy, but proteinuria may not resolve adrenocorticolysis and complete destruction of adrenocortical tis-
(Ortega etal, 1996). sue with substitution therapy for ensuing adrenocortical insuffi-
Stressful Situation.If a dog that is receiving mitotane un- ciency. Mitotane is given for 25 days (50 to 75 mg/kg/day and up
dergoes any type of stress (e.g., illness, trauma, boarding, and/ to 100 mg/kg daily for toy breeds), divided into 3 to 4 approxi-
or elective surgery), glucocorticoid therapy should be initiated mately equal and equally-spaced portions given with food. Life-
( 0.2 mg/kg, adjusted or tapered as needed). An adequately treat- long glucocorticoid and mineralocorticoid therapy is begun on
ed dog with PDH has sufcient adrenal reserve for day-to-day the third day of mitotane administration. Prednisone should be
living but may not have enough to handle major stress. initiated at a temporarily high dose (1 mg/kg b.i.d.). Fludrocorti-
Development or Reemergence of Concurrent Problems sone (0.0125 mg/kg daily) and sodium chloride (0.1 mg/kg/day,
during Therapy. The anti-inflammatory and immunosuppressive divided over 2 to 3 meals) should also be administered (Rijnberk
actions of cortisol can mask concurrent problems in dogs with and Belshaw, 1988).
A B
C D
E F
FIGURE 10-54 A Poodle with pituitary-dependent hyperadrenocorticism (PDH) (A) before therapy; (B) 2 months
after institution of mitotane therapy, showing a dramatic change in the color of the hair coat; (C) after a relapse 4
years later; and (D) after reinstitution of mitotane therapy. E, A small, mixed-breed dog with PDH before mitotane
therapy and (F) 2 months after starting therapy, showing a dramatic change in the coat color.
During the first month, owners should report by telephone at as needed to maintain normokalemia and normonatremia. Des-
least weekly or as problems arise and should stop mitotane admin- oxycorticosterone pivalate (Percorten) may be used as an alterna-
istration if any inappetence develops (Rijnberk and Belshaw, tive to fludrocortisone (see Chapter 12 for more information).
1988). In this regimen, appetite change, if seen, is a direct toxic The first follow-up visit should be 1 week after completion of
effect of the medication; cortisol deficiency is offset by the predni- mitotane administration. Serum electrolytes should be measured
sone therapy. Glucocorticoid dosage may be increased temporarily to ascertain if the fludrocortisone and salt doses are correct (Rijn-
if appetite diminishes. Usually mitotane can be resumed after 4 to berk and Belshaw, 1988). Performance of an ACTH stimulation
5 days when the appetite returns without further problem (Rijn- test may be wise to ensure adequate control of the HAC. After the
berk and Belshaw, 1988). Fludrocortisone dose should be changed first follow-up visit, ACTH stimulation tests are performed only
|
if clinical signs of HAC recur, but routine measurement of serum induction dose of mitotane for PDH is usually 400 to 500 mg/
urea nitrogen and electrolyte concentrations is required to ensure kg, whereas that for dogs on the ablative protocol for AT is often
adequate control of the hypoadrenocorticism. up to 10 times higher. The goal is complete destruction of glu-
The protocol was assessed in 129 dogs (den Hertog etal, 1999). cocorticoid-secreting tissue, so physiological doses of prednisone
The daily mitotane dose used was 31 to 125 mg/kg (median (0.2 mg/kg) should be administered concurrently (Kintzer and
59 mg/kg). Only 110 dogs received mitotane for 25 days. In four, Peterson, 1994). The same clinical signs can be used to judge the
administration was stopped due to adverse effects and not resumed; endpoint of induction as when treating PDH with a maximum
the other 15 dogs died in the first 25 days of treatment; seven died treatment span of 14 days. At the conclusion of a loading period,
from hypoadrenocorticism. In 29% of the 110 dogs, mitotane an ACTH stimulation should be performed (Fig. 10-55). When
administration was stopped temporarily due to development of performing ACTH stimulation tests for monitoring, a dose of 1
anorexia, vomiting, weakness, depression, and/or diarrhea, but it g/kg cosyntropin can be used (Aldridge etal, 2014).
was resumed within days (median 7 days; range, 1 to 63). If a partial response is seen but adequate control has not been
Convincing signs of partial or complete remission of the HAC achieved (i.e., pre- and post-ACTH cortisol concentration are
such as hair regrowth and decreased water intake, appetite, and lower than before treatment but not in the ideal range), mitotane
size were noted in 86%. Relapse occurred in 39% at a median of should be continued at the same dosage and an ACTH stimula-
402 days from the day therapy began (range, 84 to 1148). The tion test repeated every 10 to 14 days until serum cortisol con-
dogs that were free of disease after 1, 2, and 3 years were 77%, centrations fall within the ideal range. If after the initial loading
53%, and 44%, respectively. For all dogs, the survival fraction dose the ACTH response is unaltered, the daily mitotane dos-
after 1, 2, and 3 years was 80%, 69%, and 61%, respectively. For age should be increased in 50 mg/kg/day increments every 10 to
the 110 dogs that received the full 25 days of therapy, the survival 14 days as necessary, until an ACTH stimulation demonstrates a
fraction after 1, 2, and 3 years was 87%, 77%, and 69%, respec- response to the medication or drug intolerance occurs. Therapy
tively (den Hertog etal, 1999). is then continued at the dosage at which a response was seen or
In another study that used a daily mitotane dose of 75 to at the highest tolerated dosage, and ACTH stimulation testing
100 mg/kg/day in 46 dogs, median survival was approximately 2 again performed every 10 to 14 days or if clinical signs suggest an
years (Clemente etal, 2007). Although recurrence rate of HAC endpoint has been reached. In 32 dogs with an AT, total induc-
was only 29% (perhaps owing to a higher mitotane dose), 15 dogs tion time ranged from 10 days to 11 weeks with a mean of 24 days
suffered a hypoadrenal crisis during therapy. Overall incidence of (Kintzer and Peterson, 1994).
side effects was 24%. Maintenance.Once cortisol concentrations pre- and post-
Although treatment of hypoadrenocorticism may appear easier ACTH are within the ideal range (i.e., < 1 g/dL [30 nmol/L])
than that of HAC, three main disadvantages exist for the alterna- maintenance therapy should begin (75 to 100 mg mitotane/kg/
tive protocol, and its use is not recommended. First, mortality can week; Kintzer and Peterson, 1994). Daily prednisone administra-
be as high as 12% (den Hertog etal, 1999). Second, treatment of tion should continue, because these dogs are cortisol deficient. An
a hypoadrenal dog can be expensive. Third, and most importantly, ACTH stimulation test should be performed after 1 month to assess
failure to give medication to a hypoadrenal patient can be fatal, control. If pre- or post-ACTH cortisol levels are within the normal
whereas missing a dose of mitotane will not put a patient in life- resting range (i.e., 1 to 5 g/dL [30-150 nmol/L]), the mitotane
threatening danger. dose should be increased 50% and the dog should be retested in 1
month. If the cortisol levels are still above the resting range, induc-
tion therapy should be reinstituted; once ideal cortisol levels are
Functioning Adrenocortical Tumors
again achieved, maintenance should be restarted at a 50% higher
In general, the preferred treatment for dogs with an AT causing dosage than previously used. One month after a dose adjustment,
HAC is adrenalectomy. However, surgery is not always possible. ACTH stimulation should again be performed to assess control
Some dogs have inoperable tumors or metastases at the time of (Fig. 10-56). Once ongoing successful therapy is documented, an
diagnosis or are too debilitated for major surgery; some owners ACTH stimulation test should be done every 3 months or if clinical
opt not to pursue surgery for a variety of reasons. signs recur. Relapse occurs during maintenance in approximately
Two protocols have been advocated for treatment of an AT 66% of dogs, usually due either to too low an initial maintenance
with mitotane. In general, dogs with AT are more resistant to the dose or to tumor growth (Kintzer and Peterson, 1994).
effects of mitotane than dogs with PDH (Kintzer and Peterson, As are induction doses, maintenance doses required for adequate
1994; Feldman et al, 1992). In the first, the ablative protocol, control of an AT are higher than for PDH. In 32 dogs with an AT,
mitotane is used as a true chemotherapeutic drug; the goal is com- the final mean maintenance dose required was 159 mg/kg/week,
plete destruction of tumor tissue with serum cortisol concentra- slightly more than double the average maintenance dose required
tions pre- and post-ACTH below the normal resting range (e.g., to control PDH. Approximately 25% of dogs require maintenance
< 0.3 g/dL [< 10 nmol/L] on both samples) (Kintzer and Peter- doses greater than 150 mg/kg/week (Kintzer and Peterson, 1994).
son, 1994). The other approach, the non-ablative protocol, uses Adverse Effects.Adverse effects, as described earlier, oc-
mitotane with the same ideal ranges for cortisol concentrations cur in approximately 60% of dogs. They can develop as long as
as when treating PDH. The toxicity with the ablative protocol 16 months after initiation of therapy, are more common during
is likely higher. Destruction of all tumor tissue inherently makes the maintenance rather than the induction phase, and are due
sense, but which protocol provides a better prognosis is unknown. either to direct mitotane toxicity or to adrenocortical insufficiency
with the former being approximately twice as likely (Kintzer and
Ablative Protocol Peterson, 1994).
Loading. Mitotane induction dosage for treatment of an AT If severe side effects occur, mitotane should be stopped, the pred-
is 50 to 75 mg/kg/day. Although 20% of dogs with AT respond nisone dose increased to 0.4 mg/kg/day, and the dog reevaluated
to the protocol for treating PDH, higher induction dosages and as soon as possible with an ACTH stimulation test and measure-
longer induction times are generally required for AT. The cumulative ment of serum electrolyte concentrations to determine if complete
Mitotane at 50 to 75 mg/kg divided b.i.d.

and
Prednisone at 0.2 mg/kg/day
Decreased appetite, vomiting,

diarrhea or listlessness
OR
Water intake <60 mL/kg
OR
Maximum of 14 days
No change in ACTH response Response ideal Partial response
Increase mitotane dose by 50 mg/kg/wk Begin maintenance Continue mitotane and prednisone
Continue prednisone as is Mitotane: 75 to 100 mg/kg/wk 10 to 14 days
Treat 10 to 14 days or until see signs Prednisone: 0.2 mg/kg/day OR until see signs that
that loading complete; loading complete;
Repeat ACTH stim at that time Repeat ACTH stim at that time
FIGURE 10-55 Algorithm for induction therapy using mitotane for an adrenal tumor using the ablative protocol.
Ideal range for basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration is approximately
less than 1 g/dL (30 nmol/L) pre- and post-ACTH; normal resting range is approximately 1 to 5 g/dL (30 to 150
nmol/L). (In Rand J, editor: Clinical endocrinology of companion animals, Ames, IA, 2013, Wiley-Blackwell, p. 57.)
Scheduled routine recheck or if clinical signs of hyperadrenocorticism develop
Response ideal Response within normal Response above normal

resting range resting range
Continue therapy as is If no side effects of mitotane, Reinstitute induction therapy

if no side effects mitotane; increase mitotane dose 50% and follow induction protocol
if side effects, see Fig. 10-51 and repeat ACTH stim in 4 wks; including ACTH stim
if side effects, see Fig. 10-51
When control achieved

as judged by ACTH stim,
reinstitute maintenance therapy
at a 50% higher dose;
perform ACTH stim in 4 wks
FIGURE 10-56 Algorithm for maintenance therapy using mitotane for an adrenal tumor using the ablative protocol.
Ideal range for basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration is approximately
less than 1g/dL (30 nmol/L) pre- and post-ACTH; normal resting range is approximately 1 to 5 g/dL (30 to 150
nmol/L). (In Rand J, editor: Clinical endocrinology of companion animals, Ames, IA, 2013, Wiley-Blackwell, p. 58.)
|
mineralocorticoid and glucocorticoid deficiency exists. If serum stable for months or years on conservative dosages, whereas oth-
electrolytes are normal but pre- and post-ACTH serum cortisol ers receive mitotane daily at rather large doses. It is important to
concentrations are less than 1 g/dL (30 nmol/L), aldosterone tailor treatment to the needs of each dog. Return of clinical signs
concentrations should be measured. If hypocortisolemia is present, suggestive of HAC should be managed by performing an ACTH
mitotane therapy should be restarted and prednisone administra- stimulation test to conrm disease exacerbation and then, if indi-
tion continued at a dosage of 0.4 mg/kg/day to exclude cortisol cated, increasing the dose of mitotane.
deficiency as the cause of the clinical signs. If adverse effects recur In one study, 13 dogs with PDH and 13 dogs with an AT were
when mitotane is reinstituted despite an increased glucocorticoid started on the non-ablative protocol with the same monitoring
dosage, direct drug toxicity or hypoaldosteronism are likely. If the and dose adjustment protocol. Throughout the 6-month study,
adverse effects are direct mitotane toxicity, its administration can dogs with an AT were given at least four times the dose of mito-
be temporarily discontinued and then reinstituted at a 25% to tane as were dogs with PDH, yet the post-ACTH cortisol con-
50% lower dosage once signs of toxicosis have resolved. If hypo- centrations were at least three times higher in dogs with an AT.
cortisolemia, hypoaldosteronemia, hyponatremia, and hyperkale- Clinical responses assessed by owners were consistently poorer in
mia are present, the adrenocortical destruction may be permanent. dogs with an AT. Only two of the 13 dogs (15%) with an AT were
Replacement therapy for both hormones should be instituted, and judged to have an excellent response (Feldman etal, 1992).
mitotane should not be administered until adrenal recovery can be
documented via an ACTH stimulation test. TREATMENTMEDICAL MANAGEMENT
Prognosis. Of 32 dogs with an AT treated with mitotane, 66%, WITH TRILOSTANE
28%, and 6% were judged by their owners to have a good to excel-
lent, fair, and poor response, respectively. Mitotane does not appear Trilostane (Vetoryl) has been used to treat HAC for a number of years
to arrest metastatic tumor growth, and the response in dogs without in Europe and is FDA-approved for treatment of canine HAC in the
evidence of metastatic disease is better than in dogs with metasta- United States. A synthetic steroid analogue that inhibits the adrenal
ses. Mean survival time of dogs with an AT treated with mitotane is enzyme 3-HSD, trilostane suppresses production of progesterone
16 months (range, 20 days to 5.1 years) (Kintzer and Peterson, 1994). and its end-products, including cortisol and aldosterone. Additional
enzymes such as 11-hydroxylase and 11-HSD may also be affected
Non-Ablative Protocol (Sieber-Ruckstuhl, 2006). The metabolite ketotrilostane is more
Loading. The same treatment protocol is used as that for dogs potent than the parent compound (McGraw etal, 2010).
with PDH with regard to dose and ideal cortisol concentrations The advantages of using trilostane are a high efficacy and the
pre- and post-ACTH. The initial dose is 50 mg/kg/day divided and ability to monitor therapy objectively by use of an ACTH stimula-
given twice daily. When performing ACTH stimulation tests for tion test. Disadvantages are a relatively high rate of adverse effects,
monitoring, a dose of 1 g/kg cosyntropin can be used (Aldridge although potentially less than that of mitotane. Although as an
et al, 2014). If at the first recheck after an initial 7 to 10 days of enzyme inhibitor the effects of trilostane were expected to be fully
treatment the ACTH response test result demonstrates improve- reversible, adrenal necrosis can occur with resultant prolonged or
ment but post-ACTH cortisol concentrations are not in the ideal permanent cortisol deficiency with or without aldosterone defi-
range (i.e., 1 to 5 g/dL [30-150 nmol/L]), loading should be ciency. Decreased aldosterone secretory reserve can occur (Wenger
continued with the same dose for up to an additional 10 days. If etal, 2004; Sieber-Ruckstuhl etal, 2006); it is common regardless
at the first recheck, the ACTH stimulation test result is similar to of level of control of PDH and cannot be predicted by measure-
that obtained before therapy, the mitotane dose should be increased ment of electrolyte concentrations (Reid etal, 2014). Aldosterone
to 75 to 100 mg/kg/day divided and given twice daily for 7 to concentrations are best measured before and 30 minutes after
10 days, and then another ACTH stimulation test performed. Lack ACTH if using cosyntropin for the ACTH stimulation test (Reid
of signicant improvement in ACTH stimulation test results after the etal, 2014). Aldosterone deficiency can be life-threatening.
second loading phase indicates a need to continue the mitotane at the Trilostane is available as 10, 30, 60, and 120 mg capsules in
same or a higher dosage for an additional 7 to 10 days. The duration the United States. Due to huge variations in trilostane content in
of the loading phase and the dosage required are then determined on capsules purchased from compounding pharmacies (Cook et al,
an individual basis. In 13 dogs with AT treated with mitotane using 2012) and lack of knowledge regarding bioavailability and phar-
the non-ablative protocol, only one dog had cortisol concentrations macokinetics of the products supplied by compounding pharma-
within the ideal range after 30 days of therapy (Feldman et al, 1992). cies, especially liquid formulations, use of brand name product
Maintenance. The same protocol is used as for PDH (see Fig. (Vetoryl) only is recommended.
10-52). Once induction is complete, maintenance therapy should The protocol for trilostane use is the same whether treating
begin at 50 mg/kg divided weekly into as many days of treatment PDH or an AT. As with mitotane, before initiation of therapy,
each week as is logical and convenient (e.g., if a dog is scheduled the dogs mental status, activity, daily water intake, and appetite
to receive one tablet weekly, one-quarter tablet can be given 4 days should be carefully observed. Awareness of these factors aids in
per week). Dividing the dose into smaller portions can decrease assessment of treatment success or failure and in recognition of
adverse effects and make dose alteration easier if the need arises. adverse reactions or the development of new problems, such as
An ACTH stimulation test should be completed 1 and 3 months those associated with a growing pituitary tumor. The presence of a
after the start of maintenance therapy. If the cortisol concentra- decreased appetite at any time is a contraindication to the admin-
tion after ACTH administration is approximately 5 to 10 g/dL istration of trilostane without further assessment.
(150 to 275 nmol/L), the mitotane dosage should be increased
by 25% weekly with ACTH stimulation testing done to guide General Protocol
further adjustments. If the post-ACTH cortisol concentration is The reported final dose required for control of HAC has varied
more than 10 g/dL (275 nmol/L), loading should be reinitiated. greatly (Ruckstuhl etal, 2002; Braddock etal, 2003) with early
Once control is achieved, maintenance therapy should be resumed studies finding effective dosages to be higher than currently rec-
at a 50% higher dose than used previously. Some dogs remain ommended; the difference is likely due to initial inexperience.
A B
FIGURE 10-57 A, An 8-year-old mixed breed dog with pituitary-dependent hyperadrenocorticism (PDH) showing
alopecia and a distended abdomen. B, Clinical signs of hyperadrenocorticism (HAC) resolved after treatment with
trilostane. The dog is currently doing well after 33 months of treatment. (In Rand J, editor: Clinical endocrinology of
companion animals, Ames, IA, 2013, Wiley-Blackwell, p. 61.)
The author uses a dose of 1 mg/kg twice daily or 2 mg/kg once (Fig. 10-58). If the post-ACTH cortisol concentration is less than
daily, with the twice-daily dose being preferred (Fig. 10-57). 1 g/dL (30 nmol/L), the package insert states that trilostane
Dosing to some extent will be based on the sizes of the cap- administration should be suspended and restarted at a decreased
sules and the dog. Trilostane should be given with food to dose after 3 to 7 days. In the authors opinion, due to potential
increase absorption from the gastrointestinal tract. Three times prolonged effects of trilostane, administration should be reiniti-
daily dosing may be needed in some dogs (Feldman, 2011). In ated only after recovery of adrenocortical function has been dem-
any case, as with mitotane, dose adjustments will be required onstrated by an ACTH stimulation test.
in most dogs and should be based on ACTH stimulation test If the post-ACTH cortisol is 1 to 5 g/dL (30 to 150 nmol/L),
results and clinical signs. In general, larger dogs (e.g., > 25 kg the dose should continue as is. If the post-ACTH cortisol is 5 to 9
body weight) need lower doses on a per kilogram basis to control g/dL (150 to 250 nmol/L), the dose can be continued if the dog
clinical signs (Alenza etal, 2006; Feldman and Kass, 2012). is doing well clinically and the clinical signs of HAC are controlled;
If minor adverse effects are seen (see later), drug administra- if clinical signs are not controlled, twice-daily therapy should be
tion should be stopped for 3 to 5 days until they resolve and then used beginning with the same total dose. For example, if 60 mg was
restarted, giving trilostane less frequently for 1 week before con- given once daily, the new dose should be 30 mg twice daily. Alter-
tinuing with the initial dosing scheme (i.e., every other day if dos- natively, a lower dose can be given in the evening (e.g., go from 60
ing started once daily and give once daily if dosing was initiated mg once daily to 60 mg in the morning and 30 mg in the evening).
twice daily). It is important to differentiate minor adverse effects Except for the first recheck at 10 to 14 days after initiation
from hypocortisolism; ACTH stimulation testing is needed. of treatment, if the post-ACTH serum cortisol concentration is
The first ACTH stimulation test should be performed after 10 to 5 to 9 g/dL (150 to 250 nmol/L) and clinical signs of HAC are
14 days or if decreased appetite, vomiting, diarrhea, or listlessness present, the trilostane dose should be increased. If after the first
or normalization of water intake occurs. When performing ACTH recheck, the post-ACTH cortisol concentration is more than 9 g/
stimulation tests for monitoring, a dose of 1 g/kg cosyntropin can dL (250 nmol/L), the trilostane dose should be increased whether
be used (Aldridge etal, 2014). Since trilostane absorption is affected or not clinical signs are present.
by food, if the medication is usually given with food, the patient If the dog is already receiving twice-daily therapy and the cor-
should not be fasted the morning of the test. Post-pill timing is tisol concentrations are in the ideal range but the clinical signs
crucial for dogs receiving trilostane. Some recommend initiating an are not controlled, two scenarios should be considered. One is
ACTH stimulation test at 2 to 4 hours post-pill (Griebsch et al, that the dog needs to receive trilostane three times daily (Feldman,
2014). However, insufficient data exist in the literature to determine 2011). Alternatively, the clinical signs may not be due to HAC,
the optimal time. The author recommends initiating the test at 4 to and the diagnosis should be revisited.
6 hours post-pill. Keeping the timing of the test consistent for each An ACTH stimulation test should be performed 10 to 14 days
patient may also be important (i.e., for an individual patient, always after every dose adjustment. Once the clinical condition of the dog
start the ACTH stimulation test at the same post-pill interval). The and the dose have stabilized, an ACTH stimulation test should be
full effect of the drug may not be seen for approximately 30 days, performed 30 and 90 days later and then every 3 months there-
so the first recheck is mainly to ensure that overdosing has not after. The amount of dosage adjustment, either up or down, will
occurred. The dose should not be increased at the first recheck but likely be dictated by available capsule size, but it typically should
should be decreased if serum cortisol concentrations are too low. be approximately 25%.
The ideal cortisol concentrations for a dog receiving trilostane
therapy are approximately 1 to 5 g/dL (30 to 150 nmol/L) pre- Twice-Daily Dosing
and post-ACTH; a cortisol concentration up to approximately 9 Trilostane may begin to lose effectiveness at 8 to 10 hours post-
g/dL (250 nmol/L) post-ACTH is considered acceptable if the pill (Witt and Neiger, 2004; Bell etal, 2006; Vaughn etal, 2008).
patient is doing well and clinical signs of HAC are controlled Although performing an ACTH stimulation test at 8 to 12 hours
|
Trilostane
2 mg/kg once daily or 1 mg/kg b.i.d.
Decreased appetite, vomiting, diarrhea,

listlessness, or water intake 60 mL/kg/d
OR
10 to 14 days

starting 4 to 6 hr postpill
Recheck ACTH stim in 3 days. If recheck day 10 to 14 of

Restart 25% lower dose when therapy:
Clinical signs Clinical signs
cortisol ideal or higher Leave dose as is and
controlled present
recheck ACTH stim day 30.
Continue therapy. Increase to b.i.d. therapy. If recheck after 30 days

Recheck ACTH stim at Recheck ACTH stim 10 to 14 days. on therapy:
30 and, if doing well, at 90 days; (If on b.i.d. therapy, Increase dose 25%;
then every 90 to 120 days, if signs recur or increase to t.i.d. therapy) recheck ACTH stim in 7 days.
if signs cortisol insufficiency present
FIGURE 10-58 Algorithm for use of trilostane for treatment of hyperadrenocorticism (HAC). Ideal range for basal
and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration is approximately 1 to 5 g/dL (30 to
150 nmol/L) pre- and post-ACTH. Up to approximately 9 g/dL (250 nmol/L) is considered acceptable if the clinical
signs are controlled. b.i.d., Twice-daily therapy; t.i.d., three-times-daily therapy.
post-pill has been recommended for dogs on twice-daily trilostane dosing frequency was not evaluated. The consequences of control by
therapy (Alenza etal, 2006), the optimal time has not been verified, either drug regarding development of recurrent infection or throm-
and the author uses the same protocol as for once-daily therapy. boembolic disease have not been evaluated.
Twice-daily dosing might increase the likelihood of obtaining
complete remission. At evaluation after 1 year of trilostane ther- Diabetic Patients
apy for PDH, 12 of 12 dogs receiving trilostane twice daily had a For dogs with diabetes mellitus and HAC, insulin doses are
complete clinical response. In comparison, of eight dogs receiving expected to decrease with treatment of HAC because hypercor-
trilostane once daily, four had a complete clinical response, and tisolemia causes insulin resistance. For dogs with both diseases
two dogs each had partial or no clinical response, despite no dog receiving mitotane, the mean daily insulin requirement decreased
having a post-ACTH cortisol concentration more than 9 g/dL from 4.6 U/kg/day to 1.7 U/kg/day in 8 of 11 dogs; the insulin
(250 nmol/L) (Arenas etal, 2013a). requirement did not change in the other three dogs (Peterson etal,
Special consideration should be given to twice-daily dosing in 1981). In a retrospective study of six dogs with concurrent diabetes
dogs in which breaks in control of the HAC could be detrimental mellitus and HAC treated for more than 2 months with trilostane,
(e.g., dogs with concurrent diabetes mellitus or with proteinuria insulin requirements were not consistently reduced (McLauchlan
or PTE secondary to HAC). The duration of control of cortisol etal, 2010). Three dogs received trilostane once daily.
secretion afforded by trilostane varies between dogs and is not eas- Likely the same precautions apply when using trilostane in a dog
ily determined. Although clinical signs of HAC may be in remis- with diabetes mellitus as when using mitotane (see Diabetic Patients).
sion, how long cortisol secretion must be controlled to improve or Attempts to control the diabetes mellitus are not recommended until
prevent the serious complications of HAC is unknown (for exam- the HAC is in remission because the insulin dose may diminish once
ple: Is 12 hours of control out of 24 hours per day sufficient?). cortisol concentrations decrease. Administration of prednisone (0.4
Adequate control of HAC with mitotane significantly decreases mg/kg once daily) to help avoid hypoglycemia should be considered
blood pressure and proteinuria (Ortega etal, 1996). In dogs with during the early part of treatment when control is being achieved.
PDH receiving trilostane therapy in one study, blood pressure was
not significantly improved; UPCR decreased significantly, but Alternate Monitoring
approximately 38% remained proteinuric after 12 months (Smets Given the expense of ACTH stimulation testing, alternate means
etal, 2012). However, the study was small. Furthermore, some dogs for monitoring trilostane therapy have been evaluated. Although
received therapy twice daily and some once daily, and the effect of one paper suggested that basal cortisol concentrations within a
specific range was highly suggestive that a patient was well con- of HAC typically quickly resolve with control of cortisol concen-
trolled (Cook and Bond, 2010), a more recent study documented trations, but certain ones such as dermatological abnormalities
considerable overlap between excessively, adequately, and inade- can take up to 3 months. Other abnormalities such as calcinosis
quately controlled dogs (Burkhardt etal, 2013). Similarly, an early cutis or myotonia may not fully resolve. A small proportion of
paper suggested that measuring the UC:CR in a sample collected dogs with PDH are not well controlled with trilostane (Ruck-
before administration of a trilostane dose could indicate duration stuhl etal, 2002; Braddock etal, 2003; Vaughn etal, 2008).
of action (Braddock etal, 2003), but additional studies did not
confirm use of UC:CR measurement either in samples collected Efficacy for Adrenocortical Tumor
before or 6 hours after trilostane administration (Vaughn et al, Surgical removal of a cortisol-secreting AT is the recommended
2008; Galac etal, 2009). Thus, only ACTH stimulation testing treatment, but if surgery is neither possible nor desired, trilostane
can be used for monitoring trilostane therapy. can be used (Machida etal, 2007; Benchekroun etal, 2008; Helm
etal, 2011; Arenas etal, 2014). Currently, the dose recommended
Adverse Effects is the same as for PDH. Clinical impressions are that the same
Reported adverse effects for the most part are relatively mild, includ- dosage used for treatment of PDH is efficacious in dogs with AT
ing lethargy, weakness, decreased appetite, vomiting, and diarrhea. at least in the short term. However, doses required for long-term
However, fatality has occurred. Reported rates of adverse effects vary control are unknown. One dog with an AT did receive a maxi-
from 25% to 40% (Neiger etal, 2002: Ruckstuhl etal, 2002; Alenza mum dose of 17.2 mg/kg (Eastwood etal, 2003), which is higher
et al, 2006; Arenas et al, 2013a; 2014). One nonpeer-reviewed than typical for PDH.
report states mild, self-limiting side effects such as diarrhea, vomiting,
and lethargy occur in 63% of dogs receiving trilostane (Neiger, 2004). Prognosis
Safety has not been evaluated in lactating dogs and males intended for In 65 and 26 dogs with PDH treated with trilostane, median
breeding. Trilostane should not be given to pregnant females. survival time was 662 days (range, 8 to 1,971) (Barker et al,
Excess adrenal gland suppression can occur and warrants discon- 2005) and 549 days (Neiger etal, 2002), respectively. In 22 dogs
tinuing trilostane temporarily and lowering the dose (see earlier). treated with trilostane once daily for an AT, median survival
Compared with mitotane, trilostane has fewer effects on aldoste- time was 353 days (Helm etal, 2011). In eleven dogs with AT
rone concentrations but hypoaldosteronism can occur regardless treated with twice-daily trilostane, the median survival time was
of level of control of PDH (Reid etal, 2014). Caution should be 14 months (range, 3.3 to 55.0) (Arenas etal, 2014).
used in administering trilostane with an angiotensin converting
enzyme (ACE) inhibitor or an aldosterone antagonist (e.g., spi- TREATMENTMEDICAL MANAGEMENT
ronolactone) because the suppressive effect on serum aldosterone WITH KETOCONAZOLE
concentration may be cumulative.
Ketoconazole, an imidazole derivative, is an orally active, broad-
Prolonged Adrenal Suppression and Adrenal Necrosis spectrum antimycotic drug. It inhibits conversion of lanosterol to
Although, in theory, as an enzyme inhibitor, the effects of trilostane ergosterol and thus disturbs fungal membrane growth. At higher
should be reversible within 1 to 2 days, suppression can last weeks concentrations, ketoconazole affects steroid biosynthesis by inter-
to years (Braddock etal, 2003; Alenza etal, 2006; Ramsey etal, acting with the imidazole ring and the cytochrome P450 com-
2008). After only three doses, one dog developed hypocortisolism ponent of various mammalian steroidogenic enzyme systems. In
that persisted for at least 1 year (Ramsey et al, 2008). Complete normal dogs, ketoconazole administration decreases serum cor-
adrenal necrosis can occur secondary to trilostane administration as tisol and testosterone, but not mineralocorticoid, concentrations
well (Chapman etal, 2004) and likely would be permanent. How (DeCoster etal, 1984; Willard etal, 1986). Ketoconazole is cur-
often acute iatrogenic hypoadrenocorticism occurs in dogs treated rently used rarely for treatment of canine HAC.
with trilostane is unknown but is likely more common than origi-
nally believed. In one study, four of six dogs with PDH and one Protocol
of one with an AT treated with trilostane had a degree of adrenal Dosing of ketoconazole should be initiated at 5 mg/kg twice
necrosis at necropsy. In two dogs, the damage was severe enough daily by mouth for 7 days, which is a low dosage to allow an
to potentially cause hypoadrenocorticism. Both dogs had received evaluation period for development of side effects, such as gastro-
therapy with mitotane before trilostane but had been on trilostane enteritis or hepatitis. Light feeding may help ameliorate gastritis.
for 15 and 22 months (Reusch etal, 2007). Thus, the contribution If no ill effects are observed during the first week, the dosage
of each drug is unclear. Adrenal rupture, possibly secondary to adre- should be increased to 10 mg/kg b.i.d. by mouth for 14 days
nal necrosis, may have occurred (Vetoryl package insert). Interest- after which an ACTH stimulation test should be performed.
ingly, the necrosis is likely not a direct effect of trilostane but due to The dosage requirement is determined from owner opinion
severely elevated ACTH concentrations that occur with trilostane and ACTH stimulation test monitoring. The ideal ranges for
use (Burkhardt etal, 2011); as cortisol concentrations decrease with serum cortisol concentrations pre- and post-ACTH are approxi-
trilostane therapy, negative feedback on the pituitary is diminished, mately 1 to 5 g/dL (30 to 150 nmol/L). If serum cortisol con-
and ACTH concentrations rise to very high concentrations (Witt centrations are above ideal, the ketoconazole dosage should be
and Neiger, 2004). increased to 15 mg/kg b.i.d. by mouth and the dog monitored
every 14 days (Feldman etal, 1990). Doses of at least 15 mg/
Efficacy for PDH kg b.i.d. are usually needed. Dosages equal to or greater than
Trilostane is highly effective in suppressing cortisol secretion 20 mg/kg b.i.d. may be required (Feldman and Nelson, 1992;
and controlling clinical signs in more than 90% of patients with Behrend etal, 1999). At any time, if the cortisol concentrations
PDH (Neiger etal, 2002; Ruckstuhl etal, 2002; Braddock etal, are below ideal, ketoconazole administration should be stopped.
2003; Alenza etal, 2006; Clemente etal, 2007; Vaughn etal, Cortisol concentrations should return to pretreatment levels
2008; Galac et al, 2009). As with mitotane, many clinical signs within 24 hours (Feldman et al, 1990); ketoconazole therapy
|
can be reinitiated at a 25% dose reduction. If no response is seen (see Fig. 10-1). Thus, increasing dopamine concentrations or
or the disease progresses despite therapy, ketoconazole should be activity may inhibit ACTH oversecretion and be useful for
discontinued and alternative therapy begun. treatment of PDH. Elevating dopamine can only be effective
for PDH, however. Because ACTH secretion is suppressed in
Adverse Effects patients with an AT, dopamine agonism or increasing dopamine
Ketoconazole appears to be relatively safe with a low incidence concentrations would have little, if any, further effect on ACTH
of side effects. When seen, adverse effects may include anorexia, release. Moreover, because ATs function autonomously of
vomiting, elevated liver enzymes, diarrhea, and icterus (Behrend ACTH, lowering ACTH levels would not alter cortisol secretion.
et al, 1999; Lien and Huang, 2008). Gastrointestinal adverse Monoamine oxidase inhibitors, including selegiline
effects may be due to hypocortisolemia or direct drug toxicity. (L-deprenyl, Anipryl), inhibit degradation of biogenic amines,
Uncommon side effects attributed to ketoconazole administration most notably, dopamine. Unlike other monoamine oxidase
include depression, weakness, lethargy, trembling, liver failure, inhibitors, selegiline is specific for cerebral monoamines (i.e.,
polyuria and polydipsia, thrombocytopenia, and dermatological monoamine oxidase B). One study of 10 dogs suggested a
changes, such as altered coat color, poor coat condition, and scal- 20% response rate (Reusch etal, 1999). The low rate is under-
ing (Behrend etal, 1999). Ketoconazoles effect on reproductive standable because dopamine likely only inhibits intermedi-
status has not been addressed, but it does decrease testosterone ate lobe ACTH secretion and not secretion from the anterior
synthesis in healthy dogs (Willard etal, 1986) and should be used pituitary; approximately 20% of canine PDH cases originate
cautiously in male dogs intended for breeding. in the intermediate lobe. Unfortunately, only histopathology
can differentiate anterior and intermediate lobe tumors. One
Efficacy study found selegiline to be ineffective for treatment of PDH
The efficacy of ketoconazole for treating HAC is lower than that (Braddock etal, 2004).
of mitotane and trilostane. After ketoconazole therapy, basal and Use of selegiline to treat PDH is not recommended due to
post-ACTH cortisol concentrations may actually be higher than the low efficacy, but it could be tried in dogs with PDH that
those pretreatment in some dogs (Feldman and Nelson, 2004). Of cannot tolerate mitotane and trilostane. Treatment should
132 veterinary internists and dermatologists surveyed, which are begin at 1 mg/kg orally once daily for 30 days. If no response
specialists likely to treat HAC, 52% considered ketoconazole to be is seen, the dose should be doubled for an additional 30 days.
effective in less than 25% of cases, 19% reported effectiveness in Failure to respond at that time indicates the need for an alter-
25% to 49% of cases, and 14% each believed ketoconazole to be native therapy.
efficacious in 50% to 74% and 75% to 100% of cases (Behrend Selegiline therapy is relatively safe. Side effects are uncommon
etal, 1999). A recent report suggested a higher efficacy of 70% in and usually mild, including vomiting, diarrhea, and ptyalism
48 dogs (Lien and Huang, 2008), but the follow-up on treated (Reusch et al, 1999; Braddock et al, 2003). Severe neurological
dogs was inconsistent and the ideal post-ACTH cortisol concen- disturbances and pancreatitis may have been caused by selegi-
tration used in the study was not as low as recommended by most line therapy (Reusch etal, 1999), but the neurological problems
authors. Thus, although ketoconazole may lower serum cortisol may also have been due to the presence of a large pituitary mass.
concentration in dogs with PDH and clinical improvement can Chronic selegiline therapy does not result in glucocorticoid insuf-
be seen (Feldman etal, 1990; Lien and Huang, 2008), whether ficiency and, based on its mechanism of action, would not be
therapy is truly adequate in such a high percentage is unclear. expected to affect aldosterone secretion.
Three general indications previously existed for ketoconazole One disadvantage of selegiline is cost. Although the bioequiv-
use. However, trilostane is now the first choice in such cases. First, alency of generic preparations is the same among themselves,
ketoconazole was used when a patient could not tolerate mitotane. they are less bioavailable than the original product, L-deprenyl
A second consideration was as a diagnostic aid in cases in which (Eldepryl); comparisons with the animal product Anipryl are
the diagnosis of HAC is unclear. If an ACTH stimulation test not available. Thus, it may be wise to avoid the generic prod-
showed ketoconazole therapy had adequately controlled cortisol ucts. Another disadvantage of using selegiline for treating PDH
secretion, then any clinical signs present due to HAC should have is that monitoring of efficacy is based solely on subjective find-
resolved. If the disease was in remission, the diagnosis was con- ings. The results of the ACTH stimulation test do not change
firmed. If no resolution of clinical signs was seen despite control in dogs receiving selegiline. Thus, other objective measures of
of cortisol concentrations, HAC was ruled out as a diagnosis and effect, such as quantification of water intake or measurement of
ketoconazole discontinued. Ketoconazole provided a better alter- urine specific gravity should be utilized. L-deprenyl is degraded to
native to trial therapy than mitotane, because mitotanes effects amphetamine and methamphetamine. Thus, effects attributed to
may be irreversible. It should be noted that although the effects of L-deprenyl administration, such as increased activity, may be due
trilostane can be quickly reversible, they may not always be (see to the metabolic byproducts and not to an effect on the pituitary-
earlier). Third, because AT may be mitotane-resistant or the high adrenocortical axis.
doses of mitotane required to treat an AT may cause unacceptable
side effects, ketoconazole was used for medical treatment of AT or Bromocriptine
pre-adrenalectomy to prepare the patient for surgery. No study has
evaluated ketoconazole efficacy in a large number of dogs with AT. Bromocriptine, a dopamine agonist, lowers plasma ACTH
concentrations, but as with selegiline, likely only affects the
pituitary intermediate lobe. Bromocriptine was administered
TREATMENTOTHER MEDICATIONS
to 47 dogs with PDH in total (Drucker and Peterson, 1980;
Rijnberk et al, 1988b). Vomiting was a cause for treatment
L-Deprenyl
discontinuation in a large proportion, and only one of the 47
Dopamine secretion from the hypothalamus tonically inhibits responded clinically. Thus, bromocriptine is not recommended
ACTH secretion from the intermediate lobe of the pituitary for treatment of canine PDH.
size; those that extend above the sella turcica are considered large
Cyproheptadine
(typically 10 mm in maximum height) and often referred to as
Increased CNS serotonin concentrations could theoretically macrotumors, either macroadenomas or macrocarcinomas. Large
increase pituitary ACTH secretion and, therefore, increased adre- tumors may compress or invade the hypothalamus and thalamus
nal secretory activity. Cyproheptadine, a drug with antiserotonin, and cause a spectrum of neurologic signs that include change in
antihistamine, and anticholinergic effects, was used to treat nine behavior, aggression, listlessness, obtundation, inappetence, pac-
dogs with PDH for 2 monthsfive at a dose of 0.3 mg/kg/day and ing, circling, head pressing, and seizures (Theon and Feldman,
four at a dose of 1 mg/kg/day; no dog improved (Stolp etal, 1984). 1998; Kent et al, 2007). Development of neurologic signs sec-
ondary to the compressive effects of a macrotumor is referred to
as pituitary macrotumor syndrome (see Central Nervous System
Retinoic Acid
Signs). Development of pituitary macrotumor syndrome is associ-
Retinoic acid inhibits cell proliferation, growth, and invasion and ated with a shorter survival time, compared with dogs that do not
induces apoptosis and differentiation in various tumors (Castillo develop it.
and Gallelli, 2010). It decreases ACTH transcription and produc- Radiation therapy can reduce tumor size and improve neuro-
tion in tumor cells invitro and in experimental ACTH-producing logic signs. It is the only effective treatment for pituitary macro-
tumors invivo (Paez-Pereda etal, 2001). 9-cis retinoic acid was tumors. Studies in dogs have used cobalt 60 teletherapy or 4, 5,
used to treat a total of 27 dogs with PDH in two studies at a dose and 6 MV photon teletherapy using a linear accelerator to deliver
of 2 mg/kg/day. Unfortunately, measurement of eACTH and - external beam megavoltage radiation. Total radiation doses have
MSH hormone concentrations and UC:CR were used to evaluate typically ranged from 35 to 50 Gy applied in 2.5- to 4-Gy frac-
treatment, which makes the results difficult to interpret because tions delivered 3 to 5 days per week over a period of 3 to 4 weeks.
these are not the typical tests used for therapeutic monitoring. Fractionated treatment plans were developed to maximize tumor
Although the dogs treated with retinoic acid subjectively had cell death while preserving normal tissue within the radiation field.
greater resolution of clinical signs than the control group, the con- As a late responding tissue, the CNS is most sensitive to the dose
trol therapy was ketoconazole, which is much less effective than per fraction as well as the total radiation dose (Harris etal, 1997).
trilostane or mitotane; thus, retinoic acid may have had an unfair Treatment plans that decrease the dose per fraction while increas-
advantage. Interestingly, pituitary tumor size decreased signifi- ing the number of doses have been recommended in an attempt
cantly in dogs that were treated for 180 days (Castillo etal, 2006; to spare normal nervous tissue. Although this treatment approach
2009). Although results were promising, more work needs to be is effective in reducing tumor volume and minimizing severity of
done before retinoic acid therapy can be recommended, especially neurologic signs and adverse effects of irradiation, it requires mul-
when proven therapies such as mitotane or trilostane are available. tiple anesthetic procedures and extended hospitalization time.
In addition, the retinoic acid used is not readily available and, at Stereotactic radiosurgery (SRS) is a relatively new procedure
the doses used in the study, would likely be cost prohibitive to that delivers a single large radiation dose to a well-defined tar-
most owners. get while sparing surrounding tissue (Mariani etal, 2013). Sev-
eral universities in the United States are utilizing SRS for the
treatment of pituitary macrotumors in dogs with PDH and
Metyrapone and Aminoglutethimide
cats with acromegaly. At UC Davis, for example, a total dose of
Metyrapone, an 11-hydroxylase inhibitor, and aminoglutethi- 24 Gy is administered in 8-Gy fractions on three consecutive days.
mide, which inhibits conversion of cholesterol to pregnenolone, Anesthetic procedures and hospitalization time are significantly
have both been used to reduce cortisol hypersecretion in people reduced, the total radiation dose is minimized due to more accu-
alone or in combination. Aminoglutethimide was administered rate delivery of radiation to the tumor, and adverse effects have
to 10 dogs with PDH (5 mg/kg by mouth three times daily) for 1 been minimal. Studies evaluating short- and long-term efficacy of
month. A complete response was seen in only one dog and a par- SRS are currently in progress.
tial response in three. Side effects including anorexia, vomiting, Adverse radiation effects are categorized as acute and late. Acute
and weakness as well as elevations in liver enzymes were observed adverse effects occur in organs located within the treatment field that
in the majority of dogs (Alenza et al, 2002). It is possible that have rapidly dividing cells, most notably skin, pharyngeal mucosa,
longer treatment or use of other doses would have had greater and the external auditory canal. Accordingly, acute adverse effects
efficacy. However, with the current data, its use cannot be rec- include alopecia involving the skin exposed to radiation, leukotrichia,
ommended for treatment of PDH. To the authors knowledge, mucositis, and transient lethargy and disorientation (Dow etal, 1990;
although metyrapone has been used to treat cats with PDH, no Goossens etal, 1998; Kent etal, 2007). Concurrent treatment with
reports exist of metyrapone administration to dogs with HAC. low dose glucocorticoids (0.25 mg/kg prednisone once daily) dur-
Side effects in people are common. Furthermore, metyrapone is ing therapy may help decrease the occurrence of acute adverse effects.
not consistently available. Late adverse effects develop months later, are irreversible, and occur
in slowly-dividing tissues within the treatment field; they include
infarction, demyelination and necrosis of the CNS, cranial nerve
TREATMENTPITUITARY IRRADIATION
injury, pituitary-hypothalamic dysfunction, and neurologic impair-
The normal pituitary gland in adult dogs is located in the ment. Late adverse effects reported in dogs include deafness or partial
hypophyseal fossa, which is an oval depression in the basisphe- hearing loss and vestibular and trigeminal nerve injury (Dow etal,
noid bone located ventral to the hypothalamus. The com- 1990; Goossens etal, 1998; Theon and Feldman, 1998). The risk of
plex of boney structures around the pituitary gland has a late adverse effects depends on the volume of normal tissue treated,
saddle-like shape and is called the sella turcica. A normal pitu- the daily radiation dose, and the total radiation dose administered.
itary gland remains within the sella turcica. The normal height Higher total doses may improve local tumor control but increase the
of pituitary gland in dogs is 2.1 to 6.0 mm (Kooistra et al, risk of late adverse effects, whereas with lower fractions, normal nerve
1997b). Pituitary tumors in dogs with PDH are variable in tissue is more likely to be spared but reduction of tumor volume,
|
improvement in neurologic signs, and survival time may be compro- 1.00

mised (Gillette and Gillette, 1995; Brearley et al, 1999; de Fornel
etal, 2007). Most studies to date have used a dosing protocol close to
the limits of CNS tolerance (i.e., 40 to 48 Gy). 0.75
The goals of radiation therapy include shrinkage of the macrotu-
Proportion alive
mor, improvement or resolution of neurologic signs and the clinical
manifestations of HAC, and prolonged survival with a good qual- 0.50
ity of life. All studies evaluating the effect of irradiation on pitu-
itary tumor size, to date, have documented a significant decrease
in almost all dogs treated (Dow etal, 1990; Goossens etal, 1998; 0.25
Theon and Feldman, 1998; de Fornel etal, 2007; Kent etal, 2007).
In some dogs the tumor was no longer detectable on subsequent CT
imaging. The effects of radiation therapy on tumor size appeared 0.00
quickly in some dogs (within 1 month after finishing treatment); 0 500 1000 1500 2000
the tumor continued to decrease in size over several months and Time (days)
could remain stable in size for up to 20 months (de Fornel etal,
2007). If neurologic signs were present, improvement or resolution FIGURE 10-59 Survival distribution of dogs with pituitary masses that were
occurred in most but not all dogs. Improvement in neurologic signs treated with radiation therapy (RT) (dashed line) or that were not treated (solid
typically occurred within a month of beginning radiation therapy. line). Nineteen dogs were treated with RT, and 20 dogs received no therapy. These
Improvement or resolution of clinical signs of HAC did not occur curves were significantly different (log-rank test, P = 0.0039). Censored dogs are
in most dogs, suggesting that pituitary irradiation is more effec- indicated by tick marks. (From Kent MS, etal.: Survival, neurologic response, and
tive for controlling tumor growth than ACTH secretion. Pituitary prognostic factors in dogs with pituitary masses treated with radiation therapy
ACTH hypersecretion usually persisted for months after radiation and untreated dogs, J Vet Intern Med 21:1027, 2007.)
therapy, and most dogs required medical treatment of PDH to con-
trol clinical signs of HAC despite shrinkage of the pituitary tumor. The efficacy of irradiation of pituitary tumors of small relative
A correlation between tumor size and ACTH secretion after radia- size supports the importance of early diagnosis and treatment,
tion therapy was not identified in several studies (Dow etal, 1990; preferably before neurologic signs develop. One year after irradia-
Goossens etal, 1998; Theon and Feldman, 1998). tion of detectable pituitary masses measuring 3 to 14 mm in verti-
Median overall survival time after irradiation has ranged from cal height (median 6.5 mm) with a total dose of 44 Gy in six dogs
approximately 12 to 25 months (Dow etal, 1990; Theon and Feld- with PDH and no neurologic signs, the size of the pituitary tumor
man, 1998; Bley etal, 2005; de Fornel etal, 2007). In one study, had decreased by 25% in two dogs and was not detectable in four
the mean survival time was 1405 days (95% confidence interval (Goossens etal, 1998). Clinical signs of PDH resolved in three
[CI]: 1053 to 1757 days) for 19 dogs with pituitary masses (11 dogs but recurred in two of them 6 and 9 months later. Clinical
dogs had neurologic signs) irradiated with a total dose of 48 Gy signs of PDH persisted in the remaining three dogs after radiation
(Kent etal, 2007). The 1-, 2-, and 3-year estimated survival was therapy. None of the dogs developed neurologic signs. Pituitary
93%, 87%, and 55%, respectively. In contrast, the mean survival size did not correlate with the effects of radiation therapy.
time in 20 untreated control dogs with pituitary masses of compa- Accordingly, routine pituitary imaging should be considered as
rable size (16 dogs had neurologic signs) was 551 days (95% CI: part of the evaluation of a dog with newly-diagnosed PDH even if no
271 to 829 days) and the 1-, 2-, and 3-year estimated survival was clinical evidence of a large pituitary mass is present, especially if the
45%, 32%, and 25%, respectively. Dogs treated with irradiation client is willing to consider radiation therapy if a large pituitary mass is
had significantly longer survival times, compared with untreated identified (see TreatmentPituitary Irradiation). The preference is to
dogs with comparably sized pituitary masses (Fig. 10-59). perform CT imaging once clinical signs of HAC are controlled with
The ratio of pituitary tumor size to brain size has been used to cor- medical treatment (i.e., trilostane or mitotane). For dogs treated medi-
rect for variations in dog size, including the ratios of pituitary gland cally for PDH, mean survival is approximately 30 months. While the
height to brain area; of pituitary area to brain area; and of pituitary rate of tumor growth is unpredictable, it may be safest for our patients
volume to brain volume (Kooistra etal, 1997b; Theon and Feldman, to assume that a pituitary tumor will double or triple in size over a
1998). In the study by Kent and colleagues (2007), a pituitary-to- period of several years. If a dog has no visible pituitary mass (i.e., must
brain height ratio of more than 25% or a pituitary-to-brain area be < 3 mm in greatest vertical height) at the first CT and the mass
ratio of more than 5% was associated with decreased survival in dogs triples in size, the mass likely will never be large enough to be clinically
treated with irradiation. No dog with tumor heights less than 25% of signicant. Hence, no follow-up with CT imaging is recommended.
brain height or with tumors less than 5% of the cross-sectional area of If a dog has a mass of 8 mm or more in greatest vertical height at the
the brain died of their disease during the study period. time of diagnosis of PDH, the mass would not even need to double in
The severity of neurologic signs at presentation may also be a size before neurologic signs occur. Thus, radiation therapy is recom-
prognostic indicator for success of radiation therapy. In 24 dogs mended. If a pituitary mass is 3 to 7 mm in greatest vertical height,
with PDH and neurologic signs, dogs with severe neurologic signs doubling or tripling in size may or may not be problematic. Therefore,
had a 6.6-fold higher risk of death due to their pituitary tumor based on experience, the CT scan should be repeated in 12 months.
than dogs with mild neurologic signs (Theon and Feldman, 1998).
A significant correlation was detected between relative tumor size SPONTANEOUS REMISSION
(i.e., pituitary tumor size relative to calvarium size) and severity of OF HYPERADRENOCORTICISM
neurologic signs, remission of neurologic signs after radiation ther-
apy, and duration of remission of clinical signs. Dogs with a relative Spontaneous remission of HAC is a documented phenomenon in
tumor size of 12% or more had a fourfold higher risk of disease humans, either due to acute adrenal hemorrhage or pituitary infarc-
progression than dogs with a relative tumor size less than 12%. tion. One case report exists of a dog with presumed HAC, likely
PDH, which underwent spontaneous remission (Rockwell et al, weakness, and polyuria/polydipsia. Tumors secreting both min-
2005). In the dog, HAC was diagnosed by means of an ACTH eralocorticoids and glucocorticoids occur uncommonly (Beh-
stimulation test. Twelve days later, the dog had clinical signs and rend et al, 2005; Machida et al, 2007; Frankot et al, 2012), so
changes on routine biochemical tests consistent with spontaneous clinical signs of and clinicopathologic changes consistent with
hypoadrenocorticism; cortisol and aldosterone concentrations were glucocorticoid excess may also be present. The presence of severe
undetectable pre- and post-ACTH, and eACTH concentrations hypokalemia and a serum sodium concentration at the upper end
were elevated. Cytology of a fine needle aspirate of one of the adrenal of or mildly above the reference range in combination with the
glands was consistent with marked purulent inflammation. Thus, the finding of an adrenal mass on abdominal ultrasound should raise
spontaneous hypoadrenocorticism was believed to be due to adrenal suspicion for primary hyperaldosteronism. However, aldoste-
necrosis. Because elevated eACTH concentrations can potentially rone-secreting tumors can be quite small and normal ultrasound
cause adrenal necrosis (Burkhardt etal, 2011), the cause of the spon- findings do not definitively rule out a mass or idiopathic adreno-
taneous remission was speculated to be the injection of exogenous cortical hyperplasia.
ACTH given for the initial ACTH stimulation test. A similar occur- Confirmation of an aldosterone-secreting tumor requires docu-
rence has been documented in humans (Marcus etal, 1986). menting markedly increased baseline plasma aldosterone con-
Spontaneous remission has occurred in five dogs with histories, centrations (often > 3000 pmol/L) and suppressed plasma renin
physical examination ndings, and endocrine test results consis- activity (i.e., increased aldosterone-to-renin ratio) in conjunction
tent with PDH (Feldman and Nelson, 2004). Treatment for HAC with exclusion of other causes of hypokalemia (see Chapters 11
had not been pursued in any dog, because the owners believed and 12). Unfortunately, a canine plasma renin activity assay is not
they were improving. Subsequent evaluations demonstrated reso- currently available. Other findings that help confirm a diagnosis
lution of all evidence supporting a diagnosis of PDH. Given lack of primary hyperaldosteronism include systemic hypertension and
of development of hypoadrenocorticism, it is likely that remis- the presence of a metabolic alkalosis. The movement of potassium
sion of the HAC was caused by embolization of a pituitary tumor extracellularly results in a shift of hydrogen ions and an increased
rather than adrenal necrosis. renal excretion of hydrogen ions leading to metabolic alkalosis.
(Frankot etal, 2012).
PRIMARY MINERALOCORTICOID EXCESS: The diagnostic value of increased urinary aldosterone-to-cre-
PRIMARY HYPERALDOSTERONISM atinine ratio and failure of the urinary aldosterone-to-creatinine
ratio to suppress with administration of oral fludrocortisone ace-
Primary hyperaldosteronism (Conns syndrome) is an adrenocorti- tate has been evaluated in cats (Djajadiningrat-Laanen etal, 2008;
cal disorder characterized by excessive and autonomous secretion 2011). The major aldosterone forms present in human urine are
of the mineralocorticoid aldosterone. Primary hyperaldosteron- aldosterone-18-glucuronide, tetrahydroaldosterone, and free

ism is typically caused by a unilateral solitary adenoma or carci- aldosterone (Cartledge and Lawson, 2000). Commercially avail-
noma, although bilateral idiopathic adrenocortical hyperplasia has able kits for aldosterone measurement detect free aldosterone and
been identified (Breitschwerdt etal, 1985; Rijnberk etal, 2001; aldosterone-18-glucuronide (after acid hydrolysis of the glucuro-
Behrend etal, 2005; Machida etal, 2007; Frankot etal, 2012). nide). Syme and colleagues (2007) evaluated urine samples from
Primary hyperaldosteronism is perhaps the most common adrenal eight normal dogs and found canine urine contained lower con-
disease affecting cats but is rare in dogs. This disorder is covered centrations of aldosterone-18-glucuronide than human urine and,
briefly here, but see Chapter 11 for additional information on pri- unlike feline or human urine, contained no detectable free aldo-
mary hyperaldosteronism. sterone. Accordingly, urine tests may have limited to no diagnostic
The primary role of aldosterone is to maintain sodium and potas- value for primary hyperaldosteronism in dogs, but they have not
sium balance and extracellular fluid volume. The primary regulators been evaluated.
of aldosterone secretion include the renin-angiotensin-aldosterone Desoxycorticosterone-secreting tumors have been reported
system, plasma potassium and sodium concentrations, and ACTH. rarely (Reine et al, 1999; Davies et al, 2008). Clinical findings
The primary target tissue for aldosterone is the kidneys where aldo- are the same as with primary hyperaldosteronism but aldoste-
sterone promotes sodium absorption and potassium excretion. rone concentrations are low. As no assay for desoxycorticosterone
Excessive aldosterone secretion causes sodium retention and potas- measurement is commercially available, a diagnosis would be pre-
sium depletion, which is manifested as a relatively mild increase in sumptive based on the constellation of diagnostic test results.
serum sodium concentration (typically 155 to 165 mEq/L) and a Unilateral adrenalectomy is the treatment of choice for a solitary
marked decrease in serum potassium concentration (typically < 3.0 adrenal mass, especially if no evidence of distant metastasis, vas-
mEq/L). Hypokalemia causes muscle weakness, which is the most cular invasion, or infiltration of the mass into the kidney or body
common clinical sign of primary hyperaldosteronism. Hypernatre- wall is found (see Adrenalectomy). Medical therapy involving
mia and direct actions of aldosterone cause systemic hypertension, the administration of oral potassium supplements, mineralocor-
which, in turn, may cause ocular abnormalities, most notably retinal ticoid receptor blockers (e.g., spironolactone), and antihyperten-
hemorrhage. Polyuria and polydipsia have been identified in dogs sive drugs (e.g., amlodipine) should be initiated until surgery can
with primary hyperaldosteronism. The mechanism for polyuria and be performed (Sica, 2005). Medical therapy is also indicated for
polydipsia is not clear, although mineralocorticoid-induced renal the long-term management of primary hyperaldosteronism when
resistance to the actions of vasopressin and disturbed osmoregula- adrenalectomy is not performed and for dogs with suspected idio-
tion of vasopressin release has been documented (Rijnberk et al, pathic adrenocortical hyperplasia.
2001). Hyperaldosteronism-induced hypokalemia may also result In theory, autonomous aldosterone secretion from an AT
in downregulation of aquaporin-2 water channels and urea trans- should suppress normal zona glomerulosa cells within the con-
porters, thereby interfering with the ability to concentrate urine (see tralateral adrenal gland. As such, hypoaldosteronism can occur
Chapter 1) (Robben etal, 2006; Sands and Bichet, 2006). postoperatively; serum electrolyte concentrations must be moni-
Primary hyperaldosteronism is a disease of middle-aged to older tored frequently and IV fluid therapy adjusted accordingly to
dogs presenting with owner complaints of lethargy, anorexia, maintain serum potassium and sodium concentrations within or
|
near reference intervals. If hypokalemia persists, oral potassium

supplementation can be initiated once the dog tolerates oral medi-
cations. Serum ionized magnesium concentration should be mon-
itored and hypomagnesemia treated, especially if hypokalemia is
refractory to IV fluid therapy. Serum electrolyte derangements
usually resolve within 24 to 72 hours of surgery, and mineralo-
corticoid replacement therapy is typically not needed. Mineralo-
corticoid treatment (i.e., oral fludrocortisone acetate or injectable
desoxycorticosterone pivalate) is recommended if hyperkalemia
and hyponatremia develop and persist for longer than 72 hours.
Only one injection of desoxycorticosterone pivalate is required,
and the daily dose of oral fludrocortisone acetate can be tapered
and usually discontinued within a week. See Chapter 12 for more
information on these medications.
Systemic hypertension usually improves or resolves within
48 to 72 hours after adrenalectomy. Antihypertensive medications
should be initiated if hypertension persists. Attempts to wean off
antihypertensive medications should be initiated during the ensu-
ing month. Glucocorticoid replacement therapy is usually not FIGURE 10-60 Abdominal ultrasound of a healthy dog revealed an incidental 1.2
indicated postoperatively, unless the tumor was secreting a glu- cm-diameter nodule in the cranial pole of the adrenal gland (solid arrow). The
cocorticoid. An ACTH stimulation test can be performed 6 to caudal pole of the adrenal gland appeared normal (dashed arrow).
8 hours after adrenalectomy to assess the function of the zona
fasciculata and reticularis of the remaining adrenal gland. If the
tumor was known preoperatively to secrete a glucocorticoid, the contralateral adrenal gland is usually normal in size and shape. A
same precautions and recommendations apply as when removing bulbous enlargement or nodule is usually not neoplastic or func-
a cortisol-secreting tumor (see Adrenalectomy). tional (i.e., autonomously secreting a hormone). Histologic exam-
The prognosis for patients with primary hyperaldosteronism ination often reveals normal tissue, inflammation, a granuloma, or
is similar to that for other AT. Surgical removal of an adenoma a clinically irrelevant benign tumor (e.g., myelolipoma).
carries an excellent prognosis. The prognosis for a carcinoma is Less commonly, cortical tumors and pheochromocytomas in
guarded. If metastatic sites exist, hyperaldosteronism, hypoka- the early stages of development are identified. Of primary AT,
lemia, and the associated clinical signs will recur. However, the approximately 75% are adrenocortical and the remainder are of
tumor can be slow-growing with recurrence taking greater than a neuroendocrine origin (Capen, 2007). A conservative approach
year following surgery. Management of recurrence with metasta- centered on periodic monitoring with ultrasound, initially at
sectomy can be successful (Frankot etal, 2012). The prognosis for monthly intervals, for changes in size of the nodule and appear-
idiopathic adrenocortical hyperplasia is unknown and depends on ance of the adrenal gland is recommended, especially if there are
the effectiveness of medical therapy. Bilateral adrenalectomy, in no clinical signs or findings on physical examination and routine
theory, should offer a cure, but the dog will require glucocorticoid blood and urine tests to support a functional adrenal tumor (Fig.
and mineralocorticoid treatment for life. 10-61). The chance of an incidentaloma being malignant may be
between 14% and 30% (Cook etal, 2014). Of seven dogs with
UNEXPECTED DISCOVERY OF AN ADRENAL MASS an incidentaloma of any type, three lesions were not found when
ultrasound was performed again more than 4 months later. No
Ultrasonography has become a routine diagnostic tool for evalua- growth was reported after more than 6 months in two dogs. In
tion of soft tissue structures in the abdominal cavity. One conse- two dogs with initially larger tumors (16- and 25-mm in diam-
quence is the unexpected finding of a seemingly incidental adrenal eter), growth occurred. In the first, the mass grew to 25-mm
mass (i.e., an incidentaloma). The incidence of finding an adre- diameter and invaded the vena cava within 10 months; in the
nal incidentaloma has been estimated at 4% overall but increases second, the mass grew to 31-mm diameter within 8 months
with age (Cook etal, 2014). Less commonly an AT is discovered before the dog was lost to follow-up (Cook et al, 2014). In
during CT or MRI. Many factors determine the aggressiveness of nine dogs with noncortisol-secreting tumors followed for 12
the diagnostic and therapeutic approach to an adrenal inciden- months, no change was seen in seven (Arenas et al, 2013b).
taloma, including the severity of concurrent problems, the origi- An AT should be suspected when there is loss of the typical
nal reason for performing abdominal ultrasound, the age of the shape of the gland (i.e., the gland looks like a mass) regardless of
dog, the likelihood that the mass is hormonally active, the prob- size, there is asymmetry in shape and size between the affected
ability that the mass is a malignant or benign tumor, the size and and contralateral adrenal glands, or the mass has infiltrated the
invasiveness of the mass, and the clients desires and willingness phrenicoabdominal vein, vena cava, or surrounding soft tissues
to pursue the problem. An adrenal mass may also be a metastasis (Fig. 10-62). If the mass is suspected to be malignant, adrenal-
from elsewhere. The first consideration is to be certain that an AT ectomy is the preferred treatment, but it may not be indicated if
exists. Abdominal ultrasound should always be repeated to con- the mass is benign, small, hormonally inactive, and not infiltrat-
firm the mass is a repeatable finding. ing surrounding structures. Unfortunately, it can be difficult to
Bulbous enlargement or a nodule of the cranial or caudal determine whether an adrenal mass is neoplastic and malignant
pole of an otherwise normal-appearing adrenal gland is a com- or benign before surgical removal and histopathologic evaluation.
mon finding in older dogs and can be misinterpreted as an adre- If the maximum diameter of the mass is 2 cm or more, chance of
nal mass or tumor (Fig. 10-60). Bulbous enlargements or nodules malignancy (Cook etal, 2014) and growth (Arenas etal, 2013b)
have a maximum diameter typically less than 1.5 cm, and the may be high. Invasion into surrounding tissues and identification
A B
C
FIGURE 10-61 A, An 11-year-old male castrated Doberman Pinscher mix with clinical signs consistent with acute
gastroenteritis. Abdominal ultrasound identified a 1.4 cm-diameter adrenal nodule (arrow) and a normal-size
contralateral adrenal gland. The history, physical examination, and routine blood and urine tests were not support-
ive of adrenal disease, and the dog responded to symptomatic therapy for acute gastroenteritis. The adrenal nodule
was periodically evaluated with ultrasound. Over the ensuing 2 years, the dog remained healthy, and minimal
growth or change was noted in the echogenicity of the adrenal nodule. B, The adrenal nodule 1 year after presen-
tation; maximum diameter was 1.8 cm. C, The adrenal nodule 2 years after presentation; maximum diameter was
2.0 cm. (From Nelson RW, Couto CG: Small animal internal medicine, ed 5, St Louis, 2014, Elsevier Mosby, p. 859.)
of additional mass lesions with abdominal ultrasound and tho- perform appropriate tests to confirm the diagnosis, if indicated.
racic radiographs also suggest malignancy. The bigger the mass, An aggressive diagnostic and therapeutic approach is often not
the more likely it is malignant and the more likely metastasis has warranted for a small adrenal mass (< 2 cm in diameter), especially
occurred, regardless of findings on abdominal ultrasound and tho- if the dog is healthy and there are no clinical signs related to adre-
racic radiographs. Cytological evaluation of specimens obtained nal dysfunction. In these cases, it may be preferable to determine
by ultrasound-guided fine-needle aspiration of the adrenal mass the rate of growth of the mass by repeating abdominal ultrasound
may provide guidance regarding malignancy and origin of the initially at monthly intervals. If the adrenal mass has not changed
mass (i.e., adrenal cortex versus medulla). in size after 3 months, the time interval between ultrasound evalu-
After confirming the existence of an unexpected adrenal mass, ations can be increased. However, if the adrenal mass is increasing
the clinician should review the history, physical examination, and in size, changing in appearance, or compressing or infiltrating sur-
results of routine blood and urine tests for evidence of hypercor- rounding blood vessels or soft tissues, or if clinical signs affiliated
tisolism, hyperaldosteronism, or pheochromocytoma and should with an excess of cortisol, catecholamines, or aldosterone develop,
|
A B
FIGURE 10-62 Ultrasound images of the adrenal gland in an 11-year-old castrated male Golden Retriever with
adrenal-dependent hyperadrenocorticism (HAC). A, A cortisol-secreting tumor affecting the right adrenal gland
(arrows) had a maximum diameter of 1.6 cm. Normal appearing adrenal tissue was not evident. B, The left adrenal
gland had undergone marked atrophy (arrows and crosses) and had a maximum diameter less than 0.2 cm. (From
Nelson RW, Couto CG: Small animal internal medicine, ed 5, St Louis, 2014, Elsevier Mosby, p. 831.)
adrenalectomy may be warranted. For noncortisol-secreting the veterinary literature meet the definition (Norman etal, 1999;
tumors, median survival without surgery in 14 dogs was 29.8 Syme etal, 2001; Ristic etal, 2002; Benitah etal, 2005). No spe-
8.9 months (range, 1 to 96 months). Larger tumor size was associ- cific phenotype for occult HAC is apparent.
ated with shorter survival (Arenas etal, 2013b). Although SARDS (Carter etal, 2009) and hyperphosphatasemia
See Chapter 13 for additional information. in Scottish Terriers (Zimmerman etal, 2010) have been linked with
occult HAC, causative evidence is lacking. If only post-ACTH sex
OCCULT HYPERADRENOCORTICISM hormones are considered, no single sex hormone was elevated in
more than 62% of dogs with retinal degeneration, and no hormone
Due to the high incidence of HAC and relatively nonspecific was consistently elevated. Similarly, in the Scottish Terriers, no sin-
clinical signs, older dogs are commonly screened for HAC. As dis- gle hormone was consistently elevated. More Scottish Terriers with-
cussed earlier, no screening test is perfect. Because HAC occurs in out hyperphosphatasemia had elevated sex hormones than did those
older dogs, patients tested for HAC often have concurrent disease. with an enzyme elevation. Correlation is not causation.
At the least, if they do not have HAC, they have a non-adrenal
illnes (NAI) causing the clinical signs. In general, the more severe
Evidence for and Against the Existence of
the NAI is the likelihood of a false-positive test result for HAC
Occult Hyperadrenocorticism as a Sex
increases.
HormoneMediated Disease
Due to the imprecision of diagnostic tests, HAC can be a dif-
ficult diagnosis to make. Clinicians are faced with a situation in In evaluating adrenal hormone secretion, whether basal or
which their clinical impressions are that patients have HAC, but ACTH-stimulated concentrations were measured in any study
the tests do not confirm the diagnosis and no alternative diagno- must be taken into account. For the diagnosis of standard HAC,
sis is identified. Recently, in order to explain such circumstances, determination of basal cortisol concentration is not reliable and
a syndrome termed occult HAC has been postulated. The 2012 never used by itself. No evidence exists that measurement of basal
American College of Veterinary Internal Medicine Small Animal serum sex hormone concentrations are any more trustworthy for
Consensus Panel on the diagnosis of HAC defined the syndrome diagnosis of adrenal dysfunction; thus, the following discussion
of atypical or occult HAC as, [a] syndrome in which a dog will focus on ACTH-stimulated concentrations.
appears to have HAC based on history, physical examination and
clinicopathologic findings, but the LDDST, UC:CR and ACTH Adrenal Sex Hormone and Cortisol Precursor Secretion
stimulation test fall into currently accepted reference ranges as a Cause of Bilaterally Symmetrical Alopecia
(Behrend etal, 2013). Because the panel preferred the term occult Alopecia X is a condition most commonly affecting breeds, such as
over atypical, that is the name used here. Poodles and plush-coated dogs (e.g., Pomeranians, Chow Chows,
Occult HAC is supposedly caused by diversion of the normal Samoyeds, and Keeshonds). It occurs in young adult dogs regard-
adrenocortical pathways for cortisol and aldosterone synthesis less of sex or neuter status. Clinical signs include loss of guard hairs,
into overproduction of sex hormones instead. The syndrome is progressing to alopecia of the neck, tail, caudodorsum, perineum,
diagnosed by performance of an ACTH stimulation test with caudal thighs, and ultimately trunk. In addition, the skin may
measurement of serum sex hormone concentrations pre- and become intensely hyperpigmented (Schmeitzel and Lothrop,
post-ACTH. However, conclusive evidence for the existence of 1995). With Alopecia X, no systemic signs are noted. Whether
occult HAC as a sex hormone-mediated condition is lacking. The Alopecia X is a separate entity from occult HAC or represents dogs
Consensus Panel stated that sex hormones are not believed to be with occult HAC that only have cutaneous manifestations, as can
the cause of occult HAC (Behrend etal, 2013). Only 14 cases in occur with standard HAC (Zur and White, 2011), is unknown.
Evidence in Favor. Sex hormones can cause endocrine alo- Eleven dogs with typical HAC with elevated cortisol responses
pecia. Castration-responsive alopecia is recognized. Hyperestro- to ACTH were assigned to Group 1. Of 13 dogs with normal
genism as well as hyperprogesteronism associated with Sertoli ACTH stimulation test results, six had LDDST results consistent
cell tumors, for example, can lead to bilaterally symmetrical with HAC (Group 2A), four had negative LDDST results (Group
alopecia. Estrogen administration for treatment of urinary in- 2B), and three had low plasma cortisol concentrations throughout
continence has led to bilaterally symmetrical alopecia and testing, so the LDDST was not interpretable (Group 2C). Despite
histopathological changes consistent with endocrine alopecia the variation in serum cortisol concentrations on the tests for stan-
(Watson, 1985) dard HAC, all 24 dogs had elevated ACTH-stimulated 17OHP
The first report of Alopecia X described seven Pomeranians with concentrations. Because ACTH-stimulated serum 17OHP con-
bilaterally symmetrical alopecia and hyperpigmentation (Schmeit- centration was elevated in dogs with both classic and occult HAC,
zel and Lothrop, 1990). Classic HAC was ruled out on the basis it was concluded to be a marker of adrenal dysfunction (Ristic
of normal ACTH stimulation test and LDDST results. Proges- etal, 2002).
terone, 17-hydroxy-progesterone (17OHP), 11-deoxycortisol, Numerous other studies have documented sex hormone concen-
dehydroepiandrosterone sulfate (DHEAS), androstenedione, tes- tration elevations in dogs with various forms of hypercortisolemia,
tosterone, and estradiol were measured pre- and post-ACTH in either PDH or AT. Some studies were small, but elevations in
the affected dogs, twelve unaffected Pomeranians, and nineteen DHEAS, testosterone, androstenedione, estradiol, progesterone,
non-Pomeranian control dogs. Only ACTH-stimulated 17OHP 17OHP, 21-deoxycortisol, 11-deoxycortisol, and corticosterone have
concentrations differed between affected and unaffected Pomera- been found in 40% to 100% (Frank etal, 2001; Behrend etal, 2005;
nians, but ACTH-stimulated progesterone and DHEAS concen- Benitah etal, 2005; Hill etal, 2005; Sieber-Ruckstuhl etal, 2008).
trations were significantly higher in both groups of Pomeranians In cases in which cortisol and sex hormones are both elevated,
compared with controls. Given the constellation of abnormalities which hormone(s) is causing clinical signs of HAC is difficult or
in affected and unaffected dogs, the alopecia was hypothesized impossible to determine. However, sporadic reports exist of dogs
to be due to a partial deficiency of 21-hydroxylase, an enzyme with sex hormone-secreting AT and low serum cortisol concentra-
needed for cortisol synthesis. tions but in which clinical signs of HAC were present, ostensibly
In humans with 21-hydroxylase deficiency, cortisol is not syn- due to the sex hormones. Two dogs with AT had clinical signs of
thesized and its precursors, most notably 17OHP and androgens, HAC despite markedly suppressed ACTH-stimulated serum cor-
accumulate (Stewart, 2008). Because affected Pomeranians had tisol concentrations; one tumor secreted progesterone, 17OHP,
normal cortisol concentrations, the enzyme deficiency was assumed testosterone, and DHEAS, whereas the other secreted androstene-
to be partial (Schmeitzel and Lothrop, 1990). Family members of dione, estradiol, progesterone, and 17OHP (Syme etal, 2001). In
human patients have sex hormone elevations to a lesser magnitude a report of eight dogs with AT and signs of HAC, three had sup-
and no clinical signs, thus explaining the findings (i.e., increased pressed ACTH-stimulated serum cortisol concentrations and one
progesterone and DHEAS levels) in the unaffected Pomeranians had elevated 17OHP concentrations; no other sex hormones were
(many of the affected and unaffected Pomeranians in the study measured in any dog nor in the other two with subnormal cortisol
were related). Subsequently, three Alaskan Malamutes with Alope- concentrations (Norman etal, 1999).
cia X were reported to have ACTH-stimulated 17OHP concentra- Evidence Against.It is difficult to understand how sex hor-
tions above the reference range and that were significantly higher mones cause clinical signs of HAC. The sex hormone most men-
than those in three normal Alaskan Malamutes (Leone etal, 2005). tioned as a cause of occult HAC is progesterone. Due to its short
Evidence Against. Of six sex hormones assessed by Schmeitzel half-life, however, little is known about the effects of elevated serum
and Lothrop in the seven Pomeranians, only ACTH-stimulated concentrations. Chronic progesterone excesses are not unique. In
serum 17OHP concentration was significantly different between estrus and diestrus, serum progesterone concentration is elevated
affected and unaffected dogs. However, when affected males and for 60 to 90 days and is higher than in dogs with HAC; yet no
females were assessed separately, the males did not have elevated clinical signs of HAC develop (Bromel etal, 2010). In humans,
serum 17OHP concentrations (Schmeitzel and Lothrop, 1990). In clinically silent 17OHP-secreting ATs occur (Turton etal, 1992;
276 dogs with Alopecia X, including 63 Pomeranians, only 73% Bondanelli etal, 1997). Massive elevations in serum 17OHP oc-
had at least one basal or post-ACTH sex hormone concentration cur in humans with 21-hydroxylase deficiency (i.e., concentrations
above the reference range (i.e., 27% had no elevations). Despite ranging from 3000 to 40,000 ng/dL [reference range, 20 to 600])
the preponderance of elevations in sex hormone concentrations, (Grumbach and Conte, 1998); yet clinically affected patients show
no consistent sex hormone abnormalities were identified. Of the signs either of aldosterone deficiency or androgen excess, such as
ACTH-stimulated hormone concentrations, progesterone eleva- virilization or loss of female cycling (Stewart, 2008), signs not
tion was the most common abnormality, but it was found in only reported in dogs with occult HAC. Lastly, a cryptic syndrome
36% of patients. Thus, it was concluded that Alopecia X should be of 21-hydroxylase deficiency exists in which affected people lack
referred to as alopecia associated with follicular arrest rather than 21-hydroxylase and have hormonal abnormalities but no clini-
an adrenal hormone imbalance (Frank etal, 2003). cal signs. The factors that impose the phenotypic variability on
Candidate genes in which mutations could cause the abnor- the genotypic abnormality are unknown (Grumbach and Conte,
malities, including 21-hydroxylase and enzymes in the cortisol 1998), but abnormal sex hormone elevations by themselves are in-
synthesis pathway, have been cloned. No mutations affecting the sufficient to cause clinical disease. Similarly, in dogs with Alopecia
primary structure of the enzyme or gene expression have been X, serum 17OHP concentrations can be quite elevated, similar
identified in the canine 21-hydroxylase gene (Takada etal, 2002). to what is seen with dogs with purported occult HAC, yet none
of the classical systemic clinical signs such as polyuria/polydipsia,
17-Hydroxy-Progesterone, Other Sex Hormones, and Cortisol polyphagia, pot belly, and panting are reported.
Precursors as Causes of Occult Hyperadrenocorticism Two mechanisms have been proposed for progesterones abil-
Evidence in Favor. Initially, a study of 24 dogs with clinical ity to cause signs of glucocorticoid excess. Synthetic progestins,
and routine laboratory findings suggestive of HAC was reported. compounds with progesterone-like actions, may either bind GRs
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(Selman etal, 1997) or displace cortisol from its binding protein, and alters sex hormone concentrations in intact dogs (Ashley etal,
elevating serum free cortisol concentrations (Juchem and Pollow, 1999). It was administered initially in 29 dogs with Alopecia X;
1990). Indeed, progestins suppress eACTH secretion and cause 15 had partial hair regrowth at the first reevaluation (Frank etal,
adrenal atrophy, an action suggestive of glucocorticoid activity 2004). In three Alaskan Malamutes with Alopecia X, trilostane
(Selman etal, 1997). Accordingly, progesterone may do the same. administration (3.0 to 3.6 mg/kg daily by mouth) resulted in
Examination of Pomeranians with Alopecia X, however, refutes complete hair regrowth within 6 months (Leone etal, 2005). Of
the likelihood of either mechanism occurring. If elevated serum 16 Pomeranians and eight Miniature Poodles with Alopecia X,
17OHP concentration, as seen in the Pomeranians, is sufficient 14 Pomeranians and all Poodles had hair regrowth in response to
to cause clinical disease due to glucocorticoid actions of 17OHP, trilostane; the mean dose that caused hair regrowth was 11.8 mg/
eACTH concentration should be suppressed due to negative feed- kg (range, 5 to 23.5) in Pomeranians and 9 mg/kg (range, 6.1 to
back effects of glucocorticoids on the pituitary. Indeed, for dogs 15.0) per day in Poodles (Cerundolo etal, 2004). In a study on
with proven sex hormone-secreting AT and signs of HAC despite occult HAC, nine dogs treated with trilostane or mitotane all had
hypocortisolemia, measured eACTH concentrations can be low clinical improvement. Decreased ACTH-stimulated cortisol and/
(Syme et al, 2001). To the contrary, Pomeranians with elevated or 17OHP concentrations were documented in four of the nine
serum 17OHP concentrations had higher plasma ACTH concen- (Ristic etal, 2002). Lastly, in one dog with clinical signs of HAC
trations than healthy dogs (Schmeitzel and Lothrop, 1990). and normal post-ACTH-stimulated cortisol and LDDST results
How AT could have a shift in hormone synthesis activity can but an elevated ACTH-stimulated 17OHP concentration, clinical
be understood easily. Tumor cells are not normal and can undergo signs resolved with mitotane therapy (Benitah etal, 2005).
loss of differentiation, losing the ability to synthesize enzymes in Evidence Against.The response to mitotane, melatonin, or
the hormone synthesis pathways. In cases of pituitary-dependent trilostane is neither uniform nor predictable. In 15 Pomeranians
occult HAC, how or why normal adrenocortical tissue should with Alopecia X treated with melatonin (mean 1.3 mg/kg by
have altered steroid synthesis is unexplained. mouth b.i.d.; range, 1.0 to 1.7) for 3 months, only six had mild to
moderate hair regrowth (Frank etal, 2006). In the study evaluat-
Sex Hormone Panel Testing ing 29 dogs diagnosed with Alopecia X treated with melatonin
Evidence in Favor. Measurement of serum sex hormone con- or mitotane, partial or complete hair regrowth was seen in only
centrations has been advocated as a means of diagnosing occult 62% overall. On mitotane, four of six dogs had partial to com-
HAC. Use of a panel of hormones has been stated to increase sen- plete hair regrowth and two had none (Frank etal, 2004). More
sitivity and specificity of the test over measurement of a single hor- importantly, serum sex hormone concentrations did not change
mone alone. Elevations in concentrations of any hormone can be significantly in response to treatment nor correlate with whether
common, with estradiol elevations noted in approximately 40% response was seen. In dogs with partial or complete hair regrowth,
of panels submitted to one reference laboratory (Oliver, 2007). 17OHP, androstenedione, and progesterone were still elevated in
Evidence Against. It is reasonable to assume that dogs with 36%, 21%, and 64%, respectively. In 16 Pomeranians and eight
NAI (e.g., a dog with diabetes mellitus) might not have the same Miniature Poodles with Alopecia X (Cerundolo etal, 2004) and
ACTH response as healthy dogs because of adaptation of adreno- two dogs with occult HAC (Ristic et al, 2002) that responded
cortical function to the stresses of chronic illness. Many stressed to trilostane therapy, 17OHP concentrations were significantly
and sick dogs have increased cortisol concentrations and an exag- elevated by therapy. Thus, hair coat and other clinical signs im-
gerated ACTH response, but they do not have HAC (Kaplan etal, prove despite further increases in concentrations of the sex hor-
1995). In one study, post-ACTH serum cortisol and 17OHP con- mones purportedly underlying the clinical signs.
centrations were significantly correlated both in dogs with neopla-
sia and those suspected of having HAC, suggesting that as adrenal Indications for Diagnostic Testing
function is increased either by adrenal disease or nonspecifically
by NAI, production of all hormones increases proportionately The author recognizes that cases that fulfill the criteria for occult
(Behrend etal, 2005). HAC exist. However, sex hormones may simply be a marker of
For estradiol, a wide range of variability exists within and occult HAC, not the cause of it. At the current time, the recom-
between dogs; random, basal estradiol concentrations in indi- mended test is an ACTH stimulation test using the same proto-
vidual dogs often exceed the reference range (Frank etal, 2010). col as with a standard test and measurement of cortisol, but the
With regard to 17OHP, the specificity of measurement is 59% baseline and post-ACTH samples are used for measurement of sex
to 70% (i.e., the chance of a false-positive result is 30% to 41%) hormones. Unfortunately, whether the protocol is optimal has not
(Chapman etal, 2003; Behrend etal, 2005; Monroe etal, 2012). been evaluated.
The specificity of progesterone measurement was determined to Testing for occult HAC should not be undertaken if clinical indi-
be 55% (Monroe etal, 2012). In six dogs with a pheochromo- cation for testing for classic HAC does not exist (Behrend et al,
cytoma or a nonfunctional AT, androstenedione, progesterone, 2013). If the clinical picture fits, the primary indication for measur-
17OHP, testosterone, and/or estradiol concentrations were ele- ing adrenal sex hormones is when a dog is screened for HAC with
vated (Hill etal, 2005). Therefore, dogs without adrenal disease an ACTH stimulation test or LDDST and all cortisol concentra-
clearly can have elevated sex hormones as well as cortisol con- tions, including basal, are below the reference range. If administra-
centrations, but sex hormones may be more likely to be falsely tion of exogenous glucocorticoids of any form or administration
elevated by NAI as compared with cortisol. of medications that alter cortisol synthesis (e.g., ketoconazole) are
ruled out, a sex hormone-secreting AT may be present. Secretion
Response to Treatment of progesterone, 17OHP or a cortisol precursor (Reine etal, 1999;
Evidence in Favor.In dogs with either Alopecia X or pur- Syme etal, 2001) may suppress pituitary ACTH secretion and cause
ported occult HAC, treatment with agents that affect pituitary atrophy of normal adrenocortical tissue. The ultrasonographic find-
or adrenal function can resolve clinical signs. Melatonin, a neu- ing of an AT in such patients would further support the diagnosis,
rohormone, controls seasonal reproductive and hair growth cycles but the lack of one does not rule it out.
If clinical signs are mild, waiting and retesting for classic at cortisol concentrations considered normal for the general
HAC when progression is noted may be the best course of population. Accordingly, the appropriate name for the syndrome
action. If clinical signs are moderate to severe, abdominal ultra- may be suspected HAC. Third, dogs that meet the definition for
sound should be performed. If the adrenal glands are normal, occult HAC may have rare forms, such as food-dependent HAC.
the differential diagnoses for the patient should be revisited. If Other explanations may also exist.
bilateral adrenomegaly is present, pituitary imaging should be
considered to identify a pituitary tumor causing early HAC. Treatment
Lastly, food-stimulated HAC should be considered, because
in these patients fasting cortisol concentration may be low The treatment of occult HAC has not been widely studied, but it
(Behrend etal, 2013). would depend on the form of the disease. If caused by an adrenal
A few explanations exist for the existence of such cases tumor, adrenalectomy would be preferred. If a tumor is not the
(Behrend etal, 2013). First, the reference ranges and cutoff values etiology, melatonin, trilostane, and mitotane have all had some
for the LDDST need to be reestablished. The ACVIM Consen- success (see earlier). The efficacy of trilostane would depend on
sus Panel believed the cutoffs should be lower than they currently which hormone is in excess. Because it is the authors opinion that
are; a decreased cutoff would result in some dogs diagnosed with the true mediator of occult HAC is unknown but may relate to
occult HAC actually having typical HAC. Dogs with mild or early adrenal function, mitotane may be preferred, because concentra-
HAC that are normal on tests using current cutoff values may tions of all sex hormones and cortisol intermediates would be sup-
not be with revised (lower) values. Second, variable cortisol sen- pressed. Whether the protocol for using either drug for treating
sitivity exists in humans (Huizenga etal, 1998) and may occur in occult HAC should be different than when treating hypercorti-
dogs. Dogs with high sensitivity may show clinical signs of HAC solemia has never been evaluated.
REFERENCES
Adin CA, Nelson RW: Adrenal glands. In Tobias Arenas C, etal.: Clinical features, outcome and Barthez P, etal.: Ultrasonographic evaluation
KM, Johnston SA, editors: Veterinary prognostic factors in dogs diagnosed with of the adrenal glands in normal dogs and
surgery: small animal, St Louis, 2012, non-cortisol-secreting adrenal tumours within dogs with hyperadrenocorticism, J Am
Elsevier Saunders, p 2033. out adrenalectomy: 20 cases (1994-2009), Vet Med Assoc 207:1180, 1995.
Adissu HA, etal.: Cardiac myxosarcoma with Vet Record 173:501, 2013b. Behrend EN, Kemppainen RJ: Diagnosis of ca-
adrenal adenoma and pituitary hyperplasia Arenas C, etal.: Long-term survival of dogs nine hyperadrenocorticism, Vet Clin North
resembling Carney complex in a dog, Vet with adrenal-dependent hyperadrenocorti- Am Sm Anim Pract 31:985, 2001.
Pathol 47:354, 2010. cism: a comparison between mitotane Behrend EN, etal.: Effect of storage conditions
Aldridge C, etal.: Comparison of two doses for and twice daily trilostane treatment, J Vet on cortisol, total thyroxine, and free thyroxine
ACTH stimulation testing in dogs suspect- Intern Med 28:473, 2014. concentrations in serum and plasma of dogs,
ed of or treated for hyperadrenocorticism, J Ashley PF, etal.: Effect of oral melatonin admin- J Am Vet Med Assoc 212:1564, 1998.
Vet Int Med 28:1025, 2014. istration on sex hormone, prolactin and thy- Behrend EN, etal.: Treatment of hyperadre-
Alenza DP, etal.: Use of aminoglutethimide roid hormone concentrations in normal dogs, nocorticism in dogs: a survey of internists
in the treatment of pituitary-dependent J Am Vet Med Assoc 215:1111, 1999. and dermatologists, J Am Vet Med Assoc
hyperadrenocorticism in the dog, J Small Auriemma E, etal.: Computed tomography and 215:938, 1999.
Anim Pract 43:104, 2002. low-magnetic resonance imaging of the pitu- Behrend EN, etal.: Diagnosis of hyperadre-
Alenza DP, etal.: Long-term efficacy of trilo- itary gland in dogs with pituitary-dependent nocorticism in dogs: a survey of internists
stane administered twice daily in dogs with hyperadrenocorticism: 11 cases (2001- and dermatologists, J Am Vet Med Assoc
pituitary-dependent hyperadrenocorticism, 2003), J Am Vet Med Assoc 235:409, 2009. 220:1643, 2002.
J Am Anim Hosp Assoc 42:269, 2006. Badylak SF, Van Vleet JF: Sequential morpholog- Behrend EN, etal.: Corticosterone- and aldo-
Anderson CR, etal.: Surgical treatment of ic and clinicopathologic alterations in dogs sterone-secreting adrenocortical tumor in a
adrenocortical tumors: 21 cases (1990- with experimentally induced glucocorticoid dog, J Am Vet Med Assoc 226:1662, 2004.
1996), J Am Anim Hosp Assoc 37:937, hepatopathy, Am J Vet Res 42:1310, 1981. Behrend EN, etal.: Serum 17--hydroxy
2001. Bailey MQ: Use of x-ray-computed tomogra- progesterone and corticosterone concentra-
Angles JM, etal.: Use of urine corticoid: phy as an aid in localization of adrenal tions in dogs with non-adrenal neoplasia and
creatinine ratio versus adrenocortico- masses in the dog, J Am Vet Med Assoc dogs with suspected hyperadrenocorticism,
tropic hormone stimulation for monitoring 188:1046, 1986. J Am Vet Med Assoc 227:1762, 2005.
mitotane treatment of pituitary-dependent Barberet V, etal.: Intra- and interobserver vari- Behrend EN, etal.: Intramuscular adminis-
hyperadrenocorticism in dogs, J Am Vet ability of ultrasonographic measurements tration of a low dose of ACTH for ACTH
Med Assoc 211:1002, 1997. of the adrenal glands in healthy beagles, stimulation testing in dogs, J Am Vet Med
Antoni FA, Dayanithi G: Evidence for dis- Vet Radiol Ultrasound 51:656, 2010. Assoc 229:528, 2006.
tinct glucocorticoid and guanine Barker EN, etal.: A comparison of the survival Behrend EN, etal.: Diagnosis of spontaneous
3,5-monophosphate-effected inhibition times of dogs treated with mitotane or trilo- canine hyperadrenocorticism: 2012 ACVIM
of stimulated adrenocorticotropin release stane for the pituitary-dependent hyperadre- consensus statement (Small animal), J Vet
invitro, Endocrinology 126:1355, 1990. nocorticism, J Vet Int Med 19:810, 2005. Int Med 27:1292, 2013.
Arenas C, etal.: Evaluation of 2 trilostane Barrera JS, etal.: Evaluation of risk factors for Bell R, etal.: Study of the effects of once
protocols for the treatment of canine outcome associated with adrenal gland tu- daily doses trilostane on cortisol concen-
pituitary-dependent hyperadrenocorticism: mors with or without invasion of the caudal trations and responsiveness to adrenocor-
twice daily versus once daily, J Vet Intern vena cava and treated via adrenalectomy ticotrophic hormone in hyperadrenocorti-
Med 27:1478, 2013a. in dogs: 86 cases (1993-2009), J Am Vet coid dogs, Vet Rec 159:277, 2006.
Med Assoc 242:1715, 2013.
|
Bellumori TP, etal.: Prevalence of inherited Braddock JA, etal.: Inefficacy of selegiline in Castillo V, etal.: Diurnal ACTH and plasma
disorders among mixed-breed and pure- treatment of canine pituitary-dependent cortisol variations in healthy dogs and in
bred dogs: 27,254 cases (1995-2010), J hyperadrenocorticism, Aust Vet J 82:272, those with pituitary-dependent Cushings
Am Vet Med Assoc 242:1549, 2013. 2004. syndrome before and after treatment
Benchekroun G: Ultrasonography criteria for Braund KG, etal.: Subclinical myopathy as- with retinoic acid, Res Vet Sci 86:223,
differentiating ACTH dependency from sociated with hyperadrenocorticism in the 2009.
ACTH independency in 47 dogs with dog, Vet Pathol 17:134, 1980. Cerundolo R, etal.: Treatment of canine
hyperadrenocorticism and equivocal Brearley MJ, etal.: Hypofractionated RT of brain Alopecia X with trilostane, Vet Dermatol
adrenal asymmetry, J Vet Intern Med masses in dogs: a retrospective analysis of 15:2853, 2004.
24:10771085, 2010. survival of 83 cases (1991-1996), Chapman PS, etal.: Evaluation of the basal and
Benchekroun G, etal.: Trilostane therapy J Vet Intern Med 13:408, 1999. post-adrenocorticotrophic hormone serum
for hyperadrenocorticism in three dogs Breitschwerdt EB, etal.: Idiopathic hyperaldo- concentrations of 17-hydroxyprogesterone
with adrenocortical metastasis, Vet Rec steronism in a dog, J Am Vet Med Assoc for the diagnosis of hyperadrenocorticism in
163:190, 2008. 187:841, 1985. dogs, Vet Rec 153:771, 2003.
Benitah N, etal.: Evaluation of serum Bromel C, etal.: Serum 17 - Chapman PS, etal.: Adrenal necrosis in a dog
17-hydroxyprogesterone concentration hydroxyprogesterone concentrations during receiving trilostane for the treatment of
after administration of ACTH in dogs with the reproductive cycle in healthy dogs and hyperadrenocorticism, J Small Anim Pract
hyperadrenocorticism, J Am Vet Med Assoc dogs with hyperadrenocorticism, J Am Vet 45:307, 2004.
227:1095, 2005. Med Assoc 236:1208, 2010. Chastain CB, etal.: Evaluation of the hypotha-
Berry CR, etal.: Pulmonary mineralization in Bugbee AC, etal.: Effect of dexamethasone lamic pituitary-adrenal axis in clinically
four dogs with Cushings syndrome, Vet or synthetic ACTH administration on en- stressed dogs, J Am Anim Hosp Assoc
Radiol Ultrasound 35:10, 1994. dogenous ACTH concentrations in healthy 22:435, 1986.
Berry CR, etal.: Frequency of pulmonary min- dogs, Am J Vet Res 74:1415, 2013. Chauvet AE, etal.: Effects of phenobarbi-
eralization and hypoxemia in 21 dogs with Burgener IA, etal.: Empty sella syndrome, tal administration on results of serum
pituitary dependent hyperadrenocorticism, hyperadrenocorticism and megaesophagus biochemical analyses and adrenocortical
J Vet Intern Med 14:151, 2000. in a dachshund, J Small Anim Pract function tests in epileptic dogs, J Am Vet
Bertoy EH, etal.: Magnetic resonance imaging 48:584, 2007. Med Assoc 207:1305, 1995.
of the brain in dogs with recently diag- Burkhardt WA, etal.: Adrenocorticotropic Cho KD, etal.: Serum adipokine concentra-
nosed but untreated pituitary-dependent hormone, but not trilostane, causes severe tions in dogs with naturally occurring
hyperadrenocorticism, J Am Vet Med Assoc adrenal hemorrhage, vacuolization, and pituitary-dependent hyperadrenocorticism,
206:651, 1995. apoptosis in rats, Domest Anim Endocrinol J Vet Intern Med 28:429, 2014.
Bertoy EH, etal.: One-year follow-up evalu- 40:155, 2011. Choi J, etal.: Ultrasonographic adrenal gland
ation of magnetic resonance imaging of Burkhardt WA, etal.: Evaluation of baseline cor- measurements in clinically normal small
the brain in dogs with pituitary-dependent tisol, endogenous ACTH and cortisol/ACTH breed dogs and comparison with pituitary-
hyperadrenocorticism, J Am Vet Med Assoc ratio to monitor trilostane treatment in dogs dependent hyperadrenocorticism, J Vet
208:1268, 1996. with pituitary-dependent hyperadrenocorti- Med Sci 73:985, 2011.
Besso JG, etal.: Retrospective ultrasonograph- cism, J Vet Intern Med 27:919, 2013. Church DB, etal.: Effect of nonadrenal ill-
ic evaluation of adrenal lesions in 26 dogs, Cabrera Blatter MF, etal.: Blindness in dogs ness, anaesthesia and surgery on plasma
Vet Radiol Ultrasound 38:448, 1997. with pituitary dependent hyperadreno- cortisol concentrations in dogs, Res Vet Sci
Biewenga WJ, etal.: Osmoregulation of sys- corticism: relationship with glucose, 56:129, 1994.
temic vasopressin release during long-term cortisol and triglyceride concentration and Churcher RK: Hepatic carcinoid, hypercorti-
glucocorticoid excess: a study in dogs with with ophthalmic blood flow, Res Vet Sci solism and hypokalaemia in a dog, Aust
hyperadrenocorticism, Acta Endocrino- 92:387, 2012a. Vet J 77:641, 1999.
logica 124:583, 1991. Cabrera Blatter MF, etal.: Interleukin-6 and Cisneros LE, etal.: What is your neurologic
Bley CR, etal.: Irradiation of brain tumors in insulin increase and nitric oxide and diagnosis? Hyperadrenocorticism, J Am Vet
dogs with neurologic disease, J Vet Intern adiponectin decrease in blind dogs with Med Assoc 238:1247, 2011.
Med 19:849, 2005. pituitary-dependent hyperadrenocorticism, Clemente M, etal.: Comparison of non-
Blois SL, etal.: Multiple endocrine diseases Res Vet Sci 93:1195, 2012b. selective adrenocorticolysis with mitotane
in dogs: 35 cases (1996-2009), J Am Vet Cai W, etal.: Metabolic activation and binding or trilostane for the treatment of dogs with
Med Assoc 238:1616, 2011. of mitotane in adrenal cortex homogenates, pituitary-dependent hyperadrenocorticism,
Bodey AR, Michell AR: Epidemiological study J Pharmaceut Sciences 84:134, 1995. Vet Rec 161:805, 2007.
of blood pressure in domestic dogs, Capen CC: Endocrine glands. In Maxie MG, Cohen TA, Feldman EC: Comparison of IV and
J Small Anim Pract 37:116, 1996. editor: Jubb, Kennedy and Palmers pa- IM formulations of synthetic ACTH for
Bondanelli M, etal.: Evaluation of hormonal thology of domestic animals, Philadelphia, ACTH stimulation tests in healthy dogs, J
function in a series on incidentally discov- 2007, Saunders/Elsevier, p 325. Vet Intern Med 26:412, 2012.
ered adrenal masses, Metabolism 46:107, Carter CT, etal.: Elevations in sex hormones Cook AK, Bond KG: Evaluation of the use
1997. in dogs with sudden acquired retinal de- of baseline cortisol concentration as a
Boozer AL, etal.: Pituitary-adrenal axis func- generation syndrome (SARDS), J Am Anim monitoring tool for dogs receiving trilo-
tion in dogs with neoplasia, Vet Comp Hosp Assoc 45:207, 2009. stane as a treatment for hyperadrenocor-
Oncol 3:194, 2006. Cartledge S, Lawson N: Aldosterone and renin ticism, J Am Vet Med Assoc 237:801,
Bosje JT, etal.: Plasma concentrations of measurements, Annals Clin Biochem 2010.
ACTH precursors correlate with pituitary 37:262, 2000. Cook AK, etal.: Pharmaceutical evaluation of
size and resistance to dexamethasone in Castillo V, Gallelli MF: Corticotroph adenoma compounded trilostane products, J Am
dogs with pituitary-dependent hyperad- in the dog: pathogenesis and new thera- Anim Hosp Assoc 48:228, 2012.
renocorticism, Domest Anim Endocrinol peutic possibilities, Res Vet Sci 88:26, Cook AK, etal.: Clinical findings in dogs
22:201, 2002. 2010. with incidental adrenal gland lesions
Braddock JA, etal.: Trilostane treatment in Castillo V, etal.: Retinoic acid as a novel medi- determined by ultrasonography: 151
dogs with pituitary-dependent hyperadre- cal therapy for Cushings disease in dogs, cases (2007-2010), J Am Vet Med Assoc
nocorticism, Aust Vet J 81:600, 2003. Endocrinology 147:4438, 2006. 244:1181, 2014.
Davies DR, etal.: Hypokalaemic paresis, hyper- Eastwood JM, etal.: Trilostane treatment of a Feldman EC, etal.: Comparison of mitotane
tension, alkalosis, and adrenal-dependent dog with functional adrenocortical neopla- treatment for adrenal tumor versus pituitary-
hyperadrenocorticism in a dog, Aust Vet J sia, J Small Anim Pract 44:126, 2003. dependent hyperadrenocorticism in dogs,
86:139, 2008. Eberwine JH, etal.: Complex transcrip- J Am Vet Med Assoc 200:1642, 1992.
Davis MK, etal.: Ultrasonographic identifica- tional regulation by glucocorticoids and Feldman EC, etal.: Use of low- and high-dose
tion of vascular invasion by adrenal tumors corticotropin-releasing hormone of pro- dexamethasone tests for distinguishing
in dogs, Vet Radiol Ultrasound 53:442, opiomelanocortin gene expression in rat pituitary dependent from adrenal tumor
2012. pituitary cultures, DNA 6:483, 1987. hyperadrenocorticism, J Am Vet Med Assoc
Dayanithi G, Antoni FA: Rapid as well as delayed Eckersall PD, etal.: The measurement of 209:772, 1996.
inhibitory effects of glucocorticoid hormones canine steroid-induced alkaline phospha- Ferguson DC, Biery DN: Diabetes insipidus and
on pituitary adrenocorticotropic hormone tase by L-phenylalanine inhibition, J Small hyperadrenocorticism associated with high
release are mediated by type II glucocor- Anim Pract 27:411, 1986. plasma adrenocorticotropin concentration
ticoid receptors and require newly synthe- Elliott DA, etal.: Glycosylated hemoglobin and a hypothalamic/pituitary mass in a
sized messenger ribonucleic acid as well as concentrations in the blood of healthy dog, J Am Vet Med Assoc 193:835, 1988.
protein, Endocrinology 125:308, 1989. dogs and dogs with naturally develop- Ferguson DC, Peterson ME: Serum free and
DeCoster R, etal.: Endocrinological effects of ing diabetes mellitus, pancreatic -cell total iodothyronine concentrations in dogs
single daily ketoconazole administration neoplasia, hyperadrenocorticism, and with hyperadrenocorticism, Am J Vet Res
in male beagle dogs, Acta Endocrinologica anemia, J Am Vet Med Assoc 211:723, 53:1636, 1992.
107:275, 1984. 1997. Ford SL, etal.: Hyperadrenocorticism caused
de Fornel P, etal.: Effects of radiotherapy on Emms SG, etal.: Evaluation of canine hyperad- by bilateral adrenocortical neoplasia in
pituitary corticotroph macrotumors in dogs: renocorticism using computed tomography, dogs: four cases (1983-1988), J Am Vet
a retrospective study of 12 cases, Can Vet J Am Vet Med Assoc 189:432, 1986. Med Assoc 202:789, 1993.
J 48:481, 2007. Feldman BF, etal.: Hemostatic abnormalities Forrester SD, etal.: Retrospective evaluation of
den Hertog E, etal.: Results of nonselective in canine Cushings syndrome, Res Vet Sci urinary tract infection in 42 dogs with hy-
adrenocorticolysis by o,p-DDD in 129 41:228, 1986. peradrenocorticism or diabetes mellitus or
dogs with pituitary-dependent hyperadre- Feldman EC: Comparison of ACTH response both, J Vet Intern Med 13:557, 1999.
nocorticism, Vet Rec 144:12, 1999. and dexamethasone suppression as screen- Fossum TW: Small animal surgery, ed 4, St
DeNovo RC, Prasse KW: Comparison of serum ing tests in canine hyperadrenocorticism, Louis, 2012, Mosby.
biochemical and hepatic functional altera- J Am Vet Med Assoc 182:505, 1983a. Foster SF, etal.: Effect of phenobarbitone on
tions in dogs treated with corticosteroids Feldman EC: Distinguishing dogs with function- the low-dose dexamethasone suppression
and hepatic duct ligation, Am J Vet Res ing adrenocortical tumors from dogs with test and the urinary corticoid: creatinine
44:1703, 1983. pituitary-dependent hyperadrenocorticism, ratio in dogs, Aust Vet J 78:19, 2000a.
Djajadiningrat-Laanen SC, etal.: Urinary J Am Vet Med Assoc 183:195, 1983b. Foster SF, etal.: Effects of phenobarbitone on
aldosterone to creatinine ratio in cats Feldman EC: Evaluation of a combined dexa- serum biochemical tests in dogs, Aust Vet
before and after suppression with salt or methasone suppression/ACTH stimulation J 78:23, 2000b.
fludrocortisone acetate, J Vet Intern Med test in dogs with hyperadrenocorticism, Frank LA, Oliver JW: Comparison of serum
22:1283, 2008. J Am Vet Med Assoc 187:49, 1985. cortisol concentrations in clinically normal
Djajadiningrat-Laanen SC, etal.: Primary hy- Feldman EC: Evaluation of a 6-hour combined dogs after administration of freshly recon-
peraldosteronism: expanding the diagnos- dexamethasone suppression/ ACTH stimula- stituted versus reconstituted and stored
tic net, J Fel Med Surg 13:651, 2011. tion test in dogs with hyperadrenocorticism, frozen cosyntropin, J Am Vet Med Assoc
Doerr KA, etal.: Calcinosis cutis in dogs: J Am Vet Med Assoc 189:1562, 1986. 212:1569, 1998.
histopathological and clinical analysis of Feldman EC: Evaluation of twice-daily lower- Frank LA, etal.: Cortisol concentrations follow-
46 cases, Vet Dermatol 24:355, 2013. dose trilostane treatment administered ing stimulation of healthy and adrenopathic
Douglass JP, etal.: Ultrasonographic adrenal orally in dogs with naturally occurring dogs with two doses of tetracosactrin,
gland measurements in dogs without hyperadrenocorticism, J Am Vet Med Assoc J Small Anim Pract 41:308, 2000.
evidence of adrenal disease, Vet Radiol 238:1441, 2011. Frank LA, etal.: Steroidogenic response of ad-
Ultrasound 38:124, 1997. Feldman EC, Kass PH: Trilostane dose versus renal tissues after administration of ACTH
Dow SW, etal.: Perianal adenomas and hy- body weight in the treatment of naturally to dogs with hypercortisolemia, J Am Vet
pertestosteronemia in a spayed bitch with occurring pituitary-dependent hyperad- Med Assoc 218:214, 2001.
pituitary-dependent hyperadrenocorticism, renocorticism in dogs, J Vet Intern Med Frank LA, etal.: Retrospective evaluation
J Am Vet Med Assoc 192:1439, 1988. 26:1078, 2012. of sex hormones and steroid hormone
Dow SW, etal.: Response of dogs with Feldman EC, Mack RE: Urine cortisol:creatinine intermediates in dogs with alopecia, Vet
functional pituitary macroadenomas and ratio as a screening test for hyperadreno- Dermatol 14:91, 2003.
macrocarcinomas to radiation, J Small corticism in dogs, J Am Vet Med Assoc Frank LA, etal.: Adrenal steroid hormone con-
Anim Pract 31:287, 1990. 200:1637, 1992. centrations in dogs with hair cycle arrest
Drucker WD, Peterson ME: Pharmacologic Feldman EC, Nelson RW: Use of ketoconazole (Alopecia X) before and during treatment
treatment of pituitary-dependent canine for control of canine hyperadrenocorticism. with melatonin and mitotane, Vet Dermatol
Cushings disease, Program of the Sixty- In Kirk RW, Bonagura JD, editors: Current 15:278, 2004.
Second Annual Meeting of the Endocrine veterinary therapy XI, Philadelphia, 1992, Frank LA, etal.: Oestrogen receptor evaluation
Society, San Francisco, 1980, p 89. WB Saunders, p 349. in Pomeranian dogs with hair cycle arrest
Duesberg CA, etal.: Magnetic resonance imag- Feldman EC, Nelson RW: Canine hyperad- (alopecia X) on melatonin supplementa-
ing for diagnosis of pituitary macrotumors renocorticism (Cushings syndrome). In tion, Vet Dermatol 17:252, 2006.
in dogs, J Am Vet Med Assoc 206:657, Feldman EC, Nelson RW, editors: Canine Frank LA, etal.: Variability of estradiol con-
1995. and feline endocrinology and reproduction, centration in normal dogs, Vet Dermat
Dyer KR, etal.: Effects of short- and long-term St Louis, 2004, Saunders, p 252. 21:490, 2010.
administration of phenobarbital on endog- Feldman EC, etal.: Plasma cortisol response to Frankot JL, etal.: Adrenocortical carcinoma in
enous ACTH concentration and results of ketoconazole administration in dogs with a dog with incomplete excision managed
ACTH stimulation tests in dogs, J Am Vet hyperadrenocorticism, J Am Vet Med Assoc long-term with metastasectomy alone,
Med Assoc 205:315, 1994. 197:71, 1990. J Am Anim Hosp Assoc 48:417, 2012.
|
Fukuoka H, etal.: EGFR as a therapeutic tar- Goy-Thollot I, etal.: Investigation of the role Hanson JM, etal.: Expression of leukemia
get for human, canine, and mouse ACTH- of aldosterone in hypertension associ- inhibitory factor and leukemia inhibitory
secreting pituitary adenomas, J Clin Invest ated with spontaneous pituitary-dependent factor receptor in the canine pituitary
121:4712, 2011. hyperadrenocorticism in dogs, J Small gland and corticotrope adenomas,
Galac S, etal.: Urinary corticoid: creatinine Anim Pract 43:489, 2002. Domest Anim Endocrinol 38:260, 2010.
ratios in the differentiation between pitu- Granger N, etal.: Plasma pro-opiomelanocor- Harris D, etal.: Radiation therapy toxicities,
itary dependent hyperadrenocorticism and tin, pro-adrenocorticotropin hormone and Vet Clin N Amer Sm Anim Pract 27:37,
hyperadrenocorticism due to adrenocortical pituitary adenoma size in dogs with Cush- 1997.
tumour in the dog, Vet Q 19:17, 1997. ings disease, J Vet Int Med 19:23, 2005. Helm JR, etal.: A comparison of factors that
Galac S, etal.: Hyperadrenocorticism in a dog Greco DS, etal.: Concurrent pituitary and influence survival in dogs with adrenal-
due to ectopic secretion of adrenocortico- adrenal tumors in dogs with hyperadreno- dependent hyperadrenocorticism treated
tropic hormone, Domest Anim Endocrinol corticism: 17 cases (1978-1995), J Am with mitotane or trilostane, J Vet Int Med
28:338, 2005. Vet Med Assoc 214:1349, 1999. 25:251, 2011.
Galac S, etal.: ACTH-independent hyper- Griebsch C, etal.: Effect of trilostane on hormone Hess RS, etal.: Association between hy-
adrenocorticism due to food-dependent and serum electrolyte concentrations in dogs peradrenocorticism and development
hypercortisolemia in a dog: a case report, with pituitary-dependent hyperadrenocorti- of calcium containing uroliths in dogs
Vet J 177:141, 2007. cism, J Vet Intern Med 28:160, 2014. with urolithiasis, J Am Vet Med Assoc
Galac S, etal.: Urinary corticoid: creatinine Grooters AM, etal.: Evaluation of routine ab- 212:1889, 1998.
ratios in dogs with pituitary-dependent hy- dominal ultrasonography as a technique for Hill K, Scott-Moncrieff JC: Tumors of the adre-
percortisolism during trilostane treatment, imaging the canine adrenal glands, J Am nal cortex causing hyperadrenocorticism,
J Vet Int Med 23:1214, 2009. Anim Hosp Assoc 30:457, 1994. Vet Med 96:686, 2001.
Galac S, etal.: Expression of the ACTH recep- Grooters AM, etal.: Ultrasonographic param- Hill KE, etal.: Secretion of sex hormones in
tor, steroidogenic acute regulatory protein, eters of normal canine adrenal glands: dogs with adrenal dysfunction, J Am Vet
and steroidogenic enzymes in canine comparison to necropsy ndings, Vet Med Assoc 226:556, 2005.
cortisol-secreting adrenocortical tumors, Radiol Ultrasound 36:126, 1995. Hoerauf A, Reusch C: Ultrasonographic charac-
Domest Anim Endocrinol 39:259, 2010a. Grooters AM, etal.: Ultrasonographic characteristics of both adrenal glands in 15 dogs
Galac S, etal.: Expression of receptors for teristics of the adrenal glands in dogs with with functional adrenocortical tumors,
luteinizing hormone, gastric-inhibitory pituitary dependent hyperadrenocorticism: J Am Anim Hosp Assoc 35:193, 1999.
polypeptide, and vasopressin in normal comparison with normal dogs, J Vet Intern Huizenga NA, etal.: A polymorphism in the
adrenal glands and cortisol-secreting ad- Med 10:110, 1996. glucocorticoid receptor gene may be as-
renocortical tumors in dogs, Domest Anim Grumbach MM, Conte FA: Disorders of sex sociated with an increased sensitivity to
Endocrinol 39:63, 2010b. differentiation. In Wilson JD, Foster DW, glucocorticoids invivo, J Clin Endocrinol
Gallelli MF, etal.: A comparative study by age Kronenberg HM, Larsen PR, editors: Metab 83:144, 1998.
and gender of the pituitary adenoma and Williams textbook of endocrinology, Hurley KJ, Vaden SL: Evaluation of urine protein
ACTH and alpha-MSH secretion in dogs Philadelphia, 1998, WB Saunders, p 1303. content in dogs with pituitary-dependent
with pituitary-dependent hyperadrenocorti- Guptill L, etal.: Use of the urine hyperadrenocorticism, J Am Vet Med Assoc
cism, Res Vet Sci 88:33, 2010. cortisol:creatinine ratio to monitor treat- 212:369, 1998.
Gieger TL, etal.: Lymphoma as a model for ment response in dogs with pituitary- Hylands R: Veterinary diagnostic imaging:
chronic illness: effects on adrenocortical dependent hyperadrenocorticism, J Am Vet malignant pheochromocytoma of the
function testing, J Vet Int Med 17:154, Med Assoc 210:1158, 1997. left adrenal gland invading the caudal
2003. Hadley SP, etal.: Effect of glucocorticoids on vena cava, accompanied by a cortisol-
Gillette EL, Gillette SM: Principles of radia- alkaline phosphatase, alanine aminotrans- secreting adrenocortical carcinoma of the
tion therapy, Semin Vet Med Surg (Small ferase, and gamma-glutamyltransferase in right adrenal gland, Can Vet J 46:1156,
Animal) 10:129, 1995. cultured dog hepatocytes, Enzyme 43:89, 2005.
Ginel PJ, etal.: Evaluation of serum concentra- 1990. Ishino H, etal.: Ki-67 and minichromosome
tions of cortisol and sex hormones of adre- Halmi NS, etal.: Pituitary intermediate lobe in maintenance-7 (MCM7) expression in
nal gland origin after stimulation with two the dog: two cell types and high bioac- canine pituitary corticotroph adenomas,
synthetic ACTH preparations in clinically tive adrenocorticotropin content, Science Domest Anim Endocrinol 41:207, 2011.
normal dogs, Am J Vet Res 73:237, 2012. 211:72, 1981. Jacoby RC, etal.: Biochemical basis for the
Golden DL, Lothrop CD: A retrospective study Hanson JM, etal.: Efficacy of transsphenoidal hypercoagulable state seen in Cushings
of aldosterone secretion in normal and ad- hypophysectomy in treatment of dogs with syndrome, Arch Surg 139:1003, 2001.
renopathic dogs, J Vet Intern Med 2:121, pituitary-dependent hyperadrenocorticism, Jensen AL, etal.: Evaluation of the urinary
1988. J Vet Intern Med 19:687, 2005. cortisol:creatinine ratio in the diagnosis
Goldhaber SZ: Pulmonary embolism, N Engl J Hanson JM, etal.: Plasma profiles of adreno- of hyperadrenocorticism in dogs, J Small
Med 339:93, 1998. corticotropic hormone, cortisol, alpha-me- Anim Pract 38:99, 1997.
Goossens MMC, etal.: Central diabetes insipi- lanocyte-stimulating hormone, and growth Jerico MM, etal.: Chromatographic analysis
dus in a dog with a pro-opiomelanocortin- hormone in dogs with pituitary- dependent of lipid fractions in healthy dogs and dogs
producing pituitary tumor not causing hyperadrenocorticism before and after with obesity or hyperadrenocorticism, J Vet
hyperadrenocorticism, J Vet Int Med hypophysectomy, J Endocrinol 190:601, Diagn Invest 21:203, 2009.
9:361, 1995. 2006. Jimnez Pelez M, etal.: Laparoscopic
Goossens MMC, etal.: Efcacy of cobalt 60 Hanson JM, etal.: Prognostic factors for adrenalectomy for treatment of unilateral
radiotherapy in dogs with pituitary-depen- outcome after transsphenoidal hypophy- adrenocortical carcinomas: technique,
dent hyperadrenocorticism, J Am Vet Med sectomy in dogs with pituitary-dependent complications, and results in seven dogs,
Assoc 212:374, 1998. hyperadrenocorticism, J Neurosurg Vet Surg 37:444, 2008.
Gould SM, etal.: Use of endogenous ACTH 107:830, 2007. Johnson CA: Progesterone and prolactin-related
concentration and adrenal ultrasonogra- Hanson JM, etal.: Expression and mutation disorders; adrenal dysfunction and sex
phy to distinguish the cause of canine analysis of Tpit in the canine pituitary hormones. In Rand J, editor: Clinical endo-
hyperadrenocorticism, J Small Anim Pract gland and corticotroph adenomas, Domest crinology of companion animals, Ames, IA,
42:113, 2001. Anim Endocrinol 34:217, 2008. 2013, John Wiley and Sons, pp 487503.
Johnson LR, etal.: Pulmonary thromboembo- Kintzer PP, Peterson ME: Mitotane (o, p-DDD) Lien YH, etal.: Associations among systemic
lism in 29 dogs: 1985-1995, J Vet Intern treatment of dogs with cortisol-secret- blood pressure, microalbuminuria and al-
Med 13:338, 1999. ing adrenocortical neoplasia: 32 cases buminuria in dogs affected with pituitary-
Juchem M, Pollow K: Binding of oral contra- (1980-1992), J Am Vet Med Assoc 205:54, and adrenal-dependent hyperadrenocorti-
ceptive progestogens to serum proteins 1994. cism, Acta Vet Scand 52:61, 2010.
and cytoplasmic receptor, Am J Obstet Kipperman BS, etal.: Pituitary tumor size, Lien YH, Huang H-P: Use of ketoconazole to
Gynecol 163:2171, 1990. neurologic signs, and relation to endo- treat dogs with pituitary-dependent hyper-
Kantrowitz BM, etal.: Adrenal ultrasonography crine test results in dogs with pituitary- adrenocorticism: 48 cases (1994-2007),
in the dog, Vet Radiol 27:15, 1986. dependent hyperadrenocorticism: 43 J Am Vet Med Assoc 233:1896, 2008.
Kaplan AJ, etal.: Effects of disease on the cases (1980-1990), J Am Vet Med Assoc Ling GV, etal.: Canine hyperadrenocorticism:
results of diagnostic tests for use in de- 201:762, 1992. pretreatment clinical and laboratory evalu-
tecting hyperadrenocorticism in dogs, J Am Kirk GR, etal.: Effects of o,p-DDD on plasma ation of 117 cases, J Am Vet Med Assoc
Vet Med Assoc 207:445, 1995. cortisol levels and histology of the adrenal 174:1211, 1979.
Kemppainen RJ, Peterson ME: Circulating gland in the normal dog, J Am Anim Hosp Love NE, etal.: The computed tomographic
concentration of dexamethasone in healthy Assoc 10:179, 1974. enhancement pattern of the normal canine
dogs, dogs with hyperadrenocorticism, Klose TC, etal.: Evaluation of coagulation sta- pituitary gland, Vet Radiol Ultrasound
and dogs with nonadrenal illness during tus in dogs with naturally occurring canine 41:507, 2000.
dexamethasone suppression testing, Am J hyperadrenocorticism, J Vet Emerg Crit Lulich JP, Osborne CA: Bacterial infections of
Vet Res 54:1765, 1993. Care 21:625, 2011. the urinary tract. In Ettinger SJ, Feldman
Kemppainen RJ, Sartin JL: Evidence for epi- Kolevska F, Svoboda M: Immunoreactive cor- EC, editors: Textbook of veterinary medicine,
sodic but not circadian activity in plasma tisol measurement in canine urine and its Philadelphia, 1994, WB Saunders, p 1775.
concentrations of adrenocorticotropin, validity in hyperadrenocorticism diagnosis, Machida T, etal.: Aldosterone-, corticoste-
cortisol and thyroxine in dogs, J Endocrinol Acta Vet Brno 69:217, 2000. rone- and cortisol-secreting adrenocortical
103:219, 1984a. Konar M, etal.: Magnetic resonance imaging carcinoma in a dog: case report, J Vet Med
Kemppainen RJ, Sartin JL: Effects of single features of empty sella in dogs, Vet Radiol Sci 70:317, 2007.
intravenous doses of dexamethasone on Ultrasound 49:339, 2008. Maher VMG, etal.: Possible mechanism and
baseline plasma cortisol concentrations Kooistra HS, etal.: Pulsatile secretion of treatment of o, p DDD-induced hypercho-
and response to synthetic ACTH in healthy alpha-MSH and the differential effects of lesterolemia, Q J Med 305:671, 1992.
dogs, Am J Vet Res 45:742, 1984b. dexamethasone and haloperidol on the Mantis P, etal.: Changes in ultrasonographic
Kemppainen RJ, Sartin JL: Differential regula- secretion of alpha-MSH and ACTH in dogs, appearance of adrenal glands in dogs with
tion of peptide release by the canine pars J Endocrinol 152:113, 1997a. pituitary-dependent hyperadrenocorticism
distalis and pars intermedia, Front Horm Kooistra HS, etal.: Correlation between impair- treated with trilostane, Vet Radiol Ultra-
Res 17:18, 1987. ment of glucocorticoid feedback and the sound 44:682, 2003.
Kemppainen RJ, etal.: Effects of prednisone size of the pituitary gland in dogs with Marcus HI, etal.: Bilateral adrenal hemorrhage
on thyroid and gonadal endocrine function pituitary-dependent hyperadrenocorticism, during ACTH treatment of ulcerative coli-
in dogs, J Endocr 96:293, 1983. J Endocrinol 152:387, 1997b. tis, Dis Colon Rectum 29:130, 1986.
Kemppainen RJ, etal.: Regulation of adre- Kook PH, etal.: Effects of iatrogenic hypercor- Mariani CL, etal.: Frameless stereotactic radio-
nocorticotropin secretion from cultured tisolism on gallbladder sludge formation surgery for the treatment of primary intra-
canine anterior pituitary cells, Am J Vet and biochemical bile constituents in dogs, cranial tumours in dogs, Vet Comp Oncol,
Res 53:2355, 1992. Vet J 191:225, 2011. 2013. [Epub ahead of print].
Kemppainen RJ, etal.: Preservative effect of Kool MM, etal.: Activating mutations of GNAS Martin LG, etal.: Effect of low doses of cosyn-
aprotinin on canine plasma immunoreac- in canine cortisol-secreting adrenocortical tropin on serum cortisol concentrations
tive adrenocorticotropin concentrations, tumors, J Vet Intern Med 27:1486, 2013. in clinically normal dogs, Am J Vet Res
Dom Anim Endocr 11:355, 1994. Kutsunai M, etal.: The association between 68:555, 2007.
Kemppainen RJ, etal.: Use of compounded gall bladder mucoceles and hyperlipidae- Martinez NI, etal.: Evaluation of pressor
adrenocorticotropic hormone (ACTH) for mia in dogs: a retrospective case control sensitivity to norepinephrine infusion
adrenal function testing in dogs, J Am study, Vet J 199:76, 2014. in dogs with iatrogenic hyperadreno-
Anim Hosp Assoc 41:368, 2005. Kyles AE, etal.: Surgical management of corticism. Pressor sensitivity in dogs
Kent MS, etal.: Survival, neurologic response, adrenal gland tumors with and without with hyperadrenocorticism, Res Vet Sci
and prognostic factors in dogs with pitu- associated tumor thrombi in dogs: 78:25, 2005.
itary masses treated with radiation therapy 40 cases (1994-2001), J Am Vet Med Massari F, etal.: Adrenalectomy in dogs with ad-
and untreated dogs, J Vet Intern Med Assoc 223:654, 2003. renal gland tumors: 52 cases (2002-2008),
21:1027, 2007. Labelle P, etal.: Indicators of malignancy of J Am Vet Med Assoc 239:216, 2011.
Kerl ME, etal.: Evaluation of a low-dose canine adrenocortical tumors: histopathology Mattson A, etal.: Clinical features suggest-
synthetic adrenocorticotropic hormone and proliferation index, Vet Pathol 41:490, ing hyperadrenocorticism associated with
stimulation test in clinically normal 2004. sudden acquired retinal degeneration
dogs and dogs with naturally developing Lang JM, etal.: Elective and emergency surgi- syndrome in a dog, J Am Anim Hosp Assoc
hyperadrenocorticism, J Am Vet Med Assoc cal management of adrenal gland tumors: 28:199, 1992.
214:1497, 1999. 60 cases (1999-2006), J Am Anim Hosp May ER, etal.: Effects of a mock ultrasono-
Keyes ML, etal.: Pulmonary thromboembolism Assoc 47:428, 2011. graphic procedure on cortisol concentra-
in dogs, J Vet Emerg Crit Care 3:23, 1993. Lantz GC, etal.: Transsphenoidal hypophysec- tions during low-dose dexamethasone sup-
Kidney BA, Jackson ML: Diagnostic value of tomy in the clinically normal dog, Am J Vet pression testing in clinically normal adult
alkaline phosphatase isoenzyme separation Res 49:1134, 1988. dogs, Am J Vet Res 65:267, 2004.
by affinity electrophoresis in the dog, Can LaRue MJ, Murtaugh RJ: Pulmonary thrombo- McGraw AL, etal.: Determination of the
Vet J 52:106, 1988. embolism in dogs: 47 cases (1986-1987), concentrations of trilostane and keto-
Kintzer PP, Peterson ME: Mitotane (o, pDDD) J Am Vet Med Assoc 197:1368, 1990. trilostane that inhibit exvivo adrenal
treatment of 200 dogs with pituitary-de- Leone F, etal.: The use of trilostane for the treat- synthesis of cortisol, corticosterone
pendent hyperadrenocorticism, J Vet Intern ment of Alopecia X in Alaskan malamutes, J and aldosterone, Am J Vet Res 72:661,
Med 5:182, 1991. Am Anim Hosp Assoc 41:336, 2005. 2010.
|
McLauchlan G, etal.: Retrospective evalua- Neiger R, etal.: Trilostane treatment of 78 Peterson ME, etal.: Plasma cortisol response
tion of the effect of trilostane on insulin re- dogs with pituitary-dependent hyperadre- to exogenous ACTH in 22 dogs with
quirement and fructosamine concentration nocorticism, Vet Rec 150:799, 2002. hyperadrenocorticism caused by an adre-
in eight diabetic dogs with hyperadrenocor- Nelson AA, Woodard G: Severe adrenal cortical nocortical neoplasia, J Am Vet Med Assoc
ticism, J Small Anim Pract 51:642, 2010. atrophy (cytotoxic) and hepatic damage 180:542, 1982b.
McNicol AM: Pituitary morphology in canine produced in dogs by feeding 2, 2-bis (para- Peterson ME, etal.: Decreased insulin sensitiv-
pituitary-dependent hyperadrenocorticism, chlorophenyl)-1, 1-trichloroethane (DDD or ity and glucose tolerance in spontaneous
Front Horm Res 17:71, 1987. TDE), Arch Pathol 48:387, 1949. canine hyperadrenocorticism, Res Vet Sci
Meaney JFM, etal.: Diagnosis of pulmonary Nelson RW, etal.: Effect of o, p-DDD therapy 36:177, 1984a.
embolism with magnetic resonance angiog- on endogenous ACTH concentrations in Peterson ME, etal.: Effects of spontaneous
raphy, N Engl J Med 336:1422, 1997. dogs with hypophysis-dependent hyper- hyperadrenocorticism on serum thyroid
Meij BP, etal.: Residual pituitary function after adrenocorticism, Am J Vet Res 46:1534, hormone concentrations in the dog, Am J
transsphenoidal hypophysectomy in dogs 1985. Vet Res 45:2034, 1984b.
with pituitary-dependent hyperadrenocorti- Nelson RW, etal.: Pituitary macroadenomas Peterson ME, etal.: Plasma immunoreactive
cism, J Endocrinol 155:531, 1997a. and macroadenocarcinomas in dogs treat- pro-opiomelanocortin peptides and cortisol
Meij BP, etal.: Transsphenoidal hypophy- ed with mitotane for pituitary-dependent in normal dogs and dogs with Addisons
sectomy in Beagle dogs: evaluation of a hyperadrenocorticism: 13 cases disease and Cushings syndrome: basal
microsurgical technique, Vet Surg 26:295, (1981-1986), J Am Vet Med Assoc concentrations, Endocrinology 119:720,
1997b. 194:1612, 1989. 1986a.
Meij BP, etal.: Alterations in anterior pituitary Niebauer GW, Evans SM: Transsphenoidal Peterson ME, etal.: Effect of spontaneous
function of dogs with pituitary-dependent hypophysectomy in the dog: a new tech- hyperadrenocorticism on endogenous
hyperadrenocorticism, J Endocrinol nique, Vet Surg 17:296, 1988. production and utilization of glucose in
154:505, 1997c. Niebauer GW, etal.: Study of long-term the dog, Domest Anim Endocrinol 3:117,
Meij BP, etal.: Results of transsphenoidal survival after transsphenoidal hypophysec- 1986b.
hypophysectomy in 52 dogs with pituitary- tomy in clinically normal dogs, Am J Vet Phillips M, Tashjian AH: Characterization of an
dependent hyperadrenocorticism, Vet Surg Res 51:677, 1990. early inhibitory effect of glucocorticoids on
27:246, 1998. Norman EJ, etal.: Dynamic adrenal function stimulated adrenocorticotropin and endor-
Melby JC: Therapy for Cushing disease: a testing in eight dogs with hyperadreno- phin release from a clonal strain of mouse pi-
consensus for pituitary microsurgery, Ann corticism associated with adrenocortical tuitary cells, Endocrinology 110:892, 1982.
Intern Med 109:445, 1988. neoplasia, Vet Rec 144:551, 1999. Pike FS, etal.: Gallbladder mucocele in dogs:
Mesich ML, etal.: Gall bladder mucoceles and Oliver J: Steroid profiles in the diagnosis of 30 cases (2000-2002), J Am Vet Med
their association with endocrinopathies in canine adrenal disorders, Proc 25th Ann Assoc 224:1615, 2004.
dogs: a retrospective case-control study, Vet Med Forum, p 471, 2007. Puente S: Pituitary carcinoma in an Airedale
J Small Anim Pract 50:630, 2009. Ortega T, etal.: Evaluation of fasting serum terrier, Can Vet J 44:240, 2003.
Monroe WE, etal.: Concentrations of noncorti- lipid proles in dogs with Cushings syn- Ramsey IK, etal.: Hyperparathyroidism in dogs
sol adrenal steroids in response to ACTH in drome, J Vet Intern Med 9:182, 1995. with hyperadrenocorticism, J Small Anim
dogs with adrenal-dependent hyperadreno- Ortega T, etal.: Systemic arterial blood pres- Pract 46:531, 2005.
corticism, pituitary-dependent hyperadre- sure and urine protein/creatinine ratio in Ramsey IK, etal.: Persistent isolated hypo-
nocorticism, and nonadrenal illness, J Vet dogs with hyperadrenocorticism, J Am Vet cortisolism following brief treatment with
Intern Med 26:945, 2012. Med Assoc 209:1724, 1996. trilostane, Aust Vet J 86:491, 2008.
Montgomery KW, etal.: Acute blindness in Pace SL, etal.: Assessment of coagulation and Randolph JF, etal.: Use of the urinary
dogs: sudden acquired retinal degenera- potential biochemical markers for hyper- corticoid: creatinine ratio for monitoring
tion syndrome versus neurological disease coagulability in canine hyperadrenocorti- dogs with pituitary-dependent hyperad-
(140 cases, 2000-2006), Vet Ophthalmol cism, J Vet Intern Med 27:1113, 2013. renocorticism during induction treatment
11:314, 2008. Paez-Pereda M, etal.: Retinoic acid prevents with mitotane (o, p-DDD), Am J Vet Res
Montgomery TM, etal.: Basal and glucagon- experimental Cushings syndrome, J Clin 59:258, 1998.
stimulated plasma C-peptide concentra- Invest 108:1123, 2001. Rees DA, etal.: Long-term follow-up results
tions in healthy dogs, dogs with diabetes Park FM, etal.: Hypercoagulability and ACTH- of transsphenoidal surgery for Cushings
mellitus, and dogs with hyperadrenocorti- dependent hyperadrenocorticism in dogs, disease in a single centre using strict
cism, J Vet Intern Med 10:116, 1996. J Vet Intern Med 27:1136, 2013. criteria for remission, Clin Endocrinol (Oxf)
Mueller C, etal.: Low-dose dexamethasone Penninck DG, etal.: Radiologic features of 56:541, 2002.
test with inverse results: a possible canine hyperadrenocorticism caused by Reid LE, etal.: Effect of trilostane and mito-
new pattern of cortisol response, Vet Rec autonomously functioning adrenocortical tane on aldosterone secretory reserve in
159:489, 2006. tumors: 23 cases (1978-1986), J Am Vet dogs with pituitary-dependent hyperadreno-
Muller PB, etal.: Effects of long-term phe- Med Assoc 192:1604, 1988. corticism, J Vet Intern Med 28:443, 2014.
nobarbital treatment on the thyroid and Peterson ME: Hyperadrenocorticism, Vet Clin Reimers TJ, etal.: Effects of hemolysis and
adrenal axis and adrenal function tests in North Am (Small Anim Pract) 14:731, storage on quantication of hormones
dogs, J Vet Intern Med 14:157, 2000a. 1984. in blood samples from dogs, cattle, and
Muller PB, etal.: Effects of long-term pheno- Peterson ME: Pathophysiology of canine horses, Am J Vet Res 52:1075, 1991.
barbital treatment on the liver in dogs, pituitary-dependent hyperadrenocorticism, Reine NJ, etal.: Deoxycorticosterone-secreting
J Vet Intern Med 14:165, 2000b. Front Horm Res 17:37, 1987. adrenocortical carcinoma in a dog, J Vet
Naan EC, etal.: Innovative approach to lapa- Peterson ME, etal.: Diagnosis and manage- Int Med 13:386, 1999.
roscopic adrenalectomy for treatment of ment of concurrent diabetes mellitus and Reitmeyer M, etal.: The neurosurgical manage-
unilateral adrenal gland tumors in dogs, hyperadrenocorticism in 30 dogs, J Am Vet ment of Cushings disease, Molec Cell
Vet Surg 42:710, 2013. Med Assoc 178:66, 1981. Endocrinol 197:73, 2002.
Neiger, R: Hyperadrenocorticism: the animal Peterson ME, etal.: Immunocytochemical study Reusch CE: Hyperadrenocorticism. In Ettinger
perspectivecomparative efficacy and of the hypophysis in 25 dogs with pituitary- SE, Feldman EC, editors: Textbook of vet-
safety of trilostane, Proceedings 22nd Ann dependent hyperadrenocorticism, Acta En- erinary internal medicine, ed 6, Philadel-
Vet Med Forum, p 699, 2004. docrinol 101:15, 1982a. phia, 2005, Saunders/Elsevier.
Reusch CE, Feldman EC: Canine hyperadreno- Sands JM, Bichet DG: Neprogenic diabetes in- Sobel KE, Williams JE: Pneumothorax second-
corticism due to adrenocortical neoplasia, sipidus, Ann Intern Med 144:186, 2006. ary to pulmonary thromboembolism in a
J Vet Intern Med 5:3, 1991. Sanecki RK, etal.: Subcellular location of dog, J Vet Emerg Crit Care 19:120, 2009.
Reusch CE, etal.: The efcacy of L-deprenyl corticosteroid-induced alkaline phospha- Solter PF, etal.: Assessment of corticosteroid-
in dogs with pituitary-dependent hyperad- tase in canine hepatocytes, Vet Pathol induced isoenzyme as a screening test for
renocorticism, J Vet Intern Med 13:291, 24:296, 1987. hyperadrenocorticism in dogs, J Am Vet
1999. Schaer M, etal.: A case of fatal anaphylaxis Med Assoc 203:534, 1993.
Reusch CE, etal.: Histological evaluation of in a dog associated with a dexamethasone Solter PF, etal.: Hepatic total 3-alpha-hydroxy
the adrenal glands of seven dogs with hy- suppression test, J Vet Emerg Crit Care bile acid concentration and enzyme activi-
peradrenocorticism treated with trilostane, 15:213, 2005. ties in prednisone-treated dogs, Am J Vet
Vet Rec 160:219, 2007. Schmeitzel LP, Lothrop CD: Hormonal abnor- Res 55:1086, 1994.
Rewerts JM, etal.: Atraumatic rupture of the malities in Pomeranians with normal coat Stenske KA, etal.: Acute polyarthritis and sep-
gastrocnemius muscle after corticosteroid and in Pomeranians with growth hormone- ticemia from mycoplasma edwardii after
administration in a dog, J Am Vet Med As- responsive dermatosis, J Am Vet Med surgical removal of bilateral adrenal tumors
soc 210:655, 1997. Assoc 197:1333, 1990. in a dog, J Vet Int Med 19:768, 2005.
Rhodes KH, Beale KM: Alopecia, canine. In Schmeitzel LP, Lothrop CD: Congenital adrenal Stewart PM: The adrenal cortex. In Kronenberg
Rhodes KH, editor: The 5-minute veteri- hyperplasia-like syndrome. In Bonagura HM, Melmed S, Polonsky KS, Larsen PR,
nary consult clinical companion: small JD, Kirk RW, editors: Kirks current veteri- editors: Williams textbook of endocrinol-
animal dermatology, Baltimore, 2002, nary therapy XII, Philadelphia, 1995, WB ogy, Philadelphia, 2008, Saunders/
Lippincott Williams and Wilkins, p 27. Saunders/Elsevier, p 600. Elsevier, p 445.
Rijnberk A, Belshaw BE: An alternative proto- Schwartz P, etal.: Evaluation of prognostic Stolp R, etal.: Urinary corticoids in the diag-
col for the medical management of canine factors in the surgical treatment of adrenal nosis of canine hyperadrenocorticism, Res
pituitary-dependent hyperadrenocorticism, gland tumors in dogs: 41 cases Vet Sci 34:141, 1983.
Vet Rec 122:486, 1988. (1999-2005), J Am Vet Med Assoc Stolp R, etal.: Results of cyproheptadine
Rijnberk A, etal.: Assessment of two tests for 232:77, 2008. treatment in dogs with pituitary-dependent
the diagnosis of canine hyperadrenocorti- Schwarz T, etal.: Osteopenia and other radio- hyperadrenocorticism, J Endocr 101:311,
cism, Vet Rec 122:178, 1988a. graphic signs in canine hyperadrenocorti- 1984.
Rijnberk A, etal.: Effects of bromocriptine on cism, J Small Anim Pract 41:491, 2000. Stuckey JA, etal.: Long-term outcome of
corticotropin, melanotropin, and cortico- Scott-Moncrieff JCR, etal.: Validation of chemi- sudden acquired retinal degeneration
steroid secretion in dogs with pituitary- luminescent enzyme immunometric assay syndrome in dogs, J Am Vet Med Assoc
dependent hyperadrenocorticism, J for plasma adrenocorticotropic hormone in 243:1426, 2013.
Endocrinol 118:271, 1988b. the dog, Vet Clin Pathol 32:180, 2003. Swinney GR, etal.: Myotonia associated with
Rijnberk A, etal.: Aldosteronoma in a dog with Seguin MA, etal.: Persistent urinary tract infec- hyperadrenocorticism in two dogs, Aust Vet
polyuria as the leading symptom, Domest tions and reinfections in 100 dogs (1989- J 76:722, 1998.
Anim Endocrinol 20:227, 2001. 1999), J Vet Intern Med 17:622, 2003. Syme HM, etal.: Hyperadrenocorticism as-
Ristic JME, etal.: The use of Selman PJ, etal.: Effects of progestin adminis- sociated with excessive sex hormone
17-hydroxyprogesterone in the diagnosis tration on the hypothalamic-pituitary-adrenal production by an adrenocortical tumor in
of canine hyperadrenocorticism, J Vet axis and glucose homeostasis in dogs, two dogs, J Am Vet Med Assoc 219:1725,
Intern Med 16:433, 2002. J Reprod Fertil Suppl 51:345, 1997. 2001.
Robben JH, etal.: Cell biological aspects of Sepesy LM, etal.: Vacuolar hepatopathy in Syme HM, etal.: Measurement of aldosterone
the vasopressin type-2 receptor and aqua- dogs: 336 cases (1993-2005), J Am Vet in feline, canine and human urine, J Sm
porin 2 channel in nephrogenic diabetes Med Assoc 229:246, 2006. Anim Pract 48:202, 2007.
insipidus, Am J Physiol Renal Physiol Seruca C, etal.: Acute postretinal blindness: Takada K, etal.: Cloning of canine 21-hydroxy-
291:F257, 2006. ophthalmologic, neurologic, and mag- lase gene and its polymorphic analysis as
Rockwell JL, etal.: Spontaneous hypoadre- netic resonance imaging findings in dogs a candidate gene for congenital adrenal
nocorticism in a dog after a diagnosis and cats (seven cases), Vet Ophthalmol hyperplasia-like syndrome in Pomeranians,
of hyperadrenocorticism, J Vet Int Med 13:307, 2010. Res Vet Sci 73:159, 2002.
19:255, 2005. Sica DA: Pharmacokinetics and pharmaco- Taoda T, etal.: Magnetic resonance imaging
Rodriguez Pineiro MI, etal.: Accuracy of an dynamics of mineralocorticoid blocking assessment of pituitary posterior lobe
adrenocorticotropic hormone (ACTH) agents and their effects on potassium displacement in dogs with pituitary-
immunoluminometric assay for dif- homeostasis, Heart Fail Rev 10:23, 2005. dependent hyperadrenocorticism, J Vet
ferentiating ACTH-dependent from Sieber-Ruckstuhl NS, etal.: Cortisol, aldo- Med Sci 73:725, 2011.
ACTH-independent hyperadrenocorticism sterone, cortisol precursor, androgen and Teshima T, etal.: Cushings disease compli-
in dogs, J Vet Intern Med 23:850, 2009. endogenous ACTH concentrations in dogs cated with thrombosis in a dog, J Vet Med
Rodriguez Pineiro MI, etal.: Use of computed with pituitary-dependent hyperadrenocorti- Sci 70:487, 2008.
tomography adrenal gland measurement cism treated with trilostane, Domest Anim Teshima T, etal.: Expression of genes related
for differentiating ACTH dependence from Endocrinol 31:63, 2006. to corticotropin production and glucocorti-
ACTH independence in 64 dogs with Sieber-Ruckstuhl NS, etal.: Evaluation of coid feedback in corticotroph adenomas of
hyperadrenocorticism, J Vet Intern Med cortisol precursors for the diagnosis of dogs with Cushings disease, Domest Anim
25:1066, 2011. pituitary-dependent hypercortisolism in Endocrinol 36:3, 2009.
Rose L, etal.: Effect of canine hyperadreno- dogs, Vet Rec 162:673, 2008. Teshima T, etal.: Central diabetes insipidus
corticism on coagulation parameters, J Vet Smets PM, etal.: Long-term follow-up of renal after transsphenoidal surgery in dogs with
Intern Med 27:207, 2013. function in dogs after treatment for ACTH- Cushings disease, J Vet Med Sci 73:33,
Ruckstuhl NS, etal.: Results of clinical exami- dependent hyperadrenocorticism, J Vet 2011.
nations, laboratory tests, and ultrasonog- Intern Med 26:565, 2012. Teske E, etal.: Corticosteroid-induced alkaline
raphy in dogs with pituitary-dependent hy- Smiley LE, Peterson ME: Evaluation of a urine phosphatase isoenzyme in the diagnosis of
peradrenocorticism treated with trilostane, cortisol:creatinine ratio as a screening test canine hypercorticism, Vet Rec 125:12,
Am J Vet Res 63:506, 2002. for hyperadrenocorticism in dogs, J Vet 1989.
Intern Med 7:163, 1993.
|
Theon AP, Feldman EC: Megavoltage irradia- Vandenbergh AGGD, etal.: Haemorrhage from Wiedmeyer CE, etal.: Alkaline phosphatase
tion of pituitary macrotumors in dogs with a canine adrenocortical tumour: a clinical expression in tissues from glucocorticoid-
neurologic signs, J Am Vet Med Assoc emergency, Vet Rec 13:539, 1992. treated dogs, Am J Vet Res 63:1083,
213:225, 1998. Vaughn MA, etal.: Evaluation of twice-daily, 2002a.
Thuroczy J, etal.: Multiple endocrine neopla- low-dose trilostane treatment administered Wiedmeyer CE, etal.: Kinetics of mRNA
sias in a dog: corticotrophic tumour, bilat- orally in dogs with naturally occurring expression of alkaline phosphatase
eral adrenocortical tumours and pheochro- hyperadrenocorticism, J Am Vet Med Assoc isoenzymes in hepatic tissues from
mocytoma, Vet Quart 20:56, 1998. 232:1321, 2008. glucocorticoid-treated dogs, Am J Vet Res
Tobias KM, Johnston SA: Veterinary surgery: Vollmar AM, etal.: Atrial natriuretic peptide 63:1089, 2002b.
small animal, St Louis, 2012, Elsevier/ concentration in dogs with congestive Willard MD, etal.: Ketoconazole-induced
Saunders. heart failure, chronic renal failure, and changes in selected canine hormone con-
Toutain PL, etal.: Pharmacokinetics of dexa- hyperadrenocorticism, Am J Vet Res centrations, Am J Vet Res 47:2504, 1986.
methasone and its effect on adrenal gland 52:1831, 1991. Wilson SM, Feldman EC: Diagnostic value of
function in the dog, Am J Vet Res 44:212, Von Dehn BJ, etal.: Pheochromocytoma in 6 the steroid-induced isoenzyme of alkaline
1983. dogs with naturally acquired hyperadre- phosphatase in the dog, J Am Anim Hosp
Turrel JM, etal.: Computed tomographic nocorticism: 1982-1992, J Am Vet Med Assoc 28:245, 1992.
characteristics of primary brain tumors in Assoc 207:322, 1995. Witt A, Neiger R: Adrenocorticotropic hormone
50 dogs, J Am Vet Med Assoc 188:851, Voorhout G, etal.: Computed tomography in levels in dogs with pituitary-dependent
1986. the diagnosis of canine hyperadrenocorti- hyperadrenocorticism following trilostane
Turton DB, etal.: Incidental adrenal nodules: cism not suppressible by dexamethasone, J therapy, Vet Rec 154:399, 2004.
association with exaggerated 17 hydroxy- Am Vet Med Assoc 192:641, 1988 Wolfsheimer KJ, Peterson ME: Erythrocyte
progesterone response to adrenocorti- Voorhout G: X-ray-computed tomography, insulin receptors in dogs with spontane-
cotropic hormone, J Endocrinol Invest nephrotomography, and ultrasonography of ous hyperadrenocorticism, Am J Vet Res
15:789, 1992. the adrenal glands of healthy dogs, Am J 52:917, 1991.
Valencia IC, Kerdel FA: Topical corticosteroids. Vet Res 51:625, 1990. Wood FD, etal.: Diagnostic imaging findings
In Goldsmith LA, Katz SI, Gilchrest BA, Voorhout G, etal.: Assessment of survey radiog- and endocrine test results in dogs with
Paller AS, Leffell DJ, Wolff K, editors: raphy and comparison with x-ray computed pituitary-dependent hyperadrenocorticism
Fitzpatricks dermatology in general tomography for detection of hyperfunction- that did or did not have neurologic abnor-
medicine, New York, 2012, McGraw Hill ing adrenocortical tumors in dogs, J Am Vet malities: 157 cases (1989-2005), J Am
Medical, p 2659. Med Assoc 196:1799, 1990a. Vet Med Assoc 231:1081, 2007.
van der Vlugt-Meijer RH, etal.: Dynamic com- Voorhout G, etal.: Nephrotomography and Yamaji T, etal.: Plasma levels of atrial natri-
puted tomography of the pituitary gland in ultrasonography for the localization of uretic hormone in Cushings syndrome,
dogs with pituitary-dependent hyperadre- hyperfunctioning adrenocortical tumors in J Clin Endocrinol Metab 67:348, 1988.
nocorticism, J Vet Int Med 17:773, 2003. dogs, Am J Vet Res 51:1280, 1990b. Zerbe CA: Screening tests to diagnose hyperad-
van der Vlugt-Meijer RH, etal.: Dynamic Ward DA, etal.: Band keratopathy associated renocorticism in cats and dogs, Compend
computed tomographic evaluation of the with hyperadrenocorticism in the dog, Contin Educ 22:17, 2000.
pituitary gland in healthy dogs, Am J Vet J Am Anim Hosp Assoc 25:583, 1989. Zeugswetter F, etal.: The desmopressin
Res 65:1518, 2004. Waters CB, etal.: Effects of glucocorticoid stimulation test in dogs with Cushings
van der Woerdt A, etal.: Sudden acquired therapy on urine protein-to-creatinine syndrome, Domest Anim Endocrinol
retinal degeneration in the dog: clinical ratios and renal morphology in dogs, J Vet 34:254, 2008.
and laboratory findings in 36 cases, Prog Int Med 11:172, 1997. Zeugswetter F, etal.: Tailored reference limits
Vet Comp Ophthalmol 1:11, 1991. Watson ADJ: Oestrogen-induced alopecia in a for urine corticoid: creatinine ratio in dogs
Van Liew CH, etal.: Comparison of results of bitch, J Small Anim Pract 26:17, 1985. to answer distinct clinical questions, Vet
adrenocorticotropic hormone stimulation Watson ADJ, etal.: Systemic availability of Rec 167:997, 2010.
and low dose dexamethasone suppression o,p-DDD in normal dogs, fasted and fed, Zeugswetter F, etal.: Diagnostic efficacy of
tests with necropsy nding in dogs: 81 and in dogs with hyperadrenocorticism, plasma ACTH-measurement by a chemi-
cases (1985-1995), J Am Vet Med Assoc Res Vet Sci 43:160, 1987. luminometric assay in canine hyperad-
211:322, 1997. Webb CB, Twedt DC: Acute hepatopathy associ- renocorticism, Schweiz Arch Tierheilkd
van Rijn SJ, etal.: Expression of Ki-67, PCNA, ated with mitotane administration in a dog, 153:111, 2011.
and p27kip1 in canine pituitary cortico- J Am Anim Hosp Assoc 42:298, 2006. Zimmerman KL, etal.: Hyperphosphatasemia
troph adenomas, Domest Anim Endocrinol Wenger M, etal.: Effect of trilostane on serum and concurrent adrenal gland dysfunction
38:244, 2010. concentrations of aldosterone, cortisol and in apparently healthy Scottish terriers,
van Vonderen IK, etal.: Influence of veterinary potassium in dogs with pituitary-dependent J Am Vet Med Assoc 237:178, 2010.
care on the urinary corticoid:creatinine hyperadrenocorticism, Am J Vet Res Zur G, White SD: Hyperadrenocorticism in 10
ratio in dogs, J Vet Intern Med 12:431, 65:1245, 2004. dogs with skin lesions as the only present-
1998. White SD, etal.: Cutaneous markers of canine ing clinical signs, J Am Anim Hosp Assoc
van Wijk PA, etal.: Corticotropin-releasing hyperadrenocorticism, Compend Contin 47:419, 2011.
hormone and adrenocorticotropic hormone Educ 11:446, 1989.
concentrations in cerebrospinal fluid of Whittemore JC, etal.: Nontraumatic rupture of
dogs with pituitary-dependent hyperad- an adrenal gland tumor causing intraabdom-
renocorticism, Endocrinology 131:2659, inal or retroperitoneal hemorrhage in four
1992. dogs, J Am Vet Med Assoc 219:329, 2001.
van Wijk PA, etal.: Responsiveness to corti- Widmer WR, Guptill L: Imaging techniques
cotropin-releasing hormone and vasopres- for facilitating diagnosis of hyperadreno-
sin in canine Cushings syndrome, Eur J corticism in dogs and cats, J Am Vet Med
Endocrinol 130:410, 1994. Assoc 206:1857, 1995.
CHAPTER 11 Hyperadrenocorticism in Cats
Edward C. Feldman
CHAPTER CONTENTS Combined Dexamethasone Suppression Test/Adrenocorticotropic Hormone

Feline Hyperadrenocorticism (Feline Cushings Syndrome), Stimulation, 467
Hyperaldosteronism, Sex Hormone Secreting Adrenal Tumors, 452 Combination Screening and Discrimination Tests, 467
Etiology, 453 Tests to Discriminate Pituitary from Adrenal Tumor Cushings Syndrome,
Iatrogenic Cushings Syndrome, 453 468
Naturally Occurring Feline Hyperadrenocorticism, 453 Low-Dose Dexamethasone Suppression Test (LDDST), 468
Signalment (Age, Sex, Breed), 454 High-Dose Dexamethasone Suppression Test (HDDST), 468
Duration of Clinical Signs, Chief Complaint, and General History, 454 Endogenous ACTH and ACTH Precursor Concentrations, 470
Duration of Clinical Signs, 454 Abdominal Radiology, 471
Owner Chief Concern/Explanation for Being Referred, 454 Abdominal Ultrasonography, 471
Owner Observations, 456 Ultrasound-Guided Biopsy, 472
Physical Examination Abnormalities, 456 Computed Tomography (CT) and Magnetic Resonance
Explanations for History and Physical Examination Abnormalities, 456 Imaging (MRI) Scans, 472
Polyuria and Polydipsia, 456 Medical Treatment, 473
Polyphagia, 457 Introduction and the Options, 473
Weight Loss, 457 Trilostane, 473
Weakness, Lethargy, Potbelly, and Bruising, 458 Mitotane, 475
Curled Ear Tips, 458 Ketoconazole, 475
Dermatologic Abnormalities, 458 Etomidate, 475
Routine Clinical Pathology (Complete Blood Count, Metyrapone, 475
Biochemistry, Urinalysis), 459 Surgery and Laparoscopic Treatment, 476
Complete Blood Count, 459 Hypophysectomy, 476
Blood Glucose Concentrations and Diabetes Mellitus, 459 Adrenalectomy, 476
Liver Enzyme Activities, 460 Pituitary Radiation, 477
Serum Cholesterol and Thyroxine, 461 Background, 477
Blood (Serum) Urea Nitrogen, Serum Creatinine, Urinalysis, 462 Experience, 478
Serum Sodium, Serum Magnesium, Serum Potassium, and Muscle Weakness, Prognosis, 478
462 Primary Hyperaldosteronism in Cats, 478
Serum Calcium, Albumin, Globulins, and Total Protein, 463 Background, 478
Urinary Tract Infection, 463 Etiology, 479
Blood Pressure, 463 Clinical Features and In-Hospital Testing, 479
Screening Tests to Aid in Diagnosing Feline Cushings Syndrome, 463 Treatment, 480
Sensitivity and Specificity (A Simple Review), 463 Excessive Sex HormoneSecreting Adrenal Tumors in Cats, 481
Urine Cortisol-to-Creatine Ratio (UC:CR), 463 Background, 481
ACTH Stimulation Test, 464 Clinical Features, 481
Low-Dose Dexamethasone Suppression Test (LDDST), 466 Treatment and Prognosis, 481
Hair Cortisol Concentrations, 467
FELINE HYPERADRENOCORTICISM (FELINE excess circulating concentrations of glucocorticoids (cortisol). The

CUSHINGS SYNDROME), HYPERALDOSTERONISM, eponym Cushings syndrome is an umbrella term referring to all
SEX HORMONE SECRETING ADRENAL TUMORS causes of hyperadrenocorticism in people and, more recently, in
In 1932, long before the physiology of the adrenal cortex was animals.
understood and before identification of glucocorticoids, Dr. Har- There are several causes for Cushings syndrome. In addi-
vey Cushing authored a report in which he described a group of tion to the common iatrogenic condition, one of the naturally
people with a disorder that appeared to be the result of pitu- occurring disorders is caused by an autonomously function-
itary basophilism. Subsequent study of the clinical, biochemical, ing, adrenocorticotropic hormone (ACTH)-secreting, pitu-
and histologic features of these individuals are consistent with itary tumor (usually an adenoma) resulting in excess cortisol
each having had a syndrome resulting from chronic exposure to synthesis/secretion and adrenocortical hyperplasia (pituitary
452
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CHAPTER 11 Hyperadrenocorticism in Cats 453
dependent hyperadrenocorticism [PDH]). ACTH-secreting resonance imaging [MRI] scans) conrmation or histologic
pituitary tumors have been demonstrated to be derived from conrmation of the diagnosis.
a single aberrant cell line. A less common cause of naturally
occurring hyperadrenocorticism (NOH) in animals is that ETIOLOGY
caused by an autonomously functioning, cortisol-secreting,
adrenocortical tumor (adenoma or carcinoma; adrenal tumor Iatrogenic Cushings Syndrome
hyperadrenocorticism [ATH]). PDH is about five-to-six times
more common in people, dogs, and cats than ATH. Both iatro- Clinical signs of iatrogenic cortisol excess are relatively common
genic and NOH is being diagnosed with increasing frequency in dogs. Clinical signs due to iatrogenic cortisol excess are much
in cats. This rising number of cats diagnosed with hyperadre- less dramatic or common in people and seem even less obvious
nocorticism is likely associated with feline medicine becom- in cats. This can be explained, in part, by what appears to be a
ing more specialized, cats being better understood, owners relative insensitivity to the negative or deleterious side effects of
requesting more sophisticated care, awareness of this condi- chronic glucocorticoid administration in cats. In other words,
tion increasing, veterinarians becoming more familiar with the owners of dogs being treated with glucocorticoids are far more
many variations on the theme of glucocorticoid excess, and an likely to observe unwanted or worrisome side effects than are own-
expanding number of aging feline pets. ers of similarly-treated cats, simply because cats do not often dem-
NOH is unusually common in dogs, resulting in veterinary onstrate such side effects.
clinicians becoming quite familiar with the condition and the In studies on cats experimentally treated with glucocorticoids,
inevitable comparisons of dog hyperadrenocorticism and those treated for a 4-week period had few abnormalities on physical
hyperadrenocorticism in cats. There are both similarities and examination and no consistent hematologic or biochemical changes
differences. The obvious clinical features of hyperadrenocorti- (Scott etal, 1979; 1982). When treated for 9 weeks or longer, most
cism in dogs include polyuria, polydipsia, polyphagia, panting, cats continued to have no or few clinical signs (Lowe etal, 2008).
muscle weakness, thin skin, potbelly, and symmetrical alopecia. However, a minority of cats exhibited some of the following: poly-
These common and obvious signs in dogs are not noted with dipsia, polyuria, polyphagia, abdominal enlargement, lethargy,
frequency in cats with hyperadrenocorticism unless they have weakness, thin skin, and medial curling of their ear tips. Some cats
diabetes mellitus which, in turn, causes polyuria and polydipsia with iatrogenic cortisol excess developed hepatomegaly, muscle
(PU/PD). Confirming a diagnosis is more problematic in cats, wasting, ecchymoses, and skin fragility (Scott et al, 1979; 1982;
in part because the disease is far less common. Most reports Lowe et al, 2008). Many cortisol-treated cats tended to develop
in the literature describe obvious diagnoses in cats with dra- mild hyperglycemia, and a minority became overtly hyperglyce-
matic abnormalities, suggesting that confirming a diagnosis in mic due to diabetes mellitus. Less common abnormalities included
subtle cases is difficult or that the subtle cases are not often increased white blood cell numbers, a stress leukogram, increased
recognized or reported. Most dogs with NOH respond quite liver enzyme activities, hypercholesterolemia, hypertriglyceridemia,
well and live years after commencement of treatment. In cats, glycogen accumulation in hepatocytes, and a vacuolar hepatopathy.
however, treatment is more frustrating and difficult. Cataracts developed in some laboratory cats treated with topical
Since the underlying physiologic causes for hyperadreno- glucocorticoids (Brightman, 1982; Zhan etal, 1992).
corticism are similar in dogs, and cats, the reader interested in A small number of privately owned cats treated with exogenous
applied physiology and in mechanisms of disease is encouraged glucocorticoids had clinical iatrogenic FCS and were reported
to review the appropriate sections in Chapter 10. The focus of (Green et al, 1995; Schaer and Ginn, 1999; Ferasin, 2001; Lien
this chapter is to review the current state of knowledge regarding et al, 2006). Among the features likely due to chronic glucocor-
the diagnosis and treatment of feline Cushings syndrome (FCS) ticoid exposure were abdominal enlargement, muscle wasting,
in cats. As will be discussed later in this chapter, some adreno- poor hair coats, and skin fragility. The skin fragility in one report
cortical tumors in cats primarily secrete sex hormones and/or included thin skin, easy bruisability, and skin tears. Several cats had
mineralocorticoids. increased liver enzyme activities and hepatic vacuolar hepatopathy.
To aid in this discussion, information from the records of In one report, four of twelve cats developed transient diabetes mel-
56 cats diagnosed as having FCS at our hospital, including litus, and four of twelve had transient hypothyroidism (Lien etal,
some reported in the literature (Duesberg et al, 1995) were 2006). Diabetes mellitus in cats identified after initiation of gluco-
added to the information from 31 cats described in the litera- corticoid treatment may be transient. Some cats had PU/PD in one
ture (Immink et al, 1992; Daley et al, 1993; Goossens et al, study, but urine specific gravities were more than 1.035 in all cats
1995; Schwedes, 1997; Watson and Herrtage, 1998; Moore (Lien etal, 2006). Despite these observations, iatrogenic FCS usu-
etal, 2000a; Meij etal, 2001; Skelly etal, 2003; Neiger etal, ally does not cause owner-discernable concerns. Interestingly, some
2004), for a total of 87 cats with naturally occurring FCS. This features of iatrogenic cortisol excess (e.g., ear curling) in cats are
literature includes only those reports published since 1992, not commonly seen in cats with the naturally occurring condition.
to have greater confidence that valid and currently available
assays were used in the assessment of each cat and that current
Naturally Occurring Feline Hyperadrenocorticism
concepts in diagnosis and treatment were used. Before 1990,
only a few cats with this disease were mentioned in the litera- The causes of naturally occurring FCS are similar to those recog-
ture (Swift and Brown, 1976; Meijer etal, 1978; Peterson and nized in people and dogs. It has been suggested that resistance to
Steele, 1986; Zerbe etal, 1987a; Nelson etal, 1988). Further- glucocorticoid-induced side effects, likely in cats as compared with
more, in the reports that we arbitrarily chose to use, we set dogs, may help explain the relative low diagnosis rate of FCS in cats
the following selection criteria: Each cat must have had clini- as compared with dogs. In other words, if excess glucocorticoids
cal signs associated with FCS and each diagnosis must have cause few clinical signs in cats, how would the diagnosis ever be
been confirmed using an accepted screening test. Most cats had suspected in the rst place? Fewer than 100 cats have been reported
advanced imaging (computed tomography [CT] or magnetic in the veterinary literature that had been diagnosed with naturally
occurring FCS. The incidence of the FCS in cats (assessed non- TABLE 11-1 A
GE AT TIME OF FELINE
scientically) does appear similar to the incidence of the syndrome CUSHINGS SYNDROME
in human beings. However, people seem more sensitive than cats DIAGNOSIS IN 61 CATS*
(but less sensitive than dogs) to clinical side effects associated with
glucocorticoid administration. Therefore, FCS may simply be less PITUITARY DEPENDENT ADRENOCORTICAL TUMOR
common in cats as compared with dogs and people. AGE (YEARS) NUMBER OF CATS NUMBER OF CATS
The majority of cats with naturally occurring FCS (approxi-
mately 80%) have PDH. Cats with PDH have a pituitary tumor, 5 1
adenomas far more common than carcinomas, that autonomously 6 5
synthesize and secrete ACTH. The persistent excesses of ACTH, 7 2
in turn, cause excess synthesis and secretion of glucocorticoid (cor- 8 3 1
tisol) from the adrenal cortices. The excess circulating cortisol has
effects on cells within organs throughout the body, including sup- 9 4 2
pressive effects on healthy pituitary cells responsible for synthesis 10 4 1
and secretion of ACTH, luteinizing hormone (LH), follicle-stimu- 11 5 2
lating hormone (FSH), thyroid-stimulating hormone (also known
12 6 3
as thyrotropin; TSH), and growth hormone (GH). Chronic
exposure to excessive concentrations of circulating cortisol is also 13 4 2
likely to have suppressive effects on the synthesis and secretion of 14 6 2
antidiuretic hormone (ADH) from the posterior pituitary in dogs, 15 2 2
but there is little evidence of this happening in cats. Over time,
excesses in circulating ACTH cause adrenocortical hyperplasia and 16 3
somewhat symmetrical adrenal gland enlargement. 17 1
At the time of PDH diagnosis in dogs, about 50% of their Mean 11.0 11.9
pituitary tumors are microscopic in size and about 50% are large
enough to be visualized with CT or MRI scans (usually greater *46 pituitary dependent hyperadrenocorticism; 15 adrenal tumor hyperadrenocorticism.
Mean age of all 61 cats was 11.3 years
than 3 to 4 mm in greatest diameter). A similar number (approxi-
mately 50%) are grossly visible at surgery or necropsy. Approxi-
mately 20% to 30% of dogs with PDH, usually after successful Later in this chapter, syndromes in cats with adrenocortical tumors
management of the condition for a prolonged time period, develop synthesizing and secreting non-cortisol steroids will be reviewed.
pituitary tumors large enough to cause clinical signs secondary to
the compressive or invasive effects of the mass. Although many of SIGNALMENT (AGE, SEX, BREED)
these clinical scenarios have been described in cats with FCS, their
incidence is not as well established. FCS is a disease of middle-aged and older cats. As can be seen in
Approximately 20% of cats with FCS have an autonomously Table 11-1, both mean and median ages of 46 cats diagnosed as
functioning adrenocortical tumor (adrenal tumor hyperadrenocor- having PDH was 11 years (range, 5 to 17 years). The mean age of
tisolism, ATH). About 50% or more of adrenocortical tumors are 15 cats, each with a functioning adrenocortical tumor, was 11.9
adenomas and somewhat less than 50% are carcinomas. Regardless years (median 12 years), with a range of 8 to 15 years. The mean age
of their histologic classification, adrenocortical tumors that cause for all 61 cats was just over 11 years. Among these 61 cats were 31
FCS do so via the autonomous and excessive synthesis and secretion males and 29 females. All cats diagnosed as having naturally occur-
of glucocorticoids (cortisol). Chronic and persistent exposure to ring FCS at our hospital had been neutered at an early age. The most
excess cortisol, in turn, is responsible for the various problems (clin- commonly afflicted breed is the Domestic Short-Haired (DSH) cat
ical, biochemical, and so on) that are conveniently placed under the (Table 11-2)38 of 61 cats (62%), and if DSH and domestic long-
umbrella Cushings syndrome. As mentioned, cortisol affects cells haired cats are combined, the totals are 46 of 61 cats (75%). Cats
in every organ. As with PDH, the chronic and excessive amounts of representing various other breeds have been diagnosed with FCS.
circulating cortisol also cause chronic negative feedback to healthy
cells within the hypothalamus and pituitary gland. In this condi- DURATION OF CLINICAL SIGNS, CHIEF
tion, however, with both hypothalamus and pituitary suppressed, COMPLAINT, AND GENERAL HISTORY
the chronic inhibition of synthesis and secretion of ACTH causes
normal cortisol-secreting cells to atrophy within the zona fascic- Duration of Clinical Signs
ulata and zona reticularis of the adrenal cortices. Therefore, over
time, the cortex of one adrenal gland contains a functioning tumor The duration of clinical signs or the duration of specic owner
and atrophied non-tumorous cells, whereas the opposite adrenal concerns were available for 53 cats diagnosed as having FCS
cortex contains primarily atrophied cells and may appear small or (Table 11-3). The range in duration of signs was from as little as
thin on imaging studies or gross evaluation. Atrophy of the oppo- 1 month to greater than 12. Fifty-one of the 53 cats with either PDH
site (non-tumor containing) adrenal becomes clinically relevant or ATH had clinical signs for less than 1 year at the time of diagnosis.
not only on imaging studies, but when the adrenal containing the
tumor is surgically removed as a treatment for FCS. In this scenario, Owner Chief Concern/Explanation for Being Referred
the clinician must remember that the cells responsible for cortisol
synthesis and secretion in the remaining adrenal cortex will likely be The chief concern is the primary reason or reasons that an owner
unable to immediately provide adequate hormone to sustain health. seeks veterinary assistance, or in these cats, the primary reason(s)
Therefore, such individuals are treated with tapering doses of exog- for seeing a specialist. The chief concern in 32 of 58 cats with
enous glucocorticoids, allowing function to be regained over time. FCS (55%) was difcult to regulate diabetes mellitus. Most
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TABLE 11-2 B
REEDS OF CATS WITH NATURALLY OCCURRING FELINE CUSHINGS
SYNDROME (TOTAL OF 61 CATS)
Pituitary Dependent Adrenocortical Tumor

BREED NUMBER PERCENTAGE NUMBER PERCENTAGE
Domestic Short-Hair 28 65 10 66
Domestic Long-Hair 7 13 1 7
Siamese 3 4 1 7
Persian 2 4 1 7
Abyssinian 2 4
European Short-Hair 2 4
Devon Rex 1 2
Japanese Bobtail 1 7
Russian Blue 1 2 1
Maine Coon 7
Total 46 15
TABLE 11-3 D
URATION OF CLINICAL SIGNS TABLE 11-4 C
HIEF COMPLAINTS BY
PRECEDING DIAGNOSIS OF OWNERS OF CATS ULTIMATELY
FELINE CUSHINGS SYNDROME DIAGNOSED AS HAVING
IN CATS (53 CATS) CUSHINGS SYNDROME
NUMBER OF CATS WITH NUMBER OF CATS PITUITARY

PITUITARY DEPENDENT WITH ADRENOCORTI- DEPENDENT ADRENOCORTICAL
DURATION (MONTHS) DISEASE CAL TUMOR COMPLAINT (43 CATS) TUMOR (15 CATS)
1 2 Resistant diabetes mellitus (PD/ 28 4
2 6 1 PU/PP)
3 5 1 Polyuria/polydipsia (of the eight 6 2

non-diabetic)
4 3 3
Fragile (torn) skin 6 3
5 4 2
Weight loss 3 1
6 4 1
Lethargy 2 2
7 1 3
Alopecia/failure to regrow hair 2 2
8 2
Diarrhea 2
9 2 1
Weakness 1
10 3
Vomiting 1
11
Abdominal enlargement 1 1
12 4 3
Not grooming 1
> 12 2
Polyphagia 1
Total 38 15
Referral for ultrasound 1 3
Referral for Cushings syndrome 2
commonly, their diabetes mellitus was classied as difcult to reg- *Total of 58 cats; 50 of these 58 cats had diabetes mellitus, four had periodic diabetes
ulate when owners felt that their pet had persistence of polyuria mellitus, and four did not have diabetes mellitus.
despite administration of insulin (Table 11-4). Other, less frequent PD, Polydipsia; PP, polyphagia; PU, polyuria.
observations that caused owners to believe their cats diabetes mel-

litus was poorly controlled include continued weight loss, failure
to gain weight, persistent lethargy, poor grooming habits, not Owner chief concern was recorded in 58 cats. Forty-six of those
consistently utilizing the litter box, and failing to be interactive 58 FCS cats had been previously diagnosed as having diabetes melli-
with the family. Occasionally, difficult to regulate diabetic was tus, four had been documented to have episodic diabetes mellitus
designated by the referring veterinarian, rather than by the owner. prior to referral, and eight were not believed to be diabetic. Of the
Often, insulin dose and type had been altered numerous times by eight cats that did not have diabetes mellitus at the time of referral,
the primary care veterinarian in an effort to gain control of the six were believed to have PU/PD, and four of these six cats had dia-
diabetes mellitus prior to referral. betes when evaluated at our hospital. Thus, 50 of 58 FCS cats had
TABLE 11-5 O
WNER OBSERVATIONS IN CATS WITH NATURALLY OCCURRING CUSHINGS
SYNDROME (TOTAL OF 72 CATS)
Pituitary Dependent (57 Cats) Adrenocortical Tumor (15 Cats)

OBSERVATION NUMBER PERCENTAGE NUMBER PERCENTAGE
Polyuria/polydipsia 46 80 11 73
Polyphagia 39 68 8 53
Weight loss 27 47 6 40
Lethargic/sleeps more 25 44 7 47
Weakness 20 35 4 27
Alopecia/failure to regrow 18 32 12 80
hair
Stopped grooming 10 18 4 27
Coarse hair coat 9 16 2 13
Decreased appetite 4 7 2 13
Fragile (torn) skin 9 16 5 33
Weight gain/potbelly 5 9 4 27
Over grooming 2 4 1 6
Diarrhea 2 4
Periodic diabetes mellitus 4 7
Vomiting 1 2
diabetes mellitus when first seen at our hospital and four had had It has been suggested that clinical signs of FCS are not com-
episodes of diabetes. Fourteen of the 46 diabetic cats were believed monly detected by owners or veterinarians until these cats develop
to be well controlled with insulin. Among the less common primary diabetes mellitus. Results of this review are in agreement with this
owner concerns were fragile (torn) skin in nine cats (16%), lethargy concept for most afflicted cats. However, a few cats with FCS did
in four, weight loss in four, and alopecia or failure to regrow hair not have diabetes mellitus and a few had signs that preceded devel-
that had been previously shaved in four. Four cats were suspected as opment of diabetes mellitus. Thus, a suspicion of FCS may result
having FCS and were specifically referred for abdominal ultrasonog- from a history and physical examination in non-diabetic cats if
raphy. Two cats were referred for evaluation of Cushings. thin skin, skin fragility, potbelly appearance, muscle atrophy,
weakness (especially in the rear legs), or various hair coat disorders
are noted. Any combination of these issues might lead to the sus-
Owner Observations
picion of FCS in non-diabetic cats.
Owner observations, other than their chief concern, were available
from 72 cats diagnosed as having FCS (57 cats with PDH; 15 cats PHYSICAL EXAMINATION ABNORMALITIES
with ATH; Table 11-5). The most common owner observation was
PU/PD in 57 cats (79%), polyphagia in 47 (65%), weight loss or The physical examination abnormalities from 72 cats with natu-
failure to gain weight in 33 (46%), and lethargy or reports of sleeps rally occurring FCS are listed in Table 11-6. Many of the previously
more in 32 cats (44%). Weakness, usually worse in the rear legs, described owner concerns were obvious to the veterinarian perform-
was noted in 24 (33%) cats, 15 of whom had a plantigrade stance. ing the physical examination. The most common abnormalities
Concerns about skin problems were noted in a majority of observed included abdominal enlargement in 46 cats (66%; Fig.
the 62 cats; including the extremely worrisome fragile or torn 11-1), muscle atrophy (44 cats; 61%), thin skin (43 cats; 60%), and
skin noted in 14 cats (20%). Additionally, failure to grow hair an unkempt hair coat (35 cats; 49%). Less common abnormalities
after it had been shaved (usually for venipuncture or abdomi- included hair loss, rear leg plantigrade stance, hepatomegaly, skin
nal ultrasonography examination) was noted in 30 cats (42%), tears, bruising, and seborrhea. Two cats were noted to have abdomi-
having stopped grooming was a concern in 14 cats (20%), nal masses, which were confirmed to be adrenal gland tumors
and 11 owners thought their cat had abnormally coarse hair. (Immink etal, 1992). The nding of a palpable adrenal tumor is
Multiple skin problems were noted in some cats, whereas others considered quite unusual.
had none. The owners of 21 cats with PDH (from the total of
57, or 37%) and the owners of three cats with ATH (from the EXPLANATIONS FOR HISTORY AND PHYSICAL
total of 15, or 20%) did not mention any problem relative to EXAMINATION ABNORMALITIES
the skin or hair coat. In general, owners of either PDH or ATH
cats had similar observations, underscoring the nal common Polyuria and Polydipsia
denominator of chronic exposure to excess circulating cortisol.
One exception was that 32% of PDH-cat owners noted alopecia PU/PD are usually suspected after learning an owners concerns of
or failure to regrow hair, whereas 80% of ATH cat owners men- their pets inappropriate urination and finding a urine specific
tioned this concern. gravity less than 1.020. These signs are, perhaps, the most common
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TABLE 11-6 P
HYSICAL EXAMINATION ABNORMALITIES IN 72 CATS WITH NATURALLY OCCURRING CUSHINGS
SYNDROME

OBSERVATION NUMBER PERCENTAGE NUMBER PERCENTAGE
Abdominal enlargement 35 61 11 73
(potbelly)
Muscle atrophy 35 61 9 60
Thin skin 32 56 11 73
Unkempt hair coat 30 53 5 33
Hair loss 16 28 5 33
Hepatomegaly 11 19 3 20
Skin tears 11 19 2 13
Plantigrade stance 11 19 4 27
Bruising 7 12 3 20
Seborrhea 3 5 5 33
Palpable adrenal mass 2 13
in turn, is secondary to their excess circulating cortisol concentra-

tions. It is extremely unusual for such a dog to have concurrent
chronic kidney disease (CKD). Cats with FCS, on the other hand,
appear to develop PU/PD secondary to diabetes mellitus, CKD, or
both. PU/PD occurs uncommonly in non-diabetic people or cats
with naturally occurring or iatrogenic hyperadrenocorticism.
Polyuria, polydipsia, polyphagia, and weight loss are the classic
signs of diabetes mellitus. For cats with FCS that also have dia-
betes mellitus (usually secondary to chronic excesses in systemic
cortisol concentrations causing insulin resistance), the explanation
for their PU/PD is the osmotic diuresis associated with glucosuria,
especially if the diabetes is not well controlled. A small number of
non-diabetic cats with FCS have been described with PU/PD, and
most of them have had episodes of diabetes mellitus, CKD, or
A
hyperthyroidism, which are all conditions associated with PU/PD.
Although a huge majority of dogs with hyperadrenocorticism have
low-to-low-normal blood urea nitrogen (BUN) and serum cre-
atinine concentrations and randomly collected urine with specific
gravities less than 1.020, only five urine samples from 52 cats with
FCS (Table 11-7; 38 with PDH and 14 with ATH) had a specic
gravity less than 1.020 (9%) and none was less than 1.008. Each of
those ve cats had an increase in their serum urea nitrogen, creati-
nine, or both (one was also hyperthyroid). Thus the observation of
PU/PD in cats diagnosed as having FCS is noted almost exclusively
in cats with glycosuria, CKD, or some additional cause of PU/PD
(e.g., hyperthyroidism). Some non-diabetic FCS cats appear to
have episodic insulin resistance with episodes of glycosuria and
secondary PU/PD. This hyperglycemia and glycosuria may not be
demonstrable at the time that in-hospital testing is carried out.
B
FIGURE 11-1 A, 12-year-old male cat with feline Cushings syndrome (FCS). Note Polyphagia
the unkempt appearance of the hair coat. B, Note the pot-bellied appearance and
the thin skin. (The hair on the abdomen had been shaved for ultrasound evaluation.) Polyphagia is common in non-diabetic dogs with hyperadrenocor-
ticism. This side effect is not a well-understood. Polyphagia is less
common in cats with FCS, unless they are diabetic.
observations among owners of dogs with hyperadrenocorticism, yet
only about 5% of those dogs have diabetes mellitus and glucosuria.
Weight Loss
This is a much lower percentage of diabetics than is seen in cats with
FCS. It is thought that a majority of hypercortisolemic dogs have A relative or absolute deciency of insulin, definitive of diabetes
PU/PD due to central or nephrogenic diabetes insipidus which, mellitus, causes an inability to utilize glucose and a physiologic
TABLE 11-7 U
RINALYSIS RESULTS FROM the clinical consequence of this increased amount of abdominal con-
52 CATS WITH NATURALLY tent pressing down upon weakened abdominal musculature (see Fig.
OCCURING CUSHINGS 11-1) and is a classic observation in people, dogs, and cats afflicted
SYNDROME with hyperadrenocorticism. This type of abdominal distention is the
potbelly appearance that is classic of Cushings syndrome. Excess
Pituitary Dependent Adrenocortical Tumor systemic glucocorticoids are associated with a relative decrease in the
(38 Cats) (14 Cats) ability to heal due to blood vessel friability and a decrease in brous
response to injury. Further, loss of subcutaneous fat (mobilized to
URINALYSIS NUMBER OF CATS NUMBER OF CATS the abdomen), blood vessels that are more supercial after losing
Specific Gravity their fat insulation, and decreases in normal healing properties
< 1.020 3 2 increase the predisposition to bruising. In cats with FCS, bruising
1.020 to 1.040 29 6 after venipuncture or clipping of hair can be dramatic.
> 1.040 6 6
Protein
Curled Ear Tips
Negative 19 6 As a component of the catabolic state associated with chronic glu-
cocorticoid excesses, decreased strength of ligaments, tendons, and
Trace 11 3
cartilaginous structures in general can be expected. Initial reports
> Trace 8 5 on iatrogenic FCS in cats included observations of ear tip curling.
Bacterial Culture However, this clinical sign has either not been mentioned or not
Negative 36 12
observed in our experience nor in the cats comprising our review.
Positive 2 2
Dermatologic Abnormalities
Ketones
Negative 38 14 Bilaterally symmetrical nonpruritic alopecia is common in hyper-
cortisolemic dogs but not in cats. The alopecia that most FCS cat
Positive 0 0 owners observe is due to a failure to regrow hair that has been
clipped or hair that is lost as a result of normal or excessive groom-
ing (Fig. 11-2). It is difcult to know whether excessive groom-
condition analogous to starvation. The physiologic response to ing truly exists. Are these cats grooming normally but causing hair
starvation is hepatic synthesis of glucose and other sources of loss, thereby also causing owner concern or are they grooming
energy utilizing products derived from the breakdown of muscle more than usual? In addition to hair loss, thin skin (Fig. 11-3),
and fat. This catabolism of muscle and fat is the explanation for poor wound healing, skin fragility, and increased susceptibility
weight loss. Since a majority of cats with FCS have diabetes mel- to skin infections are typical sequelae to chronic excesses in cir-
litus, it is difcult for them to gain weight. This is certainly true of culating concentrations of cortisol. Chronic cortisol excess can
those cats whose diabetes is untreated. It is also true of those cats result in atrophy of the epidermis, dermis, and hair follicles. This
being treated with exogenous insulin but have resistance. Some atrophy can be traced to glucocorticoid-induced suppression of
cats are described as remaining thin (usually with a potbelly) and dermal fibroblast and keratinocyte proliferation, as well as down-
others have progressive weight loss despite insulin therapy. Nearly regulation of collagen, hyaluronic acid, sulfated glycosaminogly-
every cat with FCS that has an owner concern of weight loss (or cans, elastin, and tenascin-C expression (Schacke et al, 2002).
failing to gain weight) has concurrent diabetes mellitus. Non-dia- Chronic skin infections are likely related to a combination of easily
betic cats with FCS with CKD are also likely to lose weight. The traumatized skin in individuals that lack the ability to heal normally
third most common cause of weight loss among cats with FCS and have glucocorticoid-induced suppression of their immune
is concurrent hyperthyroidism. Weight loss or remaining thin systems. Glucocorticoids have many immunosuppressive effects,
is an important feature of FCS because acromegaly, a differential including decreased macrophage expression of inflammatory cyto-
diagnosis for insulin resistance in cats, is a condition often associ- kines, increased expression of some antiinflammatory cytokines,
ated with weight gain. decreased function and maturation of dendritic cells, decreased
T cell activation and proliferation in response to mitogens,
decreased cell-mediated lysis of target cells, decreased mitogen-
Weakness, Lethargy, Potbelly, and Bruising
induced B cell proliferation, and decreased antibody production
Explanation for these clinical signs can be directly related to the (Tuckermann etal, 2005; Lowe etal, 2008).
physiologic effects of glucocorticoids. Cortisol causes protein Skin fragility, not typical of dogs with NOH, and thin skin are
catabolism and, thus, breakdown of muscle. Muscle breakdown well recognized concerns in cats with FCS (Fig. 11-4; see Tables
leads to wasting and weakness, which is often obvious to o wners 11-5 and 11-6). Some cats have wrinkling and folding of their
(Robinson and Clamann, 1988). Alternatively, weakness may skin due to the previously described dermal atrophy and decreased
be interpreted by an owner to be lethargy or as an increased collagen expression. In some cats, their skin is so fragile as to be
amount of time spent sleeping. Furthermore, some cats with easily torn. These cats can create full-thickness, self-induced,
FCS have a plantigrade posture, which is most often related to dermal abrasions from simple grooming. It seems that the most
the diabetic neuropathy seen in cats with diabetes mellitus and, common causes of skin tears are self-induced, associated with rou-
in FCS, probably enhanced by steroid-induced muscle wasting. tine restraint, or they may be caused by owners pinching the skin
Chronic cortisol excess is recognized to cause a redistribution of to administer insulin. The combination of poor wound healing
fat from areas throughout the body to the abdominal mesentery, and increased susceptibility to infection can be serious and result
increasing the weight of abdominal content. Abdominal distention is in life-threatening sepsis.
|
B
FIGURE 11-3 A, 11-year-old male cat with feline Cushings syndrome (FCS). This
cat had a progesterone-secreting tumor (see Excessive Sex-Hormone Secreting
B Adrenal Tumors in Cats). B, Note the thin skin sometimes associated with chronic
FIGURE 11-2 A, 10-year-old female cat with feline Cushings syndrome (FCS). exposure to excess cortisol.
B, Note the hair loss sometimes associated with chronic exposure to excess cortisol.
(Gunn-Moore, 2005; Graves, 2010; Peterson, 2012). About half
ROUTINE CLINICAL PATHOLOGY (COMPLETE of 53 cats had a stress leukogram (neutrophilia and a relative
BLOOD COUNT, BIOCHEMISTRY, URINALYSIS) reduction in both lymphocytes and eosinophils). Of their total
white blood cell counts, 26 cats (49%) had a neutrophil percent-
Veterinarians working with dogs are familiar with the side effects age of more than 86%, 28 (53%) had a lymphocyte percentage
associated with chronic excesses in circulating cortisone concentra- of less than 5%, and 29 (55%) had an eosinophil percentage of
tion (hyperadrenocorticism; Cushings syndrome) because glu- less than 2%. Of the 53 cats, one was thrombocytopenic, one was
cocorticoids (cortisols) are utilized in the management of many leukopenic, and six were anemic. Of the anemic cats, only one had
canine conditions, side effects are both common and obvious, and the a hematocrit below 24% (that result was 16%), and five of the six
naturally occurring condition is also frequently encountered. Veteri- had evidence of CKD, likely a contributing issue to their anemia.
narians, hearing about side effects from almost every steroid-treated
dog owner, are repeatedly reminded of expected steroid-induced
Blood Glucose Concentrations and Diabetes Mellitus
clinical observations. Laboratory abnormalities are indistinguishable
in both iatrogenic and naturally occurring conditions. Veterinary cli- Overview
nicians expect dogs with iatrogenic or naturally occurring Cushings Hyperglycemia represents the most common biochemistry abnor-
syndrome to have PU/PD, isosthenuria/hyposthenuria, low-normal mality in cats with FCS (Gunn-Moore, 2005; Lowe et al, 2007;
or low BUN concentrations, increases in serum cholesterol concen- Graves, 2010; Peterson, 2012). Fifty of 58 cats with FCS had dia-
tration, and increases in alkaline phosphatase and alanine amino- betes mellitus when first seen at our hospital (four were diagnosed
transferase (ALT) activities. Keeping these alterations in mind, we as diabetic at our hospital) and four had had episodes of diabetes.
can state once again with condence, that cats are not small dogs. Fourteen of the 46 previously diagnosed diabetic cats were believed
to be well controlled with insulin. Because a majority of cats with
Complete Blood Count FCS were already being treated with insulin, it is not surprising that
hypoglycemia would be identified on a few random blood glucose
Complete blood count (CBC) results from 53 cats with FCS tests. On random blood glucose measurements in 52 FCS cats, 44
can be reviewed in Table 11-8. The most important feature is were hyperglycemic, six were hypoglycemic, and two were euglyce-
the lack of consistency, in agreement with other investigators mic. Both euglycemic and all six hypoglycemic cats were diabetic and
dose given when a cat appears resistant may be an overdose in the

same cat at another time. Because some cats with FCS have had
severe life-threatening hypoglycemic reactions to insulin, especially
when insulin doses are in excess of 2.2 U/kg, it is recommended to
maintain insulin doses below this admittedly arbitrary level.
Diabetes Mellitus and the Diagnosis of Feline Hyperadrenocorticism
Diabetes mellitus is among the more common conditions diagnosed
in small animal practice and, along with hyperthyroidism, one of the
two most frequently diagnosed endocrine disorders in cats. In con-
trast, FCS is considered uncommon-to-rare (Graves, 2010)having
been diagnosed in a few non-diabetic cats, a few cats with easily con-
trolled diabetes mellitus, and many cats with apparent insulin resis-
tance (Gunn-Moore, 2005). A large majority of cats with FCS are
afflicted with concurrent diabetes mellitus (approximately 92% in
A our review) because it may be easier to suspect FCS in an insulin-
resistant diabetic than in an older lethargic cat with a large abdo-
men. Thin skin, skin fragility, alopecia, failure to regrow hair after it
has been clipped, muscle weakness, and PU/PD are potential owner
concerns that may trigger testing and, ultimately, a diagnosis of FCS.
The Differential Diagnosis for Difficult-to-Control or Insulin-

Resistant Diabetics
Progression of feline diabetes mellitus is notoriously difficult to pre-
dict, and the condition can be difficult to manage. Among the con-
cerns to be addressed by the veterinary practitioner: Which poorly
controlled diabetic cat is truly insulin-resistant, and which of
those truly insulin-resistant cats are candidates for FCS? We encour-
age veterinarians having difculty controlling any diabetic cat to
prioritize the potential explanations for difcult control with the
B least expensive and most likely explanations considered first. Top-
ping this priority list should be the concept that in-hospital testing
FIGURE 11-4 A, Skin tear in a 15-year-old male cat with feline Cushings syn-
may not reflect what is happening in the home environment.
drome (FCS). B, Skin tear in a 10-year-old cat typical of the skin fragility some-
Owner opinion is the single most important monitoring tool
times associated with chronic exposure to excess cortisol.
in the long-term management of diabetes. If an owner is satised
with their cats response to therapy, decisions based on in-hospital
had received insulin on the day of testing. The implication from these test results should not supersede their opinion unless hypoglyce-
data is that virtually all the cats included in this review were hyper- mia is documented. In-hospital stress-induced hyperglycemia is
glycemic or had insulin-induced reduction in blood glucose. One fair common, and home glucose monitoring minimizes this concern.
question difficult to answer is: Was stress-induced hyperglycemia a Veterinarians should also consider the possibility of an error
factor in these results? in management when a diabetic cat fails to respond to insulin
therapy as expected. Errors include, but are not restricted to,
Hypoglycemia Versus Insulin Dose using the incorrect insulin, mixing the insulin improperly, draw-
Six of 52 cats with FCS evaluated with a randomly obtained bio- ing insulin into the syringe incorrectly, using incorrect syringes,
chemical prole in this review were found to be hypoglycemic, using outdated insulin, and improper administration technique.
despite expected cortisol-induced insulin resistance. This incidence Every time a diabetic cat is evaluated, owners should be assessed
of hypoglycemia likely underestimates its frequency. Each was dia- as they handle and administer insulin. Once these potential con-
betic and each had received insulin the day of testing. Four of those cerns have been dismissed, the veterinarian should consider the
six cats were described by their owners and referring veterinarians as possibility that the insulin being used is being given at too low a
insulin-resistant. Insulin dose (per cat or per kg) among cats with dose, too high a dose, the insulin could be too weak, too potent,
FCS being treated for diabetes varies tremendously, but was often too short acting, or too long acting. Additionally, one should con-
excessive (> 2.2 U/kg). Veterinarians are reminded that insulin can sider the possibility that a concurrent disorder exists that interferes
and frequently does induce hypoglycemia. It is also understood that with insulin sensitivity. This could include any infection (dental,
veterinary clinicians occasionally need to manage cats with diabetes urinary tract or skin, among others) or any source of non-septic
mellitus that appear to be insulin resistant. One obvious response inflammation (pancreatitis, among others). Additional conditions
is to repeatedly increase insulin dose as needed. However, increas- that could cause insulin resistance include CKD, neoplasia, heart
ing insulin dosage in an attempt to control resistant hypergly- disease, and trauma. Among the various endocrine causes for insu-
cemia in diabetic cats can become dangerous. An insulin dose in lin resistance are acromegaly, sex hormone excess, and FCS.
excess of 2.2 U/kg of body weight should be considered unsafe.
Although we do not doubt that some cats appear responsive only to Liver Enzyme Activities
extremely high insulin doses after appearing resistant to lower doses,
resistance is not a continuum. In other words, insulin resistance A dramatic increase in serum alkaline phosphatase (SAP) activity
in cats with FCS seems to fluctuate or wax and wane. If true, the (average > 1,000 IU/L) due to glucocorticoid-induction of an
|
TABLE 11-8 C
OMPLETE BLOOD COUNT RESULTS FROM 53 CATS WITH NATURALLY
OCCURRING CUSHINGS SYNDROME

NUMBER PERCENTAGE NUMBER PERCENTAGE
White Blood Cell Count
< 6000 1 2
6000 to 17,000 26 60 6 60
17,000 to 25,000 10 23 3 30
> 25,000 6 14 1 10
% Neutrophils
75 6 14 1 10
76 to 85 15 35 5 50
86 22 51 4 40
% Lymphocytes
5 22 51 6 60
6 to 15 19 44 4 40
15 2 5
% Eosinophils
2 24 56 5 50
3 to 6 13 30 4 40
7 6 14 1 10
Platelet Counts
< 180,000 1 10
180,000 to 400,000 33 77 6 60
> 400,000 10 23 3 30
Hematocrit
27 4 9 2 20
28 to 35 24 56 3 30
36 to 46 15 35 5 50
47
SAP isoenzyme is the most common serum biochemical abnor- hyperthyroidism. However, of the 52 cats with FCS that had
mality (> 85%) recognized in dogs with NOH. By contrast, thyroid testing, hyperthyroidism was only diagnosed in two.
only five of 52 cats with FCS (9%) had an increased SAP. An
important differential diagnosis for the increase in SAP in cats Serum Cholesterol and Thyroxine
with diabetes mellitus is pancreatitis causing cholestasis. Further,
the short half-life of SAP in cats as compared with dogs should Increase in serum cholesterol concentration is identied in
increase concern regarding an increase. Although steroid hepa- more than 90% of dogs with diabetes mellitus and in more
topathy has been observed in a few cats with iatrogenic hyper- than 60% of dogs with NOH (less than 5% of dogs with hyper-
adrenocorticism, the changes are usually mild (Lowe etal, 2008; adrenocorticism have concurrent diabetes mellitus). Glucocor-
Graves, 2010). The cat has no corollary to the classic steroid- ticoids inhibit lipoprotein lipase activity and increase activity
induced-isoenzyme-of-SAP known in dogs. In cats with FCS of hormone-sensitive lipase, increasing both serum cholesterol
and diabetes mellitus, SAP activity may decrease into reference and triglyceride concentrations. Increases in serum cholesterol
limits with insulin therapy alone, despite progression of the concentration, however, are not common in cats with FCS,
Cushings (Peterson, 2012). despite a majority having diabetes mellitus and, therefore,
Another common biochemical abnormality in dogs with two physiologic stimuli for hypercholesterolemia. Serum cho-
NOH (> 50%) is a mild to moderate increase in serum ALT lesterol concentrations were increased in 13 of 52 (25%) cats
activity. Increases in ALT were identified in 14 of 52 cats with with FCS in our review, each of whom had concurrent diabetes
FCS (27%). It is probable that increases in either or both liver mellitus.
enzyme activities in cats with FCS are secondary to hepatic Chronic excesses in serum cortisol concentration feedback on
changes associated with diabetes mellitus. Another cause the pituitary, decreasing TSH secretion and causing secondary
for elderly cats to have increases in liver enzyme activities is hypothyroidism. Hypothyroidism, primary or secondary, is a
TABLE 11-9 S
ERUM BIOCHEMICAL RESULTS FROM 52 CATS WITH NATURALLY OCCURRING CUSHINGS
SYNDROME
Test and Reference Range Pituitary Dependent (38 Cats) Adrenocortical Tumor (14 Cats)
NUMBER WITHIN NUMBER NUMBER NUMBER WITHIN NUMBER NUMBER
SERUM REFERENCE RANGE BELOW ABOVE REFERENCE RANGE BELOW ABOVE
Alkaline (14 to 71 IU/L) 35 3 12 2
phosphatase
ALT (28 to 106 IU/L) 24 14 12 2
Albumin (2.7 to 3.9 g/dL) 33 5 9 3 2
Globulin (2.9 to 4.3 g/dL) 17 21 9 5
Total protein (5.6 to 8.4 g/dL) 31 7 12 2
BUN (18 to 33 mg/dL) 17 21 8 6
Creatinine (0.9 to 1.8 mg/dL) 26 1 11 10 4
Cholesterol (89 to 258 mg/dL) 24 2 12 13 1
Glucose (73 to 134 mg/dL) 0 4 34 2 2 10
Calcium (9.4 to 11.4 mg/dL) 34 4 11 3
PO4 (3.2 to 6.3 mg/dL) 34 2 2 11 3
TCO2 (15 to 25 mm/L) 31 4 3 14
K (3.6 to 5.3 mm/L) 37 1 12 2
Na (145 to 156 mm/L) 36 2 12 2
T4 (1.0 to 2.5 g/dL) 33 5 12 2
Magnesium 3 0 3 2 0 1
ALT, Alanine aminotransferase; BUN, blood urea nitrogen; PO4, phosphorus; TCO2, total carbon dioxide; K, potassium; Na, sodium; T4, thyroxine.
classic cause of hypercholesterolemia. Secondary hypothyroidism, A review of the serum biochemical and urinalysis data presented
together with the direct lipolytic actions of glucocorticoids are in Tables 11-7 and 11-9 from cats with naturally occurring FCS
explanations for the increases in serum cholesterol concentration demonstrates several differences in results as compared with those
typically identied in non-diabetic dogs with hyperadrenocorti- from hypercortisolemic dogs. Not one of 52 cats with FCS had a
cism. Of the 52 cats with FCS in our review, serum thyroxine BUN concentration below the reference range. Only five of 52 cats
(T4) concentrations were lower than the reference range in five had a randomly obtained urine specic gravity less than 1.020.
(9%), three of which had serum cholesterol concentrations within Each of those cats had isosthenuria secondary to CKD. Further-
reference limits. Most cats with FCS are euthyroid. Histologically more, 27 of 52 cats (52%) had an increased BUN concentration at
confirmed thyroid disease was only identied in the two cats with the time of diagnosis. Fifteen of those 27 cats (29% of all 52) also
hyperthyroidism. had an increased serum creatinine concentration. It seems likely
that the PU/PD recognized in some cats with FCS is secondary
Blood (Serum) Urea Nitrogen, Serum Creatinine, Urinalysis to CKD. Other polyuric conditions (e.g., hyperthyroidism) may
need to be considered. There is little evidence to suggest that cats
A consistent group of abnormalities seen in dogs that have hyper- with FCS have a physiologic syndrome similar to the diabetes
adrenocorticism are those related to PU/PD. A majority (> 90%) insipiduslike condition with dilute urine that occurs in hypercor-
of hypercortisolemic dogs have urine specic gravities less than tisolemic dogs.
1.020 (especially on samples obtained by owners from dogs in
their home environment) and about 30% are less than 1.008.
Serum Sodium, Serum Magnesium, Serum Potassium,
Polyuria in dogs represents one of the most frequent explana-
and Muscle Weakness
tions for owners to seek veterinary care. In addition to PU/PD
and isosthenuria/hyposthenuria in dogs with hyperadrenocor- Cats with FCS are often described by their owners as being weak, a
ticism are their low-normal-to-low BUN and normal serum condition most commonly related to feline diabetic neuropathy
creatinine concentrations. These are classic features of canine causing posterior paresis. Other possible contributors to weakness
hyperadrenocorticism. Increases in BUN are extremely uncom- are the glucocorticoid-induced catabolic effects on muscle and
mon in dogs with hypercortisolemia and represent a serious con- hypokalemia, documented in three of the 52 cats with FCS (6%;
traindication to treatment, because poor appetite and severity of see Primary Hyperaldosteronism in Cats). We recommend that
CKD may be masked by hyperadrenocorticism. If the hyperadre- serum electrolyte concentrations be evaluated in any weak patient.
nocorticism were to be treated, there is risk of unmasking and Assuming that these hypokalemic cats did not specifically have
worsening CKD and its clinical signs. hyperaldosteronism, one may still hypothesize that circulating
|
cortisol excess could act as weak mineralocorticoids and predis- renal glucosuria is uncommon. Although not perfect, glucosuria is
pose cats to hypokalemia and muscle weakness. Serum sodium a test that is strong in both sensitivity and specificity.
concentrations are usually within reference limits. Four of nine
cats with FCS cats were hypermagnesemic, the significance of
Urine Cortisol-to-Creatine Ratio (UC:CR)
which is not yet fully appreciated.
Background in People and Dogs
One of the most sensitive and specific screening tests for a person
Serum Calcium, Albumin, Globulins, and Total Protein
suspected as having NOH is to measure the total amount of cor-
Perhaps related to the incidence of CKD in cats with FCS, seven tisol excreted in their urine over a 24-hour period as compared
of the 52 cats (13%) were mildly hypocalcemic (based on total with healthy controls (repeating the test enhances result validity).
serum calcium concentrations). However, each hypocalcemic Despite advances that have taken place since this 24-hour urine
cat also had a decreased serum albumin concentration. Eight collection was introduced as a screening test for humans suspected
of 52 cats had mild hypoalbuminemia. Hyperglobulinemia was as having hyperadrenocorticism more than 60 years ago, the test
observed on 26 of the 52 chemistry profiles (50%); this was remains a cornerstone assessment (Molitch, 2012; Nieman,
perhaps simply a normal response to chronic antigen exposure, 2012). The amount of cortisol excreted in urine over a 24-hour
which occurs in any older individual. However, the degree of period reliably reflects the total amount of cortisol synthesized and
hyperglobulinemia was such that 11 of the 52 cats (21%) had secreted over time. Assessing the 24-hour urine excretion of cor-
hyperproteinemia. tisol negates any concern of minute-to-minute pulsatile fluctua-
tions in adrenocortical secretory patterns or any concern regarding
diurnal patterns that could affect serum cortisol concentrations at
Urinary Tract Infection
any moment. The use of a randomly collected single urine sample,
Urinary tract infection was confirmed in four of the 52 cats with assessed for cortisol concentration and then compared via ratio
FCS tested (8%; Table 11-9). Because many had been referred with the urine creatinine (UC:CR) is a short-cut to the more
after being given antibiotics, perhaps this explains our failure cumbersome 24-hour collection of urine. See Chapter 10 for a
to identify infection in more cats. In contrast, dogs with NOH thorough explanation.
have a high incidence of urinary tract infection and most are also
referred after being treated with antibiotics. Background in Cats
The UC:CR is readily available to veterinary clinicians. Its ref-
erence range is higher in cats than dogs, despite their relatively
Blood Pressure
low urinary cortisol excretion rate. The higher UC:CR reference
Blood pressure assessments have not been commonly reported range in cats may be due to their higher glomerular ltration rates
from cats with FCS, and there is little data regarding the incidence and/or lower renal free cortisol reabsorption rates (Goossens etal,
of hypertension among cats with iatrogenic or NOH. However, 1995). As in dogs, UC:CR in cats is not affected by age, gender,
hypertension is quite common among human beings and dogs or neuter status. Attributes of the UC:CR include its sensitivity,
with NOH, presumably due to the weak but significant miner- low expense, east of implementation, and straight-forward inter-
alocorticoid actions of glucocorticoids. Further, hypertension is pretation. About 70% to 90% of cats with FCS have an abnor-
often a component of CKD (common in cats with FCS) or of mal UC:CR. UC:CR reliability is enhanced if owners bring urine
aldosteronism (unknown incidence). samples from home, usually using small quantities of litter or non-
absorbable litter to make urine easier to collect. Owners should be
informed that at least two samples from separate days should be
SCREENING TESTS TO AID IN DIAGNOSING
assessed and that a third sample may be necessary if the first results
FELINE CUSHINGS SYNDROME
are contradictory. Home-collected urine negates concern of spuri-
FCS is an uncommon condition, can be difficult to diagnose, and ous results due to the stress associated with travel and in-hospital
carries a guarded prognosis. Results from one of several endocrine collection.
tests may aid in discriminating cats that have naturally occurring Those who do not recommend the UC:CR mention its lack of
FCS from cats that do not. The tests most commonly employed specificity. In evaluating the UC:CR from 16 ill cats in one study,
are the ACTH stimulation test, the low-dose dexamethasone sup- three had test results consistent with FCS ( 36 106) and seven
pression test (LDDST), and the urine cortisol-to-creatinine ratio had results considered borderline (i.e., 10 36 106). Thus
(UC:CR); protocols for which can be seen in Table 11-10. Each of 10 of 16 ill cats that did not have FCS had UC:CR results that
these tests has advantages, each has disadvantages, and no test is per- could be considered consistent with that diagnosis (Henry etal,
fect. The diagnosis of FCS should be reserved for cats with clinical 1996). In a subsequent study, hyperthyroid cats were found to
signs as well as endocrine test results consistent with the diagnosis. have increased UC:CR results (de Lange etal, 2004).
Test Interpretation
Sensitivity and Specificity (A Simple Review)
Two independent studies suggested similar reference ranges for
Discussion on testing invariably includes the concepts of test sensitiv- feline UC:CR (< 28 106 and < 36 106) (Henry etal, 1996;
ity and specificity. Sensitivity, in simple terms, refers to the number Goossens et al, 1995, respectively). Both are higher than that
of patients with a condition who test positive for that condition. An for dogs ( 16 106). A UC:CR more than 36 106 is con-
extremely sensitive test, for example, is glucosuria in dogs with diabe- sistent with FCS in a cat with appropriate clinical signs and in-
tes mellitus. The test is 100% sensitive because diagnosis is restricted hospital test results. UC:CR values between 10 and 36 106 in
to dogs with glucosuria. Specificity refers to the number of patients cats with appropriate clinical signs should be considered bor-
who do not have a disease and do not test positive for that disease. derline, inconclusive, and worth repeating. It is possible for a
Using glucosuria again, it is quite specific for diabetes mellitus because cat with test results in this range to have FCS, as was true for
TABLE 11-10 A
SUMMARY OF DIAGNOSTIC TEST PROTOCOLS USED IN CATS SUSPECTED
OF HAVING CUSHINGS SYNDROME
SCREENING TESTS TEST PROTOCOL

Urine cortisol-to-creatinine ratio (UC:CR) 1 . Owner collects urine from the cat; urine is then taken to veterinary clinic.
2. Sensitivity and specificity improve if repeated on separate mornings.
Low-dose dexamethasone suppression test (LDDST) 1 . Obtain blood for baseline control.
2. Administer 0.1 mg/kg dexamethasone, IV.
3. Obtain blood for cortisol 4 and 8 hours after dexamethasone.
Hair cortisol Obtain appropriate samples for submission.
ACTH stimulation (ACTHST) Not recommended.
Combination LDDST and ACTHST Not recommended.
DISCRIMINATION TESTS TEST PROTOCOL
High-dose dexamethasone suppression test (HDDST) 1 . Owner collects two urine samples from the cat (on different days).
2. After second collection, give three doses of dexamethasone orally (0.1 mg/kg
every 8 hours: 8 am, 4 pm, and midnight).
3. Next morning, collect urine for HDDST portion of test.
Abdominal ultrasonography Excellent ultrasonographer and equipment are quite important.
Plasma endogenous [ACTH] (ACTH precursors, as well) 1 . Collect blood in chilled tube containing protease inhibitor.
2. Immediately separate plasma, freeze until assayed.
Low-dose dexamethasone suppression test (LDDST) 1 . Protocol as described earlier and used as screening test.
2. Criteria as discrimination test are distinct (> 50% decrease from
basal level); see text.
HDDST (in-hospital protocol) 1 . Obtain blood for baseline cortisol.
2. Administer 1.0 mg/kg dexamethasone, IV.
3. Obtain blood for cortisol 4 and 8 hours after dexamethasone.
Abdominal radiographs These are of limited value.
ACTH, Adrenocorticotropic hormone; [ACTH], ACTH concentration; IV, intravenous.
12 of the 48 cats in our review (Tables 11-11 and 11-12). The results when deciding whether to perform the UC:CR. Veteri-
UC:CR has high negative predictive value, meaning that a refer- narians are encouraged to consider having owners collect urine
ence range result makes the diagnosis of FCS much less likely samples on two separate mornings from their cat as an excel-
(Graves, 2010). lent means of screening for FCS (please see the section, Urine
Cortisol-to-Creatinine Ratio and High-Dose Dexamethasone
Results Suppression Test).
As can be seen from the data presented in Tables 11-11 and 11-12,
UC:CR data was collated from a total of 48 cats with FCS (34 ACTH Stimulation Test
with PDH and 14 with ATH), including cats from the literature
(Goossens etal, 1995 [six cats]; Schwedes, 1997 [one cat]; Skelly Background
et al, 2003 [one cat]; Meij et al, 2001 [seven cats]; and Neiger The adrenocorticotropic hormone stimulation test (ACTHST)
etal, 2004 [five cats]). Thirty-five of the 48 cats (71%; 27 from has been recommended as an aid for confirming a diagnosis of
the PDH group and 8 from the ATH group) had UC:CR results NOH in dogs for about 50 years. More recently, the ACTHST
above the reference range, 12 cats (25%) had borderline (13 36 has been recommended as an aid to confirm or refute the diagnosis
106) results (six from each group). One cat had a UC:CR result of FCS, presumably as an extension of its use in dogs. A complete
that was considered normal (that cat had PDH). Thus the UC:CR discussion on the physiologic basis for this test and its usefulness
appears to be a sensitive test for conrming the diagnosis of FCS in is provided in Chapter 10. In general, humans suspected of hav-
cats; in that only 1/48 cats had a result within the reference range. ing hormone deciency syndromes (e.g., hypoadrenocorticism
[Addisons disease]), are typically evaluated with provocative or
Conclusions stimulation tests to aid in diagnosis, and those suspected of hav-
The UC:CR is a sensitive diagnostic aid for distinguishing ing hormone excess syndromes (e.g., NOH), are typically evalu-
cats that have FCS from cats that do not. Sensitivity of this ated with suppression tests.
test appears to be similar to that for dogs with NOH. Because Background in Cats. Those who recommend using the
specicity remains a concern, the negative predictive value of the ACTHST point out several attributes: the test requires little time
UC:CR is emphasized (i.e., cats with a negative UC:CR are less (1 or 2 hours depending on the ACTH used), only two or three
likely to have FCS, especially if that result is repeatable). Veteri- venipunctures are needed, results are easy to interpret, it is the only
narians are encouraged to place a great deal of importance on test useful for distinguishing iatrogenic from naturally occurring
the history, physical examination, and routine in-hospital test disease, and it is the only test used in the long-term monitoring of
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TABLE 11-11 E
NDOCRINE SCREENING TEST RESULTS FROM CATS WITH NATURALLY OCCURRING
PITUITARY-DEPENDENT CUSHINGS SYNDROME
Urine Cortisol-to- Serum Cortisol (g/dL) Serum Cortisol (g/dL)

Creatinine Ratio Low-Dose Dexamethasone ACTH Stimulation
SECOND OR
PRE 4 HOUR 8 HOUR PRE FIRST POST FINAL POST
Reference range < 36 106 1-5 < 1.4 < 1.4 0-5 5-15 5-15
Borderline range 10 36 106 0.9-1.3 0.9-1.3 15-19 15-19
Number of cats included 34 46 46 43 46 35 55
Number of results within reference range 1 4 0 23 24 33
Number of results in borderline range 6 0 0 3 5
Number of results consistent with Cushings 27 42 43 8 17
syndrome
Range of test results 3 810 106 1.5-20.2 0.3-14.9 1.5-14.7 1.5-27.3 5.4-32.7 5-36.0
Mean standard deviation 48.7 31.6 6.8 3.7 4.2 2.9 4.9 2.1 6.3 3.8 12.2 5.6 14.7 10.1
Median 39 5.4 4.6 5.2 5.6 11.5 13.7
TABLE 11-12 E
NDOCRINE SCREENING TEST RESULTS FROM 14 CATS WITH CUSHINGS SYNDROME CAUSED
BY A FUNCTIONING ADRENOCORTICAL TUMOR
Urine Cortisol-to- Plasma Cortisol (g/dL) Plasma Cortisol (g/dL)

Creatinine Ratio Low-Dose Dexamethasone ACTH Stimulation
SECOND OR
PRE 4 HOUR 8 HOUR PRE FIRST POST FINAL POST
Reference range < 36 106 0.5 < 1.4 < 1.4 0-5 5-15 5-15
Borderline range 10 36 106 0.9-1.3 0.9-1.3 15-19 15-19
Number of cats included 14 12 10 12 8 6 8
Number of results within reference range 0 0 0 5 4 4
Number of results in borderline range 6 1
Number of results consistent withCushings 8 10 12 1 4
syndrome
Range of test results 11 160 106 1.5-11.0 1.5-11.6 1.8-10.2 2.6-11.8 2.7-50.0 3.3-52.8
Mean standard deviation 42 81.4 4.9 2.9 5.2 3.5 4.9 2.7 5.2 3.4 17.3 16.9 22.3 18.2
Median 3.8 4.1 4.1 5.5 3.7 13.1 21.5
medically treated NOH dogs and cats. Detractors suggest that the and 60 minutes after starting the test, and therefore both post-
test lacks sensitivity and specificity and is far more expensive than ACTH sampling times were recommended. Using the mean
either the UC:CR or the LDDST. standard deviation (SD) to establish the reference range for the
A number of studies have evaluated the ACTHST in either post-ACTH plasma cortisol resulted in a range of about 6 to 19
laboratory or privately-owned cats. One of the earliest stud- g/dL at 30 or 60 minutes after the intramuscular (IM) injection.
ies compared the use of two different doses of synthetic ACTH Response to intravenous (IV) synthetic tetracosactrin (another
(cosyntropin) with the use of natural ACTH in stimulation tests form of synthetic ACTH) was evaluated in laboratory cats given
conducted on privately-owned healthy cats. Synthetic ACTH 125 g/cat, IV. Cats demonstrated peak responses 180 minutes
was administered at doses of 125 and 250 g per cat IM with after injection (Sparkes et al, 1990). The longer duration of
blood samples obtained for cortisol analysis before administra- action and greater potency of IV versus IM administration was
tion and again at 15, 30, 60, 90, and 120 minutes after (Smith further supported in a subsequent study, again using 125 g/
and Feldman, 1987). No signicant difference was found between cat. Peak cortisol response occurred between 60 and 90 minutes
responses to the two doses of synthetic ACTH. Because two cats after starting the test (Peterson and Kemppainen, 1992a). No
vomited and remained obtunded for several hours after receiv- signicant difference was noted in drug response after IV cosyn-
ing the higher dose, the lower dose was recommended. Peaks in tropin was compared with IV tetracosactrin in another study,
plasma cortisol concentration were most often documented 30 and it was recommended that blood for cortisol be obtained
60, 90, 120, and 180 minutes after administration (Peterson and cats was about 33%. Forty-one cats with FCS (35 with PDH,
Kemppainen, 1992b). These two studies were followed by one six with ATH) had two post-ACTH administration samples ob-
in which 1.25, 12.5, and 125 g of cosyntropin were adminis- tained, allowing assessment of the middle result (see Tables
tered to cats, demonstrating comparable peak cortisol responses 11-11 and 11-12). Twenty-eight cats (68%) had results within
after each dose but a more prolonged response with the highest the reference interval, four (10%) had borderline results, and
dose (Peterson and Kemppainen, 1993). Another group dem- nine (22%) had abnormal results. There was little diagnostic
onstrated increases in hypothalamic-pituitary-adrenal activity value associated with adding the intermediate sample during
as cats age (Goossens etal, 1995), although this phenomenon ACTH stimulation testing.
does not alter reference ranges. This study was then followed by Lack of ACTHST sensitivity as a screening test for FCS,
one on overweight, older, privately-owned cats, using 125 or demonstrated in our review, has also been noted by others
250 g of IV tetracosactrin/cat. Results complemented previ- (Gunn-Moore, 2005; Graves, 2010, Peterson, 2012). In a
ous reports that had utilized young, relatively lean, laboratory more recent study, 56% of cats with FCS had an abnormal
cats. Peak cortisol concentrations after ACTH administration ACTHST result (Valentin etal, 2014). Thus, the ACTHST is
were similar to those reported in the other studies (Schoeman not sensitive as an aid in identifying cats with FCS, because so
etal, 2000). Slight variations in post-ACTH cortisol concen- many of the results are normal. Evaluation of different blood
tration reference ranges may result from the use of cosyntropin sampling times and various doses of ACTH does not improve
versus tetracosactrin, various doses, or employing IV versus IM this index of diagnostic usefulness. Even a single basal serum
administration. The critical question, however, not addressed in cortisol measurement has a greater sensitivity (67%) for detect-
any of these studies is simply whether or not the test should be ing cats with FCS than the ACTHST (Duesberg and Peterson,
employed in cats suspected of having FCS. 1997; Graves, 2010). Specificity of the ACTHST has also been
Test Interpretation. One generally agreed upon ACTHST questioned (Graves, 2010; Peterson, 2012) because a variety of
protocol for cats is to administer 125 g of synthetic ACTH, chronic illnesses not associated with FCS can influence results
IV, with blood samples obtained 60, 90, 120, and 180 minutes (Zerbe etal, 1987b). It has been suggested that stress associ-
after. (Veterinarians should use the protocol recommended by ated with chronic illness could cause adrenocortical hyperpla-
their laboratory.) Most laboratories suggest that post-ACTHST sia, accounting for an exaggerated cortisol response to ACTH
cortisol concentrations of 6 to 15 g/dL are within their refer- (Peterson, 2012).
ence interval, 15 to 19 g/dL are borderline and inconclusive, Conclusions. The attributes of ACTHST as a screening test
and results more than 19 g/dL are consistent with FCS. Some for cats suspected as having FCSthe test is brief, easy to com-
laboratories may utilize slightly lower or higher reference in- plete, and easy to interpretall lose value when collated results
tervals. Lower reference intervals could lose specificity, raising indicate that it lacks sensitivity. Further, there are tests (UC:CR
the risk that more cats without FCS are incorrectly diagnosed and LDDST) that are clearly superior. The ACTHST remains the
as having the condition. Higher reference intervals could lose best test to conrm iatrogenic hyperadrenocorticism, but this con-
sensitivity, potentially resulting in missing the diagnosis of FCS. dition is rare in cats.
As demonstrated in the study on privately owned, overweight Low-Dose Dexamethasone Suppression Test (LDDST)
cats that did not have FCS, baseline (pre-ACTH) cortisol con-
centrations were as high as 13 g/dL and post-ACTH cortisol
concentrations as high as 19.7 gdL (Schoeman etal, 2000). Just Background
the basal values, therefore, might include some cats in the FCS A complete discussion on the physiologic basis for the LDDST
group if lower cortisol concentrations were considered diagnos- and its usefulness is provided in Chapter 10. Use of the analo-
tic, and others would have been described as borderline. The gous overnight LDDST is a well-established test for confirm-
ACTHST, regardless of dose, form of ACTH, timing, and so ing the diagnosis of NOH in people, with a sensitivity and
on has been demonstrated in most reports to have unacceptably specicity similar to that of the 24-hour urine cortisol excre-
poor sensitivity and specificity regarding its use as a screening tion test. The basis of LDDST, as is true for the overnight test
for FCS. employed in people, assumes that administered dexamethasone
Results. ACTHST results were available from 65 cats with circulates throughout the body, including to the hypothala-
FCS; 55 cats diagnosed with PDH and 10 with ATH. The re- mus and pituitary, in which it has potent suppressive effects.
sults were from 51 cats in our series and 14 cats reported in The low dose of dexamethasone is the minimum necessary
the literature (Immink et al, 1992 [one cat]; Schwedes, 1997 to directly and completely suppress synthesis and secretion of
[one cat]; Watson and Herrtage, 1998 [five cats]; Moore etal, both hypothalamic corticotrophin-releasing hormone (CRH)
2000a [one cat]; Skelly etal, 2003 [one cat]; Neiger etal, 2004 and pituitary ACTH in healthy individuals, which in turn
[five cats]). All 65 cats had at least one post-ACTHST result, decreases synthesis and secretion of adrenocortical glucocorti-
56 had basal cortisol concentrations reported, and 41 had more coids (Peterson and Graves, 1988). Effect of dexamethasone
than one post-ACTHST result. If only a solitary post-ACTH is profound within an hour and persists until the dexametha-
test result was available, it was arbitrarily considered the fi- sone is metabolized, which is usually well beyond 8 to 10 hours
nal result (see Tables 11-11 and 11-12). Thirty-eight of the 65 (about 30 hours in dogs). Dexamethasone has been the tra-
cats (58%) had post-ACTHST cortisol concentrations within ditional glucocorticoid for suppression testing because early
the reference interval, five (8%) had borderline results, and cortisol assays cross-reacted with prednisone or prednisolone.
22 (34%) had abnormal results. Of the 55 cats with PDH, 33 Consistent hypothalamic-pituitary-adrenocortical axis suppres-
(60%) had results within the reference interval, five (9%) had sion, in healthy individuals as well as those with non-adrenal
borderline results, and 17 (31%) had abnormal results. Of the illness, is the single most important criterion of a reliable
10 ATH cats, five had results within the reference interval and LDDST.
five were abnormal. Thus, the sensitivity (the number of cats Individuals with ATH have an autonomous, cortisol secret-
that had FCS and tested positive) of the ACTHST for all the ing, adrenal adenoma, or carcinoma. Secretion of glucocorticoids
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from these tumors is independent of hypothalamic-pituitary con- Conclusions

trol. Glucocorticoids derived from adrenocortical tumors act the The 0.1 mg/kg dexamethasone test is an excellent and extremely
same as administered dexamethasone: it persistently and chroni- sensitive screening test in the evaluation of a cat suspected as hav-
cally suppresses hypothalamic and pituitary function. There- ing FCS. Specicity of the LDDST was not critically assessed here,
fore, administration of dexamethasone to a patient with ATH although previous studies indicate that some cats with non-adre-
should have no suppressive effects on endogenous serum cortisol nal illness will have LDDST results consistent with FCS (Zerbe
concentrations. etal, 1987b; Duesberg and Peterson, 1997). The LDDST is the
Individuals with PDH and secondary adrenocortical hyperplasia screening test of choice in evaluating a cat for FCS.
have a pituitary tumor less sensitive to glucocorticoid-associated
negative feedback, otherwise hyperadrenocorticism would never Hair Cortisol Concentrations
develop. Administration of dexamethasone to an individual with
PDH typically has one of two results: (1) the dexamethasone fails Hair cortisol concentrations were higher in dogs with NOH as
to cause lowering (suppression) of circulating cortisol concentra- compared with healthy dogs and ill dogs that did not have NOH
tions because the pituitary tumor is resistant to negative feedback (Corradini et al, 2013). This non-invasive laboratory aid could
and results of this test are indistinguishable from that seen with revolutionize the diagnosis of NOH in dogs and FCS in cats if
ATH, or (2) hypothalamic, pituitary, and then adrenocortical cor- results are both sensitive and specific.
tisol secretion is suppressed and circulating cortisol concentrations
do decrease, but this effect is far more transient than normal Combined Dexamethasone Suppression Test/
due to rapid metabolism of the administered drug. In this latter Adrenocorticotropic Hormone Stimulation
condition, dexamethasone causes a decrease in circulating cortisol
concentrations, but rather than persisting for more than 8 hours, This combination test can be completed in 1 day with collec-
it lasts far less than 8 hours and circulating concentrations of corti- tion of only three blood samples. An ACTHST is begun 3 to
sol escape from the suppression earlier in individuals with PDH 5 hours after beginning the LDDST. However, the addition of
than in healthy individuals. the unacceptably insensitive ACTHST to the quite sensitive
LDDST seems unnecessary while having the potential to pro-
Protocol vide misleading results. This test is not recommended (Peterson,
The LDDST dose and protocol established in dogs, 0.01 mg/kg of 2012).
dexamethasone IV with cortisol concentrations determined before
and 4 and 8 hours after administration, fails to cause suppression Combination Screening and Discrimination Tests
in 15% to 20% of healthy cats. Increasing the dose to 0.1 mg/kg
was consistently effective in suppressing healthy cats but not cats Urine Cortisol-to-Creatinine Ratio and High-Dose Dexamethasone
with FCS (Smith and Feldman, 1987; Hoenig, 2002; Kley etal, Suppression Test
2007). The Screening Portion of the Test. The UC:CR can be
combined with a high-dose dexamethasone suppression test
Test Interpretation (HDDST) in a practical and cost-effective alternative to more
The established reference ranges for results 4 and 8 hours after traditional testing options (Goossens etal, 1995). This test is
administration of 0.1 mg/kg of dexamethasone in healthy cats is designed to be completed in the home environment, negating
less than or equal to 0.8 g/dL. A value greater than or equal to need for cats to be brought into the hospital with its atten-
1.4 g/dL is consistent with a diagnosis of FCS due to PDH or dant stress, time, and expense. Owners are instructed to collect
ATH, in the context of a cat also having appropriate signs and urine from their cat on two separate mornings. It is not neces-
supportive evidence. The nondiagnostic range of 0.9 to 1.3 g/ sary for urine to be collected on consecutive days, but doing so
dL is meant improve both sensitivity and specicity by forcing shortens the process. There are a variety of methods for own-
additional testing. ers to obtain urine. Simply leaving their cat in a room with a
box containing insufficient litter to absorb the urine produced
Results overnight is easiest, allowing owners to pour urine into a clean
A total of 58 cats with FCS (46 with PDH and 12 with ATH) container (alternatively, use nonabsorbable litter). Collected
have their LDDST results included in Tables 11-11 and 11-12. urine is then brought to the veterinarian for measurement of
Forty-seven cats were from our series, and data from 11 cats UC:CR. This portion of the test is the screening test to aid in
were obtained from the literature (Immink et al, 1992 [two separating cats with FCS (abnormally increased UC:CR) from
cats]; Goossens etal, 1995 [three cats]; Meij etal, 2001 [three cats that do not have the disease (UC:CR result within the
cats]; Neiger et al, 2004 [three cats]). Not all cats had both reference range). The use of two separate samples is used to
4 and 8 hour post-LDDS results available. Forty-three out of improve sensitivity and specificity by not relying on one result.
43 cats with PDH and 12 out of 12 cats with ATH cats (100%) If both samples suggest FCS, one may continue to the second
had abnormal 8-hour LDDST results consistent with FCS (cor- phase of the test. If one result is within reference range and one
tisol concentrations > 1.4 g/dL), suggesting that this LDDST is abnormal, additional samples (one or two) may be collected
protocol is highly sensitive and more sensitive than either and evaluated.
UC:CR or ACTHST. Although these results indicate 100% The Discrimination Portion of the Test. Before interpreting
sensitivity, readers must understand that no test is perfect. In a this test, it is assumed that the previously obtained UC:CR results
related study, LDDST results were consistent with a diagnosis were abnormal and consistent with the strong clinical suspicion of
of FCS in 93% of afflicted cats (Valentin etal, 2014). Their con- FCS. In this second phase of the test, the owner should administer
clusion was that the screening test of choice in the evaluation of 0.1 mg/kg of dexamethasone orally every 8 hours beginning in the
a cat suspected as having FCS is the LDDST; however, there is morning (i.e., dexamethasone is administered at about 8 am, 4 pm,
no gold standard. and midnight). That night, the cat should again be restricted to a
location that allows urine to be collected on this third morning. baseline cortisol concentration proved to be far more sensitive.
The urine is delivered to the veterinarian and again assessed for Of 12 cats with FCS due to ATH, none demonstrated more than
UC:CR. Using the calculated mean from the first two samples, a 50% suppression at either 4 or 8 hours. Of 46 cats with PDH,
result less than 50% of that mean (on average) would be consis- however, 24 cats (41% of all 58 cats; 52% of cats with PDH)
tent with PDH. A result more than 50% of that mean does not demonstrated more than 50% suppression of serum cortisol con-
allow discrimination of PDH from ATH. centrations at either 4 or 8 hours (seven cats at 4 hours, two cats
Conclusions. This test was suggested in the literature about at 8 hours, and 15 cats at both 4 and 8 hours). The LDDST
two decades ago. It has not been critically evaluated, in part does have sensitivity and specificity in discriminating ATH from
because FCS is an uncommon condition. The test may have a PDH. In other words, a cat with FCS that meets any of the three
sensitivity and specificity as good as or better than other rec- established criteria for PDH on an LDDST, likely has PDH.
ommended protocols. It is not strongly recommended here only
because we have little experience with this combination test.
High-Dose Dexamethasone Suppression Test (HDDST)
In people suspected as having NOH, a single overnight dexa-
methasone suppression test is a trusted and reliable screening Background
test. Thus, the precedent for such a test in cats is solid (Molitch, The HDDST is an aid for discriminating patients with PDH from
2012; Nieman, 2012). those with ATH. Physiologic basis for this test, in part, is the same
as for the LDDST: administration of dexamethasone decreases
adrenocortical (endogenous) cortisol secretion via the suppression
TESTS TO DISCRIMINATE PITUITARY FROM
of hypothalamic synthesis and secretion of CRH, thereby decreas-
ADRENAL TUMOR CUSHINGS SYNDROME
ing pituitary ACTH synthesis and secretion. Dexamethasone also
After diagnosis of FCS has been conrmed, several tests can be directly suppresses pituitary synthesis and secretion of ACTH.
used to help discriminate individuals with PDH from those Without ACTH, adrenocortical cells cease synthesizing and secret-
with ATH. Four tests are commonly used to help discrimi- ing cortisol. As circulating cortisol is metabolized, plasma and
nate ATH from PDH. These include the LDDST, the HDDST, urine cortisol concentrations decrease quickly after administration
plasma endogenous ACTH concentrations, and abdominal ultra- (within an hour) and remain suppressed throughout the period of
sonography. Because of expense, need for specialized facilities and dexamethasone activity (30 hours in healthy dogs).
anesthesia, CT and MRI scans (although somewhat sensitive and Adrenocortical tumors function autonomously and are indepen-
quite specific) are not as widely used. The reason for discriminat- dent of hypothalamic and pituitary control. Negative feedback associ-
ing ATH from PDH is their different therapeutic options. Ideally, ated with chronic excesses in circulating glucocorticoids cause atrophy
adrenocortical tumors should be surgically removed. The most of pituitary ACTH-secreting cells in ATH patients. Therefore dexa-
effective medical option for treating cats with ATH is trilostane. methasone, regardless of dose administered, does not suppress cortisol
Pituitary tumors could also be surgically removed or treated with secretion from an adrenocortical tumor. By contrast, although pitu-
external radiation, but neither of these therapies is widely avail- itary tumors in PDH function somewhat autonomously, secretion
able. Trilostane is the medical alternative. If an owner is to refuse of ACTH by some (not all) pituitary tumors can be suppressed with
surgery in any scenario, it could be argued that discrimination low doses of dexamethasone. In dogs and cats with PDH, about
testing is unnecessary. 65% and 52%, respectively, demonstrate enough suppression on
LDDST to indicate that ATH is not an explanation for their hyper-
adrenocorticism. Using a higher dose of dexamethasone is based on
Low-Dose Dexamethasone Suppression Test (LDDST)
the concept that if some individuals with PDH demonstrate at least
Background some suppression on LDDST, a higher dose will increase the number.
The LDDST, as discussed earlier, is extremely sensitive in helping
to separate cats with FCS from cats that do not have the condi- In-Hospital Protocol
tion. Individuals with ATH typically demonstrate no response to Administer 10 times the dose of dexamethasone used for the
administration of dexamethasone, whereas some with PDH do LDDST. In cats, it is generally accepted to use a dexamethasone
demonstrate suppression but for a shorter period of time than dose of 1.0 mg/kg, IV, with blood samples obtained for cortisol
noted in healthy individuals. Three criteria define suppression concentration before and 4 and 8 hours after administration.
on the LDDST in attempting to identify dogs likely to have PDH: Remember, before employing this test, one should first confirm
a 4-hour cortisol less than a laboratory-determined absolute value that the cat has FCS.
(often < 1.4 g/dL), a 4-hour cortisol less than 50% of the base-
line value, and an 8-hour cortisol less than 50% of the baseline At-Home Protocol
value. Approximately 65% of dogs with PDH demonstrate sup- An alternative method employs the UC:CR, and the entire test is
pression, because they meet one or more of these criteria. carried out by the owner at home (described in previous section).
Results Interpretation of the In-Hospital HDDST

Forty-six cats with PDH in our review had their 4-hour cortisol Four criteria for suppression can be utilized to aid in the interpre-
concentrations assessed during LDDST, 42 had values more than tation of results: more than 50% decrease in cortisol concentration,
1.4 g/dL (no suppression) and four had values less than or equal from the basal value, at 4 or 8 hours; or cortisol concentrations less
to 0.9 g/dL. Ten cats with ATH had a 4-hour post-LDDST than 1.4 g/dL at 4 hours or 8 hours. If any one of these four crite-
blood sample assessed for cortisol, and all had both 4- and ria for suppression is met, the result is most consistent with PDH.
8-hour results more than 1.4 g/dL. Thus, use of the absolute Failure to meet any of the criteria adds support for the diagnosis of
value of less than 1.4 helped to identify only four of 56 cats FCS but is inconclusive regarding PDH versus ATH.
(7%) with FCS as having PDH. All four results were correct, but Interpretation of the At-Home Protocol. The interpretation of
sensitivity is poor. Use of more than 50% suppression from the the at-home protocol is described in previous section.
|
Results test result correctly identified cats with PDH. The five cats with
In-Hospital High-Dose Dexamethasone Suppression ATH and an 8-hour HDDST result failed to demonstrate sup-
Test. As seen in Table 11-13, HDDST results were available pression, as was expected. Also as expected, some cats (20 of 35;
from 40 cats with conrmed FCS. Basal and 4- and 8-hour 57%) with PDH failed to respond to the HDDST at 8 hours.
post-HDDST results were available from 24 cats with PDH Failure to suppress plasma cortisol concentration at 8 hours was
and four with ATH. Only baseline and 8-hour samples were a nonspecic nding that included cats with ATH and PDH.
obtained from an additional 11 cats with PDH and one with It is also of interest to note that the 8-hour test was available
ATH. There can only be two interpretations of HDDST results: from all 24 PDH cats tested at 4 hours plus an additional 11
(1) consistent with PDH can be applied to results demon- cats with PDH. However, only two additional cats with PDH
strating suppression, and (2) inconclusive regarding PDH ver- demonstrated suppression at 8 hours. All 13 cats that met at
sus ATH discrimination because none of the four criteria were least one of the two criteria for suppression at 4 hours met at
met. Thirteen of 24 cats (54%) had 4-hour HDDST results least one of the two criteria for suppression at 8 hours. It seems
that demonstrated suppression; the results were consistent with reasonable to suggest only a 4-hour post-HDDST sample be
PDH. All 13 cats had PDH. Thus suppression on the 4-hour obtained, because the 8-hour result has not offered signicant
test result was modestly sensitive but quite specic for PDH. new information.
The four cats with ATH and a 4-hour HDDST result failed to
demonstrate suppression, as was expected. Also as expected, Results
some cats (11 of 24; 46%) with PDH failed to respond to At-Home Urine High-Dose Dexamethasone Suppression
the HDDST at 4 hours. Thus failure to suppress plasma cor- Test. As can be reviewed in Table 11-14, 13 cats were tested using
tisol concentration at 4 hours was a nonspecic nding that the at-home protocol. All 13 cats had PDH (Goossens etal, 1995
included cats with ATH and PDH. [six cats]; Meij etal, 2001 [seven cats]). Ten of the 13 (77%) cats
Fifteen of 40 cats (38%) had 8-hour HDDST results that did demonstrate suppression on the UC:CR from the sample
demonstrated suppression; the results were consistent with obtained post-dexamethasone, using the mean of two basal urine
PDH. All 15 of those cats did have PDH, correctly identifying samples for the comparison. The entire test could be carried out
15 of 35 cats (43%) with PDH. Thus suppression on the 8-hour by an owner, decreasing cost and stress.
TABLE 11-13 H
IGH-DOSE DEXAMETHASONE SUPPRESSION TEST AND PLASMA ENDOGENOUS ACTH
RESULTS FROM CATS WITH CUSHINGS SYNDROME
Plasma Cortisol (g/dL) Plasma Endogenous

High-Dose Dexamethasone Test ACTH
PRE 4 HOUR 8 HOUR (pg/mL)
Pituitary Dependent Hyperadrenocorticism (PDH)
Reference range 0-5 < 1.4 < 1.4 10-60
Borderline range for PDH 10-45
Results consistent with PDH (definition) < 1.4 or > 45
< 50% baseline
Number of cats 35 24 35 45
Number of results inconclusive (consistent with PDH or ATH) 11 20 3
Number of results consistent with PDH 13 15 42
Range of test results 2.4-39.0 0.2-15 0.1-25.8 38-3653
Mean ( standard deviation) 8.8 8.8 3.0 3.6 4.9 6.2 457 619
Median 5.3 0.9 2.4 221
Adrenocortical Tumor Hyperadrenocorticism (ATH)
Reference range 0-5 < 1.4 < 1.4 10-60
Borderline range for ATH 10-45
Results consistent with ATH > 1.4 or > 50% of Undetectable
baseline cortisol
Number of cats 5 4 5 6
Number of results inconclusive 0 0 0
Number of results consistent with ATH 4 5 6
Range of test results 3.0-7.1 3.7-6.1 4.4-6.1 All undetectable
Mean ( standard deviation) 5.1 1.6 5.0 0.8 5.0 0.7
Median 4.9 4.7 4.7
ATH, Adrenal tumor hyperadrenocorticism; PDH, pituitary dependent hyperadrenocorticism.

TABLE 11-14 H
IGH-DOSE DEXAMETHASONE SUPPRESSION TEST RESULTS FROM 13 CATS
WITH PDH UTILIZING THE AT-HOME UC:CR PROTOCOL*
CAT NUMBER FIRST BASAL UC:CR SECOND BASAL UC:CR MEAN UC:CR POST-DEXAMETHASONE UC:CR POSITIVE FOR PDH?
1 139 145 142 13 Yes
2 37 64 51 5 Yes
3 75 82 78 92 No
4 125 155 140 41 Yes
5 104 103 104 26 Yes
6 228 316 272 18 Yes
7 272 18 Yes
8 80 117 No
9 119 5 Yes
10 73 17 Yes
11 72 27 Yes
12 105 119 No
13 77 7 Yes
All results compiled from Goossens MMC etal.: Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats, Domestic Anim Endocrinol 12:355, 1995; and Meij BP,
etal: Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats, Vet Surg 30:72, 2001.
PDH, Pituitary dependent hyperadrenocorticism; UC:CR, urine cortisol-to-creatinine ratio.
*Suppression is defined as a post-dexamethasone UC:CR < 50% of the mean of two basal UC:CR. (All UC:CR results multiplied by 106.)
Conclusions The attributes of assessing endogenous ACTH include requir-

The in-hospital HDDST is relatively easy to perform and inter- ing only one blood sample, being easy to interpret and rela-
pret, not expensive, and not harmful. Suppression, after adminis- tively reliable. However, it is important that blood samples for
tering 1.0 mg/kg of dexamethasone IV, is consistent with PDH. determination of endogenous ACTH concentration be handled
Cats with ATH usually do not demonstrate suppression, whereas as directed by your laboratory. ACTH is a labile protein that
52% of cats with PDH meet at least one criterion of suppression. degrades quickly in plasma. Samples usually must be collected
The 0.1 mg/kg dexamethasone dose resulted in identification of directly into a tube containing ethylenediaminetetraacetic acid
only 22% of PDH cats. It is noted that the 1.0 mg/kg dexametha- (EDTA) anticoagulant, tubes must be made of plastic or silicone-
sone dose was most effective in identifying PDH at 4 hours. No cat coated glass (most glass EDTA collection tubes are siliconized);
with ATH demonstrated suppression at either 4 or 8 hours of the samples should be placed immediately on ice and centrifuged
HDDST, but some cats with PDH also fail to suppress. Therefore, (ideally in a cold centrifuge). Harvested plasma must be placed in
failure to demonstrate suppression should be considered an incon- plastic tubing, frozen until assayed, and shipped on ice (Graves,
clusive result and is similar to results in human beings and dogs. 2010). Mishandled samples may falsely lower values suggesting
The at-home HDDST is easier to perform and interpret than an adrenal tumor (Peterson, 2012). Test results are not always
the in-hospital protocol. In addition, at-home test results were denitive. Some people and dogs with hyperadrenocorticism due
superior to those utilizing the in-hospital tests in correctly dis- to either ATH or PDH have ACTH concentrations that over-
criminating PDH from ATH. Assuming an owner can administer lap with the reference range. These drawbacks, together with the
dexamethasone, it seems reasonable to recommend the at-home availability and diagnostic specificity of imaging studies (e.g.,
protocol for both screening and discrimination testing, because ultrasonography) have limited the use of endogenous ACTH
this protocol is generally easier to perform, less expensive, easier to assessment.
interpret, safer (less bruising and no chance of skin trauma), and Some pituitary pars intermedia (PI) cells stain positively for
as-good-as or more specific and sensitive. ACTH as do virtually all pars distalis (PD) cells. In contrast, some
PI cells cleave ACTH to melanocyte-stimulating hormone
Endogenous ACTH and ACTH Precursor (MSH) and corticotropin-like intermediate lobe peptide (CLIP),
Concentrations suggesting that increases in plasma -MSH concentrations could
be expected in cats with PI adenomas. However, cats with the
Background highest -MSH concentrations were those with PD adenomas
Circulating endogenous ACTH concentrations have been used (Halmi and Krieger, 1983; Rijnberk, 1996; Meij etal, 2001). One
to help discriminate people with PDH from those with ATH explanation could be that the gene encoding the cleavage enzyme
since the 1970s, and they have been used for the same purpose (proconvertase 2) may become de-repressed in the course of
in dogs and cats since the 1980s. Individuals with ATH have neoplastic transformation of PD corticotrophs (Low etal, 1993).
autonomously functioning adrenocortical tumors that chronically Alternatively, as in people, some PD adenomas may originate
suppress circulating concentrations of endogenous ACTH and from a sparse population of melanocyte cells (Coates etal, 1986).
its precursors. Those with PDH have an ACTH-secreting tumor Cat PI and PD adenoma cells stain positively for both ACTH and
associated with normal-to-increased concentrations. -MSH (Peterson etal, 1982).
|
TABLE 11-15 L
ENGTHS AND WIDTHS OF ADRENAL GLANDS MEASURED ULTRASONOGRAPHICALLY IN
20 HEALTHY AWAKE CATS
LENGTH OF RIGHT WIDTH OF RIGHT LENGTH OF LEFT WIDTH OF LEFT

NUMBER OF CATS PARAMETER ADRENAL GLAND ADRENAL GLAND ADRENAL GLAND ADRENAL GLAND
20 Range (cm) 0.7-1.4 0.3-0.45 0.45-1.3 0.3-0.5
Median (cm) 1.0 0.4 0.9 0.4
From Zimmer C, etal.: Ultrasonographic examination of the adrenal gland and evaluation of the hypophyseal-adrenal axis in 20 cats, J Small Anim Pract 41:156, 2000.
Interpretation of Test Results ATH. However, since the diagnostic value, availability, and cost-
The reference range for endogenous ACTH concentrations in cats effectiveness of imaging studies are excellent, use of endogenous
is slightly lower than for dogs (Feldman, 1981; Smith and Feldman, ACTH testing is not common.
1987). Most cats with PDH have endogenous ACTH concentra-
tions from mid-reference range to several times higher than the
Abdominal Radiology
upper limit of the assay. Cats with ATH (as well as cats with iat-
rogenic hyperadrenocorticism) have results that range from unde- Changes noted on radiography of cats with FCS are similar
tectable to the lower portion of most reference ranges. However, to those seen in dogs. These changes include excellent con-
some cats with iatrogenic hyperadrenocorticism, ATH, or PDH trast (due to fat deposition into the mesentery), hepatomeg-
have inconclusive results (Peterson et al, 1994; Duesberg and aly (which is usually secondary to diabetes mellitus in cats, as
Peterson, 1997; Benchekroun etal, 2012). opposed to being more frequently secondary to steroid-induced
hepatomegaly in dogs), and a pot-bellied appearance (caused
Results by steroid-induced abdominal muscle weakness). Use of radi-
Plasma endogenous ACTH concentrations were available from ography has been replaced, for the most part, by abdominal
51 cats with FCS. Thirty-eight of these cats were from our ultrasonography as the key abdominal imaging study for cats
series, and 13 were from the literature (Goossens et al, 1995 known or suspected to have naturally occurring FCS. Ultraso-
[six cats]; Meij etal, 2001 [seven cats]). All 13 cats from the nography is favored simply because adrenal glands are not rou-
literature had PDH, 32 cats from our series had PDH and tinely visualized via radiography unless the gland(s) is calcied
six had ATH. As can be seen from Table 11-13, the results of or extremely enlarged (both situations are rare). By contrast,
endogenous ACTH testing were excellent. All six cats (100%) canine and feline adrenal glands can be routinely visualized on
with ATH had undetectable concentrations, and 42 of 45 cats ultrasonography.
(93%) with PDH had concentrations more than 45 pg/mL.
Nondiagnostic results from three cats with PDH (38, 40, and
41 pg/mL) were still distinct from the results obtained from
cats with ATH. Twenty-ve of 45 cats with PDH had results Background
typical of those noted in dogs (45 to 450 pg/mL). However, Knowledge regarding adrenal gland imaging in dogs developed
17 cats with PDH (38%) had plasma endogenous ACTH con- sooner than cats (Barthez et al, 1995; Horauf and Reusch,
centrations in excess of 450 pg/mL (range, 487 to 3850 pg/ 1995). A study on ultrasound appearance of adrenals in anes-
mL; mean, 1002 pg/mL a SD of 731). Why so many cats thetized healthy cats (Cartee and Finn-Bodner, 1993) was fol-
with PDH had extremely increased plasma endogenous ACTH lowed by a study on awake cats. In the latter report, both glands
concentrations (> 450 pg/mL) is not well understood. Is it that were visualized in each cat. Further, both left and right adrenal
their pituitary tumors produce more ACTH, is the assay less glands were virtually identical in size and shape, with both being
reliable in cats, is the assay more reliable in cats, is the assay oblong and oval-to-beanshaped (Table 11-15; Zimmer et al,
also measuring precursors in the cat, or is there some other 2000). In general, the adrenal glands of cats are less echogenic
explanation? The extremely high concentrations of ACTH, as than the surrounding tissues and the right adrenal may be tech-
noted in many cats from our series, were also noted by Meij nically more difcult to image. The central area of the adrenals
and colleagues (2001). These authors pointed out that in one were identified as more echogenic than the cortex in six of 20
cat, the ACTH assay results as measured by an immunoradio- cats. Readers are reminded that ultrasonography is a subjec-
metric assay (IRMA) was only about 20% of the value obtained tive diagnostic tool. In other words, results are dependent on
with an assay employing a polyclonal antibody. It is possible, skill and experience of the ultrasonographer, as well as on the
therefore, that the polyclonal antibody assay is suspect. Per- equipment used.
haps these pituitary tumors secreted precursor-molecule
pro-opiomelanocortin (POMC) or POMC-derived peptides Results
recognized as ACTH by the assay. Precursors of ACTH were Results of abdominal ultrasonography in cats with FCS are sum-
above the reference range in eight of nine cats that had PDH marized in Table 11-16. Forty-one cats were evaluated: Thirty-five
(Benchekroun etal, 2012). cats from our series and six cats with results taken from the lit-
erature (Daley etal, 1993 [one cat]; Watson and Herrtage, 1998
Conclusions [four cats]; Moore etal, 2000a [one cat]). Thirty-four of the 41
Measuring endogenous ACTH or its precursor concentrations in abdominal ultrasound results correctly identified either bilaterally
cats with confirmed FCS has value for discriminating PDH from symmetrical adrenals consistent with PDH or an adrenal nodule
TABLE 11-16 ABDOMINAL ULTRASOUND Computed Tomography (CT) and Magnetic

INTERPRETATIONS Resonance Imaging (MRI) Scans
FROM 41 CATS WITH
Background
NATURALLY OCCURRING
HYPERADRENOCORTICISM It is recommended that the diagnosis of FCS due to PDH
be confirmed before pursuing pituitary imaging using CT
POSSIBLE FINDING NUMBER OF CATS or MRI scanning. These imaging modalities provide a non-
invasive means of visualizing some pituitary tumors; however,
Cats With Adrenal Tumor Hyperadrenocorticism (ATH) each technique requires specialized facilities and cats must be
(9 Cats) anesthetized. MRI scanning has been the imaging modality
R mass, L small 3 of choice for the pituitary gland area in people (Chakere etal,
L mass, R small 0 1989; Stein etal, 1989). Compared with CT scans, MRI scans
R mass, L not seen 2 have superior anatomic resolution and soft tissue contrast. Also,
MRI scans are less likely to create distracting artifacts when the
L mass, R not seen 2 middle and caudal fossae of the brain are imaged (Kaufman,
Both adrenals enlarged 1 1984). MRI scanning allows acquisition of images oriented in
No adrenals seen 1 any plane, which is an important feature when examining the
pituitary fossa.
Cats with Pituitary Dependent
The purpose of considering a sophisticated diagnostic aid such
Hyperadrenocorticism (PDH) (32 Cats)
as CT or MRI in a cat suspected of having FCS is to determine
Both adrenals normal 5 whether or not an obvious pituitary mass can be visualized prior to
Both adrenals enlarged 22 radiation therapy or surgery. In our experience, both CT and MRI
L normal or enlarged, R not seen 2 scans consistently allow visualization of pituitary masses more
than 3 mm in greatest diameter. Therefore, if only one modality
R normal or enlarged, L not seen 1 is available, we would encourage using that tool. If both imag-
No adrenals seen 2 ing modalities are available, we encourage veterinarians to choose
whichever tool is less expensive or whichever tool requires the
L, Left adrenal gland; R, right adrenal gland.
shortest duration of anesthesia.
In a study of healthy cats, the pituitary gland was measured
using post-gadolinium (postcontrast) MRI studies in 17 cats. The
consistent with ATH. Three of the 41 cats (7%) had inconclu- cats were 1 to 15 years of age and weighed between 2.9 and 6.5 kg.
sive studies, because no adrenal tissue was identied (two of these Mean ( SD) pituitary length was 0.54 cm ( 0.06 cm) and the
cats had PDH, and one had ATH). Four of the 41 cats (10%) width was 0.5 cm ( 0.08 cm). Pituitary gland height measured on
had potentially misleading results: Three of 32 cats (9%) with sagittal and transverse images was about 0.33 cm ( 0.05). Mean
PDH had one normal-to-increased-sized adrenal gland, with the pituitary volume was about 0.05 cm3. There were no signicant
other gland not visible, and one cat with ATH was thought to correlations between weight, age, and pituitary volume. The pitu-
have enlargement of both glands. Twenty-seven of the 32 cats itary gland appearance on the precontrast scan had mixed signal
(84%) with PDH had both adrenal glands visualized and cor- intensity, whereas on postcontrast scans the pituitary appeared to
rectly described as being relatively equal-sized. A unilateral adre- have uniform enhancement (Wallack etal, 2003).
nal mass with the opposite gland being small or not visible was Abdominal imaging may be of interest prior to adrenalectomy.
correctly observed in seven of nine cats (78%) with ATH. Thus, Specifically, imaging may identify vascular or local invasion.
ultrasound results were correct in a total of 34 of 41 cats with Assessment of the liver and other structures for evidence of meta-
FCS (83%). In a subsequent study of 32 FCS cats, the accuracy static disease or other concerns may be worthwhile.
of ultrasound correctly discriminating PDH from ATH was 93%
(Valentin etal, 2014). Results
Pituitary imaging scan results were reviewed from 48 cats with
Conclusions confirmed PDH (Table 11-17). A visible mass (5 to 11 mm in
Abdominal ultrasonography is not a screening test for separating greatest diameter) was identied in 34 cats (70%; Fig. 11-5). Thir-
cats with FCS from cats that do not have the condition. It is an teen of 22 cats (59%) from three different studies utilizing CT
excellent discrimination test for separating cats with ATH from scans had a visible mass (Goossens etal, 1995; Meij etal, 2001;
those with PDH. Correct discrimination has been documented Benchekroun etal, 2012); in the UC Davis series, visible masses
consistently in about 80% to 90% of cats with FCS (Duesberg were identified in six of nine cats evaluated with CT and four
and Peterson, 1997; Kley etal, 2007; Valentin etal, 2014). The of six evaluated with MRI. As veterinarians develop an ability to
reader is reminded that ultrasound examination results are subjec- identify cats with PDH earlier in the course of disease progres-
tive and success will vary. sion, the sensitivity of CT and MRI scans for detecting pituitary
tumors should decrease, because earlier diagnosis will be made
in cats with smaller less detectable masses. Cats with conrmed
Ultrasound-Guided Biopsy
PDH without a detectable mass should be assumed to have pitu-
Cats with FCS have undergone successful percutaneous biopsy of itary tumors simply too small to be seen.
suspected adrenal masses. Although percutaneous biopsy can be
completed with ultrasound guidance, one must weigh the benefit Conclusions
of obtaining a histologic description of adrenal tissue against risks Pituitary imaging serves several potential roles. Either CT or MRI
of complication. scans could be used to help conrm a diagnosis of FCS (see Table
|
TABLE 11-17 C
OMPUTED TOMOGRAPHY (CT) AND MAGNETIC RESONANCE IMAGING (MRI) SCAN RESULTS FROM
48 CATS* WITH PDH
NOT SPECIFIED
RESULTS CT SCAN MRI SCAN CT/MRI
Normal study (no mass seen) 12 cats 2 cats 0 cats
Visible mass (5 to 11 mm in greatest diameter) 19 cats 6 cats 9 cats
Total 31 cats 8 cats 9 cats
*15 cats from UC Davis series; 9 cats from Benchekroun G, etal.: Plasma ACTH precursors in cats with pituitary-dependent hyperadrenocorticism, J Vet Intern Med 26:575, 2012; 9 cats
from Valentin SY, etal.: Comparison of diagnostic tests and treatment options for feline hyperadrenocorticism: a retrospective review of 32 cases, J Vet Intern Med 28:481, 2014.
7 cats from Meij BP, etal.: Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats, Vet Surg 30:72, 2001; 6 cats from Goossens MMC,
etal.: Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats, Domestic Anim Endocrinol 12:355, 1995; 2 cats from Sellon RK, etal.: Linear-accelerator-
based modified radiosurgical treatment of pituitary tumors in cats: 11 cases (1997-2008), J Vet Intern Med 23:1038, 2009.
CT, Computed tomography; MRI, magnetic resonance imaging.
Trilostane
Background
Trilostane is an orally active reversibly competitive 3- hydroxysteroid
dehydrogenase inhibitor of adrenocortical and gonadal steroid syn-
thesis. (A full description of trilostane can be found in Chapter 10.)
Trilostane inhibits synthesis of both glucocorticoids and mineralo-
corticoids. Although not efficacious for people with hyperadrenocor-
ticism, trilostane therapy has successfully led to resolution of clinical
and biochemical abnormalities associated with hyperadrenocorticism
in dogs and cats. As an enzyme blocker, trilostane is effective only
when administered consistently, usually once or twice daily. If medi-
FIGURE 11-5 Computed tomography (CT) scan of the pituitary brain region from a cation is not given, the effect dissipates in hours. A small number of
cat with pituitary-dependent hyperadrenocorticism (PDH) demonstrating a pituitary trilostane treated dogs have developed adrenal necrosisan effect
mass. not described in cats. The number of cats treated with trilostane and
reported in the literature (at least 30) is limited, but no other thera-
peutic modality has been used much more often and no other has
11-17). This would be an expensive and insensitive approach, con- had greater success (Skelly et al, 2003 [1 cat]; Neiger et al, 2004
sidering that UC:CR or LDDST results are much more sensitive, [5 cats]; Mellett Keith et al, 2013 [15 cats]; Valentin et al, 2014
require no anesthesia, and are less expensive. Either CT or MRI [9 cats]. Twenty-nine of these 30 cats had PDH. We have used trilo-
scanning could be used as a discrimination test to help distinguish stane for the treatment of 5 cats with FCS. Although trilostane is not
cats with PDH from those with ATH. This, too, is an expensive recommended for dogs with pre-existing liver disease, kidney disease,
and insensitive approach because cats with ATH would have nor- or both, such parameters are often abnormal in cats with FCS, but
mal (unremarkable) scans along with those conrmed to have PDH influence of these conditions on response to therapy is not known.
but whose pituitary masses are too small for visualization. Thus a
normal scan would yield virtually no information other than sug- Indications
gesting that a cat may have ATH or, if a cat has PDH, the tumor is The primary indication for using trilostane is for long-term treat-
small. The recommendation here is that CT or MRI scans be used ment of PDH or ATH in cats. Among the reasons for using tri-
to screen cats that might be scheduled to undergo hypophysec- lostane for a cat with ATH are owner refusal to consider surgery,
tomy, pituitary radiation, or radiosurgery. Either CT or MRI scans presence of metastases, tumor size or location that negates surgery
could be used to evaluate a cat with central nervous system (CNS) as an option, or one of many concurrent conditions making sur-
signs to determine the likelihood of the macrotumor syndrome. gery an unacceptable risk (fragile skin, kidney disease, heart dis-
ease, and so on). Before surgery is performed on any cat with FCS,
treatment with trilostane should be employed in an attempt to
MEDICAL TREATMENT
gain full control of the disease for a period of time (4 to 8 weeks).
In this manner, many of the complications associated with surgery
Introduction and the Options
and the perioperative period can be minimized.
Trilostane is the most efficacious medical treatment option effec-
tive in cats with PDH or ATH. Surgical management of FCS High Dose, Low Frequency Trilostane
includes bilateral adrenalectomy or hypophysectomy for cats The starting dose of trilostane, reported for 21 cats with FCS,
with PDH. Surgical removal of an adrenocortical tumor is the varied from about 15 mg per cat once daily to 60 mg b.i.d.
preferred treatment for cats with ATH. External beam radiation (twice a day; 120 mg/cat/day); 4.2 to 13.6 mg/kg, once or twice
therapy can be utilized for cats with PDH, especially if the cat has daily (Skelly etal, 2003; Neiger etal, 2004; Mellett Keith etal,
a large (macro) pituitary tumor. No treatment modality has been 2013). Recommended starting doses are about 20 to 30 mg/
employed in a large enough group of cats to allow solid recom- cat orally per day, administered once daily or divided between
mendations, but experience with trilostane is promising. feeding times (Peterson, 2012). The initial doses used in one
study averaged 4.3 mg/kg, once daily (13 cats) and 3.3 mg/ will reduce insulin antagonism and enhance insulin action. An
kg b.i.d. (2 cats) (Mellett Keith etal, 2013). Trilostane should attempt to avoid severe hypoglycemia is imperative, because such
always be administered during a meal or within 30 minutes of reactions are traumatic and dangerous for the patient as well as
meal completion to enhance absorption of the drug. being frustrating, disappointing, and traumatic for owners.
Owners of cats with FCS and diabetes can provide their veteri-
Low-Dose, High-Frequency Trilostane narian with extremely valuable information. We encourage own-
After experience with low-dose trilostane being effective in treat- ers to monitor, as best they can, their cats appetite, water intake,
ing dogs with NOH (Vaughan etal, 2008), a similar approach urine output, litter box usage, activity, muscle strength, interest
was used in 4 FCS cats3 with PDH and 1 with ATH (all man- in family members, grooming behavior, skin wound appearance
aged by the author). Each cat was treated with about 1 mg/kg of (healing?), and any other pertinent information. If owners are
body weight (rounded up to the next full kg of weight if needed), willing and able, we recommend collection of an overnight urine
t.i.d. (three times a day). Purchased Vetoryl was compounded sample (usually simply by removing most of the litter from the
into appropriate-sized capsules, and good response in lower- box or using nonabsorbable litter and restricting the cat to that
ing cortisol concentrations and in resolving signs of FCS were room overnight). Urine should be obtained the morning of any
achieved. In 3 cats, the dose was not changed, and in 1 cat, the planned in-hospital testing. This allows veterinary personnel to
dose was increased 20%. Trilostane should always be given dur- assess, at the least, specific gravity, glucosuria, and UC:CR. If
ing a meal or within 30 minutes of completion to enhance drug owners are capable, we also recommend checking blood glucose
absorption. concentrations, using the ear vein technique, every 2 hours over
10 hours every 5 to 7 days in the first month or so of trilostane
Initial Home Treatment and Monitoring Recommendations treatment. Hyperglycemia is common. Euglycemia may be indica-
Medical therapy for cats with FCS is best carried out in their tive of diabetes resolving or of the cat becoming more sensitive
familiar home environment. Thus, treatment becomes the owners to insulin. Hypoglycemia always indicates insulin overdose. Some
responsibility. This is easy to discuss in a textbook but often quite overdosed cats are no longer diabetic and others require an insulin
difficult in reality. Remind owners that missing a dose occasion- dose reduction. Most cats with FCS and diabetes mellitus remain
ally should not be a problem. Assuming that an owner can con- diabetic despite trilostane therapy. We are encouraged that using
sistently administer oral medication, treatment of FCS remains the low-dose trilostane protocol, two of three cats with PDH had
complicated. Therefore, prior to initiating therapy, the veterinar- resolution of both FCS and diabetes mellitus. Chapter 7 is dedi-
ian is obligated to educate the owner as much as possible about cated to feline diabetes mellitus and should be consulted.
FCS, the treatment plan, treatment goals, and potential com- Feline Hyperadrenocorticism Cats with Chronic Kidney Dis-
plications. Treatment goals should never be a certain blood test ease (CKD).Valuable information can be gained from owners
result. Rather, the primary goal should be to have the owner see of a cat with FCS and CKD. As with owners of diabetic cats, we
improvement in their pets health and, therefore, therapy should encourage these owners to monitor, as best they can, their cats
be individualized to the needs of each cat. The patient should be appetite, water intake, urine output, litter box usage, activity,
thoroughly assessed before treatment with at least a body weight, muscle strength, interest in family members, grooming behav-
history, physical examination, CBC, serum chemistry profile ior, skin wound appearance (healing?), and any other pertinent
(including blood glucose and electrolytes), and urinalysis. Hav- information. Concerns regarding worsening kidney function will
ing this information from samples taken before treatment may be be raised if the appetite is abnormally poor, if weight loss is sus-
helpful when attempting to determine the explanation for predict- pected, or if the cat has vomiting or worsening PU/PD. Resolu-
able or unpredictable responses. tion of NOH may be associated with unmasking severe CKD.
Cats with a Poor Appetite. No cat should be treated for FCS
if inappetent or anorexic. Appetite issues should be understood In-Hospital Monitoring
and resolved prior to starting treatment because control of hyper- In-hospital rechecks should be planned 7 to 10 days after starting
adrenocorticism is always associated with a reduction in appetite. trilostane, again after a month, and then every 90 to 120 days.
If appetite decreases with therapy, the veterinarian would want Schedules should be individualized. In the ideal situation, we ask
to know whether it is the result of treatment. In such a scenario, owners to collect urine from their cat the morning of any scheduled
blood and urine tests become a valid means of detecting changes recheck, as described. While repeatedly obtaining blood from FCS
that likely took place after treatment began. cats is problematic, it is difficult to avoid the ACTHST. While the
Conditions to Monitor.At a minimum, one must monitor ACTHST lacks sensitivity and is not recommended as a screening
the effects of trilostane on FCS, diabetes mellitus (if present), test for FCS, it remains the most informative and objective test used
and kidney function. Veterinarians should also be aware of drug- for monitoring response to trilostane administration. ACTHST
induced side effects as well as changes in other concurrent condi- should be started 2 to 3 hours after feeding and trilostane adminis-
tions. Among the reported causes of death or euthanasia in treated tration. Whatever the time period from trilostane administration,
FCS cats are kidney failure, worsening diabetes, or diabetes-related future ACTHST should begin using the same time interval.
complications (ketoacidosis, hypoglycemic reactions, progressive Assessment of Trilostane Dose and Frequency. Together with
weakness, and so on), overwhelming infection (especially of skin the UC:CR result from owner collected urine, results of ACTHST
wounds), and perceived poor quality of life. FCS may mask con- will aid in determining if and what kind of adjustments in tri-
current conditions that become obvious as treatment progresses. lostane therapy are needed. A UC:CR result within the labora-
Feline Hyperadrenocorticism Cats with Diabetes Melli- tory reference range indicates that a cat is receiving the correct
tus.Beginning with the first day of trilostane therapy, insulin dose or too much trilostane and that the frequency of admin-
dose in diabetic cats should be decreased by about 50% or to doses istration is correct. The correctly dosed cat should be described
of 0.1 to 0.5 units per kg of body weight per dose, whichever is by the owner as doing well, whereas the overdosed cat may be
deemed appropriate. Reducing insulin dose anticipates the physi- described as listless, inappetent, having diarrhea, and/or vomit-
ologic effect that decreases in circulating cortisol concentration ing. The appropriately dosed cat should have a post-ACTHST
|
cortisol concentration of about 2 to 6 g/dL, whereas an over- (Peterson et al, 1994; Duesberg and Peterson, 1997; Peterson,
dosed cat will have a cortisol concentration less than 2 g/dL if 2012). We have experience in using mitotane in four cats with
the ACTHST is carried out at the correct time post-trilostane. If FCS (Nelson etal, 1988). Mitotane does not effectively suppress
the UC:CR is above the reference limit, an increase in trilostane adrenocortical function nor alleviate clinical signs of FCS, and its
dose is indicated if the post-ACTHST cortisol concentration is use is not recommended.
more than 6 g/dL. If the UC:CR is above the reference limit, an
increase in the frequency of trilostane administration is indicated
Ketoconazole
if the post-ACTHST result is in the desired range. This recom-
mendation for repeatedly collecting urine is based on experience. Ketoconazole, an imidazole derivative, is an orally active
Assessment of Cats Not Doing Well. Ideally, if the trilostane broad-spectrum antimycotic drug that has been used success-
dose is correct, the ACTHST result should be about 2 to 6 g/dL. fully in treating fungal disease in human beings and animals.
But these are not magic numbers with guaranteed results. Sug- At adequate doses, it inhibits both 11--hydroxylase and
gestions here are aids to achieving a positive response. Although cholesterol side-chain cleavage enzymes, inhibiting mamma-
ACTHST and UC:CR results are objective, owner opinion lian steroid biosynthesis. Ketoconazole also has the potential
regarding response to therapy remains most important. If owner to inhibit pituitary synthesis of ACTH by inhibiting adenyl
opinion and UC:CR or ACTHST results seem discordant, owner cyclase activity in pituitary corticotrophs (Stalla etal, 1988).
opinion should take precedence. Doses used for mycotic infection can lead to signicant reduc-
For example, an owner believes the cat is doing great but test tion in serum androgen concentrations, and at higher doses,
results suggest underdose. In this scenario, no change in dose or decreases in serum cortisol (Engelhardt et al, 1991). Keto-
frequency would be made. What if an owner believes the cat is conazole is an efcacious oral medication for the treatment of
doing great but test results suggest overdose? Here, we would rec- human beings with PDH.
ommend lowering the dose. Alternatively, an owner believes that Ketoconazole does not seem to consistently suppress adreno-
the cat is doing poorly but UC:CR and ACTHST results look cortical function in either normal cats or cats with FCS. A study
excellent. First, any cat described as being ill should have the tri- of four healthy male cats given 30 mg/kg/day for 30 days failed
lostane discontinued because overdose is always a possibility and, to demonstrate signicant changes in plasma testosterone or cor-
even if not overdosed, continued treatment may negatively impact tisol concentrations. Serum testosterone concentrations tended to
the cats ability to respond to another condition. Our initial dif- decrease after the rst 7 days of treatment, but in two of the four
ferential diagnoses would include worsening in diabetes control, cats, values returned to near-pretreatment concentrations by day 30
pancreatitis, or CKD. Other problems may be encountered. (Willard etal, 1986). Our experience has been limited to using
this drug in ve cats with naturally occurring PDH. Three of
Results the ve cats responded moderately well but not completely. One
In a study of five cats treated with trilostane, two died after 16 and cat demonstrated no response, and the fth cat developed severe
120 days of treatment, respectively. The remaining cats did improve thrombocytopenia (which may or may not have been associated
and were alive at 6, 11, and 20 months (Neiger etal, 2004). In with the drug) several weeks after treatment was initiated. Use of
the study on 15 cats, survival ranged from 87 to 1280 days. ketoconazole for the treatment of cats with FCS is not recom-
The median survival was about 21 months. In this latter study, mended (Peterson, 2012).
only cats treated for 60 days or longer were included, leaving the
possibility that some trilostane treated cats failed to remain on the
Etomidate
drug or survive 60 days (Mellett Keith etal, 2013). In both stud-
ies, cats with diabetes mellitus remained diabetic, although the Etomidate is a short-acting intravenously administered anesthetic
condition was usually more responsive to treatment. agent used for anesthesia induction. Because it has been shown
The four cats treated with low-dose trilostane included one with to have minimal deleterious effect on the cardiovascular system,
ATH that improved and had its adrenocortical tumor surgically this drug has been used to induce anesthesia in high-risk patients
removed with resolution of FCS. The three cats with PDH all that are critically ill, hypovolemic, in shock, or have pre-existing
improved clinically, no adverse side effects were noted, and two cardiovascular disease. It has also been shown that administration
of the three experienced resolution of their diabetes mellitus. One of this drug suppresses adrenocortical function in people, dogs,
cat whose diabetes resolved died from pancreatic adenocarcinoma and cats. One study on cats demonstrated profound suppression
10 months after treatment started, and the other two are each alive of adrenocortical function during 2 hours of anesthesia (Moon,
after about 1 year. 1997). Use of a sustained-release form of this drug could be an
effective mode of therapy for cats with FCS.
Mitotane
Metyrapone
A number of different protocols using mitotane (Lysodren; o,p-
DDD) for the medical management of cats with PDH have been Metyrapone (Novartis; East Hanover, NJ) is an orally active drug
used with varying levels of short-term success. Long-term results that inhibits the enzymatic action of 11--hydroxylase, which is
have been discouraging (Peterson, 1998). It is interesting to point responsible for converting 11-deoxycortisol to cortisol. Because
out that human beings with PDH, like their feline counterparts, cortisol precursors have little or no biologic activity, inhibition of
are not nearly as sensitive to o,p-DDD as dogs. (See Chapter 10 cortisol synthesis has the potential to resolve clinical signs and bio-
for a complete discussion of o,p-DDD.) When o,p-DDD was chemical changes due to hyperadrenocorticism. In people, drugs
given to clinically normal cats, only 50% demonstrated any adre- like metyrapone have been recommended for short-term control
nocortical suppression (Zerbe etal, 1987a). Adverse effects such prior to surgery, to resolve hyperadrenocorticism while waiting for
as anorexia, vomiting, and lethargy have been described as com- radiation therapy to take effect, or to provide palliative treatment
mon, even in cats that did not have discernable cortisol response for metastatic disease (Verheist etal, 1991; Feelders et al, 2010).
Metyrapone has been documented to be effective in people with at the time that the report was written and were in complete
either PDH or ATH. Although adverse reactions are not com- remission. Two of the five long-term survivors had resolution of
mon, transient hypocortisolemia has been reported. Chronic use diabetes mellitus (Meij etal, 2001).
of metyrapone has been demonstrated to result in a compensatory
endogenous ACTH concentration increase and override of adre- Conclusions
nal blockade of cortisol synthesis (Orth, 1978). The number of cats treated with hypophysectomy has been lim-
There are several reports of using metyrapone in cats with FCS. ited. However, as more experience is gained, there is no doubt that
Clinical response without side effects (other than hypoglycemia) this could be the treatment of choice for cats with PDH, as it is for
was achieved in two cats using 30 to 70 mg/kg orally, twice daily similarly afflicted human beings and dogs. Limiting factors include
(Daley etal, 1993; Moore etal, 2000b). The lower end of the need for expertise and facilities to perform the surgery and the peri-
dose range should be used for the first 2 to 4 weeks, rechecking operative medical care. As expertise improves, it is anticipated that
the cat and possibly completing an ACTHST. The dose can be specic removal of ACTH-secreting tumors will be accomplished
increased, as needed, by small increments. Doses greater than while preserving the healthy portion of the pituitary.
70 mg/kg, twice daily, are not recommended. Higher doses have
been mentioned, although these higher doses have been asso- Adrenalectomy
ciated with a strong suspicion of drug-induced vomiting and
inappetence. Subjective clinical improvement was observed in Background
three cats: One was lost to follow-up after 10 months of treat- Pituitary surgery should provide a permanent cure. Bilateral adre-
ment, whereas two cats were treated for 21 days and 6 months, nalectomy for PDH is another, rarely used means of permanently
respectively, before each had successful bilateral adrenalectomy resolving FCS. Adrenal nodule or mass removal should be cura-
(Moore et al, 2000a). One of two additional cats was treated tive for ATH. Perhaps the most important questions to consider
and reported to have had slight improvement (Peterson, 1988). prior to surgery are whether the cat is a reasonable surgical and
Another cat demonstrated transient reduction in ACTHST anesthesia risk and, after trilostane treatment for 4 to 12 weeks
cortisol concentrations, had resolution of clinical signs, and prior to surgery to control FCS, what would be gained from the
underwent subsequent successful adrenalectomy (Daley et al, surgery that has not been achieved with trilostane? One answer to
1993). Metyrapone is often difficult to obtain. There has not this latter question is the cat would no longer need to be medi-
been a documented case of rising endogenous ACTH concen- cated, although diabetes mellitus and its need for therapy may not
trations in cats, overriding adrenocortical blockade with either resolve. Again, consider risk versus reward, and be certain that the
metyrapone or trilostane. owner is well informed.
Managing Cats Pre- and Post-Adrenalectomy

SURGERY AND LAPAROSCOPIC TREATMENT
Conservative volumes of IV fluids (2.5% dextrose if the cat is dia-
betic) should be started after withdrawal of food and water prior to
Hypophysectomy
surgery. During surgery and in the first days following, fluid ther-
Background and Results apy should be directed at maintaining hydration, being aggressive
The treatment of choice for people with PDH is surgical removal in the assumption that some of these cats will develop postsurgical
of their pituitary tumor, thus eliminating the cause (Melby, 1988; pancreatitis, but not overloading a compromised cardiovascular
Thorner etal, 1992). Pituitary tumors are primary and not caused system. General vague guidelines suggesting individualization of
by excessive hypothalamic stimulation. Their removal results in therapy is the only reasonable recommendation that can be made.
permanent resolution of PDH (Scholten-Sloof et al, 1992; Van Use of an antibiotic specific for an identified infection, based on
Wijk et al, 1992). Hypophysectomy in cats has been used for culture and sensitivity results, may represent the best opportu-
both physiologic and pharmacologic studies (Reaves etal, 1981; nity to avoid resistance. Insulin treated diabetics should be given
Sallanon etal, 1988). In addition, transsphenoidal hypophysec- 50% of the usual morning dose. Insulin dosing from this point
tomy in cats has been described in detail for advanced microsurgi- until the cat is eating and drinking on its own will be challenging.
cal training of physician neurosurgeons (Snyckers, 1975). When the surgeon begins removal of an adrenal tumor or the rst
Microsurgical trans-sphenoidal hypophysectomy is an effective of a bilateral adrenalectomy, dexamethasone should be adminis-
means of treating cats with PDH (Meij et al, 2001). However, tered (0.2 mg/kg, IV). That dose should be repeated IM when
this form of therapy requires CT or MRI imaging facilities to surgery is complete, and 0.1 mg/kg should be given between 10
identify the mass, assess its size, establish location for the burr pm and midnight. Some protocols utilize hydrocortisone. Those
slot needed to perform the procedure, and determine if surgery cats undergoing adrenocortical tumor removal will be predisposed
is appropriate prior to the procedure. In addition to requiring to low cortisol concentrations because adrenocortical cells in the
an experienced surgeon, having facilities for perioperative care is remaining gland will likely be atrophied. After bilateral adrenalec-
imperative. Cats undergoing this procedure had both soft palate tomy, no adrenal tissue remains.
and mucoperiosteum incised to expose the sphenoid bone. Access The morning after surgery, an ACTHST should be completed.
to the pituitary fossa was completed using a burr and punches, There should be an Addisonian resultboth the basal and post-
the dura mater was incised, and the pituitary carefully extracted ACTHST cortisol concentration less than 2 g/dL. If the result
(Meij etal, 1997; 2001). The procedure is safest in cats with a is as anticipated, surgery may have been a success. If results after
small pituitary tumor. Regardless of tumor size, this procedure surgery are similar to those obtained before, adrenal tissue or func-
is associated with risk of surgical and medical problems. After tioning metastatic sites remain.
the procedure, some cats develop transient or permanent hypo- After obtaining the ACTHST, begin giving 0.1 mg/kg of dexa-
pituitarism. This hypocortisolism, hypothyroidism, and diabetes methasone subcutaneous (SC), b.i.d. The switch to oral prednisolone
insipidus requires at least short-term substitution therapy. Two of replacement (Graham-Mize etal, 2004) should begin about 24 hours
seven cats were alive 15 and 46 months after surgery, respectively, after the cat begins to eat without vomiting. Cats that had bilateral
|
adrenalectomy are permanent Addisonians that will require gluco- wounds. Preoperative treatment with trilostane for a sufficient
corticoid and mineralocorticoid replacement the remainder of their length of time to resolve as many FCS-related issues as possible
lives. They usually have their prednisolone replacement dose deter- should dramatically reduce complication rates.
mined over a period of weeks to months. Those that had an adreno-
cortical tumor removed usually have their glucocorticoids tapered Long-Term Complications, Including the Pituitary
over a period of 2 to 4 months before discontinuing treatment. Macrotumor Syndrome
After bilateral adrenalectomy, desoxycorticosterone pivalate The consequences of a growing pituitary tumor are well described
(DOCP; Novartis, East Hanover, NJ) should be administered in dogs and information on cats is expanding. Questions exist
(2.2 mg/kg, IM). That dose should be repeated 21 to 25 days regarding the effect of bilateral adrenalectomy or long-term inhi-
later, SC. Long-term dose and timing requirements should be bition of cortisol synthesis with drugs like trilostane on rate of
individualized (see Chapter 12). It is not common for dogs or cats pituitary tumor growth. Some believe that removal of cortisol
undergoing solitary adrenocortical tumor removal to need miner- negative feedback results in an increased rate of growth, a condi-
alocorticoid medication. If hyponatremia, hyperkalemia, or both tion called Nelsons syndrome in people. Some believe that tumor
are documented after surgery, DOCP should be given. ATH cats growth rate is independent of physiologic influence. The possibil-
given DOCP, usually receive 50% of that dose when due in 25 ity of enhanced pituitary tumor growth rate should be discussed
days and then another 50% reduction is made for the final dose with decision makers before surgery.
due at 50 days. From this time, it is quite uncommon for DOCP
to be needed. During this entire period, monitoring serum elec- Experience
trolyte concentrations is important. Experience with surgical management of FCS is limited and results
Serum renal parameters and electrolyte and glucose concentra- have varied. Most cats survive surgery, and postsurgical complica-
tions should continue to be assessed at the end of unilateral or tions are common. We have reviewed the experience of 21 cats
bilateral adrenalectomy that evening, the next morning, and then that had PDH and bilateral adrenalectomy. These include 15 cats
daily until the cat is returned to the owner or until it is eating on its in our series and 6 cats from the literature (Watson and Herrtage,
own without vomiting. The diabetes mellitus should be monitored 1998 [4 cats]; Daley et al, 1993 [1 cat]; Moore et al, 2000a
and treated as if the cat were newly diagnosed, using conservative [1 cat]). Eight cats from our series have been reported (Duesberg
doses of insulin. The combination of resolved FCS, parenteral and etal, 1995). Thirteen of 21 cats survived surgery, had complete
then oral steroids, the stress of surgery and recovery, and a mul- resolution of FCS, and lived for months or for more than 1 year
titude of other factors make diabetes management challenging. (Daley et al, 1993; Watson and Herrtage, 1998; Moore et al,
Until the dose of oral glucocorticoids is discontinued in ATH cats 2000). Five cats did not survive an appreciable period of time
or until the dose is stable after being tapered to that necessary for after surgery. One of the five died about 12 hours after surgery;
long-term health, insulin requirements are unpredictable. no explanation was available. The second of five died from acute
kidney failure 20 days after surgery (Watson and Herrtage, 1998).
Protocol: Surgery Two of the five cats died of sepsis within 1 month of surgery, both
If an obvious adrenal tumor is identified, it should be removed, due to severely infected fragile skin. One of the five cats died of
especially if the opposite adrenal gland appears atrophied. If dis- pulmonary thromboembolism about 3 weeks after surgery. Three
crimination test results are denitive for PDH, both adrenal glands additional cats from our series survived the surgery, had complete
should be removed regardless of whether they appear normal or resolution of their FCS, but died within months of surgery. One
enlarged. If discrimination tests are not performed or inconclu- died 4 months following surgery due to pancreatic carcinoma, and
sive, the surgeon together with those managing the medical aspects two died from apparent hypoadrenal crises 3 and 6 months after
should be prepared for intraoperative decisions. If the adrenals surgery, respectively.
appear symmetrical in size and shape, they should be removed,
whereas if one is obviously larger, that gland might be removed. Conclusions
Surgical resolution of FCS is difficult. Just the risk of exposing a
Protocol: Laparoscopy cat with FCS to celiotomy is signicant. Risk can be reduced with
Removal of adrenal masses via laparoscopy is becoming more a combination of patient selection, preoperative trilostane therapy,
common in veterinary practice (Smith et al, 2012). Mass size, minimal time for anesthesia and surgery, and thorough care after
location, presence of tumor thrombi, and invasion of local struc- surgery. However, these remain older cats that often have serious
tures are all factors in deciding which animal is a candidate for this problems involving other organ systems. Perhaps this is the reason
procedure as opposed to celiotomy. Laparoscopic adrenalectomy that many cases of FCS are not treated. Bilateral adrenalectomy
has the advantage of reducing perioperative complications. for PDH or tumor removal for ATH is an alternative to long-term
oral trilostane therapy, hypophysectomy, or pituitary radiation.
Short-Term Complications
Complications are frequently encountered in cats undergoing PITUITARY RADIATION
surgery for FCS. Complications that are terminal or that lead
a veterinarian to recommend euthanasia can be extremely dis- Background
heartening to the owner and the entire veterinary team. Potential
complications must be thoroughly explained to all decision mak- Ionizing radiation can be used in an attempt to destroy a benign or
ers before surgery. Some serious potential complications include malignant tumor. This is a consultative discipline requiring a vet-
sepsis, pancreatitis, thromboembolism, wound infection and/or erinary radiation oncologist and appropriate facilities. The objective
dehiscence (surgical site or previous skin wounds due to fragility), of radiation therapy is tumor eradication with preservation of nor-
and adrenocortical insufciency (Duesberg etal, 1995). Sepsis is mal tissue structure and function (Theon, 2000). Facilities typically
common because FCS predisposes to infection via immunosup- needed are a cobalt-60 photon irradiation unit or a linear accelerator
pression and those with fragile skin can have seriously infected photon unit. Treatment usually involves delivery of a predetermined
total dose of radiation. Some protocols call for a large single dose, with trilostane to resolve FCS before surgery. Pituitary radiation
whereas others recommend smaller doses delivered in fractions over is limited by facilities required, expense, and the multiple anes-
a period of several weeks. We are currently evaluating efficacy of thetic procedures that are part of some protocols. Hypophysec-
a two-dose protocol, which still limits anesthesia, while possibly tomy is limited by the few veterinarians who have this expertise.
improving on disappointing experience with a single-dose approach. Again, there are the problems of expense and patient debilitation.
Radiation therapy should always have potential benet for Experience with successful therapies (adrenalectomy [unilateral
the pet, even though outcome may not be entirely predictable. or bilateral], radiation, hypophysectomy) has resulted in less than
Because months may be required for effects of radiation therapy to 50% of cats surviving well beyond 1 year. Remember, most cats
be fully appreciated, many cats might benefit from prior trilostane that have FCS are not treated. Most of the treated cats are those
control of FCS. Then, one can determine if the cat is a reason- considered most stable. Therefore, 50% survival at 1 year (an opti-
able anesthesia risk. Trilostane should be continued for about 4 mistic number) does not include those cats never treated. Also, as
to 6 months after completion of radiation therapy. If a protocol success improves in treating FCS, the incidence and severity of
calls for multiple treatment/anesthesia sessions, rapid anesthesia large pituitary tumors (macrotumor syndrome) is likely to increase.
recovery is imperative. This provides cats with enough conscious
time to eat prior to the obligatory cessation of food hours before PRIMARY HYPERALDOSTERONISM IN CATS
the next scheduled anesthesia.
Background
Experience
The hormone aldosterone regulates both circulating concentra-
Radiation therapy has been used with partial success to treat a tions of sodium and potassium and intravascular fluid volume
limited number of FCS cats with PDH (Peterson et al, 1994; homeostasis. It is the principle mineralocorticoid synthesized and
Duesberg and Peterson, 1997; Feldman and Nelson, 2004; Mayer secreted by the zona glomerulosa, the outermost zone of adre-
etal, 2006; Sellon etal, 2009). The most commonly noted benefit nal cortices, whose cells lack the capacity to synthesize cortisol.
has been tumor shrinkage, prolonging survival in cats with large and/ Increases in serum potassium directly stimulate release of aldo-
or invasive pituitary masses. Radiation offers a potential for cure, but sterone. Decreases in blood pressure, primarily sensed within the
resolution of FCS has only been reported in a minority of cats. kidneys, stimulates synthesis and release of renin which, in turn,
Our experience in treating PDH cats with pituitary radiation is stimulates the angiotensins to stimulate secretion of aldosterone.
limited to only seven cats with sufcient follow-up to determine After synthesis and secretion, aldosterone acts on the distal neph-
response. Each had obvious clinical signs and five had insulin- ron to promote sodium reabsorption and excretion of potassium
resistant diabetes mellitus. Each cat had been evaluated either with and hydrogen ions. In conserving sodium, aldosterone indirectly
a CT scan (3 cats) or an MRI scan (4 cats). Each of the seven cats conserves water, raising blood volume and, in turn, blood pressure.
had a visible pituitary mass (5 to 11 mm in greatest diameter). Aldosterone directly increases blood pressure via enhancement of
Four cats were treated with 15 fractions of radiation divided over total peripheral resistance. This hormone is also synthesized in tis-
a period of 3 weeks. One cat demonstrated no response and was sues within the heart, brain, and vasculature where it is thought to
euthanized 7 months after radiation because of continuing signs have paracrine or autocrine action (Djajadiningrat-Laanen etal,
of diabetes mellitus and fragile skin. The two non-diabetic cats 2011).
appeared to improve by losing weight, becoming more active, and Excess production of aldosterone can be primary or secondary.
demonstrating healthier skin. However, one of these two cats died Primary hyperaldosteronism (PHA) is dened as the autonomous
of unknown reasons 3 months after completion of treatment, and secretion of the hormone by abnormal cells within the adrenal
the other died 14 months after completing radiation as a result cortex. PHA is characterized by circulating aldosterone excess
of renal failure. The fourth and youngest cat (8 years old at the and renin suppression. For several decades after this condition
time of diagnosis) responded quite well to pituitary radiation with was described by Conn (1955) it was considered rare. With bet-
improvement in various parameters plus complete resolution of its ter understanding, it is now thought to occur in about 6% of all
diabetes mellitus. This cat has lived for 32 months. Each of three people with arterial hypertension and about 11% of people with
cats was treated with a single large dose of radiation. None of these therapy-resistant hypertension (Fogari etal, 2007; Douma etal,
cats had resolution of their FCS, and none had appreciable mass 2008). Approximately two thirds of people with PHA have bilat-
shrinkage. However, experience with seven cats is far too few to eral hyperplasia of the zona glomerulosa in whom plasma renin
draw any conclusions. Pituitary radiation has potential to become activity may be incompletely suppressed. About one-third of
a reasonable approach to management of PDH, but many more people with PHA have a solitary adenoma in which plasma renin
cats will need to be treated before opinions can be established. activity is completely suppressed. Unilateral hyperplasia and aldo-
sterone-producing carcinomas are uncommon-to-rare (White,
PROGNOSIS 1994; Young, 2007). Afflicted patients typically have no abnor-
malities in cortisol production, plasma cortisol concentrations, or
FCS is a serious condition that carries a guarded to grave prog- in cortisol metabolism. Secondary hyperaldosteronism is the result
nosis. The deleterious effects of chronic hyperadrenocorticism on of a condition (e.g., heart failure and CKD) that stimulates renin
skin fragility, pancreatic endocrine function (diabetes mellitus), secretion to begin the cascade of enzyme activity resulting in aldo-
and the immune system are frequently responsible for morbidity sterone synthesis and secretion. Thus, secondary hyperaldosteron-
and death of both treated as well as untreated cats. Treatment can ism is associated with enhanced renin concentrations.
be expensive, emotional (to the owner), and stressful (to the cat) Sodium retention, associated with primary or secondary aldo-
without guarantee of success. Medical therapy with trilostane has steronism, increases extracellular fluid volume and blood pressure
great promise. Abdominal surgery has not been routinely success- (hypertension). Despite increases in total body sodium content,
ful because of the debilitated condition of most cats with FCS. serum sodium concentrations are usually normal. In cats, because
This problem should be less of a concern if cats can be treated glucocorticoids, estrogens, and progestagens are primarily excreted
|
via bile into the intestines, it is likely that there are similar excre- PU/PD have been described in less than 20% of cats with
tory pathways for aldosterone. PHA. PU/PD may be due to a concurrent condition (e.g., diabe-
PHA has been described rather commonly in cats. Underdiag- tes mellitus, and/or CKD). Alternatively, hypokalemia can cause
nosis, which seems likely, may be traced to the concept that pro- acquired and reversible nephrogenic diabetes insipidus (Harvey
gression of CKD can lead to hypertension, hypokalemia, or both. and Refsal, 2012). Systemic hypertension and hypokalemia have
However, it appears that CKD may also be the result of PHA. been associated with progressive loss of kidney function (Dja-
Regardless, PHA may cause hypertension, hypokalemia, or both jadiningrat-Laanen et al, 2013). About 20% of PHA cats have
(Javadi etal, 2005; Djajadiningrat-Laanen etal, 2011). Hyperten- had decreases in appetite, about 10% have polyphagia, and a few
sion and hypokalemia in cats with CKD are often treated symp- have had worrisome weight loss. Other signs may be related to the
tomatically without further investigation of cause. insulin antagonistic effects of progestagen excess that also is seen
in some cats with PHA.
Etiology Physical examination findings are usually related to hypokale-
mia or to hypertension. Hypertensive ocular signs include reti-
Adrenocortical Neoplasia nal detachment, hemorrhage, tortuous retinal vessels, and retinal
Classically, PHA in cats is caused by a unilateral solitary adre- edema. Weakness due to hypokalemia is consistent with owner
nocortical adenoma or carcinoma. The incidence of malignant observations. Some cats have had muscle atrophy, heart murmur,
tumors (19 reported cases) exceeds that of solitary benign adeno- arrhythmias, palpable adrenal masses (three cats), and fragile skin
mas (11 reported cases). Feline PHA was first reported in 1983 (Djajadiningrat-Laanen etal, 2011).
by Eger and colleagues. In the past 15 years, cats with PHA have
been reported more commonly (Flood etal, 1999; MacKay etal, In-Hospital Routine Testing
1999; Maggio et al, 2000; Moore et al, 2000b; Rijnberk et al, The one abnormality on laboratory testing typical for PHA is
2001; Reimer etal, 2005; Ash etal, 2005; DeClue etal, 2005; hypokalemia, documented in 42 of 50 cats with an adrenal tumor.
Rose etal, 2007; Briscoe etal, 2009; Renschler and Dean, 2009; Several of the remaining eight cats had serum potassium concen-
Djajadiningrat-Laanen etal, 2011; 2013; Lo etal, 2014). Bilat- trations that were low-normal. Only a few differential diagno-
eral adrenal adenomas were identified in two cats. One cat with ses for low potassium are considered common: CKD, diabetic
PHA also had an insulin secreting pancreatic tumor and a para- ketoacidosis (the condition itself, under supplemented IV fluids,
thyroid hormone secreting adenoma. Some cats with PHA have insulin, and bicarbonate all predispose to hypokalemia), acute
had concurrent progestagen excess (DeClue etal, 2005; Briscoe gastrointestinal disease (vomiting, diarrhea, anorexia), and PHA.
etal, 2009), possibly due to enhanced production of intermediary By contrast, about half of cats with adrenal hyperplasia have had
products (Harvey and Refsal, 2012). normal serum potassium concentrations and the others have had
mild hypokalemia (Javadi etal, 2005). Volume expansion due to
Adrenocortical Hyperplasia sodium retention is classic for PHA, but serum sodium con-
Nontumor-related PHA has been described in 13 cats (Javadi centrations are usually within the reference range. About 85% of
et al, 2005; Djajadiningrat-Laanen et al, 2013). Afflicted cats, PHA cats are persistently hypertensive.
at necropsy, were demonstrated to have bilateral adrenocortical A number of cats described as having PHA secondary to adre-
hyperplasia, and most had evidence of CKD. Some cats had zona nal hyperplasia have had CKD with abnormal increases in serum
glomerulosa nodular hyperplasia, renal arteriolar sclerosis, glo- urea and creatinine concentrations. The combination of CKD and
merular sclerosis, tubular atrophy, and interstitial fibrosis (Javadi hypertension would tend to steer clinicians away from a separate
etal, 2005; Harvey and Refsal, 2012). investigation of the hypertension. Cats with adrenal tumors usually
do not have evidence of CKD. Progressive renal damage associated
with aldosterone excess has been implicated in some people due
Clinical Features and In-Hospital Testing
to a combination of increased intraglomerular capillary pressure,
Signalment and Signs inflammation, and fibrosis. This may be associated with excesses
There does not appear to be a breed predisposition among cats in angiotensin II and the chronic hypokalemia of CKD. Hypergly-
diagnosed with PHA. The mean age at diagnosis is about 12 to cemia is not common, nor are abnormalities in serum phosphate.
13 years and most are more than 10 years of age. Both genders Abdominal ultrasonography is a valuable diagnostic aid when
have been represented, and most have been neutered. The most assessing unexplained hypertension. Ultrasonography provides
common clinical sign has been persistent and progressive weak- information regarding renal and adrenal anatomy, especially when
ness associated with hypokalemia, called hypokalemic polymyopathy searching for an adrenal nodule. Cats with an adrenocortical
(Harvey and Refsal, 2012). Usually seen at serum potassium con- tumor evaluated with ultrasonography typically have had a 1 to 5
centrations less than 3 mg/dL, the most common owner obser- cm diameter adrenal mass (Harvey and Refsal, 2012). The contra-
vations have included cervical ventriflexion, hind limb weakness lateral adrenal is usually considered small. Bilateral adrenal tumors
(sometimes plantigrade), difficulty jumping, listlessness, and are not common (Quante etal, 2009). Adrenal masses that extend
ataxia. A few cats have had limb rigidity, dysphagia, or collapse. into or invade the vena cava or other vessels are called tumor
Some cats had episodic signs and a few had signs that were sudden thrombi. The liver, retroperitoneum, and other areas should be
in onset. Weakness was less worrisome in cats with adrenal hyper- evaluated for evidence of metastases or unsuspected abnormalities.
plasia (Javadi etal, 2005). Abdominal CT or MRI examinations correctly detected a mass
The second most common owner-perceived concern in cats with or hyperplasia in 32 of 38 cats with confirmed PHA (Flood etal,
PHA has been associated with hypertension. Some hypertensive 1999; MacKay etal, 1999; Rijnberk etal, 2001; Ash etal, 2005;
cats have had acute blindness and/or sudden change in eye color, DeClue etal, 2005; Javadi etal, 2005; Rose etal, 2007; Renschler
usually due to intraocular hemorrhage or retinal detachments. and Dean, 2009; Djajadiningrat-Laanen et al, 2013; Lo et al,
Ocular signs are not as common in cats with adrenal tumors as 2014). Cats with non-tumor PHA do not have abnormal adrenals
they are in those with adrenal hyperplasia. other than a few with subtle increases in adrenal echogenicity.
Confirming a Diagnosis: Plasma Aldosterone Concentrations and Provocative Mineralocorticoid Function Testing
Abdominal Imaging The combination of owner-observed weakness, hypokale-
PHA should be strongly considered in any cat with an adrenal mia documented on routine blood chemistry, an adrenal
nodule identified on ultrasonography and unexplained hypoka- nodule visualized on ultrasonography, and an increased ran-
lemia or hypertension. The condition should also be suspected domly obtained circulating aldosterone concentration have
in hypertensive cats refractory to therapy. Randomly obtained proven quite sensitive and specific for diagnosing PHA. It
plasma aldosterone concentrations (PACs) have been above the is assumed that cats early in the course of their disease and
reference range in 43 of 50 cats with a solitary adrenal mass those with a mild condition may not have all these abnor-
(Djajadiningrat-Laanen etal, 2011; Lo etal, 2014). In this sce- malities. Assessing aldosterone concentrations before and after
nario, PHA is the most likely diagnosis, and a recommendation ACTHST has not improved sensitivity and is not recom-
of surgery is supported. Aldosterone assays are widely available mended. However, cats with PHA have been reported to have
through commercial veterinary laboratories. Sample collection normal-to-low baseline serum cortisol concentrations with
requirements are routine (Harvey and Refsal, 2012). Extremely subnormal cortisol responses to ACTH (DeClue et al, 2011;
high PACs have been reported in cats with PHA and in cats with Harvey and Refsal, 2012; Eiler etal, 2013). Excesses in aldoste-
CKD (Yu and Morris, 1998). rone, its precursors, or other adrenocortical products may sup-
Diagnostic imaging with ultrasonography, MRI, and CT has press endogenous ACTH synthesis and secretion sufficiently to
been utilized to identify adrenal abnormalities, to evaluate for account for the apparent decreases in cortisol. If true, this may
vascular invasion, and to attempt visualization of local or dis- help explain the poor appetite observed in some PHA cats.
tant metastases. Absence of vascular invasion seen on imaging Fludrocortisone (a synthetic mineralocorticoid described
is not a guarantee that it does not exist. Although logic suggests in Chapter 12) promotes sodium retention, water retention,
that some adrenal masses may be too small to be detected, most and an increase in blood volume. In cats with a healthy renin-
have been easily visualized. Visualizing an adrenal mass does not angiotensin-aldosterone system, fludrocortisone administration
indicate its function. In a study on people, 38% of CT/MRI should suppress renin and aldosterone concentrations. Cats with
scans did not accurately identify the source of aldosterone excess PHA should be refractory to this effect. In studies of 23 healthy
(Kempers etal, 2009). Thus, while extremely helpful, imaging and one PHA cat, fludrocortisone given for 4 days at a dose of
is not a perfect screening test for PHA (Djajadiningrat-Laanen 0.05 mg/kg b.i.d. caused significant decreases in the healthy cats
etal, 2011). Use of positron emission tomography (PET) or sin- UA:CR but not so for the cat with PHA (Djajadiningrat-Laanen
gle photon emission computed tomography (SPECT) may prove etal, 2008; 2011; Matsuda etal, 2013). In a subsequent study of
valuable but have not yet been assessed. nine PHA cats and 10 non-PHA cats that were hypertensive and/
or hypokalemic, results were not as sensitive as simply measur-
Confirming a Diagnosis: Ratio of Urine Aldosterone to Creatinine ing the serum aldosterone concentration. PACs were abnormal
The urine aldosterone-to-creatinine ratio (UA:CR) theoreti- in all PHA cats, whereas results were within or near the limit of
cally provides a reflection of aldosterone concentrations over the reference range in the non-PHA cats (Djajadiningrat-Laanen
time. This test is not widely available. It has the advantages of etal, 2013). Guidelines for provocative testing in people include
urine not needing to be immediately frozen, and urine is easily assuring that serum potassium concentrations are normal before
collected. The UA:CR is often abnormal in cats with PHA, but testing. Also, before testing, discontinuation of most medica-
sensitivity was less than with the random serum aldosterone tions for 2 to 4 weeks is recommended. Use of provocative test-
assessment. The reference interval of the UA:CR is large and ing may prove valuable as additional studies are completed. At
did not facilitate differentiation between healthy cats and those this time, our recommended approach to a cat that may have
with PHA (Djajadiningrat-Laanen et al, 2008). A cat whose PHA is to assess each adrenal via ultrasonography and to mea-
PAC is lower than anticipated may be in the early stages of sure PAC if a nodule or mass is identified or suspected.
this condition or may have simple minute-to-minute serum
fluctuations. Treatment
Confirming a Diagnosis: Plasma Aldosterone Removal of an adrenal tumor is the treatment of choice for cats with
and Renin Concentrations PHA (Rose et al, 2007). Such masses can be removed via celiotomy
Ideally, circulating aldosterone concentrations should be co- or laparoscopy. Assessing each cat for tumor thrombi and for metas-
assessed with the renin concentration. Individuals with PHA tases is imperative before considering surgery. Preoperatively, hypo-
(tumor) should have increases in plasma aldosterone and kalemia should be treated with oral and/or parenteral potassium.
decreases in plasma renin concentrations, whereas both would After surgery, a high sodium diet has been recommended, although
be increased in CKD. The aldosterone-to-renin ratio (ARR) most PHA cats have not been so-treated (Djajadiningrat-Laanen
has been utilized to improve sensitivity and specificity, but et al, 2011). Temporary administration of oral fludrocortisone
reliable renin assays are not yet widely available, those results acetate or injectable DOCP could be administered post-surgically
reported in PHA cats have been variable and not highly spe- to manage hypoaldosteronism, but this has not usually been nec-
cific (Harvey and Refsal, 2012). In cats with adrenal tumors, essary (Lo etal, 2014). Perioperative complications have included
the ARR can be quite increased, but in cats with idiopathic hemorrhage, lethargy, anemia, anorexia, vomiting, dysphagia,
bilateral nodular hyperplasia, the ARR may be less impressive. hyperthermia, upper respiratory infection, and acute kidney failure
Although the ARR is the gold standard for PHA screening, (Djajadiningrat-Laanen etal, 2011; Lo etal, 2014). Hemorrhage
disadvantages of this test include the necessity for large blood was not predicted by tumor type, location, size, or vascular invasion.
samples, plasma must be instantly frozen, renin values may The cats that have survived the perioperative period have generally
vary among laboratories, and repeat testing may be required normalized and have an excellent long-term prognosis.
because an unremarkable result does not rule out PHA (Javadi Cats with an unresectable mass, metastases, owners who choose
etal, 2004; 2005; Djajadiningrat-Laanen etal, 2011) not to have surgery on their cat, and cats with adrenal hyperplasia
|
are managed medically via potassium supplementation and con- In-Hospital Testing
trol of the hypertension. Spironolactone is the aldosterone recep- The veterinarian, when learning any of these owner concerns
tor blocker most often employed at a dose of 2 mg/kg of body or in attempting to treat a cat for diabetes or hypertension, for
weight orally b.i.d. to help control the hypokalemia. Doses in example, will attempt to find an explanation by conducting a
excess of 4 mg/kg have been associated with anorexia, vomiting, logical, practical, and cost effective approach. This often begins
and diarrhea. Hypertension may be treated with dihydropyridine with routine blood and urine testing. Other than persistent
calcium channel antagonists (e.g., amlodipine) either alone or in hyperglycemia and glycosuria in some cats, CBC or serum
combination with a beta-adrenergic blocker or an angiotension- biochemistry abnormalities are not common in cats with sex-
converting enzyme inhibitor (Brown etal, 2007). Cats with bilat- hormone-secreting adrenocortical tumors. Imaging studies are
eral adrenal hyperplasia have more mild increases in PAC and can the next tests utilized. Thoracic radiographs as a health screen
be maintained on medical therapy for extended time periods, but usually follow abdominal ultrasound. Ultrasound is preferred
their prognosis is far more guarded (Djajadiningrat-Laanen etal, over radiographs because the concerns established for these cats
2011; Harvey and Refsal, 2012; Lo etal, 2014). involve potential pancreatic or adrenal abnormalities. Ultra-
sound is superior in evaluating these structures. Virtually every
cat diagnosed with an adrenocortical tumor has had an adre-
EXCESSIVE SEX HORMONESECRETING ADRENAL
nal mass visualized on abdominal ultrasonography. Once such
TUMORS IN CATS
a mass is identified, the logical next step is to rule out meta-
static disease. The ultrasound examination should have included
Background
thorough evaluation of the area around the suspected mass for
Adrenocortical tumors have the potential for synthesizing and vascular or tissue invasion and the liver for possible spread. The
secreting a variety of steroid products other than cortisol and lungs should be screened as well via radiographs. This allows
aldosterone. This physiologic process may be associated with neo- thorough evaluation of the thorax for suspected or unsuspected
plasia-related aberrant biosynthetic pathways and/or enzyme defi- issues. Assuming that an owner wishes to proceed and, ideally,
ciencies. Specific precursors may accumulate due to one of these if no evidence of metastasis is seen, hormone testing should be
biosynthetic pathway blockages that would enhance alternative considered.
biochemical pathways to be followed, with synthesis of alternate Most cats with a progestagen or androgen producing adrenal
products. Androgen, estrogen, and progestagen-secreting adreno- tumor have had low-normal or low basal and post-ACTHST
cortical tumors have been diagnosed in people, dogs, and cats. plasma cortisol concentrations. Similar results have been noted
Natural progesterone has a half-life in the blood of only a few min- for LDDST and UC:CR. Thus, if a cat appears to have FCS
utes and serves as a precursor for androgens, estrogens, mineralo- but does not have the expected abnormalities on screening
corticoids, and glucocorticoids in many mammals. Progesterone test results, consideration of a sex hormone disorder is reason-
binds to albumin as well as cortisol-binding and sex-hormone- able. Hormone concentrations that may be increased include
binding proteins. Theoretically, chronic excesses in progesterone 17-hydroxyprogesterone, progesterone, estradiol, testoster-
results in excess free cortisol via their ability to competitively one, and/or androstenedione (Melian, 2012). Most cats with a
bind to cortisol-binding proteins in the circulation, simulating the sex-hormone secreting adrenocortical tumor have had excessive
actions of glucocorticoids. These physiologic processes, including basal concentrations of the hormone. Thus, for these adrenal
insulin resistance, have been demonstrated in people, dogs, and tumors, basal hormone evaluations appear indicative of the
cats (Selman et al, 1994; 1996; Syme et al, 2001). It has been underlying physiologic abnormalities. This should negate need
suggested that adrenal tumors that synthesize steroids other than for ACTHST. However, the test is recommended to further sub-
cortisol are usually carcinomas (Melian, 2012). stantiate one of these unusual diagnoses (Millard et al, 2009;
Melian, 2012).
Clinical Features
Signalment and Signs Treatment and Prognosis
A relatively limited number of cats with increased secretion of pro- Surgical or laparoscopic removal of an adrenocortical tumor is the
gestagens or other sex hormones from adrenal gland tumors has treatment of choice. Readers are encouraged to review that section
been described (Boord and Grifn, 1999; Rossmeisl etal, 2000; earlier in the chapter regarding perioperative and long-term care.
Boag etal, 2004; DeClue etal, 2005; Millard etal, 2009; Blois Whenever a cat has clinical evidence of FCS, preoperative treat-
etal, 2010; Meler etal, 2011). Some cats have had excesses in pro- ment with trilostane may reduce morbidity and mortality. Readers
gestagens with typical signs of FCS. A few cats have had increased are encouraged to review the sections on trilostane earlier in this
androgen concentrations (Rossmeisl etal, 2000; Boag etal, 2004; chapter. Prognosis depends on presence of metastasis, successful
Millard etal, 2009). A cat with androgen excess may have facial removal of the tumor, how stable the cat is prior to treatment, and
enlargement, typical male territorial urine spraying behavior, pro- a myriad of other factors.
duce urine with an unusually strong odor, and act aggressively. A One male cat in our series was treated with aminoglutethimide
castrated male cat developed penile spines (Millard etal, 2009). (AGT; a drug we no longer recommend) for about 6 weeks in
Cats with excess progestagens are most likely to have clinical signs preparation for surgery. The cat did clinically improve dramati-
of FCS. To summarize, owners may be concerned about nonpru- cally with resolution of its thin fragile skin and diabetes mellitus.
ritic, progressive, symmetric alopecia; greasy and unkempt hair; or As the cat improved, it also developed dramatic mammary gland
thin, easily bruised, fragile skin (see Fig. 11-3). Some owners may be enlargement likely due to rapid decrease in plasma progesterone
concerned about their cats diabetes mellitus or be frustrated with the concentrations that stimulated, in turn, synthesis and secretion of
difficulty in controlling the diabetes. Other owners have observed prolactin. After AGT was discontinued, our surgeons were able
weakness, sudden blindness or changes in eye color (hypertension), to successfully remove the adrenal tumor. Successful surgery has
polyphagia, unusual behavior, PU/PD, or abdominal distension. also been reported in several other cats (Boord and Grifn, 1999).
REFERENCES
Ash RA, etal.: Primary hyperaldosteronism in Djajadiningrat-Laanen SC, etal.: Primary Graves TK: Hypercortisolism in cats (feline
the cat: a series of 13 cases, J Feline Med hyperaldosteronism: expanding the diagnos- Cushings syndrome). In Ettinger SJ,
Surg 7:173, 2005. tic net, J Feline Med Surg 13:641, 2011. Feldman EC, editors: Textbook of veteri-
Barthez PY, etal.: Ultrasonographic evaluation Djajadiningrat-Laanen SC, etal.: Evaluation of nary internal medicine, ed 7, St Louis,
of the adrenal glands in dogs, J Am Vet the oral fludrocortisone suppression test 2010, Saunders/Elsevier, p 1840.
Med Assoc 207:1180, 1995. for diagnosing primary hyperaldosteronism Green CE, etal.: Iatrogenic hyperadrenocorti-
Benchekroun G, etal.: Plasma ACTH precur- in cats, J Vet Intern Med 27:1493, 2013. cism in a cat, Feline Pract 23:7, 1995.
sors in cats with pituitary-dependent Douma S, etal.: Prevalence of primary hyper- Gunn-Moore D: Feline endocrinopathies, Vet
hyperadrenocorticism, J Vet Intern Med aldosteronism in resistant hypertension: a Clin Small Anim 35:171, 2005.
26:575, 2012. retrospective observational study, Lancet Halmi NS, Krieger D: Immunocytochemistry
Blois SL, etal.: Multiple endocrine diseases in 371:1921, 2008. of ACTH-related peptides in the hypophy-
cats: 15 cases (1997-2008), J Feline Med Duesberg CA, etal.: Adrenalectomy for sis. In Bhatnagar AS, editor: The anterior
Surg 12:637, 2010. treatment of hyperadrenocorticism in cats: pituitary gland, New York, 1983, Raven
Boag AK, etal.: Trilostane treatment of bilat- 10 cases (1988-1992), J Am Vet Med Press, pp 115.
eral adrenal enlargement and excessive sex Assoc 207:1066, 1995. Harvey AM, Refsal KR: Feline hyperaldosteron-
hormone production in a cat, J Small Anim Duesberg CA, Peterson ME: Adrenal disorders ism. In Mooney CT, Peterson ME, editors:
Pract 45:263, 2004. in cats, Vet Clin North Am Small Anim Manual of small animal endocrinology,
Boord M, Grifn C: Progesterone secreting Pract 27:321, 1997. ed 4, Cheltenham, 2012, British Small
adrenal mass in a cat with clinical signs of Eger CE, etal.: Primary aldosteronism (Conns Animal Veterinary Association, p 204.
hyperadrenocorticism, J Am Vet Med Assoc syndrome) in a cat: a case report and re- Henry CJ, etal.: Urine cortisol:creatinine ratio
214:666, 1999. view of comparative aspects, J Small Anim in healthy and sick cats, J Vet Int Med
Brightman AH: Ophthalmic use of glucocorti- Pract 24:293, 1983. 10:123, 1996.
coids, Vet Clin North Am Small Anim Pract Eiler KC, etal.: Comparison of intravenous Hoenig M: Feline hyperadrenocorticismwhere
12:33, 1982. versus intramuscular administration of are we now? J Feline Med Surg 4:171,
Briscoe K, etal.: Hyperaldosteronism and corticotropin-releasing hormone in healthy 2002.
hyperprogesteronism in a cat, J Feline Med cats, J Vet Intern Med 27:516, 2013. Horauf A, Reusch C: Darstellung der nebennie-
Surg 11:758, 2009. Engelhardt D, etal.: The influence of ketocon- ren mittels ultraschall: untersuchungen bei
Brown S, etal.: Guidelines for the identifica- azole on human adrenal steroidogenesis: gesunden hunden, hunden mit nicht en-
tion, evaluation, and management of incubation studies with tissue slices, Clin dokrinen Erkrankungen sowie mit Cushing-
systemic hypertension in dogs and cats, Endocrinol 35:163, 1991. Syndrom, Kleintierpraxis 40:337, 1995.
J Vet Intern Med 21:542, 2007. Feelders RA, etal.: Medical treatment of Cush- Immink WF, etal.: Hyperadrenocorticism in four
Cartee RE, Finn-Bodner ST: Ultrasound exami- ings syndrome: adrenal-blocking drugs cats, Vet Q 14:81, 1992.
nation of the feline adrenal gland, J Med and ketaconazole, Neuroendocrinology Javadi S, etal.: Plasma renin activity and plas-
Sonography 9:327, 1993. 92(Suppl 1):111, 2010. ma concentrations of aldosterone, cortisol,
Chakere DW, etal.: Magnetic resonance imag- Feldman EC: The effect of functional adre- adrenocorticotropic hormone, and alpha-
ing of pituitary and parasellar abnormali- nocortical tumors on plasma cortisol and melanocyte-stimulating hormone in healthy
ties, Radio Clin North Am 27:265, 1989. corticotropin concentrations in dogs, J Am cats, J Vet Intern Med 18:625, 2004.
Coates PJ, etal.: The distribution of Vet Med Assoc 178:823, 1981. Javadi S, etal.: Primary hyperaldosteronism,
immunoreactive-melanocyte-stimulating Feldman EC, Nelson RW: Hyperadrenocorti- a mediator of progressive renal disease
hormone cells in the adult h uman pitu- cism in cats (Cushings syndrome). In in cats, Domest Anim Endocrinol 28:85,
itary gland, J Endocrinol 111:335, 1986. Feldman EC, Nelson RW, editors: Canine 2005.
Conn JW: Primary hyperaldosteronism: a new and feline endocrinology and reproduction, Kaufman B: Magnetic resonance imaging of
clinical syndrome, J Lab Clin Med 45:3, ed 3, Philadelphia, 2004, Elsevier/Saun- the pituitary gland, Radio Clin North Am
1955. ders, p 358. 22:795, 1984.
Corradini PA, etal.: Evaluation of hair cortisol Ferasin L: Iatrogenic hyperadrenocorticism in a Kempers MF, etal.: Systematic review: diag-
in the diagnosis of hypercortisolism in cat following a short therapeutic course of nostic procedures to differentiate unilateral
dogs, J Vet Intern Med 27:1268, 2013. methylprednisolone acetate, J Feline Med from bilateral adrenal abnormality in
Daley CA, etal.: Use of metyrapone to treat Surg 3:87, 2001. primary aldosteronism, Ann Intern Med
pituitary-dependent hyperadrenocorticism Flood SM, etal.: Primary hyperaldosteron- 151:329, 2009.
in a cat with large cutaneous wounds, ism in two cats, J Am Anim Hosp Assoc Kley S, etal.: Evaluation of the low-dose
J Am Vet Med Assoc 202:956, 1993. 35:411, 1999. dexamethasone suppression test and
DeClue AE, etal.: Hyperaldosteronism and Fogari R, etal.: Prevalence of primary hyperal- ultrasonographic measurements of the
hyperprogesteronism in a cat with an dosteronism among unselected hyperten- adrenal glands in cats with diabetes mel-
adrenal cortical carcinoma, J Vet Intern sive patients: a prospective study based on litus, Schweizer Archiv fur Tierheilkunde
Med 19:355, 2005. the use of an aldosterone/renin ratio above 149:493, 2007.
DeClue AE, etal.: Cortisol and aldosterone 25 as a screening test, Hypertens Res Lien Y, etal.: Iatrogenic hyperadrenocorti-
response to various doses of cosyntropin 30:111, 2007. cism in 12 cats, J Am Anim Hosp Assoc
in healthy cats, J Am Vet Med Assoc Goossens MMC, etal.: Urinary excretion of 42:414, 2006.
238:176, 2011. glucocorticoids in the diagnosis of hyper- Lo AJ, etal.: Treatment of aldosterone-secreting
de Lange MS, etal.: High urinary corticoid/ adrenocorticism in cats, Domestic Anim adrenocortical tumors in cats by unilateral
creatinine ratios in cats with hyperthyroid- Endocrinol 12:355, 1995. adrenalectomy: 10 cases (2002-2012),
ism, J Vet Intern Med 18:152, 2004. Graham-Mize CA, etal.: Absorption, bioavail- J Vet Int Med 28:137, 2014.
Djajadiningrat-Laanen SC, etal.: Urinary ability and activity of prednisone and pred- Low MJ, etal.: Post-translational processing
aldosterone to creatinine ratio in cats nisolone in cats. In Hillier A, Foster AP, of pro-opiomelanocortin (POMC) in mouse
before and after suppression with salt or Kwochka KW, editors: Advances in pituitary melanotroph tumors induced by
fludrocortisone acetate, J Vet Intern Med veterinary dermatology, vol 5. Vienna, a POMC-Simian virus 40 large T antigen
22:1283, 2008. 2004, Blackwell Publishing, p 152. transgene, J Biol Chem 268:24967, 1993.
|
Lowe AD, etal.: A comparison of the diabe- Neiger R, etal.: Trilostane therapy for treat- Renschler JS, Dean GA: What is your diagno-
togenic effects of dexamethasone and ment of pituitary-dependent hyperadre- sis? Abdominal mass aspirate in a cat with
prednisolone in cats, Twenty-second Pro- nocorticism in 5 cats, J Vet Intern Med an increased Na:K ratio, Vet Clin Pathol
ceedings of the North American Veterinary 18:160, 2004. 38:69, 2009.
Dermatology Forum, Kauai 178, 2007. Nelson RW, etal.: Hyperadrenocorticism in Rijnberk A: Pituitary-dependent hyperadreno-
Lowe AD, etal.: Clinical, clinicopathological cats: seven cases (1978-1987), J Am Vet corticism. In Rijnberk A, editor: Clinical
and histological changes observed in 14 Med Assoc 193:245, 1988. endocrinology of dogs and cats, Dordrecht,
cats treated with glucocorticoids, Vet Rec Nieman LK: Adrenal cortex. In Goldman L, The Netherlands, 1996, Kluwer Academic
162:777, 2008. Schafer AI, editors: Goldmans Cecil medi- Publishers, pp 7483.
MacKay AD, etal.: Successful surgical treat- cine, ed 24, Philadelphia, 2012, Elsevier/ Rijnberk A, etal.: Hyperaldosteronism in a cat
ment of a cat with primary aldosteronism, Saunders, p 1463. with metastasised adrenocortical tumour,
J Feline Med Surg 1:117, 1999. Orth DN: Metyrapone is useful only as adjunc- Vet Q 23:38, 2001.
Maggio F, etal.: Ocular lesions associated with tive therapy in Cushings disease, Ann Robinson AJ, Clamann HP: Effects of gluco-
systemic hypertension in cats: 69 cases Intern Med 89:128, 1978. corticoids on motor units in cat hindlimb
(1985-1998), J Am Vet Med Assoc Peterson ME: Endocrine disorders in cats: four muscles, Muscle Nerve 11:703, 1988.
217:695, 2000. emerging diseases, Compend Contin Educ Rose SA, etal.: Adrenalectomy and caval
Matsuda, etal.: Suppression of serum aldoste- Pract Vet 10:1353, 1988. thrombectomy in a cat with primary hy-
rone following oral administration of fludro- Peterson ME: Feline hyperadrenocorticism. In peraldosteronism, J Am Anim Hosp Assoc
cortisone acetate in healthy cats (abstract), Torrance AG, Mooney CT, editors: Manual 43:209, 2007.
J Vet Intern Med 27:687, 2013. of small animal endocrinology, ed 2, Rossmeisl JH, etal.: Hyperadrenocorticism
Mayer NM, etal.: Outcomes of pituitary tumor Cheltenham, 1998, British Small Animal and hyperprogesteronemia in a cat with
irradiation in cats, Veterinary Association, p 215. an adrenocortical adenocarcinoma, J Am
J Vet Intern Med 20:1151, 2006. Peterson ME: Feline hyperadrenocorticism. In Anim Hosp Assoc 36:512, 2000.
Meij BP, etal.: Transsphenoidal hypophysecto- Mooney CT, Peterson ME, editors: Manual Sallanon M, etal.: Hypophysectomy does not
my in beagle dogs: evaluation of a microsur- of small animal endocrinology, ed 4, disturb the sleep-waking cycle in the cat,
gical technique, Vet Surg 26:295, 1997. Cheltenham, 2012, British Small Animal Neurosci Lett 88:173, 1988.
Meij BP, etal.: Transsphenoidal hypophysec- Veterinary Association, p 190. Schacke H, etal.: Mechanisms involved in the
tomy for treatment of pituitary-dependent Peterson ME, Graves TK: Effects of low dosag- side effects of glucocorticoids, Pharmacol
hyperadrenocorticism in 7 cats, Vet Surg es of intravenous dexamethasone on serum Ther 96:23, 2002.
30:72, 2001. cortisol concentrations in the normal cat, Schaer M, Ginn PE: Iatrogenic Cushings syn-
Meijer JC, etal.: Cushings syndrome due to Res Vet Sci 44:38, 1988. drome and steroid hepatopathy in a cat,
adrenocortical adenoma in a cat, Tijdschr Peterson ME, Kemppainen RJ: Comparison of J Am Anim Hosp Assoc 35:48, 1999.
Diergeneesk 103:1048, 1978. intravenous and intramuscular routes for Schoeman JP, etal.: Cortisol response to two
Melby JC: Therapy of Cushings disease: a administering cosyntropin for corticotropin different doses of intravenous synthetic
consensus for pituitary microsurgery, Ann stimulation testing in cats, Am J Vet Res ACTH (tetracosactrin) in overweight cats,
Int Med 109:445, 1988. 53:1392, 1992a. J Small Anim Pract 41:552, 2000.
Meler EN, etal.: Cyclic estrous-like behavior Peterson ME, Kemppainen RJ: Comparison of Scholten-Sloof BE, etal.: Pituitary-dependent
in a spayed cat associated with excessive the immunoreactive plasma corticotropin hyperadrenocorticism in a family of Dandie
sex-hormone production by an adrenocorti- and cortisol responses to two synthetic Dinmont terriers, J Endocrinol 135:535,
cal carcinoma, J Feline Med Surg 13:473, corticotropin preparations (tetracosactrin 1992.
2011. and cosyntropin) in healthy cats, Am J Vet Schwedes CS: Mitotane (o,p-DDD) treatment
Melian C: Investigation of adrenal masses. In Res 53:1752, 1992b. in a cat with hyperadrenocorticism,
Mooney CT, Peterson ME, editors: BSAVA Peterson ME, Kemppainen RJ: Dose response J Small Anim Pract 38:520, 1997.
manual of canine and feline endocrinol- relation between plasma concentrations of Scott DW, etal.: Some effects of short-term
ogy, ed 4, Gloucester, 2012, British Small corticotropin and cortisol after administra- methylprednisolone therapy in normal cats,
Animal Veterinary Association, p 272. tion of incremental doses cosyntropin for Cornell Vet 69:104, 1979.
Mellett Keith AM, etal.: Trilostane therapy for corticotropin stimulation testing in cats, Scott DW, etal.: Iatrogenic Cushings syn-
treatment of spontaneous hyperadrenocor- Am J Vet Res 54:300, 1993. drome in the cat, Fel Pract 12:30, 1982.
ticism in cats: 15 cases (2004-2012), Peterson ME, Steele P: Pituitary-dependent Sellon RK, etal.: Linear-accelerator-based
J Vet Intern Med 27:1471, 2013. hyperadrenocorticism in a cat, J Am Vet modified radiosurgical treatment of pituitary
Millard RP, etal.: Excessive production of sex Med Assoc 189:680, 1986. tumors in cats: 11 cases (1997-2008),
hormones in a cat with an adrenocortical tu- Peterson ME, etal.: Immunocytochemical J Vet Intern Med 23:1038, 2009.
mor, J Am Vet Med Assoc 234:505, 2009. study of the hypophysis in 25 dogs with Selman PJ, etal.: Progestin treatment in
Molitch ME: Anterior Pituitary. In Goldman L, pituitary-dependent hyperadrenocorti- the dog, II: effects on the hypothalamic-
Schafer AI, editors: Goldmans Cecil medi- cism, Acta Endocrinol (Copenh) 101:15, pituitary-adrenocortical axis, Eur J
cine, ed 24, Philadelphia, 2012, Elsevier/ 1982. Endocrinol 131:422, 1994.
Saunders, p 1431. Peterson ME, et al.: Endocrine diseases. In Selman PJ, etal.: Binding specicity of me-
Moon PF: Cortisol suppression in cats after Sherding RG, editors: The cat: diagnosis droxyprogesterone acetate and proligestone
induction of anesthesia with etomidate, and clinical management, ed 2, New York, for the progesterone and glucocorticoid re-
compared with ketamine-diazepam combi- 1994, Churchill Livingstone, pp 1404. ceptor in the dog, Steroids 61:133, 1996.
nation, Am J Vet Res 58:868, 1997. Quante S, etal.: Hyperprogesteronism due to Skelly BJ, etal.: Use of trilostane for the
Moore LE, etal.: Hyperadrenocorticism treated bilateral adrenal carcinomas in a cat with treatment of pituitary-dependent hyperad-
with metyrapone followed by bilateral ad- diabetes mellitus, Schweizer Archiv fur renocorticism in a cat, J Small Anim Pract
renalectomy in a cat, J Am Vet Med Assoc Tierheilkunde 151:437, 2009. 44:269, 2003.
217:691, 2000a. Reaves TA Jr, etal.: Vasopressin release by Smith MC, Feldman EC: Plasma endogenous
Moore LE, etal.: Use of abdominal ultrasonog- nicotine in the cat, Peptides 2:13, 1981. ACTH concentrations and plasma cortisol
raphy in the diagnosis of primary hyperal- Reimer SB, etal.: Multiple endocrine neoplasia responses to synthetic ACTH and dexa-
dosteronism in a cat, J Am Vet Med Assoc type 1 in a cat, J Am Vet Med Assoc methasone sodium phosphate in healthy
217:213, 2000b. 227:101, 2005. cats, Am J Vet Res 48:1719, 1987.
Smith RR, etal.: Laparoscopic adrenalectomy Thorner MO, etal.: Approach to pituitary Watson PJ, Herrtage ME: Hyperadrenocorticism
for management of a functional adre- disease. In Wilson JD, Foster DW, editors: in six cats, J Small Anim Pract 39:175,
nal tumor in a cat, J Am Vet Med Assoc Williams textbook of endocrinology, ed 8, 1998.
241:368, 2012. Philadelphia, 1992, WB Saunders, White PC: Disorders of aldosterone biosynthesis
Snyckers FD: Transsphenoidal selective anterior p 246. and action, N Engl J Med 331:250, 1994.
hypophysectomy in cats for microsurgical Tuckermann JP, etal.: Molecular mechanisms Willard MD, etal.: Effect of long-term admin-
training: technical note, J Neurosurgery of glucocorticoids in the control of inflam- istration of ketoconazole in cats, Am J Vet
43:774, 1975. mation and lymphocyte apoptosis, Crit Rev Res 47:2510, 1986.
Sparkes AH, etal.: Assessment of adrenal Clin Lab Sci 42:71, 2005. Young WF: Primary aldosteronism: renaissance
function in cats: response to intravenous Valentin SY, etal.: Comparison of diagnostic of a syndrome, Clin Endocrinol 66:607,
synthetic ACTH, J Small Anim Pract 31:2, tests and treatment options for feline hyper- 2007.
1990. adrenocorticism: a retrospective review of Yu S, Morris JG: Plasma aldosterone concentra-
Stalla GK, etal.: Ketoconazole inhibits cortico- 32 cases, J Vet Intern Med 28:481, 2014. tion of cats, Vet J 155:63, 1998.
tropic cell function invitro, Endocrinology Van Wijk PA, etal.: Corticotropin-releasing Zerbe CA, etal.: Hyperadrenocorticism in
122:618, 1988. hormone and adrenocorticotropic hormone a cat, J Am Vet Med Assoc 190:559,
Swift GA, Brown RH: Surgical treatment of concentrations in cerebrospinal fluid of 1987a.
Cushings syndrome in the cat, Vet Rec dogs with pituitary-dependent hyperadreno- Zerbe CA, etal.: Effect of nonadrenal illness on
99:374, 1976. corticism, Endocrinology 131:2659, 1992. adrenal function in the cat, Am J Vet Res
Syme HM, etal.: Hyperadrenocorticism as- Vaughan MA, etal.: Evaluation of twice daily, 48:451, 1987b.
sociated with excessive sex hormone low-dose trilostane treatment administered Zhan GL, etal.: Steroid glaucoma: corticoste-
production by an adrenocortical tumor in orally in dogs with naturally occurring roid-induced ocular hypertension in cats,
two dogs, J Am Vet Med Assoc 219:1725, hyperadrenocorticism, J Am Vet Med Assoc Exp Eye Research 54:211, 1992.
2001. 232:1321, 2008. Zimmer C, etal.: Ultrasonographic examination
Stein AL, etal.: Computed tomography versus Verheist JA, etal.: Short and long-term of the adrenal gland and evaluation of the
magnetic resonance imaging for the evalu- responses to metyrapone in the medical hypophyseal-adrenal axis in 20 cats,
ation of suspected pituitary adenomas, management of 91 patients with Cushings J Small Anim Pract 41:156, 2000.
Obstet Gynecol 73:996, 1989. syndrome, Clin Endocrinol 35:169, 1991.
Theon A: Practical radiation therapy. In Wallack ST, etal.: Mensuration of the pituitary
Ettinger SJ, Feldman EC, editors: Textbook gland from magnetic resonance images in
of veterinary internal medicine, ed 5, Phila- 17 cats, Vet Radiol Ultrasound 44:278,
delphia, 2000, WB Saunders, p 489. 2003.
CHAPTER 12 Hypoadrenocorticism
CHAPTER CONTENTS Plasma Aldosterone Concentration, 506

Background, 485 Aldosterone-to-Renin Ratio, 507
Adrenal Physiology, 486 Cortisol-to-Creatinine Ratio, 507
Glucocorticoids, 486 Critical Illness Induced Corticosteroid Insufficiency (Relative Adrenal
Mineralocorticoids, 486 Insufficiency), 508
Primary Versus Secondary Hypoadrenocorticism, 489 Treatment of Hypoadrenocorticism, 508
Glucocorticoid Deficiency Versus Mineralocorticoid Deficiency, 489 Acute Management, 508
Primary Adrenocortical Failure, 490 Long-Term (Maintenance) Therapy, 510
Polyglandular Autoimmune Syndromes, 492 Glucocorticoid Therapy, 510
Secondary Adrenocortical Failure, 492 Mineralocorticoid Therapy, 511
Spontaneous Secondary Hypoadrenocorticism, 492 Treatment of Hypoadrenocorticism in the Absence
Iatrogenic Secondary Hypoadrenocorticism, 492 of Electrolyte Abnormalities, 513
Signalment, 492 Poor Response to Therapy, 513
History, 493 Confirming the Diagnosis After Treatment has Already been Initiated, 513
Physical Examination, 494 Management of Hypoadrenocorticism During Stressful Events, 513
Clinical Pathology, 494 Prognosis, 513
Hematology, 494 Iatrogenic Hypoadrenocorticism, 514
Serum Electrolyte Abnormalities, 495 Medical Treatment of Hyperadrenocorticism, 514
Azotemia, 498 Withdrawal of Chronic Glucocorticoid Therapy, 514
Low Urine Specific Gravity, 498 Feline Hypoadrenocorticism, 514
Hypoglycemia, 498 Etiology, 514
Hypoalbuminemia and Hypocholesterolemia, 498 Signalment and Clinical Signs, 514
Hepatic Dysfunction, 498 Laboratory, Radiographic, and Electrocardiogram Abnormalities, 514
Acid-Base Status, 499 Differential Diagnosis, 515
Radiography, 499 Conrming the Diagnosis, 516
Abdominal Ultrasound, 500 Plasma Endogenous Adrenocorticotropic Hormone, 516
Electrocardiography, 501 Treatment, 516
Confirming the Diagnosis, 501 Acute Management, 516
Basal Cortisol Concentrations, 501 Long-Term (Maintenance) Therapy, 516
Adrenocorticotropic Hormone Stimulation Test, 501 Prognosis, 516
Endogenous Adrenocorticotropic Hormone Concentration, 504 Congenital Adrenal Hyperplasia, 516
Cortisol-to-Adrenocorticotrophic Hormone Ratio, 505
In 1930, crude lipid extracts from the adrenal cortex were

BACKGROUND
demonstrated to contain substances that maintained the lives of
The presence of the suprarenal glands was recognized by early adrenalectomized cats, and in 1933, sodium deciency was dem-
anatomists, but their importance was not apparent until Thomas onstrated by Loeb to be a major component of Addisons disease.
Addison described a clinical syndrome in humans that he associated Cortisol and corticosterone were isolated from beef and porcine
with their dysfunction (Addison, 1855). Included in his descrip- adrenal glands in 1937, and synthetic desoxycorticosterone ace-
tion were anemia, general languor, debility, remarkable feebleness tate (DOCA) was shown to be of benet in treatment of adrenal
of the hearts action, and irritability of the stomach. Autopsies insufciency by Thorn and his co-workers in 1942. By the mid-
usually revealed either tuberculous destruction or atrophy of the 1950s, it was recognized that there were three major hormone
adrenal glands. At that time, no therapy was known, and patients types produced by the adrenal cortex: glucocorticoids (cortisol),
who developed the disease died. About the same time that Thomas mineralocorticoids (aldosterone), and androgens.
Addison described the clinical picture of adrenal insufciency, In Naturally occurring adrenocortical insufciency in a dog was
1856, Brown-Sequard demonstrated that adrenalectomy resulted initially reported as a clinical entity in 1953, and by the 1980s,
in death in experimental animals, thus documenting the necessity brief accounts and then several series appeared in the veterinary
of the adrenal glands for maintaining life. literature (Willard etal, 1982). Since 1980, our knowledge of the
485
pathogenesis, diagnosis, and treatment of canine Addisons disease catecholamines. Glucocorticoids are also important in maintain-
has continued to expand. Feline hypoadrenocorticism was first ing normal blood pressure, counteracting the effects of stress,
described in the 1980s, and knowledge about the disease in this and for maintaining normal function and maintenance of the
species is still limited. gastrointestinal mucosa (Peterson etal, 1996). Glucocorticoids
influence the digestion and intestinal absorption of nutrients
and increase intestinal brush border and mitochondrial enzymes
ADRENAL PHYSIOLOGY
(Langlais-Burgess et al, 1995). Glucocorticoids also suppress
The adrenal glands are made up of the adrenal medulla, which vasopressin secretion due to negative feedback on vasopressin
secretes catecholamines, and the adrenal cortex, which secretes release by the periventricular nucleus. Cortisol binds to miner-
glucocorticoids, mineralocorticoids, and androgens. Adrenal ste- alocorticoid receptors as avidly as aldosterone but typically has
roids are derived from cholesterol and all contain the cyclopen- only weak mineralocorticoid activity, because it is inactivated
tanoperhydrophenanthrene (CPPP) nucleus. Enzymes present in to cortisone by the aldosterone sensitive cells in the collecting
the adrenal cortex (P450scc, 17-hydroxylase, 3-hydroxysteroid tubules (Rose, 2001).
dehydrogenase, 21-hydroxylase, 11-hydroxylase, and aldoste-
rone synthase), catalyze formation of the different adrenal ste- Consequences of Glucocorticoid Deficiency
roids (Fig. 12-1; Table 12-1). The major secretory products of the Glucocorticoid deficiency results in hypotension, hypoglycemia,
adrenal glands in dogs and cats are cortisol, aldosterone, and the anorexia, vomiting, diarrhea, weight loss, decreased mobilization
androgensdehydroepiandrosterone and androstenedione. Other of protein and fat from tissues leading to muscular weakness,
hormones such as progesterone and 17-hydroxyprogesterone increased susceptibility to stress, and inability to maintain vascu-
are synthesized in the adrenal gland, but only small amounts are lar tone and endothelial integrity. The pathogenesis of gastroin-
secreted into the systemic circulation in normal animals. Adrenal testinal signs in dogs with glucocorticoid deficiency is believed to
derived androgens serve as substrates for synthesis of estrogen and be multifactorial. Factors that may play a role include decreased
testosterone in peripheral tissues. gastrointestinal motility, increased vascular permeability, poor
The adrenal cortex is composed of three histopathologic layers, tissue perfusion, hypovolemia, and vascular stasis, which can lead
the zona glomerulosa (ZG), the zona fasciculata (ZF), and the to mucosal hemorrhages, ulcers, and atrophy and inflammation
zona reticularis (ZR) (Fig. 12-2). The ZG is the outermost layer of the gastric mucosa. Atrophy and mild inflammatory changes
of the adrenal gland and is the only layer capable of synthesizing in the gastric mucosa have been documented both in humans
and secreting aldosterone, because it contains the aldosterone syn- with Addisons disease and in adrenalectomized animals (Peter-
thase enzyme (P450c11AS). The ZG does not contain the enzyme son etal, 1996). Hyponatremia, although usually attributed to
17-hydroxlase (P450 c17), so it is incapable of synthesizing cor- mineralocorticoid deficiency, may also occur with glucocorticoid
tisol or androgens. The ZF and ZR both synthesize androgens and deficiency secondary to stimulation of vasopressin secretion.
cortisol. Vasopressin secretion is stimulated both by hypovolemia and lack
of negative feedback of cortisol on the paraventricular nucleus.
Hyponatremia and loss of the renal medullary concentration gra-
Glucocorticoids
dient can lead to polyuria in isolated glucocorticoid deficiency
Regulation of Secretion (IGD).
Synthesis and secretion of cortisol by the adrenal glands is regu-
lated by the hypothalamic pituitary adrenal (HPA) axis (Fig. 12-3). Mineralocorticoids
Corticotrophin-releasing hormone (CRH) secreting neurons in
the hypothalamus have axons that terminate in the anterior pitu- Regulation of Secretion
itary gland. CRH stimulates secretion of adrenocorticotropic hor- Synthesis and secretion of aldosterone is regulated by the renin-
mone (ACTH) from the pituitary gland. ACTH is released into angiotensin axis, the plasma potassium concentration, and, to
the blood, attaches to receptors in the adrenal cortex, and stimu- a minor extent, the plasma sodium and ACTH concentrations
lates synthesis and secretion of cortisol. As the plasma cortisol con- (see Fig. 12-3). Increased plasma potassium concentrations and
centration rises, cortisol inhibits CRH and ACTH release from angiotensin II both markedly increase aldosterone release from
the hypothalamus and pituitary by negative feedback. Increased the adrenal cortex. Increased angiotensin synthesis is stimulated
ACTH concentration also inhibits CRH release from the hypo- by decreased extracellular fluid (ECF) volume, which results in
thalamus. Although in people ACTH is secreted in a circadian increased renin secretion from the juxtaglomerular cells that sur-
rhythm with the highest concentrations of ACTH secreted in the round the afferent arterioles as they enter the glomeruli. Renin
early morning, a diurnal rhythm has not been documented in dogs acts on angiotensinogen to form angiotensin I, which is then con-
and cats. Factors that stimulate CRH release include stress, hypo- verted to angiotensin II by angiotensin converting enzyme pri-
glycemia, and physical exercise. Other factors in addition to CRH marily in the lungs. Angiotensin II causes increased aldosterone
that stimulate ACTH release include arginine vasopressin, angio- synthesis and secretion by increasing conversion of cholesterol
tensin II, cholecystokinin, atrial natriuretic factor, and vasoactive to pregnenolone and corticosterone to aldosterone. Increased
peptides (Stewart, 2011). plasma potassium also directly stimulates secretion of aldosterone
by the adrenal gland. Total absence of ACTH decreases aldoste-
Effects of Glucocorticoids rone secretion, but ACTH has little effect in controlling the rate
Glucocorticoids have a variety of effects throughout the body of aldosterone secretion, and hypophysectomy does not result in
that make them crucial to normal homeostasis. Glucocorticoids mineralocorticoid deficiency (Meij etal, 1997).
stimulate hepatic gluconeogenesis and glycogenesis, and enhance
protein and fat catabolism. They have a permissive action on Effects of Mineralocorticoids
many metabolic reactions (e.g., lipolysis and calorigenesis), Mineralocorticoids increase absorption of sodium and secretion
and they are important in maintaining vascular reactivity to of potassium in the kidney, sweat glands, salivary glands, and
|
CHAPTER 12 Hypoadrenocorticism 487
Dehydroepian-
drosterone
Androstenedione
Cortisol
Aldosterone
FIGURE 12-1 Major biosynthetic pathways of adrenocortical steroid biosynthesis. The major secretory products are
underlined. Enzymes present in the adrenal cortex catalyze formation of the different adrenal steroids. (See Table
12-2 for nomenclature of adrenal steroid enzymes.) The zona glomerulosa (ZG), which produces aldosterone, lacks
17-hydroxylase and therefore cannot synthesize 17-hydroxypregnenolone and 17-hydroxyprogesterone, which
are the precursors of cortisol and the adrenal androgens. The zona fasciculata (ZF) and zona reticularis (ZR) pro-
duce cortisol, androgens, and small amounts of estrogens. These zones do not contain the aldosterone synthetase
and therefore cannot convert 11-deoxycorticosterone to aldosterone. (From Ettinger SJ, Feldman EC: Textbook of
veterinary internal medicine, ed 7, St Louis, 2010, Saunders/Elsevier.)
TABLE 12-1 N
OMENCLATURE OF ADRENAL
STEROID ENZYMES AND THEIR
GENES
ENZYME NAME ENZYME FAMILY GENE

P450 cholesterol Cytochrome P450 type I CYPIIA1
side-chain cleavage
(SCC) desmolase
3-hydroxysteroid Short-chain alcohol dehydroge- HSDB32
dehydrogenase (3-HSD) nase reductase superfamily
17-hydroxylase /17, Cytochrome P450 type II CYP17A1
20 lyase
21-hydroxylase Cytochrome P450 type II CYP21A2
11-hydroxylase Cytochrome P450 type I CYP11B1
Aldosterone synthase Cytochrome P450 type I CYP11B2
Adapted from Melmed S, etal.: Williams textbook for endocrinology, ed 12, Philadelphia,
2011, Saunders/Elsevier.
FIGURE 12-3 Regulation of cortisol and aldosterone secretion from the adrenal
glands by the hypothalamic pituitary adrenal (HPA) axis and renin angiotensin
system. (From Ettinger SJ, Feldman EC: Textbook of veterinary internal medicine,
ed 7, St Louis, 2010, Saunders/Elsevier.)
in the intercalated cells of the cortical collecting tubules. Thus

a deficiency of aldosterone causes a mild metabolic acidosis.
FIGURE 12-2 Histopathology of a normal adrenal gland showing the three lay- Aldosterone also reduces the concentration of sodium and raises
ers of the adrenal cortex. Stain hematoxylin and eosin (H and E) 100 magni- the concentration of potassium in sweat, saliva, and colonic
fication. (Courtesy of Dr. M. Miller, Professor Department Comparative Patho- secretions.
biology, Purdue University, West Lafayette, IN. In Ettinger SJ, Feldman EC:
Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders/Elsevier.) Consequences of Mineralocorticoid Deficiency
AM, Adrenal medulla; ZF, zona fasciculate; ZG, zona glomerulosa; ZR, zona reticularis. Hyponatremia and Hypochloremia.In adrenocortical
insufciency, lack of aldosterone secretion results in impaired
intestinal epithelial cells. Thus aldosterone is critical in conserv- ability to conserve sodium and chloride and to excrete potassium
ing body salt. The main site of action in the kidneys is the distal and hydrogen ions, leading to hyponatremia, hypochloremia, hy-
nephron (principal cells of the connecting segment and collect- perkalemia, and metabolic acidosis. Loss of sodium and chloride
ing tubules) where aldosterone promotes tubular resorption of lead to concurrent loss of water. Thus inability to retain sodium
sodium and chloride and excretion of potassium (Rose, 2001). and chloride causes a reduced ECF volume that leads to progres-
In the connecting segment and cortical collecting tubule, aldo- sive development of hypovolemia, hypotension, reduced cardiac
sterone increases the number of sodium and potassium chan- output, and decreased glomerular ltration rate (GFR) leading to
nels in the luminal membrane and increases the activity of the prerenal azotemia.
sodium-potassium adenosine triphosphatase (ATPase) pump in With an adequate sodium-chloride intake, mild aldosterone
the basolateral membrane. Chloride is passively absorbed via the deciency may be compensated for by increased sodium intake;
paracellular pathway. Potassium is exchanged for sodium by the however, if sodium intake diminishes due to anorexia or a change
sodium-potassium ATPase pump and then secreted from the cell in diet or if sodium loss increases because of vomiting and/or diar-
into the lumen. Aldosterone also enhances sodium reabsorption rhea, continued loss of sodium and chloride through the gastro-
but not potassium secretion in the papillary collecting tubules intestinal tract and kidneys leads to depletion of total body salt
and causes secretion of hydrogen ions in exchange for sodium stores and severe volume depletion.
|
Hypothalamus Hypothalamus
CRF CRF?
P P
Cortisol ACTH Cortisol ACTH

(negative decreased increased
feedback)
A A A A
A B
FIGURE 12-4 The pituitary-adrenal axis in normal dogs
Hypothalamus Hypothalamus
(A); in dogs with loss of adrenocortical function and ex-
cess adrenocorticotropic hormone (ACTH) secretion due
CRF? CRF? to a lack of negative feedback (the most common form
P P of hypoadrenocorticism) (B); in dogs with failure to se-
crete ACTH and secondary atrophy of the adrenal cortex,
Cortisol ACTH ACTH specically the zona fasciculata (ZF) and zona reticularis
decreased decreased decreased
(ZR) (C); and in dogs that are chronically overtreated
with exogenous glucocorticoids, causing insufciency
Chronic in pituitary ACTH secretion and secondary atrophy of
A A iatrogenic A A the adrenal cortex (D). (From Ettinger SJ: Textbook of
corticosteroids veterinary internal medicine, ed 2, Philadelphia, 1983,
suddenly
C D stopped WB Saunders.) A, Adrenal; CRF, corticotropin-releasing
factor (hormone); P, pituitary.
Hyperkalemia.Mineralocorticoid deficiency results in pro- GLUCOCORTICOID DEFICIENCY VERSUS

gressively worsening hyperkalemia as a result of diminished re- MINERALOCORTICOID DEFICIENCY
nal perfusion, which reduces glomerular ltration and depresses
cation exchange by the distal convoluted renal tubules. Hyper- In dogs, measurement of decreased cortisol concentration is used
kalemia is worsened by metabolic acidosis, which promotes a to confirm glucocorticoid deficiency; concurrent low aldosterone
shift of potassium ions from the intracellular to the extracellu- concentration is assumed if appropriate electrolyte abnormalities
lar space. The most prominent manifestation of hyperkalemia is (hyponatremia and hyperkalemia) are present. In secondary hypo-
the deleterious effect on cardiac function. Hyperkalemia causes adrenocorticism, mineralocorticoid secretion is preserved because
decreased myocardial excitability, an increase in the myocardial ACTH is only a minor player in control of aldosterone secretion, so
refractory period, and slowed conduction. Hypoxia, secondary to electrolyte abnormalities are not expected, although mild hyponatra-
hypovolemia and poor tissue perfusion, contributes to myocar- mia can occur due to glucocorticoid deficiency alone. In most cases of
dial dysfunction. Ventricular brillation or cardiac standstill may primary hypoadrenocorticism, both cortisol and aldosterone secretion
eventually occur as the plasma potassium concentration exceeds from the adrenal glands are impaired, resulting in hypocortisolemia
10 mEq/L. and electrolyte abnormalities (e.g., hyponatremia and hyperkalemia);
Acidosis. Mild metabolic acidosis develops as a result of im- however up to 30% of dogs with primary hypoadrenocorticism have
paired ability to reabsorb bicarbonate and chloride ions in the re- normal electrolyte concentrations at the time of initial diagnosis. This
nal tubules, as well as from failure of the poorly perfused kidneys has been referred to in the literature as atypical or glucocorticoid
to excrete metabolic waste products and hydrogen ions. deficient hypoadrenocorticism. It has been hypothesized that aldo-
Polyuria/Polydipsia.Polyuria with compensatory polydipsia sterone concentrations in these dogs are normal due to sparing of the
may result from aldosterone deficiency due to natriuresis and re- ZG; however, in most reported cases, the aldosterone concentration
sultant loss of the renal medullary concentration gradient. was not directly measured. In a recent study of aldosterone secretion
in dogs with hypoadrenocorticism, four dogs that exhibited neither
hyponatremia nor hyperkalemia had extremely low aldosterone con-
PRIMARY VERSUS SECONDARY
centrations, implying that maintenance of normal aldosterone con-
HYPOADRENOCORTICISM
centrations cannot be the only reason by which normal electrolyte
Primary hypoadrenocorticism due to bilateral adrenal gland concentrations are maintained in dogs with atypical hypoadrenocor-
destruction accounts for the majority (more than 95%) of cases of ticism (Fig. 12-5; Baumstark etal, 2014). It is possible that increased
canine hypoadrenocorticism. Loss of more than 90% of adreno- dietary sodium intake compensates for increased natriuresis in some
cortical function is required before clinical signs of glucocorticoid dogs with atypical hypoadrenocorticism. Increased renin concen-
and mineralocorticoid deficiency develop, so clinical hypoadre- trations indicating compensated failure of the ZG has been docu-
nocorticism only occurs when both adrenal cortices are destroyed mented in humans with primary hypoadrenocorticism and normal
(Fig. 12-4). Secondary hypoadrenocorticism due to reduced secre- electrolytes (Oelkers et al, 1992; Shiah, 1995). Isolated glucocorti-
tion of ACTH from the pituitary gland is a much rarer cause of coid deficiency (IGD) in people is a rare autosomal recessive disorder
adrenocortical failure. Loss of ACTH causes atrophy of the adre- characterized by early onset of primary adrenocortical insufficiency
nal cortices (sparing the ZG) and impaired secretion of glucocor- without mineralocorticoid deficiency (Tsigos etal, 1995). Mutations
ticoids but not mineralocorticoids. of the ACTH receptor gene have been reported in several families
p 0.0001 cortices is usually a gradual process, initially resulting in a partial

deciency syndrome characterized by inadequate adrenal reserve,
p 0.0001 with symptoms manifesting only during times of stress induced
by surgery, trauma, infection, or changes of environment such as
2000
boarding. Basal hormone secretion in the unstressed state may be
1200 adequate to maintain near-normal plasma electrolyte concentra-
1000 tions and minimal clinical signs. For these dogs, the diagnosis can
750
Aldosterone (pg/mL)
be conrmed only by measurement of adrenocortical reserve. As

destruction of the adrenal cortices continues, hormone secretion
becomes inadequate even under non-stressful conditions, and a
500 metabolic crisis can result without any obvious inciting event.
The most common cause of primary adrenal failure in humans
is immune mediated adrenalitis; however in some areas of the
250 world, granulomatous adrenalitis due to tuberculosis is an
important cause of hypoadrenocorticism (Box 12-1). In people,
hypoadrenocorticism due to adrenalitis is 1.5 to 3.5 times more
0 common in women than men (Mitchell and Pearce, 2012). Fol-
0 60 0 60 0 60
HA Other dx Healthy
lowing the development of serum autoantibodies (usually to the
(n=70) (n=22) (n=19) steroidogenic enzyme 21-hydroxylase) there is a prolonged period
of subclinical disease characterized by increased concentrations
FIGURE 12-5Baseline (0) and adrenocorticotropic hormone (ACTH) stimulated
of ACTH and renin, before symptomatic adrenal failure devel-
(60) serum aldosterone concentrations in dogs with hypoadrenocorticism (HA;
ops (Mitchell and Pearce, 2012). Histologic examination of the
n = 70), dogs with diseases mimicking HA (Other dx; n = 22), and healthy dogs
adrenals reveals widespread inltrates consisting of lymphocytes,
(Healthy; n = 19). (From Baumstark ME, etal.: Evaluation of aldosterone
plasma cells, and macrophages. In advanced stages, the cortex is
concentrations in dogs with hypoadrenocorticism, J Vet Intern Med 28:154, 2014.)
replaced by brous tissue.
Large case series describing the underlying histopathologic
with IGD. Whether this syndrome is the cause of some cases of atypi- abnormalities in dogs with hypoadrenocorticism have not been
cal hypoadrenocorticism in dogs is unknown. Pathology studies of published, likely because most cases of hypoadrenocorticism are
dogs with lymphocytic plasmacytic adrenalitis have identified cases in either successfully treated or the dog dies without a necropsy being
which there is partial sparing of the ZG (Frank etal, 2013). Whether performed. In most confirmed cases of hypoadrenocorticism the
such cases have normal aldosterone concentrations has yet to be deter- typical findings are of severe lymphoplasmacytic inflammation and
mined. Other proposed causes of normal electrolytes in dogs with adrenocortical atrophy involving all layers of the adrenal cortex
primary hypoadrenocorticism include disparity in rate of destruction (Fig. 12-6). In a study of 33 dogs with adrenalitis, inflammation
of glucocorticoid and mineralocorticoid secreting cells and influence was lymphoplasmacytic in 17 dogs, lymphocytic in four, lym-
of concurrent diseases such as hypothyroidism on the metabolic rate. phohistiocytic in one, granulomatous in three, and neutrophilic
Deficiency of mineralocorticoid secretion but normal glucocor- in eight dogs (Frank etal, 2013). Severe adrenocortical atrophy
ticoid secretion may also occur rarely in dogs. Isolated hypoaldo- was observed predominantly in the dogs with lymphoplasmacytic
steronism is a rare syndrome in humans due either to inadequate inflammation. These dogs typically had nearly complete loss of
secretion of renin by the kidneys (hyporeninemic hypoaldosteron- cortical cells; however the ZG was partially spared in three dogs
ism) or mutations in the biosynthetic cascade of aldosterone syn- with lymphoplasmacytic adrenalitis and severe cortical atrophy.
thesis (hyperreninemic hypoaldosteronism) (White, 2004). The Non-lymphoid inflammation of the adrenal glands was usually
distinction between the two syndromes is based on measurement multifocal, associated with systemic disease, and not associated
of renin concentrations. If the cause of hypoaldosteronism is pri- with severe adrenocortical atrophy. Anti-adrenal antibodies have
mary adrenal dysfunction, renin concentrations should be high, been detected in two dogs with primary hypoadrenocorticism, and
whereas if it is due to kidney dysfunction, renin concentrations it is believed that immune mediated adrenalitis is the most likely
are low. Isolated case reports of hyporeninemic hypoaldosteron- etiology for the majority of spontaneous cases of canine primary
ism in a dog with renal failure and hyperreninemic hypoaldoste- hypoadrenocorticism (Schaer etal, 1986); however, in most dogs
ronism in a dog that also had a heart base chemodectoma have with hypoadrenocorticism the cause is not proven and the etiology
been reported in the veterinary literature, but both syndromes are is classified as idiopathic. Although antibodies to adrenal cell anti-
exceedingly rare (Lobetti, 1998; Kreissler and Langston, 2011). gens have been demonstrated by indirect immunofluorescence, no
Mineralocorticoid deficiency occurring prior to development of specific autoantibodies against a specific enzyme (e.g., the steroid
glucocorticoid deficiency was reported in a dog with primary 21-hydroxylase) have been identified in dogs with hypoadrenocor-
hypoadrenocorticism and hypothyroidism (McGonigle et al, ticism (Schaer etal, 1986). Dogs treated for hypoadrenocorticism
2013). Although renin was not measured, the progression from for any length of time have complete loss of measurable cortical
aldosterone deficiency to combined mineralocorticoid and glu- tissue with only mild residual mononuclear, lymphocytic, or lym-
cocorticoid deficiency in the absence of renal disease suggested phoplasmacytic inflammation and a thick fibrous capsule (Boujon
isolated hyperreninemic hypoaldosteronism. etal, 1994; Frank etal, 2013). The pituitary gland is normal his-
tologically in primary immune-mediated adrenocortical atrophy,
but increased ACTH immunoreactivity has been identified in the
PRIMARY ADRENOCORTICAL FAILURE
anterior pituitary gland (Boujon etal, 1994).
Development of the clinical syndrome associated with adrenocor- Other rare causes of adrenalitis and primary hypoadrenocor-
tical insufciency is believed to require at least 90% destruction ticism in dogs include granulomatous destruction (e.g., blas-
of adrenal cortices. Naturally occurring destruction of the adrenal tomycosis, histoplasmosis, and cryptococcosis), amyloidosis,
|
BOX 12-1 E
tiology of Adrenocortical Insufficiency in
Humans (Excluding Congenital Adrenal
Hyperplasia)
Primary Causes: Addisons Disease

Autoimmune
Sporadic
Autoimmune polyendocrine syndrome type I (Addisons disease, chronic
mucocutaneous candidiasis, hypoparathyroidism, dental enamel A
hypoplasia, alopecia, primary gonadal failure)
Autoimmune polyendocrine syndrome type II (Schmidt syndrome)
(Addisons disease, primary hypothyroidism, primary hypogonadism,
insulin-dependent diabetes, pernicious anemia, vitiligo)
Infections
Tuberculosis
Fungal infections
Cytomegalovirus
B
HIV
Metastatic tumor FIGURE 12-6 A, Histopathology of normal adrenal gland. B, Histopathology of
Infiltrations adrenal gland with severe adrenocortical atrophy. Stained with H and E. The long
Amyloid black line marks the thickness of the entire gland, the short line the medullary
Hemochromatosis thickness bar, 1 mm. (From Frank CB, etal.: Correlation of inflammation with
Intra-adrenal hemorrhage (Waterhouse-Friderichsen syndrome) after adrenocortical atrophy in canine adrenalitis, J Comp Pathol 149:268, 2013.)
meningococcal septicemia
Adrenoleukodystrophies hemorrhagic infarction, and metastatic neoplasia (Labelle and De
Congenital adrenal hypoplasia Cock, 2005; Rockwell et al, 2005; Reusch etal, 2007; Frank etal,
DAX-1 (NR0B1) mutations 2013). The adrenal glands are a common site for tumor metasta-
SF1 mutations sis in dogs; 21% of dogs with disseminated neoplasia have adre-
ACTH resistance syndromes nal metastases. The most common tumors that metastasize to
MC2R gene mutations the adrenal glands in dogs include pulmonary, mammary, pros-
MRAP gene mutations tatic, gastric, and pancreatic carcinomas and melanoma (Labelle
AAAS (ALADIN) gene mutations (triple-A syndrome) and De Cock, 2005); however, only lymphoma and bilateral
Bilateral adrenalectomy anaplastic neoplasia has been reported to cause adrenal gland
Secondary Causes failure in dogs (Labelle and De Cock, 2005; Kook et al, 2010).
Exogenous glucocorticoid therapy Hemorrhagic infarction of the adrenal gland (secondary to trauma,
Hypopituitarism infection, necrosis, or coagulopathy) has been reported in dogs but
Selective removal of ACTH-secreting pituitary adenoma is rare, and hypoadrenocorticism due to bilateral abscessing adrenal-
Pituitary tumors and pituitary surgery, craniopharyngiomas itis has been reported (Korth etal, 2008). Bilateral adrenal infarc-
Pituitary apoplexy tion secondary to a presumed increase in endogenous ACTH in a
Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma) dog with previously diagnosed hyperadrenocorticism has also been
Secondary tumor deposits (breast, bronchus) described (Rockwell et al, 2005). Interestingly, in humans, intra-
Postpartum pituitary infarction (Sheehan syndrome) adrenal hemorrhage with resultant necrosis is an important cause
Pituitary irradiation (effect usually delayed for several years) of adrenal gland failure, particularly in children with Pseudomonas
Isolated ACTH deficiency aeruginosa infection and meningococcal septicemia (Stewart, 2011).
Idiopathic Iatrogenic primary hypoadrenocorticism may be caused by
Lymphocytic hypophysitis drugs such as mitotane, and trilostane (Reusch etal, 2007). Mito-
TPIT (TBX19) gene mutations tane is cytotoxic to the adrenal gland and is well documented to
PCSK1 gene mutation (POMC processing defect) cause adrenal gland necrosis in dogs. Although the glucocorti-
POMC gene mutations coid deficiency that occurs in many dogs during the induction
Multiple pituitary hormone deficiencies phase of mitotane treatment for hyperadrenocorticism is usually
HESX1 gene mutations transient once treatment is discontinued, 5% of dogs with hyper-
LHX4 gene mutations adrenocorticism treated with mitotane develop permanent min-
SOX3 gene mutations eralocorticoid deficient hypoadrenocorticism (Kintzer, 1991).
PROP1 gene mutations Adrenal suppression caused by trilostane is usually reversible, but
permanent primary hypoadrenocorticism due to adrenal necrosis
From Melmed S, etal.: Williams textbook for endocrinology, ed 12, Philadelphia, and hemorrhage has also been reported in association with this
drug (Reusch etal, 2007). Adrenal necrosis associated with trilostane
ACTH, Adrenocorticotropic hormone; HIV, human immunodeficiency virus; POMC,
pro-opiomelanocortin.
treatment has been speculated to be caused by high circulating
ACTH concentrations. This hypothesis is supported by studies
in rats, showing that ACTH administration causes adrenal gland
necrosis, vacuolization, and apoptosis of adrenocortical cells
(Burkhardt et al, 2011). Primary hypoadrenocorticism has also
been reported in Beagles exposed to aerosols of plutonium-238 to suppress the hypothalamic-pituitary axis is susceptible to sec-
(Weller etal, 1996). ondary adrenal atrophy. Adrenal suppression can occur within
a few days of administration of ACTH-inhibiting doses of cor-
ticosteroids, although suppression is markedly variable among
POLYGLANDULAR AUTOIMMUNE SYNDROMES
individuals. This individual variation is reflected in the fact that
Immune-mediated destruction of the adrenal glands in humans is some dogs quickly develop clinical signs of iatrogenic Cushings
commonly associated with other immune disorders. Two distinct syndrome from relatively low doses of glucocorticoids, whereas
immunoendocrinopathy syndromes have been described, auto- others show no effect from higher doses. If adrenal suppression
immune polyglandular disease type I and type II. Type I disease occurs, adrenal function usually recovers gradually (over a period
involves adrenal insufciency, hypoparathyroidism, and chronic of weeks) after hormone administration is stopped, usually tak-
mucocutaneous candidiasis. Type II disease (also called Schmidt ing more time if long-acting depot forms of glucocorticoids were
syndrome) involves adrenal insufciency, thyroiditis, and insulin- used. Pituitary suppression has been documented not only with
dependent diabetes mellitus. Enzymes involved in steroidogenesis injectable and oral glucocorticoids but also with topical derma-
such as 17-hydroxylase, 21-hydroxylase, and the side-chain tologic, ophthalmic, and otic preparations (Roberts et al, 1984;
cleavage enzyme are target autoantigens in autoimmune Addisons Moriello etal, 1988; Murphy etal, 1990). Although estimates of
disease in humans. the relative biologic effectiveness of synthetic steroids vary, studies
Polyglandular autoimmune disease is rare in dogs. Most canine have shown prednisone/prednisolone to be ve times more potent
reports resemble human type II autoimmune polyendocrine syndrome than cortisol in suppressing ACTH secretion and dexamethasone
with hypoadrenocorticism and hypothyroidism being the most com- to be 50 to 150 times more potent. Relatively small dosages of
mon concurrent disorders (Melendez, 1996; Blois, 2011). Two other dexamethasone, therefore, may be sufcient to produce adrenal
diseases with possible immune mediated pathogenesis, diabetes mel- atrophy. The long-acting depot injectable corticosteroids (e.g.,
litus, and hypoparathyroidism may also occur in dogs with hypoadre- betamethasone) may suppress the pituitary-adrenocortical axis of
nocorticism (Bowen et al, 1986; Kooistra et al, 1995; Blois et al, 2011). dogs for as long as 5 weeks (Kemppainen etal, 1981; 1982). It is
Lymphocytic adenohypophysitis was documented in a dog with important to allow enough time for recovery of adrenal suppres-
adrenalitis and primary thyroid atrophy (Adissu etal, 2010). In sion after administration of glucocorticoids when planning testing
a study of 225 dogs with hypoadrenocorticism, a concomitant of the pituitary adrenal axis. The length of time required depends
endocrinopathy was diagnosed in 5% of dogs (Peterson et al, upon the potency of the glucocorticoid product used, the dose,
1996). In a case series of 10 dogs with concurrent hypoadreno- and the duration of administration. If only one dose of dexametha-
corticism and hypothyroidism, hypothyroidism was identified as sone is administered, an ACTH stimulation test can be performed
a cause of poor response to treatment in dogs with hypoadreno- immediately because dexamethasone is not detected by assays for
corticism (Melendez, 1996). Hypothyroidism should be consid- cortisol and because the amount of adrenal suppression that will
ered in any dog with hypoadrenocorticism that has a poor clinical result is mild enough that the response of a patient with spontane-
response to initial treatment for hypoadrenocorticism. ous hypoadrenocorticism can be distinguished from the effects of
glucocorticoid suppression. If other glucocorticoids are adminis-
tered, time must be allowed for both metabolism and excretion
SECONDARY ADRENOCORTICAL FAILURE
of the administered glucocorticoid and recovery of adrenal gland
atrophy. The waiting time necessary before being able to inter-
Spontaneous Secondary Hypoadrenocorticism
pret the results of adrenal function testing ranges from as short as
Reduced secretion of ACTH by the pituitary gland results in 48 hours in patients treated with one dose of prednisone or pred-
decreased synthesis and secretion of adrenocortical hormones, nisolone to as long as 6 to 8 weeks in patients treated with a single
especially glucocorticoids (see Fig. 12-4). Reduced secretion of dose of a depot preparation of glucocorticoid such as triamcinolone
CRH by the hypothalamus may also result in secondary adreno- acetonide or methylprednisolone acetate (Behrend and Kemp-
cortical failure. In humans destructive lesions in the pituitary or painen, 1997). Oral administration of shorter acting or less potent
hypothalamus resulting in ACTH or CRH deficiency (or both) glucocorticoids results in a quicker recovery of the adrenal axis.
are usually caused by neoplasia; inflammation and trauma are In one study of dogs treated with 5 weeks of prednisone at a dose
less common causes (Velardo et al, 1992; Thodou et al, 1995; of 0.55 mg/kg every 12 hours, complete HPA axis recovery was
Platt et al, 1999; see Box 12-1). Pituitary hypopexy can result reported by 2 weeks after cessation of therapy (Moore and Hoenig,
in an Addisonian crisis or spontaneous resolution of pituitary 1992). Suppression of the HPA axis in dogs treated with topical
dependent hyperadrenocorticism. Pituitary hypopexy has been glucocorticoid therapy can last as long as 4 weeks depending upon
reported in dogs and resulted in acute neurologic signs and sud- the preparation. In some cases sequential stimulation tests may
den death but adrenocortical function in these cases was not need to be performed to document full return of adrenal function.
reported (Bertolini etal, 2007).
SIGNALMENT
Iatrogenic Secondary Hypoadrenocorticism
The prevalence of hypoadrenocorticism in dogs has been estimated
Hypophysectomy for the treatment of pituitary dependent at approximately 0.06% to 0.28% (Kelch et al, 1998). The dis-
hyperadrenocorticism results in secondary hypoadrenocorti- ease is inherited as an autosomal recessive trait in the Standard
cism, which is usually permanent unless there is disease relapse Poodle, Portuguese Water dog, and Nova Scotia Duck Tolling
(Hanson, 2005). Retriever and is also heritable in the Bearded Collie, although in
More commonly, iatrogenic adrenal insufciency is second- this breed the mode of inheritance is not clear. In these four breeds,
ary to withdrawal of exogenous corticosteroid administration, the estimated prevalence is higher than that in the general popula-
although this only rarely results in clinical signs (see Fig. 12-4). tion although the reported rates may be artificially high because
Any dog chronically receiving amounts of corticosteroids sufcient of biased sampling of dogs from concerned owners and breeders
|
TABLE 12-2 E
STIMATES OF HERITABILITY, TABLE 12-3 B
REEDS REPORTED TO
ESTIMATED PREVALENCE OF BE EITHER AT INCREASED
HYPOADRENOCORTICISM, OR DECREASED RISK OF
AND SEX PREDISPOSITION HYPOADRENOCORTICISM
IN BREEDS WITH HERITABLE
HYPOADRENOCORTICISM BREED INCREASED RISK DECREASED RISK
Airedale Terrier X
SEX
MODE OF ESTIMATED PREDIS- Basset Hound X
BREED HERITABILITY INHERITANCE PREVALENCE POSITION Bearded Collie X
Standard 0.75 Autosomal 8.6% None Boxer X
Poodle recessive Chihuahua X
Portuguese 0.49 Autosomal 1.5% None Cocker Spaniel X
Water dog recessive
Dalmatian X
Nova Scotia 0.98 Autosomal 1.4% None
Golden Retriever X
Duck Tolling recessive
Retriever Great Dane X
Bearded Collie 0.76 Unknown 9.4% None Lhasa Apso X
Nova Scotia Duck Tolling X
From Ettinger SJ, Feldman EC: Textbook of veterinary internal medicine, ed 7, St Louis, Retriever
Pit Bull Terrier X
Pomeranian X
(Tables 12-2 and 12-3; Shaker, 1988; Burton, 1997; Oberbauer Portuguese Water Dog X
etal, 2002; 2006; Famula etal, 2003; Hughes etal, 2007). Pri-
mary hypoadrenocorticism was also reported in a family of Leon- Rottweiler X
bergers (Smallwood and Barsanti, 1995). Two disease associated Saint Bernard X
loci on canine autosomes CFA 12 and 37, which are syntenic with Shetland Sheepdog X
the human DRB1 histocompatibility locus alleles HLA-DRB1*04
Shih Tzu X
and DRB1*0301, have been identified in Portuguese Water dogs
with hypoadrenocorticism (Chase et al, 2006). Dog leucocyte Springer Spaniel X
antigen (DLA) haplotypes are also associated with disease fre- Standard Poodle X
quency in other dog breeds (Hughes 2010; 2011). For example West Highland White Terrier X
in the Springer and Cocker Spaniel the DLA-DRB1*015:01
DQA1*006DQB1*023:01 haplotype is significantly associated Wheaten Terrier X
with disease risk (Massey etal, 2013). Markers on CFA 12 were Yorkshire Terrier X
associated with an increase in the frequency of the disease, whereas
From Ettinger SJ, Feldman EC: Textbook of veterinary internal medicine, ed 7, St Louis,
markers on CFA37 were associated with a decrease in frequency
of the disease. Two markers on CFA12 FH2202 and FH2975 are
within the canine DLA region, supporting the assumption that
canine hypoadrenocorticism is an autoimmune disease (Chase
HISTORY
etal, 2006). Many other breeds have been shown to have either
an increased or decreased risk of hypoadrenocorticism (see Table Clinical signs in dogs with hypoadrenocorticism may be either acute
12-3; Peterson etal, 1996; Kelch etal, 1998; Adler, 2007; Thomp- or gradual in onset and commonly wax and wane. The clinical signs
son etal, 2007). Further genetic studies are necessary to establish can be insidious in onset and owners may not realize the duration
the genetic cause of inherited hypoadrenocorticism in dogs. It has or severity of illness until treatment results in a dramatic improve-
been proposed that canine hypoadrenocorticism may be a useful ment in activity level. Sometimes clinical illness is triggered by a
model for studying the mode of inheritance of human Addisons stressful event. A history of episodic illness or gastrointestinal upset
disease. Some of the same genes that are associated with suscep- (lethargy, vomiting, diarrhea, and/or dehydration) that improves
tibility to Addisons disease in humans are also associated with with supportive care (fluids, cage rest, and glucocorticoid admin-
canine hypoadrenocorticism (Short etal, 2013). There is a female istration) should alert the clinician to the possibility of hypoadre-
predisposition for hypoadrenocorticism with approximately 70% nocorticism, especially if clinical signs are recurrent. Clinical signs
of affected dogs being female; however, no sex predisposition has of hypoadrenocorticism are vague and none are pathognomonic
been demonstrated in the Standard Poodle, Portuguese water dog, for the disease. Anorexia, vomiting, lethargy/depression, weakness,
Nova Scotia Duck Tolling Retriever, or Bearded Collie. In one weight loss, diarrhea, and shaking or shivering are all common;
study, neutered females and neutered males were each about three polyuria, polydipsia, and abdominal pain may also be observed. All
times more likely to develop the disease than their intact counter- of these clinical signs may be caused by glucocorticoid deficiency
parts (Kelch etal, 1998). Median age of onset for all breeds is 4 alone; however when mineralocorticoid deficiency is also present,
years (range, 4 months to 14 years), and the majority are young to polyuria, polydipsia, hypovolemic shock, collapse, and dehydration
middle-aged dogs (Peterson etal, 1996). The disease has a younger are more prominent, and the clinical signs tend to be more severe.
age of onset in the Nova Scotia Duck Tolling Retriever, in which Less common clinical manifestations of hypoadrenocorticism
the median age of onset was 3 years (Hughes etal, 2007). include seizures due to hypoglycemia, episodic muscle cramping,
and gastrointestinal hemorrhage (Saito, 2002; Medinger etal, 1993; TABLE 12-4 COMMON CLINICOPATHOLOGIC
Levy, 1994; Syme and Scott-Moncrieff, 1998). CHANGES OBSERVED IN
DOGS SUFFERING FROM
PHYSICAL EXAMINATION HYPOADRENOCORTICISM
Abnormalities found on physical examination in dogs with CLINICOPATHOLOGIC CHANGES PERCENTAGE AFFECTED
hypoadrenocorticism are also vague and nonspecific. Poor body
condition, lethargy, weakness, severe dehydration, abdominal Complete Blood Count
pain, bradycardia, weak pulses, hypothermia, decreased capil- Eosinophilia 20
lary refill time, and other signs of hypovolemic shock may be Lack of stress leukogram 92
evident on physical examination. The presence of bradycardia Lymphocytosis 10
in a dog with other evidence for hypovolemic shock should be
a red flag for the possibility of hypoadrenocorticism. Melena or Neutrophilia 32
hematochezia may occur and occasionally results in pale mucous Nonregenerative anemia 27
membranes, weakness, and collapse due to anemia (Medinger Biochemical Panel
etal, 1993). In some dogs with hypoadrenocorticism, especially
Azotemia 88
those with glucocorticoid deficiency alone, the physical exami-
nation may be unremarkable (Peterson etal, 1996; Thompson Hypercalcemia 31
etal, 2007). Hyperkalemia 95
Blood Pressure. Many dogs with hypoadrenocorticism have sys- Hyperphosphatemia 68
tolic hypotension at the time of initial evaluation. In one study of
53 dogs with hypoadrenocorticism, median systolic blood pressure Hypoalbuminemia 6 to 39
was 90 mm Hg (range, 40 to 150 mm Hg), whereas in 110 dogs Hypochloremia 42
with other causes of illness, median blood pressure was 140 mm Hg Hypocholesterolemia 7
(range, 50 to 210 mm Hg; Seth etal, 2011).
Hypoglycemia 17
Hyponatremia 81
CLINICAL PATHOLOGY
Increased liver enzymes 30 to 50
The classic clinicopathologic abnormalities of dogs with hypoad- Metabolic acidosis 40
renocorticism include hyponatremia, hyperkalemia, non-regen-
erative anemia, and lymphocytosis; however these changes are Urine specific gravity < 1.030 60
not present in all cases. Although diagnosis of a typical case of From Ettinger SJ, Feldman EC: Textbook of veterinary internal medicine, ed 7, St Louis,
hypoadrenocorticism is usually straightforward, some dogs with 2010, Saunders/Elsevier.
hypoadrenocorticism have none of these classic clinicopathologic
abnormalities. This less typical presentation can be a significant
diagnostic challenge. Failure to consider hypoadrenocorticism as a
differential diagnosis will result in a missed or incorrect diagnosis, anemia, eosinophilia, neutrophilia, and lymphocytosis; how-
leading to owner frustration or even death of the patient. It is ever, these changes are seen in only 10% to 30% of dogs (see
therefore very important that the clinician considers hypoadreno- Table 12-4). The anemia is typically of mild to moderate severity
corticism as a possible differential diagnosis for any dog with vague with hematocrits of 20% to 35% being typical. The anemia in
clinical signs of illness. Although a low sodium-to-potassium ratio hypoadrenocorticism is attributed to lack of red cell production
and a normal lymphocyte count in a sick dog increase the index of due to cortisol deficiency in combination with gastrointestinal
suspicion for hypoadrenocorticism, the diagnosis cannot be either blood loss. Approximately 15% of dogs with hypoadrenocorti-
confirmed or ruled out on this basis alone. cism have evidence of melena or hematochezia, and in approxi-
Abnormalities that may be observed on the complete blood count mately 5% of dogs, this can result in severe anemia (Medinger,
(CBC), biochemical panel, and urinalysis in dogs with hypoadreno- 1993; Peterson et al, 1996). In some dogs, the mild anemia is
corticism are shown in Table 12-4 (Peterson etal, 1996; Feldman initially masked by dehydration, and the anemia is only revealed
and Nelson, 2004). It is important to recognize that the clinico- after fluid rehydration. Dogs with hypoadrenocorticism that
pathologic abnormalities seen in hypoadrenocorticism may mimic lack electrolyte changes (so called atypical Addisons disease or
those observed in other diseases, such as hepatic failure (hypogly- glucocorticoid deficient hypoadrenocorticism) are more likely
cemia, hypoalbuminemia, hypocholesterolemia, and increased to be anemic than those with evidence of concurrent mineralo-
alanine aminotransferase [ALT] and alkaline phosphatase [ALP]), corticoid deficiency (Thompson et al, 2007). This may relate
renal failure (anemia, azotemia, hypercalcemia, hyperphosphate- to the longer duration of illness in these dogs and the fact that
mia, and low urine specific gravity), insulinoma (hypoglycemia, dehydration is less severe and less likely to mask anemia in this
increased ALT, and ALP), and protein losing enteropathy (hypo- subgroup of dogs.
albuminemia, hypocholesterolemia, and non-regenerative anemia); The most common abnormality on the leukogram in dogs with
so unless the clinician maintains a high index of suspicion for a hypoadrenocorticism is the absence of a stress leukogram, which
diagnosis of hypoadrenocorticism, the diagnosis may be missed. is an unexpected finding in the presence of systemic illness. The
characteristics of a stress leukogram include lymphopenia, neutro-
philia, and eosinopenia; dogs with Addisons disease may have lym-
Hematology
phocytosis, eosinophilia (Box 12-2), or may have an unexpectedly
Typical hematologic abnormalities in dogs with hypoadrenocor- normal neutrophil count or lymphocyte count. Cortisol causes
ticism include a nonregenerative, normocytic normochromic lymphopenia due to redistribution of recirculating lymphocytes;
|
BOX 12-2 P
otential Causes of Eosinophilia in Dogs TABLE 12-5 S
ENSITIVITY AND SPECIFICITY
and Cats OF THE SODIUM-TO-POTASSIUM
RATIO OR LYMPHOCYTE
Parasitism COUNT FOR PREDICTING
Heartworm disease HYPOADRENOCORTICISM
Gastrointestinal IN DOGS WITH A
Dermatologic CLINICAL SUSPICION OF
Other HYPOADRENOCORTICISM
Asthma
Nonparasitic dermatologic disease SENSITIVITY, % SPECIFICITY, %
Mast cell tumor, other neoplasia (95% CI) (95% CI)
Hypoadrenocorticism (Addisons disease) Sodium-to-Potassium Ratio
Eosinophilic myositis < 40 100 (93-100) 15 (9-23)
Eosinophilic pneumonitis/rhinitis/conjunctivitis
< 35 94 (84-99) 35 (26-44)
Eosinophilic enterocolitis (allergic colitis)
Eosinophilic leukemia < 28 74 (60-84) 84 (75-90)
Eosinophilic granuloma complex < 27 70 (56-82) 94 (87-97)
Eosinophilic vasculitis < 24 62 (48-75) 96 (91-990)
Drug reaction
< 20 51 (37-65) 100 (97-100)
Lymphocyte Count (cells 103/L) (Reference Range: 0.9
to 5.5)
1.0
> 0.75 100 (93-100) 35 (27-45)
> 1.0 92 (82-98) 46 (37-56)
0.8 > 1.2 89 (77-96) 56 (47-66)
> 1.4 87 (75-95) 69 (60-78)
> 1.6 79 (66-89) 77 (68-84)
0.6 > 1.8 64 (50-77) 83 (74-89)
Sensitivity
> 2.0 58 (44-72) 85 (76-91)

> 2.2 57 (42-70) 89 (82-94)
0.4
> 2.4 49 (25-63) 92 (85-96)
> 5.0 19 (9-32) 99 (95-100)
> 6.0 9 (3-21) 100 (97-100)
0.2
From Seth M, etal.: White blood cell count and the sodium to potassium ration to screen
for hypoadrenocorticism in dogs, J Vet Intern Med 25:1351, 2011.
CI, Confidence interval.
0.0
0.0 0.2 0.4 0.6 0.8 1.0
1 - Specificity than 0.75 cells 103/L had a sensitivity of 100%, meaning that
all the dogs with hypoadrenocorticism had a lymphocyte count
Na:K ratio
above this value (Fig. 12-7; Seth etal, 2011). Specificity of a lym-
Lymphocyte count phocyte count above 0.75 cells 103/L was 35%, indicating that
Na:K ratio and lymphocyte count logistic model 35% of the dogs with lymphocyte counts more than 0.75 cells
Reference line 103/L were Addisonian (Table 12-5). Thus in this study the pres-
FIGURE 12-7 Receiver operating characteristic (ROC) curves for the Na : K ratio
ence of lymphopenia excluded a diagnosis of hypoadrenocorticism
(coarse dashed line), absolute lymphocyte count (fine dashed line), and a logistic re-
(Seth etal, 2011). In the same study, dogs with hypoadrenocorti-
gression model combining both of these variables (solid bold line) for discerning dogs
cism had a higher eosinophil count and a lower neutrophil count,
with hypoadrenocorticism (HA) from dogs with a clinical suspicion of HA. The combined
but these parameters were less useful in differentiating dogs with
Na : K ROC curve is above and to the left of the other ROC curves at almost all values,
hypoadrenocorticism from dogs with other causes of systemic ill-
indicating consistently superior sensitivity and specificity when compared to either vari-
ness (Seth etal, 2011).
able alone. (From Seth M, etal.: White blood cell count and the sodium to potassium
ration to screen for hypoadrenocorticism in dogs, J Vet Intern Med 25:1351, 2011.) Serum Electrolyte Abnormalities
In a retrospective study of 225 dogs with hypoadrenocorticism,
they remain transiently sequestered in the lymph nodes and bone 96% of dogs were hyperkalemic and 81% were hyponatremic
marrow rather than entering the efferent lymph and blood. This (Peterson et al, 1996). Other electrolyte abnormalities in dogs
does not occur in the absence of cortisol. In one study, only 8% with hypoadrenocorticism may include hypochloremia, hyper-
of dogs with hypoadrenocorticism had lymphopenia on the CBC phosphatemia, and hypercalcemia (see Table 12-4). Hypocalce-
(Peterson etal, 1996). In another study, a lymphocyte count more mia occurs less commonly (9% of dogs) and is usually attributable
to concurrent hypoalbuminemia (see Total Calcium/Ionized Cal- time of referral was attributed to anorexia, diarrhea, and administration
cium). Other serum biochemical abnormalities that have been of potassium-free fluids.
reported in dogs with hypoadrenocorticism include azotemia, Concurrent diseases causing anorexia and decreased metabolic
hypoalbuminemia, hypocholesterolemia, hypoglycemia, and rate due to hypothyroidism can also mask the typical electrolyte
increased liver enzymes. Appropriate treatment of hypoadreno- changes of hypoadrenocorticism. Some dogs with primary adre-
corticism results in complete resolution of these changes. nal failure will initially have normal electrolytes and later develop
electrolyte abnormalities indicative of mineralocorticoid defi-
Hyponatremia and Hyperkalemia ciency weeks to months later. In a retrospective study of eleven
Hyponatremia and hyperkalemia are caused by aldosterone defi- dogs with hypoadrenocorticism that lacked electrolyte changes at
ciency with a resultant failure of the kidneys to conserve sodium time of diagnosis, only one dog ultimately progressed to miner-
(see Consequences of Mineralocorticoid Deficiency). Because alocorticoid deficiency over a follow up time of 1 to 4 years
sodium ions are exchanged for either potassium or hydrogen ions, (Thompson et al, 2007). Other studies also suggest that only a
impairment of renal tubular potassium and hydrogen secretion small percentage of dogs with hypoadrenocorticism later progress
causes hyperkalemia and metabolic acidosis. Failure to conserve to mineralocorticoid deficiency (Lifton et al, 1996; Sadek and
sodium results in profound fluid loss, shift of K+ ions to the Schaer, 1996; Baumstark et al, 2014). Most dogs that progress
extracellular compartment, prerenal azotemia due to decreased to develop evidence of mineralocorticoid deficiency do so within
renal perfusion, and progressive hypovolemia. Glucocorticoid the first year after diagnosis. Because of the recognition of this
deficiency also contributes to hyponatremia due to increased less common presentation of hypoadrenocorticism, the absence of
secretion of vasopressin. hyponatremia or hyperkalemia in a dog with suspected hypoadre-
Sodium-to-Potassium Ratio.The normal Na:K ratio ranges nocorticism should not exclude the diagnosis; conversely reliance
from 27:1 to 40:1. Because of hyponatremia and hyperkalemia, on measurement of electrolytes alone for diagnosis of hypoadre-
the Na:K ratio is often low in dogs with hypoadrenocorticism, and nocorticism is misleading, because there are many other causes
this ratio can be used as a guide for planning emergency diagnosis of hyperkalemia and hyponatremia (Box 12-3). A suspicion of
and treatment while waiting for definitive test results. It is impor-
tant to remember that electrolyte concentrations, and therefore
the Na:K ratio, can be completely normal in dogs with both pri- BOX 12-3 D
ifferential Diagnosis for Hyperkalemia and/or
mary and secondary hypoadrenocorticism. Hyponatremia in Dogs and Cats
In a retrospective study of 76 dogs with hypoadrenocorticism
and 200 control dogs, a Na:K ratio less than 24 was 100% specific I. Hypoadrenocorticism
for a diagnosis of hypoadrenocorticism (Adler etal, 2007); how- II. Renal and urinary tract disease
ever, other studies have reported much lower specificity for the A. Primary acute renal failure
Na:K ratio. In two studies evaluating dogs with Na:K ratios less B. Chronic severe oliguric or anuric renal failure
than 24 to 27, the proportion of dogs that had hypoadrenocorti- C. Urethral obstruction longer than 24 hours duration
cism was 17% to 24%, suggesting that many other disorders can D. Urine leakage into the peritoneal cavity
cause marked changes in the Na:K ratio (Roth and Tyler, 1999; III. Severe liver failure
Nielsen et al, 2008). Problems other than hypoadrenocorticism A. Cirrhosis
that were commonly associated with a low Na:K ratio included B. Neoplasia
renal and urinary tract disease, gastrointestinal disease, cardiore- IV. Severe gastrointestinal disease
spiratory disease, and sample contamination with potassium eth- A. Parasitic infection
ylenediaminetetraacetic acid (EDTA). B. Salmonellosis
Normal Electrolytes in Hypoadrenocorticism. Although hypo- C. Viral enteritis (parvovirus)
natremia and hyperkalemia are the classic hallmarks of hypoadre- D. Gastric torsion
nocorticism, it is now recognized that as many as 30% of dogs with E. Duodenal perforation
hypoadrenocorticism lack these changes. This has been referred to F. Gastrointestinal malabsorption
as atypical hypoadrenocorticism or glucocorticoid deficient hypoadreno- V. Severe metabolic or respiratory acidosis
corticism. In a study of 25 Nova Scotia Duck Tolling Retrievers with A. Diabetic ketoacidosis
hypoadrenocorticism, 32% lacked both hyperkalemia and hypona- B. Pancreatitis
tremia at the time of diagnosis (Hughes et al, 2007). In a retro- VI. Pleural effusion
spective study of 46 dogs with hypoadrenocorticism presented to a A. Chylous effusion
veterinary teaching hospital, 24% lacked hyponatremia and hyper- B. Repeated drainage of effusions
kalemia (Thompson etal, 2007). Dogs without electrolyte changes VII. Congestive heart failure (hyponatremia)
tend to be older, have a longer duration of clinical signs, and are VIII. Massive tissue destruction
more likely to be anemic, hypoalbuminemic, and hypocholesterol- A. Crush injury
emic. Reasons for normal electrolytes in dogs with hypoadrenocor- B. Extensive infection
ticism include secondary hypoadrenocorticism, selective destruction C. Hemolysis
of the ZF and reticularis, early stage disease in which destruction of IX. Primary polydipsia (hyponatremia)
the ZG is not complete, compensation for natriuresis by increased X. Artifact
salt intake, or concurrent illnesses (e.g., hypothyroidism) that can A. Hyperkalemia
mask electrolyte changes. In one report of dogs with hypoadreno- 1. Blood storage and hemolysis (especially from Akitas)
corticism that had symptoms of gastrointestinal hemorrhage, typical 2. Extreme leukocytosis or thrombocytosis
electrolyte changes were present initially, but by the time of referral B. Hyponatremia
the dogs were either normokalemic or even hypokalemic (Medinger 1. Lipemia
etal, 1993). The decrease in serum potassium concentration by the
|
hypoadrenocorticism based on the presence of abnormal electro- retention. Stimulation of thirst, impairment of free water excre-
lytes should always be confirmed by an ACTH stimulation test. tion, and decreased renal distal tubular flow, combined with de-
Differential Diagnosis for Hyperkalemia and Hyponatremia. creased sodium intake contribute to hyponatremia in this scenario
Dogs with hypoadrenocorticism must be distinguished from (Willard etal, 1991).
those with non-adrenal causes of hyperkalemia (see Box 12-3). Iatrogenic and/or Drug Therapy. Excess potassium intake
Although the acute management of hyperkalemia is similar regard- is an uncommon cause of hyperkalemia except in patients with
less of its cause (except for the need for specific treatment of uri- renal insufciency. Hyperkalemia can develop with overzealous
nary obstruction), the clinician must be certain of the diagnosis of potassium supplementation in intravenous fluids, use of potas-
hypoadrenocorticism because it requires lifelong therapy. sium containing salt substitutes, or administration of parenteral
Renal and Urinary Tract Disorders. The most common non- feeding solutions high in potassium. Potassium-sparing diuretics,
adrenal causes of hyperkalemia are acute renal failure, urethral angiotensin-converting enzyme inhibitors, and nonsteroidal anti-
obstruction, and rupture of the bladder or ureter. Hyperkalemia inflammatory drugs (NSAIDs) also have the potential to cause
is less common in chronic renal failure unless the dog or cat is mild hyperkalemia (Willard, 1989). Renal excretion of potassium
terminally anuric or oliguric. may also be decreased by drugs (e.g., trimethoprim), which block
Gastrointestinal Disease. Gastrointestinal disorders may also the luminal sodium ion channel in the cortical collecting tubule
result in serum electrolyte abnormalities consistent with Addisons (Rubin et al, 1998).
disease. These electrolyte disturbances have been reported in dogs Artifact. In vitro increases in the serum potassium concen-
with intestinal parasitism (trichuriasis, ancylostomiasis), intestinal tration may occur due to sample contamination with potassium
infection (salmonellosis), perforated duodenal ulcers, and gastric EDTA, or in some breeds if separation of red blood cells from
torsion (DiBartola et al, 1985; DiBartola, 1989; Roth and Tyler, plasma is delayed. The Akita breed appears to have unusually large
1999). Similar serum electrolyte abnormalities have been encoun- concentrations of potassium in the red blood cells. In one study,
tered in puppies with parvovirus infection or canine distemper. six of eight Akitas had high erythrocyte potassium concentra-
Severe malabsorption syndromes also occasionally cause hyperka- tions, and plasma from affected dogs displayed pseudohyperka-
lemia or hyponatremia or both. Hyponatremia in dogs with gas- lemia after being refrigerated in contact with red cells for longer
trointestinal disease is due to replacement of sodium lost from the than 4 hours (Rich etal, 1986). The rise in the plasma potassium
gastrointestinal tract due to diarrhea by free water. Hyperkalemia concentration (pseudohyperkalemia) was progressive with pro-
is the result of hypovolemia, metabolic acidosis, and most impor- longed red cell contact and was accompanied by a fall in plasma
tantly decreased renal distal tubular flow rate. Potassium secretion sodium. Extreme leukocytosis (> 100,000 mm3) or thrombocyto-
in the renal distal tubule depends on the serum potassium concen- sis (> 1,000,000 mm3) may allow sufficient amounts of potassium
tration, the cellular sodium-potassium ATPase activity induced to be released into the serum during clotting to also falsely elevate
by aldosterone, the electrochemical gradient that results from the serum potassium value.
sodium reabsorption, and the luminal potassium concentration. Lipemia. Lipemia may cause a false decrease in the plasma so-
Decreased distal tubular flow rate, especially in conjunction with dium concentration by displacing the aqueous plasma phase in
hyponatremia, impairs potassium secretion because of poor so- which sodium ions are found. When the plasma sodium is mea-
dium delivery (decreased electrochemical gradient) and potassium sured, it is calculated based on the total volume of plasma includ-
saturation of the luminal fluid (decreased concentration gradient) ing the lipid phase, which results in an artifactual hyponatremia.
despite normal or increased concentration of aldosterone (Rose,
2001; Bissett etal, 2001). Dogs with trichuriasis, hyponatremia, Miscellaneous Disorders
and hyperkalemia do not have decreased serum concentrations of Low sodium:potassium ratios have been described in dogs with
aldosterone (Graves etal, 1994). pyometra, perhaps as a result of acidosis, gastrointestinal signs,
Acidosis, Pancreatitis, and/or Trauma. Rapid cellular release and severe dehydration. Hyperkalemia and hyponatremia have
of potassium and resultant hyperkalemia may occur as a result of also been described in three near-term pregnant Greyhounds
severe acidosis or tissue destruction after surgery, crush injury, or (Schaer et al, 2000) and in dogs with disseminated neoplasia,
inflammation. Although not common, examples of disorders that congestive heart failure, and mushroom toxicity (Roth and Tyler,
can cause hyperkalemia are pancreatitis, diabetic ketoacidosis, aor- 1999).
tic thrombosis, and rhabdomyolysis secondary to heat stroke or
prolonged exercise. These conditions may also be associated with Total Calcium/Ionized Calcium
impaired renal excretion of potassium. An increase in total calcium concentration occurs in 30% to
Acidosis and insulin deficiency in diabetic ketoacidosis may 40% of dogs with hypoadrenocorticism (Peterson and Feinman,
lead to hyperkalemia, whereas hyperglycemia and hyperosmolality 1982; Peterson etal, 1996; Adamantos and Boag, 2008), whereas
may result in concurrent hyponatremia (Roth and Tyler, 1999). 18% of dogs have ionized hypercalcemia (Adler et al, 2007).
Pleural Effusions. Hyperkalemia and hyponatremia have Increased total calcium may occur together with either increased
been identied in some dogs with chylous pleural effusion after or decreased ionized calcium (Adler etal, 2007; Adamantos and
repeated pleural drainage procedures (Willard etal, 1991). Simi- Boag, 2008). The mechanisms by which hypercalcemia occurs
lar serum electrolyte abnormalities were identied in a dog with in Addisons disease are poorly understood, but volume con-
nonseptic, nonchylous effusion (Zenger, 1992). The incidence of traction, decreased GFR, increased intestinal absorption of
these serum electrolyte abnormalities appears to be low, because calcium, and decreased urinary excretion of calcium have been
only two of 17 dogs with experimentally induced chylothorax had proposed. In eight dogs with concurrent hypoadrenocorticism
hyperkalemia and hyponatremia (Fossum and Birchard, 1986; and hypercalcemia, parathyroid hormone, parathyroid hormone
Willard etal, 1991). Hyperkalemia and hyponatremia may result related peptide, and 1,25 dihydroxyvitamin D concentrations
from sodium loss in situations in which the effusion is drained, or were within their respective reference ranges in the majority of
from decreased effective circulating volume that causes activation cases (Gow etal, 2009). An inverse relationship between venous
of the renin-angiotensin-aldosterone axis and sodium and water pH and ionized calcium has been documented in dogs with
hypoadrenocorticism, suggesting that acidosis may contribute

to ionized hypercalcemia (Adler etal, 2007). Acidemia can lead BOX 12-4 O
verlapping Clinical Manifestations of
to mild ionized hypercalcemia by decreasing protein binding Hypoadrenocorticism Versus Other Diseases
of calcium. See Chapter 15 for more information regarding
hypercalcemia. I. Renal disease
A. Weight loss, poor appetite, vomiting, and diarrhea
B. Increased BUN, creatinine, acidosis; low albumin
Azotemia C. Urine specic gravity 1.008 to 1.020, when ill
Azotemia is common in hypoadrenocorticism due to hypovole- D. Responsive to IV fluids
mia, hypotension, and decreased renal perfusion (see Table 12-4). II. Gastrointestinal disease
Delayed treatment of hypoadrenocorticism may result in second- A. Weight loss, poor appetite, vomiting, and diarrhea
ary renal damage, although permanent renal failure is uncommon. B. Decreased serum albumin and cholesterol
In dogs with hypoadrenocorticism that are azotemic, serum cre- C. Abnormal serum biochemistries correct with IV fluids
atinine concentrations are less likely to be increased than blood D. Abnormal biopsies may be obtained
urea nitrogen (BUN) and sometimes are not increased to the III. Hepatic disease
same degree as BUN. One possible explanation for this disparity A. Weight loss, poor appetite, vomiting, and diarrhea
is hemorrhage into the gastrointestinal tract, which is common B. Decreased albumin, cholesterol, glucose BUN
in Addisons disease. Gastrointestinal bleeding provides substrate C. Microhepatia: Radiography or ultrasonography
for the production of ammonia, which is then absorbed into the D. Abnormal liver enzyme activity liver function test results
portal circulation and converted to urea (BUN) by the liver. In E. Abnormal liver biopsy results
such animals, BUN will be higher than predicted by the serum BUN, Blood urea nitrogen; IV, intravenous.
creatinine concentration.
Low Urine Specific Gravity

hypoadrenocorticism (Langlais-Burgess etal, 1995; Thompson
The urine specic gravity in a dog with normal renal function et al, 2007). This may be because dogs without electrolyte
and prerenal uremia secondary to dehydration and decreased car- abnormalities are less likely to be hypovolemic and because
diac output should be greater than 1.030, whereas urine specic these cases often have a longer duration of clinical signs prior
gravity in a dog with primary renal failure is within or near the to diagnosis (Thompson et al, 2007). Hypocholesterolemia
isosthenuric range (1.008 to 1.020). Most dogs with hypoadre- in dogs with hypoadrenocorticism may be the result of either
nocorticism have an impaired ability to concentrate urine because decreased fat absorption, or concurrent hepatopathy (Lifton
chronic urinary sodium loss causes a reduction in the renal medul- etal, 1996). Glucocorticoids are believed to be important in fat
lary sodium content, loss of the normal medullary concentration absorption, and steatorrhea occurs in some people with hypo-
gradient, and impaired capacity for water resorption by the renal adrenocorticism. The cause of hypoalbuminemia in dogs with
collecting tubules. Hyponatremia also interferes with stimulation hypoadrenocorticism is unknown, but proposed mechanisms
of vasopressin release by reducing serum osmolality. As a result, include anorexia, gastrointestinal blood loss due to mucosal
60% of dogs with hypoadrenocorticism have urine specic gravity ulceration, decreased synthesis due to hepatopathy, and pro-
consistent with that expected in a dog with primary renal failure tein losing enteropathy. Glucocorticoids have been reported
(see Table 12-4). Thus it may be difficult to distinguish hypoad- to influence digestion and intestinal absorption of nutrients,
renocorticism from primary renal failure without measurement especially amino acids. Increased vascular permeability has
of serum cortisol concentrations (Box 12-4); hypoadrenocorti- been documented in animals with glucocorticoid deficiency
cism should always be considered in an ill dog with azotemia and and could be the cause of protein losing enteropathy (Langlais-
isosthenuria. Burgess et al, 1995). Albumin is a negative acute phase pro-
tein, and thus hypoalbuminemia could also occur in dogs with
hypoadrenocorticism and concurrent inflammation; however,
Hypoglycemia
most dogs with hypoadrenocorticism do not have evidence of
Hypoglycemia occurs in up to 30% of dogs with hypoadrenocor- concurrent inflammation.
ticism and may be severe enough to cause seizures (Levy, 1994;
Syme and Scott-Moncrieff, 1998; Lifton etal, 1996). Glucocor- Hepatic Dysfunction
ticoid deficiency causes decreased hepatic gluconeogenesis and
increased peripheral sensitivity to insulin. Most, but not all dogs Thirty percent of dogs with hypoadrenocorticism have mild
with hypoglycemia have other biochemical findings supportive increases in hepatic enzymes, and because these dogs may have
of hypoadrenocorticism, such as hypocholesterolemia, hypoal- concurrent hypoalbuminemia, hypocholesterolemia, and hypo-
buminemia, and azotemia. Insulin concentrations in dogs with glycemia, hypoadrenocorticism can mimic hepatic failure. Abnor-
hypoadrenocorticism do not differ from those of dogs with non- malities in liver function tests (bile acids, ammonia tolerance
adrenal illness (Gow etal, 2012). See Chapter 9 for more informa- test) have been reported in some dogs with hypoadrenocorticism
tion regarding hypoglycemia. (Feldman and Nelson, 2004). It has been speculated that immune
mediated hepatitis may occur concurrently with hypoadreno-
corticism in some dogs. Alternatively the liver could be second-
Hypoalbuminemia and Hypocholesterolemia
arily affected due to hypotension and impaired tissue perfusion.
Hypoalbuminemia and hypocholesterolemia are common Regardless, hepatic abnormalities detected in dogs with hypoadre-
in dogs with hypoadrenocorticism, and both abnormali- nocorticism resolve with no specific treatment other than that for
ties are more common in dogs with glucocorticoid deficient hypoadrenocorticism.
|
C
FIGURE 12-8 A and B, Radiographs of a 3-year-old Rhodesian Ridgeback that was brought to the hospital in a
shock-like state secondary to hypoadrenocorticism. Note the small heart on both views and the small pulmonary
vasculature due to poor cardiac output. C, Lateral thoracic view radiograph of a 5-year-old hypoadrenal dog with
microcardia, a flattened caudal vena cava, and a dilated, air-lled esophagus. The esophageal dilation, which is
seen occasionally in hypoadrenocorticism, is reversible with appropriate hormonal therapy for the primary disease.
Acid-Base Status
(Fig. 12-8) (Melin etal, 1999). Changes occur as a result of
Hypoaldosteronism impairs renal tubular hydrogen ion secretion, hypovolemia; therefore they are more likely to be present in
which in conjunction with hypotension and poor perfusion of tis- dogs with electrolyte abnormalities. Megaesophagus or esopha-
sues, most likely accounts for the mild acidosis documented in geal dilation that is reversible with treatment of hypoadreno-
many dogs suffering from hypoadrenocorticism. The metabolic corticism has been reported to occur in a small proportion of
acidosis is typically mild and rarely requires specic treatment. dogs with classic hypoadrenocorticism as well as those with
Adequate fluid and mineralocorticoid replacement therapy should glucocorticoid deficiency alone (Bartges and Nielson, 1992;
restore renal perfusion, which in turn enhances urinary hydrogen Whitley, 1995; Lifton et al, 1996). In one study of 225 dogs
ion excretion. with hypoadrenocorticism, one dog with megaesophagus was
reported (Peterson et al, 1996); however, in a study of dogs
with secondary hypoadrenocorticism, four of eleven dogs that
RADIOGRAPHY
had thoracic radiographs taken were diagnosed with mega-
Most untreated dogs with hypoadrenocorticism have one or esophagus (Lifton etal, 1996). Why some dogs with Addisons
more radiographic abnormalities on thoracic and abdominal disease develop esophageal dilation is not clear. It has been pro-
radiographs, including microcardia, small cranial lobar pul- posed that the condition might be attributable to the effect
monary artery, narrow posterior vena cava, or microhepatia of abnormal serum sodium and potassium concentrations on
P<0.001 P<0.001
P<0.001 P<0.05 P<0.001 P<0.05
9 9
8 8
7 7
Thickness (mm)
Thickness (mm)
6 6
5 5
4 4
3 3
2 2
1 1
0 0
Group 1 Group 2 Group 3 Group 1 Group 2 Group 3
A Left adrenal gland B Right adrenal gland
P<0.05
35 35
30 30
25 25
Length (mm)
Length (mm)
20 20
15 15
10 10
5 5
0 0
Group 1 Group 2 Group 3 Group 1 Group 2 Group 3
C Left adrenal gland D Right adrenal gland
FIGURE 12-9 Measurements of the thickness of the (A) left and (B) right adrenal glands, and the length of the (C)
left and (D) right adrenal glands for three groups of dogs. Group 1, Dogs with primary hypoadrenocorticism; Group
2, healthy control dogs; Group 3. dogs with diseases mimicking adrenal insufficiency. P values are indicated where
differences between groups are significant. Note that in A the overlap between Groups 1 and 2 is limited to one
dog indicated by X. (From Wenger M, etal.: Ultrasonographic evaluation of adrenal glands in dogs with primary
hypoadrenocorticism and mimicking diseases, Vet Rec 167:207, 2010.)
membrane potential and neuromuscular function (Burrows, those of healthy dogs (Fig. 12-9; Wenger etal, 2010). The best
1987); however, abnormal serum electrolyte concentrations are discrimination between dogs with hypoadrenocorticism and
not always documented (Bartges and Nielson, 1992; Whitley, those with normal adrenal function was obtained by measure-
1995). Cortisol deciency and its associated muscle weakness ment of the thickness of the left adrenal gland. Twenty eight
may be the cause of megaesophagus because the condition typi- of 29 dogs with hypoadrenocorticism had left adrenal gland
cally resolves with treatment. thickness less than 3.2 mm, and there was minimal overlap
between the groups. The right adrenal gland could not be visu-
alized in eight dogs and was less than 3.2 mm in 18 of 22 dogs.
ABDOMINAL ULTRASOUND
Although there is some overlap, a left adrenal gland measuring
Most dogs with hypoadrenocorticism have a measurable reduc- less than 3.2 mm is strongly suggestive of hypoadrenocorti-
tion in size of the adrenal glands on ultrasound examination, cism. It is important to remember that identification of nor-
and sometimes the adrenal glands, particularly the right adre- mal sized adrenal glands on ultrasound examination does not
nal gland, cannot be identified by ultrasonography (Hoerauf, preclude a diagnosis of hypoadrenocorticism, and the presence
1999). In a study of thirty dogs with hypoadrenocorticism, 14 of small adrenal glands, although supportive of a diagnosis of
healthy dogs, and 10 dogs with other causes of hyperkalemia hypoadrenocorticism, is not adequate for confirmation. Nor-
and hyponatremia, the dogs with hypoadrenocorticism had mal adrenal gland size in Addisonian dogs may be the result of
significantly thinner adrenal glands than the other two groups inflammation early in the disease process or more rarely may
and their left adrenal glands were also significantly shorter than suggest granulomatous destruction, necrosis, or infiltrative
|
disease, such as lymphoma or metastatic neoplasia (Parnell concentrations are less commonly measured because the assay
et al, 1999; Labelle and De Cock, 2005; Korth et al, 2008; is not routinely run by commercial diagnostic laboratories.
Kook et al, 2010). Measurement of increased resistive index Aldosterone deficiency is presumed in dogs with hypocorti-
due to abnormal renal blood flow has been documented in a solemia that have hyponatremia and hyperkalemia. There are
dog with hypoadrenocorticism (Koch et al, 1997). This pre- some weaknesses to this approach (see Glucocorticoid Defi-
sumably reflects renal vasoconstriction due to increased activity ciency Versus Mineralocorticoid Deficiency). Some dogs with
of the renin-angiotensin system. hypoadrenocorticism that have normal electrolytes have low
aldosterone concentrations, and some dogs with electrolyte
ELECTROCARDIOGRAPHY abnormalities consistent with mineralocorticoid deficiency
have normal or only slightly decreased aldosterone concentra-
Potassium plays an important role in cell function and neu- tions (Baumstark etal, 2014).
romuscular transmission and the effects of hyperkalemia in
patients with hypoadrenocorticism can be life threatening. The
Basal Cortisol Concentrations
most significant clinical effect of hyperkalemia is disturbed car-
diac conduction, which can lead to bradycardia, ventricular Plasma cortisol concentrations can be measured by radioimmuno-
fibrillation, or ventricular standstill, and can result in cardiac assay, chemiluminescent assay, or enzyme-linked immunosorbent
arrest. Plasma hyperkalemia decreases the ratio between intracel- assay (ELISA; Russell et al, 2007). Reference ranges for plasma
lular potassium and plasma potassium resulting in a decrease in cortisol differ depending upon the specific assay. In-house cortisol
the resting membrane potential. Although this should increase assays are also available, but validation data have not been pub-
membrane excitability, because persistent depolarization inacti- lished in the peer reviewed literature; so results should be inter-
vates sodium channels in the cell membrane, there is actually a preted with caution. Cortisol is stable in plasma and urine at 4 C
net decrease in excitability manifested clinically as muscle weak- and 25 C for 5 days but decreases in serum at 4 C, 25 C, and 37
ness and disturbed cardiac conduction (Rose, 2001). C (compared to 20 C; Behrend, 1995).
Hyperkalemia results in a characteristic sequence of changes on Measurement of a normal resting (basal) cortisol concentra-
the electrocardiogram (ECG) that reflect the effects of hyperka- tion is a useful test that can be used to exclude a diagnosis of
lemia on atrial and ventricular depolarization (P wave and QRS hypoadrenocorticism. This approach is particularly helpful in
complex changes) and repolarization (represented by changes dogs that have chronic clinical signs of illness. In a study of
in the T wave for ventricular repolarization). Thus the ECG is 123 dogs evaluated for suspicion of hypoadrenocorticism (110
a useful tool for rapid detection of hyperkalemia (Fig. 12-10). with non-adrenal illness and 13 with hypoadrenocorticism),
The earliest changes observed with mild hyperkalemia (potas- measurement of a basal cortisol less than 2 g/dL was 100%
sium concentrations of 6.0 to 7.0 mEq/L) include peaking of T sensitive for diagnosis of hypoadrenocorticism (Lennon etal,
waves and a shortened QT interval. As the potassium rises above 2007; Fig. 12-11). In a study investigating 28 dogs with non-
7.0 mEq/L, there is prolongation of the PR interval and wid- adrenal illness, pre-ACTH cortisol concentrations were less
ening of the QRS complex and decreased amplitude, widening than 2.0 g/dL in only 15 of 56 (27%) samples, suggesting
and eventual loss of the P wave when the potassium concentra- that an ACTH stimulation test would have been unnecessary
tion exceeds 7.5 to 8.0 mEq/L. The final change that typically to rule out a diagnosis of hypoadrenocorticism in 73% of dogs
occurs as the potassium concentration increases greater than 10 (Fig. 12-12). Although a basal cortisol concentration more
to 11 mEq/L is a sine-wave pattern as the widened QRS complex than 2.0 g/dL is helpful in ruling out hypoadrenocorticism, it
merges with the T wave, followed by ventricular fibrillation or is important to understand that documentation of a low basal
standstill. cortisol concentration is not adequate to confirm the diagnosis,
It is important to remember that these potassium concentra- because some normal dogs with a normal adrenal axis have a
tions are only guidelines. Other factors such as hyponatremia, low basal cortisol concentration yet have a normal response to
hypocalcemia, acidemia, and a rapid change in the potassium ACTH administration.
concentration enhance the effects of hyperkalemia, whereas
hypercalcemia and hypernatremia counteract the membrane Adrenocorticotropic Hormone Stimulation Test
changes of hyperkalemia and decrease the cardiac effects of
hyperkalemia; thus there is significant inter-patient variability in The ACTH stimulation test is a test of adrenal reserve and is con-
the cardiac effect of a certain potassium concentration. Regard- sidered the gold standard test for confirmation of a diagnosis of
less of its cause, marked hyperkalemia is an emergency situation hypoadrenocorticism. Initial emergency treatment may need to be
that demands a quick therapeutic response. In addition to pro- based on presence of characteristic clinical signs and electrolyte
viding a tool for early recognition of hyperkalemia, the ECG also abnormalities; however the diagnosis should always be confirmed
allows the clinician to easily, reliably, and inexpensively monitor with an ACTH stimulation test prior to initiating long term
therapy. As the hyperkalemia is treated, the various abnormali- treatment. Once treatment has been initiated, it is very difficult
ties present on an ECG resolve. if not impossible to confirm the diagnosis without withdrawing
treatment for several weeks. Synthetic polypeptides containing
the biologically active first 24 amino acids of ACTH (Cortro-
CONFIRMING THE DIAGNOSIS
syn [cosyntropin] or Synacthen [tetracosactrin]) are the products
Hormones that can be measured in the diagnostic approach of choice for performing an ACTH stimulation test (Behrend,
to dogs with suspected hypoadrenocorticism include cortisol, 2013). Not all of these products have been directly compared in
aldosterone, endogenous ACTH, and renin concentrations. dogs but they are considered interchangeable. The lowest dose of
Although most dogs with hypoadrenocorticism have a defi- ACTH that stimulates maximal secretion of cortisol in healthy
ciency of cortisol and aldosterone, routine diagnostic testing dogs is 0.5 g/kg (Martin, 2007). The lowest dose shown to result
relies on measurement of cortisol concentrations. Aldosterone in maximal cortical stimulation in dogs with suspected adrenal
AA
BB
CC
FIGURE 12-10 Serial electrocardiogram (ECG) segments obtained from two dogs with hypoadrenocorticism and hyperkalemia. A and AA both illustrate the effect of
severe hyperkalemia, with the dog in A having a serum potassium concentration of 8.6 mEq/L and the dog in AA a measurement of 9.4 mEq/L. Note the lack of visible
P waves, the short and wide QRS complexes, and the T waves, which are not of excessive amplitude. The ECG in A also reveals a bizarre-looking QRS complex following
a more normal-appearing QRS complex. This bizarre wave represents a ventricular escape beat that could be the result of hypoxia or hyperkalemia or both. B and BB
are ECGs from the same dogs as in A and AA, respectively. They were each obtained approximately 1 hour after institution of intravenous normal saline administration
as the only treatment. The serum potassium concentrations had decreased to 7.6 mEq/L and 7.9 mEq/L, respectively. Two important factors to note: (1) improvement
is seen in each case with the return of P waves, a more rapid heart rate, and disappearance of ventricular escape beats; and (2) abnormalities are still present, most
obviously the prolonged P-R intervals (rst-degree heart block), which alone suggest hyperkalemia, especially when associated with a widened QRS complex and a
short Q-T interval. There are numerous other causes of P-R interval prolongation. In C and CC, the serum potassium concentrations are considerably lower, 6.2 mEq/L
and 5.9 mEq/L, respectively. The P-R interval and P, QRS, and T waves are of shorter duration, and the R waves are taller. D, ECG from the dog in A; the serum potas-
sium concentration is 5.6 mEq/L and a more spiked T wave is seen. (From Ettinger SJ: Textbook of veterinary internal medicine, ed 2, Philadelphia, 1983, WB Saunders.)
|
dysfunction is 5 g/kg (Lathan, 2008). No differences in peak cor- there are differences in peak concentration and duration of ACTH
tisol response between dosages of 5 g/kg or 250 g/dog have been when administered intravenously versus intramuscularly, there
documented in either healthy dogs or dogs with clinical signs of is no difference in peak cortisol concentration in response to
hypoadrenocorticism; therefore a dose of 5 g/kg is recommended cosyntropin administered either intravenously or intramuscularly
to decrease the cost of testing (Kerl, 1999; Frank et al, 2000; (Hansen etal, 1994; Cohen and Feldman, 2012). Blood samples
Behrend et al, 2006; Lathan et al, 2008; Fig. 12-13). Although for measurement of serum cortisol should be collected prior to and
60 to 90 minutes after administration of ACTH (Frank etal, 2000;
Frank et al, 2004). Most protocols recommend that the second
19
18 sample is collected at 60 minutes. Synthetic ACTH can be recon-
17 stituted and frozen at 20 o C in plastic syringes for 6 months with
16
Cortisol concentration (g/dL)
15 no adverse effects on bioavailability (Frank and Oliver, 1998). Use

14 of compounded ACTH gel is an alternative if synthetic ACTH is
13
12 not available; however potential variability between compounding
11 pharmacies makes this a less than ideal choice (Hill, 2004). In one
10 study, cortisol concentrations at 60 minutes after administration
9
8 were no different when compounded ACTH was administered at
7
6
a dose of 2.2 U/kg IM compared to cosyntropin at 5 g/kg IV,
5 although there were differences at later time points (Kemppainen
4
3
etal, 2005). Depot tetracosactide (250 g intramuscularly [IM])
2 produced similar cortisol responses to cosyntropin at a dose of 5
1 g/kg IV in healthy dogs, but it has not been evaluated in dogs
0
with adrenal dysfunction (Ginel etal, 2012). Dogs do not exhibit
Hypoadrenocorticism Non-adrenal illness
a circadian rhythm in cortisol secretion, so the ACTH stimulation
FIGURE 12-11 Basal serum or plasma cortisol concentrations in 13 dogs with test can be performed at any time of day. In dogs with suspected
hypoadrenocorticism and 110 dogs with non-adrenal gland illnesses. Samples hypoadrenocorticism, the ACTH stimulation test should be per-
with no detectable cortisol (< 1.0 g/dL) were plotted with a value of 0. (From formed as soon as logistically possible. Fasting is not necessary
Lennon EM, etal.: Use of basal serum or plasma cortisol concentrations to rule unless the cortisol assay used is influenced by lipemia.
out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005), J Am If it is clinically necessary to administer corticosteroids prior to
Vet Med Assoc 231:413, 2007.) performing the ACTH stimulation test, dexamethasone should be
Basal cortisol
16
Healthy
14
Cortisol concentration
Non-adrenal illness
12
Hypoadrenocorticism
10
(g/dL)
8
6
4
2 FIGURE 12-12Basal cortisol concentrations in

0 healthy dogs, dogs with hypoadrenocorticism, and
dogs with non-adrenal illness.
50
250 g/dog
40 5 g/kg
Cortisol concentration
30
(g/dL)
20
FIGURE 12-13 Plasma cortisol concentrations
before and 1 hour following administration of
10 cosyntropin at two different dosages in 28 dogs
with suspected hypoadrenocorticism. The cor-
0
tisol responses to adrenocorticotropic hormone
(ACTH) were statistically equivalent.

18 BOX 12-5 C
auses of an Inadequate Response in
Adrenocorticotropic Hormone Stimulation Test
16
Primary hypoadrenocorticism
14 Secondary hypoadrenocorticism
Prior glucocorticoid administration*
12 Treatment with drugs that suppress adrenal gland function (trilostane,
Cortisol (g/dL)
mitotane, ketoconazole)
10 Loss of potency of ACTH
Use of inappropriate dosage or form of ACTH
8
Errors in ACTH administration or sample collection
6 Sex hormone secreting adrenal tumors*
Critical illness related adrenal insufficiency*
4
ACTH, Adrenocorticotropic hormone.
*These animals may have clinical signs of hyperadrenocorticism.
2
0
Pre Post et al, 1996). Critical illness related adrenal insufficiency (CIRCI,
relative adrenal insufficiency) may decrease the relative change in
Normal Equivocal Hypo-A cortisol concentration after ACTH administration, but in this situ-
ation the pre-cortisol is usually increased above the reference range
FIGURE 12-14Response to adrenocorticotropic hormone (ACTH) showing a (see Critical Illness Related Adrenal Insufficiency [Reactive Adrenal
normal response, borderline response, and lack of suppression consistent with Insufficiency]; Martin etal, 2008). Whether dogs with CIRCI ben-
hypoadrenocorticism (post-cortisol < 2.0 g/dL). efit from glucocorticoid supplementation is not yet known. In dogs
in which no cause for a subnormal response can be established, the
administered because of assay dependent cross reactivity among ACTH stimulation test should be repeated 1 to 4 weeks later to
other steroids (prednisolone, prednisone, methylprednisolone, rule out whether there was a problem in performing the test and to
fludrocortisone, cortisone, and hydrocortisone). Even one dose of identify possible progressive adrenal failure. Concurrent measure-
dexamethasone will suppress post ACTH cortisol concentration; ment of endogenous ACTH concentration in a sample collected
however cortisol suppression after one dose of up to 5 mg/kg of prior to ACTH administration may be helpful in interpretation of
dexamethasone did not exceed 35% of control, so it is unlikely the follow up ACTH stimulation test.
that one dose would completely abolish the response to ACTH It is important to understand the limitations of the ACTH
(Kemppainen et al, 1989). stimulation test. The results of ACTH stimulation testing do not
The criteria for confirmation of the diagnosis of hypoadrenocorti- distinguish between dogs with naturally occurring primary adre-
cism are a pre- and post-ACTH cortisol concentration less than the nocortical disease and those with secondary insufciency due to
reference range for basal cortisol (usually 2 g/dL). In most dogs pituitary failure, secondary insufciency due to chronic iatrogenic
with hypoadrenocorticism both the pre- and post-cortisol con- corticosteroid administration, or dogs with primary adrenocorti-
centrations are less than 1 g/dL. Although there is usually a clear cal destruction caused by o,p-DDD (mitotane) or trilostane over-
distinction between the response to ACTH in a dog with hypo- dose. Therefore a detailed history is an important component of
adrenocorticism and that of a dog with adequate adrenal reserve, test interpretation. It should also be recognized that if hypoadre-
sometimes borderline results occur (post ACTH cortisol concentra- nocorticism is not present in a dog with systemic illness there may
tions between 2 and 8 g/dL) (Fig. 12-14). Causes of inadequate actually be an abnormally high response on the ACTH stimulation
response to ACTH stimulation other than hypoadrenocorticism, test. This should prompt investigation for other causes of systemic
include prior glucocorticoid administration, treatment with mito- illness rather than pursuit of a diagnosis of hyperadrenocorticism.
tane, trilostane, or ketoconazole, poor potency of compounded
ACTH gel, loss of potency of the ACTH product that was adminis-
Endogenous Adrenocorticotropic Hormone Concentration
tered due to poor or extended storage, use of an inappropriate form
or dose of ACTH, and errors in administration or sample collec- Both a radioimmunoassay and a chemiluminescent assay have been
tion (Box 12-5). Rarely, dogs with sex hormone secreting adrenal validated for measurement of plasma ACTH in dogs (Scott-Mon-
tumors have a suppressed response to ACTH; however, these dogs crieff, 2003). Blood collected for measurement of ACTH must be
usually have overt signs of hyperadrenocorticism rather than signs handled with care because plasma ACTH is very labile. To avoid
of hypoadrenocorticism. In some cases, no other underlying cause erroneously low values, blood specimens should not be allowed to
of adrenal suppression can be identified. It is possible that dogs with stand at room temperature for even short periods. Contact with
progressive loss of adrenal function may initially have borderline glass must be avoided during collection, separation, and storage,
results, but this is currently poorly documented. In secondary hypo- because the ACTH molecule adheres to glass causing erroneously
adrenocorticism, the ACTH stimulation test shows no response low results. Blood samples should be collected in siliconized tubes
because of adrenocortical atrophy due to lack of stimulation by containing EDTA as the anticoagulant. Plasma ACTH concentra-
ACTH. These cases may have more borderline cortisol concentrations can be stored for later assay by freezing plasma samples in
tions after ACTH stimulation. Although individual data were not plastic containers and freezing (ideally at 20 C or lower). The
reported in a publication of 18 dogs with secondary hypoadreno- protocol for sample collection and handling depends upon the
corticism, the mean post-ACTH plasma cortisol concentration was assay utilized, and the individual laboratory should be consulted
less than 2.0 g/dL, and the highest value was 4.4 g/dL (Lifton for handling recommendations and reference ranges.
|
2500
2000
1500
1000
Plasma ACTH (pg/ml)
500
400
300
200
100
80
60
40
FIGURE 12-15 Plasma endogenous adrenocorticotropic hormone (ACTH)
20 concentrations in normal dogs, dogs with primary adrenocortical failure
causing lack of negative feedback to the pituitary, dogs with pituitary
0
Normal Primary Secondary o,p'-DDD Chronic failure to secrete ACTH (secondary adrenal insufciency) causing adre-
dogs adrenal adrenal overdose glucocorticoid nocortical atrophy, dogs overdosed with the adrenocorticolytic agent o,p-
insufficiency insufficiency therapy DDD (mitotane), and dogs chronically treated with glucocorticoids.
In dogs with confirmed hypoadrenocorticism that have normal 1000 1000 1000
electrolyte concentrations, measurement of an endogenous (basal)
ACTH concentration is recommended to distinguish primary 100
from secondary hypoadrenocorticism (Fig. 12-15). This allows 100 100
the clinician to determine whether long-term monitoring of elec- 10
trolyte concentrations is necessary. Measurement of an ACTH
concentration above the reference range confirms a diagnosis of
10 10 1
primary hypoadrenocorticism, whereas an ACTH concentration
within or below the reference range is consistent with a diagno-
sis of secondary hypoadrenocorticism. In a study of 40 dogs with 0.1
hypoadrenocorticism in which basal ACTH was measured, ACTH 1 1
concentration in 35 dogs with primary hypoadrenocorticism 0.01
ranged from 44 to 1254 pmol/L, and in five dogs with second-
ary hypoadrenocorticism it ranged from 1 to 2 pmol/L (reference 0.1 0.1 0.001
range, 2.2 to 20 pmol/L; Peterson etal, 1996). Dogs with second-
ary hypoadrenocorticism would not be expected to ever require Cortisol (nmol/L) ACTH (pmol/L) Cortisol/ACTH
mineralocorticoid supplementation, whereas dogs with primary
hypoadrenocorticism are at risk for progression to complete adre- Healthy dogs Dogs with primary hypoadrenocorticism
nal failure and ultimately may require mineralocorticoid as well as FIGURE 12-16 Box plots of plasma concentration of cortisol, adrenocorticotropic
glucocorticoid supplementation. Interestingly, in one retrospective hormone (ACTH), and the cortisol-to-ACTH ratio (CAR) in 60 healthy dogs and 22
study that included 11 dogs with glucocorticoid deficient hypoad- dogs with primary hypoadrenocorticism. Outlying data points are represented by
renocorticism, only one dog ultimately developed mineralocorti- dots and open circles. (From Javadi S, etal.: Aldosterone-to-renin and cortisol-
coid deficiency, despite the fact that the majority of dogs (9 out of to-adrenocorticotrophic hormone ratios in healthy dogs and dogs with primary
11) were diagnosed as having primary hypoadrenocorticism based hypoadrenocorticism, J Vet Intern Med 20:556, 2006.)
on measurement of ACTH concentrations greater than 25 pmol/L
(Thompson etal, 2007). In another study of 18 dogs with hypoad-
renocorticism that had normal electrolytes, two out of 18 dogs pro- despite increased ACTH concentrations. In 22 dogs with pri-
gressed to develop evidence of mineralocorticoid deficiency (Lifton mary hypoadrenocorticism and 60 healthy dogs in which corti-
etal, 1996). The number of dogs in this study that had primary sol and ACTH concentrations were measured, there was overlap
versus secondary hypoadrenocorticism was not determined. between the groups for all basal hormone concentrations, how-
ever there was no overlap between the groups for the CAR (Javadi
etal, 2006; Fig. 12-16). This finding was confirmed in another
Cortisol-to-Adrenocorticotrophic Hormone Ratio
study evaluating healthy dogs, dogs with non-adrenal illness,
Measurement of cortisol-to-ACTH ratio (CAR) has been pro- and dogs with hypoadrenocorticism (Lathan, 2014; Fig. 12-17).
posed as an alternative diagnostic test for primary hypoadreno- These studies suggest that the CAR could potentially be used in
corticism in dogs (Javadi etal, 2006). In healthy dogs, cortisol place of the ACTH stimulation test for diagnosis of hypoadreno-
increases in response to an increase in ACTH concentration. corticism. The advantage of the CAR over the ACTH stimula-
In primary hypoadrenocorticism, hypocortisolemia is present tion test is the need for collection of only one blood sample and
20 1200
1000
800
18
600
16 400
14
200
ACTH (pg/mL)
Cortisol (g/dL)
12
10
8
30
6
0
H HAD NAI H HAD NAI
A Group B Group
5
3
2
1
0.1
Cortisol/ACTH
0.01
0.001
0.0001
H HAD NAI
C Group
FIGURE 12-17 Box and whiskers plots comparing baseline cortisol (A), adrenocorticotropic hormone (ACTH) con-
centrations (B), and cortisol-to-ACTH ratio (CAR) (C) between three groups of dogs. H, Healthy, HAD, hypoadreno-
corticism, NAI, non-adrenal illness. The box represents the interquartile range from the 25th to 75th percentile,
the horizontal bar through the box represents the median, the diamond in the box represents the mean, and the
whiskers represent the minimum and maximum values (range).
the cost savings that result from avoiding the ACTH stimulation measured; this is primarily because plasma aldosterone assays
test. Disadvantages include the special sample handling needed are not as widely available as cortisol assays (Willard etal, 1987;
for samples submitted for measurement of endogenous ACTH Golden and Lothrop, 1988). Most studies investigating aldoste-
and the higher cost of ACTH assays. Whether the CAR would be rone concentrations in dogs have used a commercially available
helpful in diagnosis of secondary hypoadrenocorticism requires radioimmunoassay that has been validated for use in dogs (Coat-
further investigation. A-Count Aldosterone, Diagnostic Products Corp., Los Angeles,
CA) (Sieber-Ruckstuhl, 2006). Samples may be stored refrigerated
at 2 to 8 C for 7 days, or they may be stored frozen at 20 C for
Plasma Aldosterone Concentration
up to 2 months. Results are not affected by severe icterus, hemo-
Diagnosis of hypoadrenocorticism has historically relied on cor- lysis, lipemia, or the serum protein concentration. In humans, a
tisol concentration as an indicator of adrenal reserve, whereas high sodium intake tends to suppress serum aldosterone, whereas
plasma aldosterone concentrations (PACs) are more rarely a low sodium intake may increase values.
|
350 10
10,000
300
1
250
1000
200
0.1
150
100
100
0.01
50
FIGURE 12-18 Box plots of plasma concentration of aldosterone

0 10 0.001 (PAC), plasma renin activity (PRA), and the aldosterone-to-renin
ratio (ARR) in 60 healthy dogs and 22 dogs with primary hypoadre-
PAC (pmol/l/s) PRA (fmol/l/s) ARR nocorticism. Outlying data points are represented by dots and open
circles. (From Javadi S, etal.: Aldosterone-to-renin and cortisol-to-
Healthy dogs adrenocorticotrophic hormone ratios in healthy dogs and dogs with
Dogs with primary hypoadrenocorticism primary hypoadrenocorticism, J Vet Intern Med 20:556, 2006.)
It is recommended that aldosterone concentrations are mea- to maintenance of normal sodium and potassium in these dogs.
sured before, 30 minutes, and 60 minutes after administration of There have been few studies investigating aldosterone concentra-
ACTH because aldosterone concentrations are higher at 30 min- tions in dogs with secondary hypoadrenocorticism. In 14 dogs
utes than 60 minutes in healthy dogs (Carlson, 2010). In dogs with secondary hypoadrenocorticism, aldosterone concentrations
with pituitary hyperadrenocorticism treated with mitotane or tri- ranged from normal to low (Feldman and Nelson, 2004). Further
lostane, a significantly higher percentage of dogs had decreased studies are necessary to evaluate the value of measurement of PAC
aldosterone reserve detected at 30 minutes than at 60 minutes concentration in dogs with hypoadrenocorticism. It is also impor-
(Reid etal, 2014). However, in a study of seven dogs with hypo- tant to recognize that circulating aldosterone concentrations in
adrenocorticism and 22 dogs with non-adrenal illness, aldosterone people are affected by sodium intake and whether the patient is
concentrations were not different at 30, 45, or 60 minutes after standing or recumbent. These are factors that veterinarians cannot
ACTH administration, suggesting that earlier sampling times for easily control, which makes evaluation of aldosterone concentra-
measurement of aldosterone are not necessary in dogs with sus- tions potentially less reliable.
pected hypoadrenocorticism (Baumstark etal, 2014).
In theory, measurement of PAC in dogs with hypoadreno-
Aldosterone-to-Renin Ratio
corticism should allow differentiation of secondary from pri-
mary hypoadrenocorticism and be useful in diagnosis of isolated Measurement of aldosterone-to-renin ratio (ARR) has been inves-
hypoaldosteronism. In the majority of dogs with primary hypoad- tigated in dogs with primary hypoadrenocorticism (Javadi etal,
renocorticism, aldosterone concentrations would be expected to 2006). In dogs with primary hypoadrenocorticism and hypoal-
be low, whereas in secondary hypoadrenocorticism PAC should dosteronism, plasma renin activity should be high. In 22 dogs
be normal because ACTH has only a minor influence on aldoste- with primary hypoadrenocorticism and 60 normal dogs in which
rone secretion. In most dogs with primary hypoadrenocorticism, aldosterone and renin concentrations were measured, there was
basal and ACTH stimulated aldosterone concentrations are below overlap between the groups for basal renin activity and aldoste-
the reference range (typically 7 to 105 pg/mL), although there rone concentration; however, there was clear distinction between
is overlap with both healthy dogs and dogs with non-adrenal ill- the groups when the ARR was calculated (Javadi etal, 2006; Fig.
ness (Javadi etal, 2006; Baumstark etal, 2014). In a study of 70 12-18). Although measurement of the ARR has potential for
dogs with hypoadrenocorticism, baseline and ACTH-stimulated diagnosis of hypoadrenocorticism, renin assays are not widely
aldosterone concentrations were undetectable in 64 out of 70 available and this test is rarely performed.
dogs and low in three dogs (Baumstark etal, 2014; see Fig. 12-5).
In three dogs with hypoadrenocorticism, aldosterone concentra-
Cortisol-to-Creatinine Ratio
tions were unexpectedly within the reference range despite the
presence of hyperkalemia and hyponatremia. There was no cor- The cortisol-to-creatinine ratio has not been evaluated for diagnosis
relation between sodium and aldosterone concentrations in dogs of spontaneous hypoadrenocorticism in dogs; however, it has been
with hypoadrenocorticism in this study, and there was only a weak evaluated in dogs with mitotane and trilostane induced hypoadre-
correlation between aldosterone and serum potassium concentra- nocorticism. Studies suggest that the cortisol-to-creatinine ratio is
tions (Baumstark et al, 2014). Additionally, in four dogs with insensitive for detection of impending adrenocortical insufficiency in
primary hypoadrenocorticism that did not have characteristic mitotane and trilostane treated dogs and is thus unlikely to be help-
electrolyte abnormalities, aldosterone concentrations were unde- ful in diagnosis of dogs with suspected adrenocortical insufficiency
tectable, suggesting that other mechanisms must have contributed (Angles, 1997; Guptill, 1997; Randolph, 1998; Galac, 2009).
BOX 12-6 Emergency Management of Hypoadrenocorticism
Place IV catheter in cephalic or jugular vein. IV glucose (1 to 2 g/unit of insulin) and insulin (0.2 U/kg) to rapidly
If in hypovolemic shock, 0.9% saline as 90 mL/kg bolus (given as 20 to 30 lower serum potassium followed by continued IV infusion of 5% dextrose
mL/kg boluses). in fluids.
Continue fluid therapy with 0.9% saline IV, at 40 to 80 mL/kg/hour for next Correction acidosis (if serum bicarbonate < 10 mEq/L) or to aid in nor-
1 to 2 hours, depending upon severity of hypotension and hyperkalemia. malizing potassium concentration. Administer 25% to 50% of calcu-
Then continue fluids at rate calculated based on maintenance requirements lated dose IV over 6 hours. In most cases this is unnecessary because
plus dehydration and ongoing losses. Take care to account for polyuria and metabolic acidosis resolves rapidly with appropriate fluid therapy.
polydipsia when considering maintenance requirements. Maintenance re- Estimated deficit = 0.3 BW (kg) (24-patient HCO3)
quirements may be higher than usual (90 to 120 mL/kg/day). Consider blood transfusion and synthetic colloids in dogs with anemia due
If animal is hemodynamically unstable, administer one dose of dexametha- to gastrointestinal blood loss.
sone (0.1 to 2.0 mg/kg IV). Administer IV dextrose in dogs with hypoglycemia as a diluted bolus (25%)
Collect blood and urine samples for CBC, biochemical profile (with electro- or a 5% solution in fluids.
lytes), urinalysis, and basal cortisol. Consider administration of one dose of an injectable mineralocorticoid
Administer synthetic ACTH IV (5 g/kg up to a maximum of 250 g). (Percorten V; 2.2 mg/kg IM) while waiting for diagnosis to be confirmed if
Collect second blood sample for measurement of post ACTH cortisol 1 hour later. clinical suspicion of hypoadrenocorticism is high.
If glucocorticoids have not yet been administered, administer one dose of
Monitor
glucocorticoids after collection of the second blood sample:
Serum electrolytes
Dexamethasone 0.1 to 2.0 mg/kg, or
Blood glucose
Prednisolone sodium succinate 1 to 2 mg/kg IV, or
Acid-base status
Hydrocortisone hemisuccinate or hydrocortisone phosphate 5 mg/kg or
Blood pressure
0.3 mg/kg/hour IV.
Urine output and central venous pressure (if severe azotemia)
Continue dexamethasone every 12 hours (0.05 to 0.1 mg/kg) or predniso-
ECG (if hyperkalemia)
lone (0.5 mg/kg) every 6 hours or hydrocortisone 1 mg/kg every 6 hours
until you can switch to oral glucocorticoids. Follow-Up
If hyperkalemia is severe (> 6.5 mEq/L) or ECG changes (e.g., bradycardia, Continue IV fluids until oral intake begins.
loss of P waves, or prolonged P-R interval) are present consider: Continue injectable glucocorticoids until oral medications can be substituted.
IV 10% calcium gluconate over 10 to 15 minutes (0.5 mL/kg or 2 to 10
mL/dog) to protect myocardium from effects of hyperkalemia.
ACTH, Adrenocorticotropic hormone; BW, body weight; CBC, complete blood count; ECG, electrocardiogram; HCO3, bicarbonate; IV, intravenous.
CRITICAL ILLNESS INDUCED CORTICOSTEROID increased mortality (Burkitt etal, 2007; Martin etal, 2008). The most
INSUFFICIENCY (RELATIVE ADRENAL common clinical problem associated with CIRCI in human patients
INSUFFICIENCY) is hypotension refractory to fluid resuscitation, requiring vasopres-
sor therapy. In a study of dogs with critical illness, those with a delta
Cortisol is an important part of the physiologic response to stress, cortisol less than 3.0 were more likely to be receiving treatment with
and critical illness produces dramatic changes in the HPA axis due vasopressors (Martin etal, 2008). CIRCI is easily distinguished from
to increased ACTH and resultant cortisol concentrations due to the true hypoadrenocorticism because basal cortisol concentrations are
actions of circulating proinflammatory cytokines (Kaplan etal, 1995; usually well within the reference range and the abnormality resolves
Prittie etal, 2002; Martin, 2011). The increase in cortisol during criti- once the illness resolves (Martin, 2011). Human patients with CIRCI
cal illness is proportional to the severity of illness, and studies in both given treatment with supplemental corticosteroids are more likely to
humans and dogs have shown a positive association between serum be weaned off vasopressor and ventilator support, and there is a sur-
cortisol concentration and mortality (Schoeman et al, 2007; Martin, vival advantage for some groups of patients (Martin, 2011). Whether
2011). The syndrome of CIRCI, which was previously called relative treatment of CIRCI with physiologic doses of glucocorticoids in dogs
adrenal insufficiency, is characterized by an inadequate production of and cats with CIRCI improves outcome is currently unknown.
cortisol in response to critical illness and has been most commonly
described in human patients with sepsis (Martin, 2011). Possible
TREATMENT OF HYPOADRENOCORTICISM
underlying causes of CIRCI include decreased glucocorticoid synthe-
sis caused by necrosis, thrombosis, or hemorrhage of the hypothala- The approach to treatment of hypoadrenocorticism depends upon
mus, pituitary gland, or adrenal glands, and effects of drugs on the whether the patient is presented in an adrenal crisis or has more
HPA axis. Reduced access of glucocorticoids to target tissues and cells chronic clinical signs of illness.
due to changes in pro-inflammatory cytokines, changes in concentra-
tion of binding proteins, and cortisol degradation at the tissue level
ACUTE MANAGEMENT
may also contribute to changes in cellular cortisol concentrations.
In patients with CIRCI, the basal cortisol concentration is usually Prompt treatment of dogs with suspected Addisons disease that
normal or high, but there is a blunted cortisol response to ACTH present in an adrenal crisis is vital for a good outcome, especially
administration. In veterinary patients, CIRCI is most commonly if profound electrolyte abnormalities are present. Hyperkalemia in
diagnosed on the basis of the absolute change in cortisol concentra- particular can be life-threatening if not treated expeditiously. Aims
tion (delta cortisol) after ACTH administration. In some but not all of emergency treatment in dogs with suspected hypoadrenocorti-
studies, a delta cortisol less than 3.0 g/dL has been associated with cism include correction of hypotension, hypovolemia, electrolyte
|
imbalances, metabolic acidosis, hypoglycemia, and anemia if pres- physiologic requirements but even higher doses have been empirically
ent. It is also important to confirm the diagnosis of hypoadrenocorti- recommended by some authors. Higher doses are typically recom-
cism at the time of initial presentation, because once replacement mended in dogs that are hemodynamically unstable. Our recommen-
glucocorticoid therapy has been initiated, it is very difficult to retro- dations for glucocorticoid dosage are shown in Box 12-6.
spectively confirm the diagnosis. Although long term treatment of
hypoadrenocorticism requires provision of adequate exogenous glu- Mineralocorticoid Replacement
cocorticoids and usually mineralocorticoids; in the short term, aggres- Prior to confirmation of the diagnosis of hypoadrenocorticism,
sive fluid therapy is the mainstay of treatment and will temporarily administration of one dose of an injectable mineralocorticoid
correct the majority of life-threatening electrolyte abnormalities. (desoxycorticosterone pivalate [DOCP]) should be considered,
The recommended approach to management of dogs with sus- depending upon the initial response of the patient to fluid ther-
pected hypoadrenocorticism that present with severe systemic signs of apy and the anticipated timeline for results of cortisol testing to
illness or hypovolemic shock is shown in Box 12-6. The goal should be available. Point-of-care cortisol assays (e.g., SNAP Cortisol,
be to treat the manifestations of shock while at the same time con- IDEXX Laboratories) may be useful for initial confirmation of a
firming the diagnosis by performing an ACTH stimulation test. If diagnosis of hypoadrenocorticism, but the diagnosis should always
the animal is assessed to be in hypovolemic shock, treatment of shock be confirmed by results from a reference laboratory because vali-
should take precedence over establishing an immediate diagnosis. dation of point-of-care assays has not been published in the peer
reviewed literature. No clinically significant adverse effects have
Fluid Therapy been demonstrated resulting from one dose of DOCP in dogs that
Initial fluid support should be infusion of up to 90 mL/kg of a crys- do not have hypoadrenocorticism; the main disadvantage of treat-
talloid solution given as 20 to 30 mL/kg boluses (each over approxi- ing with DOCP prior to confirmation of the diagnosis is the cost
mately 20 minutes) until the patient is hemodynamically stable. An of the medication (Chow etal, 1993; Kaplan and Peterson, 1995).
IV bolus of a synthetic colloid such as hetastarch (5 mL/kg over 30
minutes) should be considered in hypotensive patients that are hypo- Management of Hyperkalemia
proteinemic (total protein < 4.5 g/dL). In patients with hypoadre- In most dogs with hypoadrenocorticism, the serum potassium
nocorticism, 0.9% saline is traditionally recommended as the most concentration rapidly decreases with fluid therapy. If severe hyper-
appropriate fluid for emergency treatment because of hyponatremia kalemia (potassium > 7.0 mEq/L) does not rapidly improve after
and hyperkalemia; however disadvantages include the tendency for institution of fluid therapy, or if bradyarrhythmias do not improve
0.9% saline to be acidifying and the potential concern of increasing rapidly with fluid therapy, consideration should be given to emer-
the sodium concentration too rapidly, which can theoretically result gency treatment of hyperkalemia (see Box 12-6). Treatment with
in delayed central pontine myelinosis (OBrien, 1994; Brady etal, 10% calcium gluconate (0.5 mL/kg) does not decrease the serum
1999; see Chapter 1). Complications resulting from rapid correc- potassium but temporarily counteracts the impairment of myo-
tion of hyponatremia are believed to be more likely when hypona- cardial excitability induced by hyperkalemia. This effect occurs
tremia has persisted for longer than 24 hours and fortunately are rare rapidly but only lasts about 20 minutes. Intravenous administra-
in dogs. It is recommended that sodium concentration should not tion of dextrose (1 to 2 g/unit of insulin) and insulin (0.2 U/kg)
increase by more than 10 to 12 mEq/L/day, and therefore treatment decreases the serum potassium concentration by driving potassium
with hypertonic saline for fluid resuscitation should be avoided in intracellularly. The effect lasts for 15 to 30 minutes, and the blood
patients with hyponatremia (Churcher etal, 1999). glucose must be monitored frequently (every 30 to 60 minutes)
Because of the potential disadvantages of 0.9% saline, some because of the risk of hypoglycemia especially in patients that are
clinicians prefer using a buffered isotonic crystalloid solution already predisposed to hypoglycemia. Correction of metabolic
containing low concentrations of potassium (4 to 5 mEq/L; e.g., acidosis will also promote intracellular movement of potassium
lactated Ringers solution or Normosol-R). These types of fluids (Fig. 12-19). The ECG or point-of-care potassium assays should
still decrease the serum potassium by dilution and increased renal be used to monitor response during treatment of hyperkalemia.
perfusion, as well as by improving metabolic acidosis, which will
drive potassium intracellularly (Brown etal, 2008; Fig. 12-19). Management of Metabolic Acidosis
In most dogs with hypoadrenocorticism, metabolic acidosis
Glucocorticoid Replacement resolves with appropriate fluid therapy, and the authors rarely
If immediate glucocorticoid supplementation is considered necessary use sodium bicarbonate in dogs with hypoadrenocorticism. If
prior to performing an ACTH stimulation test; because the patient hyperkalemia is severe and does not respond to the prior man-
is hemodynamically unstable, dexamethasone (0.1 to 2.0 mg/kg IV) agement strategies, or if severe acidosis (pH < 7.1 or Total CO2
should be the drug of choice because dexamethasone does not have < 10 mEq/L) does not improve with fluid therapy, treatment with
cross reactivity with most cortisol assays. Although dexamethasone a conservative dose of sodium bicarbonate may be considered (see
does decrease the cortisol response to ACTH by up to 35% for 1 to 3 Box 12-6). Twenty-five percent to 50% of the calculated deficit
days depending upon the dose administered, the results of dogs with should be administered over 4 to 6 hours. The bicarbonate deficit
non-adrenal illness can still be differentiated from the flat-line response can be estimated based on the patients bicarbonate concentra-
of dogs with hypoadrenocorticism (Kemppainen et al, 1989). Ide- tion (see Box 12-6). Adverse effects of bicarbonate administration
ally glucocorticoid supplementation should be delayed until after the include metabolic alkalosis, paradoxical central nervous system
ACTH stimulation test is complete, and at this point any rapid acting (CNS) acidosis, and ionized hypocalcemia (Brown, 2008).
glucocorticoid such as hydrocortisone, dexamethasone, or predniso-
lone sodium succinate is appropriate. The recommended doses for Other Supportive Care
glucocorticoid support in acute management of hypoadrenocortical Blood transfusion and colloidal support (plasma or synthetic
crisis vary widely and are based upon clinical experience rather than colloid) is required in patients that have severe anemia due to
prospective or retrospective studies of outcome (see Box 12-6). The gastrointestinal blood loss. Gastrointestinal protectants (sucral-
recommended doses typically range from three to 10 times normal fate, H2 blockers, and proton pump inhibitors), antiemetics
1 2 3
H+ H+ H+ H+ H+ H+
K+ K+ K+ K+ K+ K+
Normal sis
alo
pH Alk
H+ H+
K+ K+ Ac
id
os
ECF ICF is
1 2 3
H+ H+ H+ H+ H+ H+
K+ K+ K+ K+ K+ K+
FIGURE 12-19 Redistribution of extracellular fluid (ECF) and intracellular fluid (ICF) potassium (K+) and hydrogen
(H+) ions in response to changes in ECF pH. Alkalosis: 1, The H+ concentration decreases; 2, H+ moves out of cells
and down its concentration gradient and K+ moves into cells to maintain electrical neutrality; 3, this contributes
to the hypokalemia associated with alkalosis. Acidosis: 1, The H+ concentration increases; 2, H+ moves into cells
and down its concentration gradient, and K+ moves out of cells to maintain electrical neutrality; 3, the result of
electrolyte shifts, that is, the hyperkalemia associated with acidosis. The size of the arrow represents the degree
of change from normal. (From Gabow P: Disorders of potassium metabolism. In Schrier RW, editor: Renal and elec-
trolyte disorders, Boston, 1976, Little, Brown & Co.)
(metoclopramide, ondansetron, and maropitant citrate), and anti- TABLE 12-6 L

ONG-TERM TREATMENT OF
biotics may be indicated in individual patients with vomiting and PRIMARY ADRENOCORTICAL
diarrhea, gastrointestinal ulceration, or gastrointestinal ileus. INSUFFICIENCY*
Complications of Hypoadrenal Crisis
Mineralocorticoid DOCP injectable, approximately 2 mg/kg IM or SC
Although most dogs with acute signs of hypoadrenocorticism every 14 to 35 days.
respond rapidly to treatment within 24 to 48 hours of starting ther-
Glucocorticoid Prednisone as needed, < 0.05 to 0.2 mg/kg daily
apy, some dogs have a more prolonged recovery. Potential complica-
or every other day.
tions that may be encountered during treatment of a hypoadrenal
crisis include severe gastrointestinal ulceration and hemorrhage, or
disseminated intravascular coagulation, sepsis due to bacterial Mineralocorticoid Fludrocortisone 0.02 mg/kg once a day or divided
translocation from the gastrointestinal tract, aspiration pneumo- twice a day.
nia secondary to megaesophagus, and disseminated intravascular Glucocorticoid Prednisone if needed, 0 to 0.2 mg/kg daily, or
coagulation (DIC). Patients with gastrointestinal ulceration and every other day.
hemorrhage severe enough to require blood transfusion are rare
but typically require much longer for recovery than other dogs Clinical follow-up Recheck monthly until dose stabilized then
with hypoadrenocorticism. Bleeding into the respiratory tract has every 3 to 6 months.
occasionally been reported in dogs with severe hypoadrenal crisis. Patients should maintain normal weight and
The cause is unknown but could potentially be caused by DIC. In activity.
dogs with hypoadrenocorticism that do not respond to treatment as Electrolytes and BUN should be normal.
expected, consideration should be given to investigation for more Salt No special addition if commercial diet.
uncommon causes of hypoadrenocorticism, such as adrenal necrosis Times of stress Increase glucocorticoid therapy.
and granulomatous or neoplastic destruction of the adrenal glands.
BUN, Blood urea nitrogen; DOCP, desoxycorticosterone pivalate; IM, intramuscular;
SC, subcutaneous.
LONG-TERM (MAINTENANCE) THERAPY *Owner education is imperative.
See Table 12-6.
Prednisone is the glucocorticoid supplement of choice in dogs.
Glucocorticoid Therapy The starting dose is 0.1 to 0.22 mg/kg/day initially; the dose
should then be gradually tapered over several weeks until the
Once the diagnosis of hypoadrenocorticism has been confirmed lowest dose that will control the clinical signs has been identi-
and there has been a positive clinical response to parenteral treat- fied. Excessive prednisone supplementation should be avoided,
ment, long-term oral treatment with glucocorticoids should be because this will cause clinical signs of hyperadrenocorticism,
initiated. Oral treatment should not begin until the patient is sys- which is the most common cause of polyuria and polydipsia in
temically well, is no longer vomiting, and has a good appetite. dogs treated for hypoadrenocorticism. In a study of 205 dogs with
|
Serum [Na] (mEq/L) 155 155
Serum [Na] (mEq/L)

150 150
145 145
140 140
135 135
130 130
125 125
120 120
0 14 25 39 50 64 75 0 14 25 39 50 64 75
8 8
Serum [K] (mEq/L)
Serum [K] (mEq/L)

FIGURE 12-20Serum biochemical values
7 7 from 60 dogs given desoxycorticosterone
6 6 pivalate (DOCP) intramuscularly for treat-
5 5 ment of hypoadrenocorticism. A, Top, Se-
4 4
rum sodium concentrations; middle, serum
potassium concentrations; bottom, blood
3 3
0 14 25 39 50 64 75 0 14 25 39 50 64 75 urea nitrogen (BUN) concentrations. B, Se-
80 80
rum biochemical values (top, middle, and
bottom same as for A) for nine dogs given
Blood urea nitrogen
Blood urea nitrogen

60 60 DOCP for treatment of recently diagnosed
hypoadrenocorticism. Shaded areas indicate
(mg/dL)
(mg/dL)
40 40 reference ranges for each value. Results

are reported as mean standard deviation
20 20
(SD). (From Lynn RC, etal.: Efficacy of mi-
0 0 crocrystalline desoxycorticosterone pivalate
0 14 25 39 50 64 75 0 14 25 39 50 64 75 for treatment of hypoadrenocorticism in
A Days B Days dogs, J Am Vet Med Assoc 202:392, 1993.)
hypoadrenocorticism, the dose of prednisone used for long-term of treatment. The 15-day recheck allows titration of the dose, and the
management ranged from less than 0.05 to 0.4 mg/kg/day (Kintzer 25-day recheck allows adjustment of the frequency of administration
and Peterson, 1997). Prednisone can be completely discontinued required. If the electrolyte concentrations remain normal at 25 days,
in as many as 50% of dogs being treated with fludrocortisone for the interval between injections can be gradually increased to every
mineralocorticoid replacement because of the intrinsic glucocorti- 30 days; monthly injections are the most convenient for owners. In
coid activity of fludrocortisone. In contrast, because DOCP lacks dogs that are well controlled on DOCP, electrolytes should remain
glucocorticoid activity, dogs treated with DOCP should be treated within the reference range for the complete duration of the treat-
with a low daily or every other day dose of prednisone. ment period. Many dogs with hypoadrenocorticism require much
lower doses than the recommended starting dose to achieve normal
Mineralocorticoid Therapy electrolyte concentrations. In one study, the dose of DOCP necessary
for good control of hypoadrenocorticism, ranged from 0.8 to 3.4 mg/
Dogs with evidence of mineralocorticoid deficiency (hyperkale- kg/dose administered at intervals ranging from 14 to 35 days (Kintzer
mia or hyponatremia) should also be treated with a mineralocor- and Peterson, 1997). Only six of 33 dogs ultimately required a dose
ticoid, such as fludrocortisone or DOCP. The first dose of DOCP more than 2.2 mg/kg. In a more recent study of 49 dogs with hypo-
is either administered during the acute crisis when there is a high adrenocorticism, 36 dogs were treated with an initial DOCP dose
index of suspicion for hypoadrenocorticism or immediately after less than 2.2 mg/kg, and 19 of the dogs were treated with doses less
confirmation of the diagnosis once the results of an ACTH stimu- than 1.0 mg/kg. No statistically significant relationship was found
lation test are available. between initial DOCP dose and survival or posttreatment serum
sodium or potassium concentrations and the authors concluded that
Desoxycorticosterone Pivalate initial doses less than 2.2 mg/kg may be effective in management of
DOCP (Percorten V, Novartis Corp.) is the only drug approved by dogs with primary hypoadrenocorticism (Bates etal, 2013).
the Food and Drug Administration (FDA) for treatment of hypoad- In our opinion it is not possible to predict which dogs can be
renocorticism in dogs, and is the treatment of choice in most dogs effectively managed with lower doses of DOCP, so the most effec-
with hypoadrenocorticism. DOCP is a long-acting ester of DOCA, a tive approach is to start at a dose of 2.2 mg/kg and then taper the
synthetic mineralocorticoid that is no longer available in the United dose by 10% a month while monitoring the sodium and potas-
States. DOCP has no glucocorticoid activity and is formulated for sium concentrations prior to each injection. Once the sodium
veterinary use in a microcrystalline suspension for IM injection (Lynn and potassium concentrations start to trend outside the reference
and Feldman, 1991; Fig. 12-20). The drug may also be administered range prior to the next injection the next dose should be increased
subcutaneously but should not be given intravenously (McCabe etal, to the previous dose that resulted in normal electrolytes for the
1995; Fig. 12-21). DOCP has a rapid onset of action and is effective whole time period. A small minority of dogs require higher doses
within a few hours of injection, so no overlap is necessary when tran- or a higher frequency of administration (every 14 to 24 days).
sitioning to DOCP from fludrocortisone. DOCP is administered at Once the final dose of DOCP has been established, some own-
a starting dose of 2.2 mg/kg IM or subcutaneous (SC) every 25 days ers are interested in learning how to administer DOCP at home
initially (Melin and Peterson, 1996). Serum electrolytes should be and the frequency of veterinary reevaluation can be decreased to
checked at 15 and 25 days after injection for the first 1 to 2 months once every 3 to 6 months. It is important to note that especially
155 9
150 8 8 newly diagnosed cases

4 previously treated cases
Potassium (mEq/L)
Sodium (mEq/L)
145 7
140 6
135 5
8 newly diagnosed cases
130 4 previously treated cases 4
125 3
0 14 25 39 50 64 75 0 14 25 39 50 64 75
A Days B Days
60
8 newly diagnosed cases
50 4 previously treated cases
40
BUN (mg/dL)
30
20
10
0
0 14 25 39 50 64 75
C Days
FIGURE 12-21 Serum biochemical valuessodium (A), potassium (B), blood urea nitrogen (BUN) (C)from 12
dogs given desoxycorticosterone pivalate (DOCP) subcutaneously for treatment of hypoadrenocorticism. Mean val-
ues ( range) from newly diagnosed dogs (dashed line) and previously treated dogs (solid line) are separated;
normal values are indicated by the solid horizontal lines. Outliers are indicated by squares (newly diagnosed dogs)
or dots (previously diagnosed dogs) above or below the range lines. On day 75, one dog was hyperkalemic, and the
same dog was azotemic on days 64 and 75. These abnormalities were resolved by administering the DOCP every 21
days rather than every 25 days.
in dogs maintained on lower doses of DOCP, the dose require- The dose of fludrocortisone required for control of clinical signs in
ments of individual dogs may unexpectedly change over time, so a study of 190 dogs with hypoadrenocorticism ranged from 0.01 to
it is important to reevaluate serum electrolyte concentrations on a 0.08 mg/kg/day, and the required dose typically increased over time
regular basis (ideally every 3 months or if there is a change in body (Kintzer and Peterson, 1997). Whether this reflects ongoing adrenal
weight or clinical signs). Some clinicians recommend extend- gland destruction, or is due to changes in metabolism or absorption
ing the dosing frequency of DOCP longer than 1 month rather of fludrocortisone is unknown. Interestingly, the average dose in a
than tapering the dose administered. We do not recommend this human with Addisons disease is 0.05 to 0.1 mg (one half to one
approach, because it can lead to problems with owner compliance tablet) daily. Because humans require a dramatically lower dose than
and increase the risk of unexpected hypoadrenal crisis. dogs, it is presumed that dogs do not absorb the drug from the gas-
Some dogs treated with DOCP develop polyuria and polydip- trointestinal tract as effectively or that they metabolize the drug more
sia, which may be worse in the week after each injection. This rapidly than humans. As with DOCP, the sodium and potassium
can be due to either excessive glucocorticoid supplementation or concentration should be within the reference range in dogs that are
excessive dosing of DOCP, resulting in excess circulating miner- well controlled on fludrocortisone. In some dogs, the dose required
alocorticoids. In this situation the dose of glucocorticoids should to achieve this either results in clinical signs due to the effects of
be tapered first, and then the dose of DOCP should be tapered excess glucocorticoid activity or becomes prohibitively expensive. In
until the polyuria and polydipsia resolve. the past, salt supplementation has been recommended to decrease
the dose required to maintain the sodium concentration within the
Fludrocortisone Acetate reference range; however, this is not very effective and is no longer
Fludrocortisone acetate (Florinef, Squibb) is an orally active syn- advocated. In one study, there was no difference in dose of fludrocor-
thetic mineralocorticoid that is an alternative option for miner- tisone required between dogs that were treated with salt supplements
alocorticoid supplementation if daily oral therapy is preferred. and those that were not (Kintzer and Peterson, 1997). A change to
Fludrocortisone also possesses some intrinsic glucocorticoid activity, treatment with DOCP is a more effective approach if the electrolyte
and additional glucocorticoid supplementation may not be required. concentrations are not effectively normalized with fludrocortisone.
The drug comes in 0.1 mg tablets, and the starting dose in dogs is Some dogs treated with fludrocortisone develop clinical signs of
0.02 mg/kg by mouth either as a single dose or divided twice a day. hyperadrenocorticism (e.g., polyuria and polydipsia) even at usual
|
doses of fludrocortisone. The first step in this situation should be glucocorticoid supplementation at a dose higher than the physiologic
to withdraw any additional glucocorticoid supplementation. If the requirement. If a dog diagnosed with hypoadrenocorticism requires
problem persists, it is possible that the clinical signs are due to the a prednisone dose of 0.5 mg/kg or greater to control clinical signs,
intrinsic glucocorticoid activity of fludrocortisone, and again consid- this should be an indication to question the diagnosis and to inves-
eration should be given to changing to treatment with DOCP. tigate for the presence of other concurrent illness. The presence of
megaesophagus or severe gastrointestinal hemorrhage can also com-
Hydrocortisone Acetate plicate response to treatment and prolong recovery. The most com-
Treatment with hydrocortisone is often considered as an option mon adverse effect of therapy is polyuria and polydipsia, which is
for long term management of hypoadrenocorticism, because it most commonly associated with excessive glucocorticoid supplemen-
is much cheaper than either fludrocortisone or DOCP. Unfortu- tation, an excessive dose of DOCP, or the intrinsic glucocorticoid
nately the ratio of glucocorticoid to mineralocorticoid activity of activity of fludrocortisone. If polyuria and polydipsia are a problem,
hydrocortisone is approximately 1:1, so an excessive glucocorti- the glucocorticoid dose should be tapered or discontinued in dogs
coid dose must be administered in order to achieve an adequate treated with fludrocortisone; and in dogs treated with DOCP, the
mineralocorticoid effect. This results in clinical signs of hyperad- dose should be gradually decreased. If the problem persists, consid-
renocorticism and this approach is therefore not recommended. eration should be given to switching to an alternative mineralocor-
ticoid treatment. If there is no improvement, further evaluation for
other causes of polyuria and polydipsia should be considered.
Treatment of Hypoadrenocorticism in the Absence
of Electrolyte Abnormalities
CONFIRMING THE DIAGNOSIS AFTER TREATMENT
Dogs without electrolyte abnormalities at the time of diagnosis ini- HAS ALREADY BEEN INITIATED
tially only require glucocorticoid supplementation. These dogs either
have secondary hypoadrenocorticism, or more commonly have atypi- Unfortunately some dogs with suspected Addisons disease are
cal primary hypoadrenocorticism (see Glucocorticoid Deficiency treated based on suspicion rather than confirmation of the diag-
Versus Mineralocorticoid Deficiency). Dogs with secondary hypoad- nosis. The expense of treatment may later prompt the owners to
renocorticism can be identified by measurement of an endogenous request that the diagnosis is confirmed. There are limited options
ACTH concentration and identifying results either within or below in this situation because chronic glucocorticoid administration
the reference range for healthy dogs. These dogs do not develop elec- causes iatrogenic adrenocortical atrophy and a suppressed cortisol
trolyte abnormalities because ACTH is not required for aldosterone response to ACTH stimulation. The influence of mineralocor-
secretion from the adrenal cortex, and these cases never require min- ticoid treatment on the response to ACTH has not been inves-
eralocorticoid supplementation. Some dogs with atypical primary tigated in dogs, but at least fludrocortisone would likely cause
hypoadrenocorticism do later progress to complete adrenal failure and adrenocortical atrophy due to the intrinsic glucocorticoid activity
require mineralocorticoid supplementation, but the risk is difficult to of the drug. Thus the only way to confirm the diagnosis of hypo-
predict in the individual patient. In one study, two dogs with glu- adrenocorticism is to withdraw therapy and monitor closely for
cocorticoid deficient hypoadrenocorticism died within a few days of clinical signs and electrolyte abnormalities. An ACTH stimula-
discharge from the hospital due to progression to complete adrenal tion test should be postponed if possible until at least 2 weeks after
failure (Kintzer and Peterson, 1997); however, many other dogs do not withdrawal of glucocorticoid supplementation. If clinical signs
progress over years of monitoring (Lifton et al., 1996; Hughes etal, develop earlier, an ACTH stimulation test should be performed
2007; Thompson etal, 2007; Baumstark etal, 2014). Because only a prior to reinstitution of therapy, but the test may be difficult to
proportion of dogs later develop electrolyte abnormalities, mineralo- interpret depending upon the length of time that glucocorticoid
corticoid treatment is not recommended as part of the initial treatment treatment has been withheld. Alternatively the dose of mineralo-
in dogs without electrolyte abnormalities at diagnosis; however, care- corticoids can be gradually decreased, but this requires frequent
ful monitoring is recommended. Electrolyte concentrations should monitoring of electrolytes each time that the dose is decreased.
be monitored every 1 to 3 months for at least the first 12 months
after diagnosis, and the owners should be educated about monitor- MANAGEMENT OF HYPOADRENOCORTICISM
ing for clinical signs of mineralocorticoid deficiency. Most dogs that DURING STRESSFUL EVENTS
progress to complete adrenal failure do so within 1 year of diagnosis
of glucocorticoid deficient hypoadrenocorticism (Lifton et al., 1996; The dose of glucocorticoids required for normal maintenance may
Thompson et al, 2007). In human patients with hypoadrenocorti- not be adequate during periods of stress. Examples of potentially
cism, measurement of renin concentrations are used to guide need stressful events include increased exercise or competition in work-
for mineralocorticoid treatment (Stewart, 2011), but measurement of ing dogs or other unusual activities, such as boarding, veterinary
renin concentration is not widely available in veterinary medicine. visits, treatment of medical illness, or surgical interventions. It is
recommended that the glucocorticoid dose is doubled in these
situations to ensure that an adequate dose is provided.
POOR RESPONSE TO THERAPY
Some dogs with confirmed hypoadrenocorticism do not respond PROGNOSIS
well to treatment or have adverse effects associated with therapy. The
most important cause of poor response to treatment is an inadequate The prognosis for dogs with both primary and secondary hypo-
mineralocorticoid dose. This is most commonly a problem in dogs adrenocorticism is usually excellent, although the expense of
treated with fludrocortisone. Other causes include incorrect diagno- mineralocorticoid supplementation especially in large breed dogs
sis, failure to provide glucocorticoid supplementation in dogs treated may cause some owners to consider euthanasia. In a study of 205
with DOCP, or the presence of an undiagnosed concurrent illness, dogs treated for hypoadrenocorticism, the median survival time
such as hypothyroidism, neoplasia, or fungal disease. One indica- was 4.7 years (range, 7 days to 11.8 years) (Kintzer and Peter-
tion that a concurrent disease has been overlooked is the need for son, 1997). Factors such as age, breed, sex, and weight did not
significantly influence survival time. The most important factor in TABLE 12-7 C
LINICAL FINDINGS IN
the long-term response to therapy is owner education. The disease 10 CATS WITH PRIMARY
must be carefully described, and owners must be warned of the HYPOADRENOCORTICISM
consequences of apparently mild illnesses. All owners should have
glucocorticoids available to administer to their dogs in times of CLINICAL FINDINGS NUMBER OF CATS (%)
stress. The prognosis is more guarded in patients with underlying
granulomatous or neoplastic causes of hypoadrenocorticism. Historic Owner Complaints
Lethargy/depression 10 (100)
IATROGENIC HYPOADRENOCORTICISM Anorexia 10 (100)
Weight loss 9 (90)
Medical Treatment of Hyperadrenocorticism Vomiting 4 (40)
Dogs treated medically for hyperadrenocorticism with either Waxing-waning course of illness 4 (40)
mitotane or trilostane sometimes develop hypoadrenocorticism. Previous response to non-specific therapy 3 (30)
The diagnosis of hypoadrenocorticism must be confirmed by an
Polyuria/polydipsia 3 (30)
ACTH stimulation test, because these drugs can also cause direct
gastrointestinal toxicity. If clinical signs of cortisol deciency (i.e., Physical Examination Findings
anorexia, vomiting, diarrhea, and/or weakness) are present but Depression 10 (100)
serum sodium and potassium concentrations are within reference Weakness 9 (90)
ranges, only glucocorticoid treatment is required; this can then
typically be tapered over a period of several weeks. If hyperka- Dehydration 9 (90)
lemia and hyponatremia indicate concurrent mineralocorticoid Hypothermia 8 (80)
deficiency, the treatment protocol is similar to that recommended Slow capillary rell time 5 (50)
for naturally occurring hypoadrenocorticism. Although miner-
Weak pulse 5 (50)
alocorticoid deciency induced by trilostane is usually reversible,
mineralocorticoid deficiency induced by mitotane may be perma- Collapse/unable to rise 3 (30)
nent and require life-long treatment (see Chapter 10). Bradycardia 2 (20)
Painful abdomen 1 (10)
Withdrawal of Chronic Glucocorticoid Therapy
From Peterson ME, etal.: Primary hyperadrenocorticism in ten cats, J Vet Intern Med 3:55,
Clinical signs due to iatrogenic hypocortisolism caused by chronic 1989.
use of glucocorticoids that have been acutely discontinued are rare in
dogs. Such cases should be treated by placing the dog back on a short-
acting glucocorticoid (e.g., prednisone) and then slowly tapering the Short-Haired cats. An equal number of males and females have
dose over a period of 1 to 2 months. We usually decrease glucocorti- been described, and all cats had been neutered.
coid therapy to a physiologic dose (approximately 0.25 mg/kg/day) as The clinical signs and physical examination abnormalities are
quickly as possible (within a week). If that dose is tolerated for a week similar to those described for dogs (Table 12-7). The duration of
without recurrence of clinical signs, the dosage is reduced by adminis- signs noted by owners has been as short as a few days and as long
tering the drug every other day rather than daily. After 2 weeks at this as 3 to 4 months. The most common owner observations include
dose, the frequency is again reduced by giving the drug every 3 days. lethargy, depression, anorexia, and weight loss. Less frequently
After 2 to 3 weeks at this dose, the prednisone can be discontinued. noticed signs include vomiting, waxing-waning course of illness,
If signs recur after any dose reduction, the previous amount is usually polyuria, polydipsia, and previous response to nonspecic therapy,
reinstituted. If clinical signs continue to recur, complete reevaluation such as intravenous fluids or glucocorticoids. Diarrhea has not
of the dog is recommended. been reported (Peterson etal, 1989).
The most common physical examination abnormalities
identied in these cats are depression, weakness, dehydra-
FELINE HYPOADRENOCORTICISM
tion, hypothermia, slow capillary rell time, and weak femoral
pulses. Less commonly observed examination ndings included
Etiology
collapse, inability to rise, bradycardia, and painful abdomen
Primary hypoadrenocorticism is a rare disease in cats. Since the rst (Peterson etal, 1989).
report in 1983, fewer than 40 cases have been described in the veteri-
nary literature (Johnessee etal, 1983; Freudiger, 1986; Peterson etal, Laboratory, Radiographic, and Electrocardiogram
1989; Berger and Reed, 1993; Parnell etal, 1999). An additional fifteen Abnormalities
cases have been reported in book chapters (Hardy, 1995; Feldman
and Nelson, 2004). The cause has been described as idiopathic adre- Hematologic abnormalities were not common but included
nocortical atrophy in one cat with traumatically induced disease mild anemia. Rarely, lymphocytosis, or eosinophilia has been
(Berger and Reed, 1993), and the condition occurred secondary to noted. All of the cats have been hyponatremic, and all but
lymphoma of the adrenals in two cats (Parnell etal, 1999). one were hyperkalemic (Table 12-8). Hypochloremia, azo-
temia, and hyperphosphatemia were identied in almost all
cats. Every cat had an abnormal sodium-to-potassium ratio
Signalment and Clinical Signs
(< 24:1). The hyperkalemia was not as severe as has been
The reported age of cats with Addisons disease has ranged from observed in dogs, with values of 5.4 to 7.6 mEq/L reported.
1 to 14 years. All have been Domestic Long-Haired or Domestic Three of 10 cats were mildly acidotic, and one was hypercalcemic
|
TABLE 12-8 RESULTS OF LABORATORY TESTS IN 10 CATS WITH HYPOADRENOCORTICISM
TEST MEAN STANDARD DEVIATION RANGE NORMAL RANGE

Packed cell volume (%) 29.5 5.8 21.239.2 2538
Erythrocyte count 106/mm3 6.4 1.5 4.69.0 68.5
Hemoglobin (g/dL) 10.3 1.7 7.312.6 815
Leukocytes/mm 11.656 4335 720020,100 700015,000
Mature neutrophils 7586 3514 432015,875 350011,250
Band neutrophils 144 151 0344 0450
Lymphocytes 3348 2233 11188410 14006000
Eosinophils 598 935 1453015 1401400
Monocytes 178 204 0612 70600
Serum glucose (mg/dL) 99.2 24.9 71139 70150
Alanine aminotransferase (IU/L) 62.0 21.0 43100 1080
Alkaline phosphatase (IU/L) 36.0 29.7 10108 1080
Total bilirubin (mg/dL) 0.39 0.23 0.10.8 00.5
Total protein (mg/dL) 6.5 0.8 5.67.5 5.37.9
Albumin (mg/dL) 2.9 0.5 2.33.5 2.33.8
Blood urea nitrogen (mg/dL) 55.6 16.5 3180 530
Creatinine (mg/dL) 3.2 1.5 1.66.0 0.51.5
Total CO2 (mEq/L) 18.6 3.8 1324 1625
Inorganic phosphorus (mg/dL) 7.3 0.94 6.19.1 3.06.0
Calcium (mg/dL) 10.7 3.4 8.614.0 7.611.0
Sodium (mEq/L) 130.6 8.1 111138 140155
Potassium (mEq/L) 6.2 0.6 5.47.6 3.55.5
Chloride (mEq/L) 96.3 9.7 74108 100120
Sodium-to-potassium ratio 21.0 1.7 17.923.7 > 26
Urine specic gravity 1.028 0.014 1.0081.045 1.0011.080
Serum cortisol (g/dL)
Basal 0.26 0.28 0.10.8 0.55.0*
1-hour post-ACTH 0.29 0.37 0.11.1 4.513.0*
2-hour post-ACTH 0.39 0.44 0.11.3 4.014.5*
Plasma ACTH (pg/mL) 3767 2667 5008000 10125
From Peterson ME, etal.: Primary adrenocorticism in ten cats. J Vet Intern Med 3:55, 1989.
ACTH, Adrenocorticotropic hormone; SD, standard deviation.
*ACTH stimulation tests were performed in 33 clinically normal cats; mean SD: basal, 1-hour post-ACTH, and 2-hour post-ACTH cortisol concentrations were 2.1 1.5 g/dL, 7.9 2.9
g/dL, and 8.1 2.7 g/dL, respectively.
Immunoreactive plasma ACTH concentrations were determined in 50 clinically normal cats; the mean ( SD) value was 36.7 36.0 pg/mL.
(serum calcium concentration of 14 mg/dL). Hypoglycemia premature contractions in one cat. The characteristic changes in the
was reported in one cat. T wave, P wave, P-R interval, and QRS complexes seen with hyper-
The urine specic gravity was less than 1.030 in seven of 10 cats kalemia in dogs were not identied in these cats. The lack of these
with naturally occurring Addisons disease. All 10 cats were dehy- classic abnormalities on ECG is probably due to the relatively mild
drated and azotemic. The BUN concentration ranged from 31 to 80 hyperkalemia documented in each of the cats.
mg/dL with a mean of 55 mg/dL. As with dogs, similarities between
the clinical descriptions, physical ndings, and test results for cats Differential Diagnosis
with renal disease (which is common) and those with hypoadrenocor-
ticism (which is rare) make diagnosis of the latter condition difcult. The differential diagnosis for abnormal serum sodium and potas-
Microcardia was identied on thoracic radiographs of ve cats. sium concentrations should include gastrointestinal disease, renal
This nonspecic nding supports the observed dehydration, hypo- disease, and ascites (Bissett etal, 2001). The differential diagnosis
volemia, and hypotension thought to be present in these cats. Other for low plasma cortisol concentrations with inadequate response
cardiovascular abnormalities were not observed. Identied ECG to ACTH stimulation includes naturally occurring hypoadreno-
abnormalities consisted of sinus bradycardia in two cats and atrial corticism, chronic glucocorticoid administration, and chronic
megestrol acetate administration, and failure to administer ACTH. therapy involves oral fludrocortisone acetate (0.05 to 0.10 mg
The differential diagnosis of hypoadrenocorticism should include b.i.d.) or injectable DOCP. Glucocorticoid replacement, as
lymphoma, because this form of cancer is common in cats and needed, is usually accomplished with prednisolone (starting
adrenal involvement has been demonstrated (Parnell etal, 1999). dose 2.5 to 5 mg/day tapered to the minimal dose that controls
clinical signs). Long-term oral administration of medication can
be challenging in some cats, so other routes of administration
Conrming the Diagnosis
(e.g., parenteral or transdermal) may need to be considered in
Adrenocorticotropic Hormone Stimulation Test some cats. Regular physical examinations (in addition to peri-
The ACTH stimulation test is the gold standard for diagnosis in odic monitoring of owner opinion regarding clinical response),
cats, just as it is in dogs. However, the protocol in cats is slightly dif- serum electrolyte concentrations, and BUN levels are strongly
ferent. Half a vial (125 g) of synthetic ACTH (Cortrosyn) should recommended (just as for dogs) to ensure that treatment is
be administered intramuscularly with blood samples obtained appropriate.
immediately before and 30 and 60 minutes after injection.
The expected results in hypoadrenocorticism are similar to Prognosis
those in dogs: The pre-ACTH plasma cortisol concentration is
usually undetectable or low-normal, and the post-ACTH plasma The long-term prognosis for cats with hypoadrenocorticism is
cortisol concentration is similar to the pre-ACTH value. As in excellent unless underlying disease (e.g., lymphoma) is the cause
dogs, both pre-ACTH and post-ACTH cortisol concentrations of hypoadrenocorticism. As with dogs, committed cat owners who
in Addisonian cats were less than 2.0 g/dL (see Table 12-8). The are well informed about the disease tend to have the best success.
basal plasma cortisol concentrations ranged from 0.1 to 0.8 g/dL Frequent rechecks to ensure that glucocorticoid and mineralocor-
(reference range is 0.5 to 5.0 g/dL). The 1- and 2-hour results ticoid supplementation is optimal is valuable. Six of seven cats
were 0.1 to 1.1 g/dL and 0.1 to 1.3 g/dL, respectively (normal that survived the hypoadrenal crisis were alive for a mean of 34
is 4.5 to 13.0 g/dL) (see Table 12-8; Peterson etal, 1989). months (Peterson etal, 1989).
Plasma Endogenous Adrenocorticotropic Hormone CONGENITAL ADRENAL HYPERPLASIA

Plasma ACTH concentrations were measured in seven of 10 Congenital adrenal hyperplasia (CAH) is a group of inherited
cats with naturally occurring disease. Each cat had abnormally diseases that result from a deficiency of one or more of the
increased concentrations consistent with the diagnosis of primary enzymes required for cortisol and aldosterone synthesis in the
adrenocortical disease. The values ranged from 500 to 8000 pg/ adrenal cortex. CAH is the most common genetic endocrine
mL with a mean of 3767 pg/mL (reference range for that assay is disorder in humans, and the hormonal abnormalities and clini-
< 10 to 125 pg/mL; see Table 12-8). cal manifestations depend upon the particular enzyme that is
deficient. Clinical manifestations may include abnormal genital
TREATMENT development, pseudohermaphroditism, virilization of females,
salt wasting, and hypertension. Inheritance of all forms of CAH
Acute Management in humans is autosomal recessive, with an overall worldwide
prevalence of 1 in 15,000 live births. Although mutations of
The principles of therapy for cats are no different from those in dogs. any of the five adrenal enzymes required for cortisol biosyn-
Initial therapy includes aggressive intravenous administration of 0.9% thesis can result in CAH, mutations of the genes encoding the
normal saline over 2 to 4 hours to replace fluid decits and restore 21-hydroxylase enzyme and 11-hydroxylase enzyme are the
blood pressure. After that has been accomplished, maintenance fluid most common forms in people.
therapy should be continued until the cat is eating and drinking with CAH is very rare in dogs and cats. Two cats with CAH due to
no vomiting or diarrhea. Glucocorticoid decits should be replaced 11-hydroxylase deficiency and one dog with 17-hydroxylase
with dexamethasone (0.1 to 2 mg/kg IV or IM every 12 hours). Ide- deficiency have been described (Breitschwert, 1989; Knighton,
ally, the ACTH stimulation test should be completed prior to admin- 2004; Owens, 2012). In one male and one female cat with
istration of glucocorticoids. Mineralocorticoids can be administered 11-hydroxylase deficiency, clinical signs included polyuria and
in the form of DOCP prior to disease confirmation if appropriate polydipsia, foul smelling urine, presence of barbs on the penis
(2.2 mg/kg IM every 25 days). of a castrated male cat and virilization of a female cat, hyper-
One feature of hypoadrenocorticism that is somewhat different tension and behavioral changes (Fig. 12-22). The diagnosis was
in cats than in dogs is the slow response to therapy. Cats appear to made by demonstration of hypocortisolemia and hypoaldoste-
remain weak, lethargic, and depressed for 3 to 5 days despite institu- ronemia and increases in plasma ACTH, desoxycorticosterone,
tion of appropriate therapy. Three of 10 cats were euthanized after dihydroepiandrosterone, 11-desoxycortisol, and pregnenolone
only 2 to 5 days of treatment because of poor response. It is possible (Knighton, 2004; Owens, 2012). Treatment with physiologic
that they may have survived had they been treated for a longer period. doses of prednisolone resolved the clinical signs and hormonal
abnormalities. Congenital hyperplasia should be considered in
Long-Term (Maintenance) Therapy the differential diagnosis for cats with unexplained hyperten-
sion, polyuria, polydipsia, presence of secondary sex charac-
As with acute management, long term treatment is no different teristics after neutering, and behavioral abnormalities, such as
from that recommended for dogs. Chronic mineralocorticoid inter-cat aggression.
|
A B
C
FIGURE 12-22 Three year old male cat with 11-hydroxylase deficiency. A, The cat had a small body frame. B, Barbs were present on the penis despite evidence that
the cat had previously been castrated. The barbs resolved with treatment. C, Gynecomastia was noted in this male castrated cat. This also resolved with treatment.
REFERENCES
Adamantos S, Boag A: Total and ionized Baumstark ME, etal.: Evaluation of aldosterone Bissett SA, etal.: Hyponatremia and hyperkale-
calcium concentrations in dogs with hypo- concentrations in dogs with hypoadrenocor- mia associated with peritoneal effusion in
adrenocorticism, Vet Rec 163:25, 2008. ticism, J Vet Intern Med 28:154, 2014. four cats, J Am Vet Med Assoc 218:1590,
Addison T: On the constitutional and local Behrend EN, Kemppainen RJ: Glucocorticoid 2001.
effects of disease of the suprarenal therapy: pharmacology, indications, and Blois SL, etal.: Multiple endocrine diseases
capsules, London, 1855, Highley. complications, Vet Clin Small Animal in dogs: 35 cases (1996-2009), J Am Vet
Adissu HA, etal.: Lymphocytic adenohypophysi- 27:187, 1997. Med Assoc 238:1616, 2011.
tis and adrenalitis in a dog with adrenal and Behrend EN, etal.: Effects of storage condi- Boujon CE, etal.: Pituitary gland changes in
thyroid atrophy, Vet Pathol 47:1082, 2010. tions on cortisol, total thyroxine and free canine hypoadrenocorticism: a functional
Adler JA, etal.: Abnormalities of serum electro- thyroxine concentrations in serum and and immunocytochemical study, J Comp
lyte concentrations in dogs with hypoadreno- plasma of dogs, J Am Vet Med Assoc Pathol 111:287, 1994.
corticism, J Vet Intern Med 21:1168, 2007. 212:15641568, 1995. Bowen D, etal.: Autoimmune polyglandular
Angles JM, etal.: Use of the urine Behrend EN, etal.: Diagnosis of spontaneous syndrome in a dog: a case report, J Am
cortisol:creatinine ratio versus adrenocorti- canine hyperadrenocorticism: 2012 ACVIM Anim Hosp Assoc 22:649, 1986.
cotrophic hormone stimulation testing for Consensus Statement (Small Animal), Brady CA, etal.: Severe neurologic sequelae in
monitoring mitotane treatment of pituitary- J Vet Intern Med 27:1292, 2013. a dog after treatment of hypoadrenal crisis,
dependent hyperadrenocorticism in dogs, Behrend EN, etal.: Intramuscular adminis- J Am Vet Med Assoc 215:222, 1999.
J Am Vet Med Assoc 211:1002, 1997. tration of a low dose of ACTH for ACTH Breitschwert EB, etal.: Congenital adre-
Bartges J, Nielson D: Reversible megaesopha- stimulation testing in dogs, J Am Vet Med nal hyperplasia in a dog because of
gus associated with atypical primary Assoc 229:528, 2006. 17-hydroxylase deficiency, in: Research
hypoadrenocorticism in a dog, J Am Vet Berger SL, Reed J: Traumatically induced abstract program of the 7th annual ACVIM
Med Assoc 201:889, 1992. hypoadrenocorticism in a cat, J Am Anim Meeting, J Vet Intern Med 3:120, 1989
Bates JA, etal.: Lower initial dose desoxycorti- Hosp Assoc 29:337, 1993. (abstract).
costerone pivalate for treatment of canine Bertolini G, etal.: Pituitary apoplexy-like dis- Brown AJ, etal.: Fluid therapy for vomiting and
primary hypoadrenocorticism, Aust Vet J ease in 4 dogs, J Vet Intern Med 21:1251, diarrhea, Vet Clin Small Anim 38:653,
91:77, 2013. 2007. 2008.
Burkhardt WA, etal.: Adrenocorticotrophic Freudiger U: Literaturubersicht uber Johnessee JS, etal.: Primary hypoadreno-
hormone, but not trilostane, causes severe NebennierenrindenErkrankungen der corticism in a cat, J Am Vet Med Assoc
adrenal hemorrhage, vacuolization and Katze und Beschreibung eines Falles von 183:881, 1983.
apoptosis in rats, Dom Anim Endocrinology primarer NebennierenrindenInsufzienz, Kaplan AJ, Peterson ME: Effects of desoxy-
40:155, 2011. Schweiz Arch Tierheilk 128:221, 1986. corticosterone pivalate administration
Burkitt JM, etal.: Relative adrenal insufficien- Galac S, etal.: Urinary corticoid:creatinine on blood pressure in dogs with primary
cy in dogs with sepsis, J Vet Intern Med ratios in dogs with pituitary-dependent hy- hypoadrenocorticism, J Am Vet Med Assoc
21:226, 2007. percortisolism during trilostane treatment, 206:327, 1995.
Burrows C: Reversible megaesophagus in a dog J Vet Intern Med 23:1214, 2009. Kaplan AJ, etal.: Effects of disease on the
with hypoadrenocorticism, J Small Anim Ginel PJ, etal.: Evaluation of serum concentra- results of diagnostic tests for use in de-
Pract 28:1073, 1987. tions of cortisol and sex hormones of adre- tecting hyperadrenocorticism in dogs, J Am
Burton S, etal.: Hypoadrenocorticism in young nal gland origin after stimulation with two Vet Med Assoc 207:445, 1995.
related Nova Scotia duck tolling retrievers, synthetic ACTH preparations in clinically Kelch WJ, etal.: Canine hypoadrenocorticism
Can Vet J 38:231, 1997. normal dogs, Am J Vet Res 73:237, 2012. (Addisons disease), Comp Small Anim
Carlson KJ, etal.: Optimization of a test Golden D, Lothrop CJ: A retrospective study of Pract 20:921, 1998.
protocol to assess aldosterone secretory aldosterone secretion in normal and adreno- Kemppainen RJ, etal.: Adrenocortical sup-
capacity in dogs, J Vet Intern Med 24:685, pathic dogs, J Vet Intern Med 2:121, 1988. pression in the dog after a single dose of
2010 (abstract). Gow AG, etal.: Calcium metabolism in eight methylprednisolone acetate, Am J Vet Res
Chase K, etal.: Understanding the genetics of au- dogs with hypoadrenocorticism, J Small 42:822, 1981.
toimmune disease: two loci that regulate late Anim Pract 50:426, 2009. Kemppainen RJ, etal.: Adrenocortical suppres-
onset Addisons disease in Portuguese Water Gow AG, etal.: Insulin concentrations in dogs sion in the dog given a single intramus-
dogs, Int J Immunogenet 33:179, 2006. with hypoadrenocorticism, Res Vet Sci cular dose of prednisone or triamcinolone
Chow E, etal.: Toxicity of desoxycorticosterone 93:97, 2012. acetonide, Am J Vet Res 43:204, 1982.
pivalate given at high dosages to clinically Graves TK, etal.: Basal and ACTH-stimulated Kemppainen RJ, etal.: Effects of a single
normal Beagles for six months, Am J Vet plasma aldosterone concentrations are nor- intravenously administered dose of dexa-
Res 54:1954, 1993. mal or increased in dogs with trichuriasis- methasone on response to the adrenocor-
Churcher RK, etal.: Suspected myelinosis fol- pseudohypoadrenocorticism, J Vet Intern ticotrophic hormone stimulation test in
lowing rapid correction of hyponatremia in a Med 8:287, 1994. dogs, Am J Vet Res 50:1914, 1989.
dog, J Am Anim Hosp Assoc 35:493, 1999. Guptill L, etal.: Use of the urine Kemppainen RJ, etal.: Use of compounded
Cohen TA, Feldman EC: Comparison of IV and cortisol:creatinine ratio to monitor treat- adrenocorticotrophic hormone (ACTH) for
IM formulations of synthetic ACTH for ment response in dogs with pituitary- adrenal function testing in dogs, J Am
ACTH stimulation tests in healthy dogs, dependent hyperadrenocorticism, J Am Vet Anim Hosp Assoc 30:41, 2005.
J Vet Intern Med 26:412, 2012. Med Assoc 210:1158, 1997. Kerl ME, etal.: Evaluation of a low-dose
DiBartola SP: Hyponatremia, Vet Clin North Am Hardy RM: Hypoadrenocorticism. In Ettinger SJ, synthetic adrenocorticotropic hormone
Small Anim Pract 19:215, 1989. Feldman EC, editors: Textbook of Veterinary stimulation test in clinically normal
DiBartola SP, etal.: Clinicopathologic ndings Internal Medicine, ed 4, Philadelphia, dogs and dogs with naturally developing
resembling hypoadrenocorticism in dogs 1995, WB Saunders. hyperadrenocorticism, J Am Vet Med Assoc
with primary gastrointestinal disease, J Am Hansen BL, etal.: Synthetic ACTH (Cosyn- 214:1497, 1999.
Vet Med Assoc 187:60, 1985. tropin) stimulation tests in normal dogs: Kintzer PP, Peterson ME: Treatment and long-
Famula TR, etal.: Heritability and complex comparison of intravenous and intramuscu- term follow-up of 205 dogs with hypoadre-
segregation analysis of hypoadrenocorti- lar administration, J Am Anim Hosp Assoc nocorticism, J Vet Intern Med 11:43, 1997.
cism in the standard poodle, J Small Anim 30:38, 1994. Kintzer PP, Peterson ME: Mitotaine (op-DDD)
Pract 44:8, 2003. Hill K, etal.: ACTH stimulation testing: a treatment of 200 dogs with pituitary-de-
Feldman EC, Nelson RW: Canine and feline review and a study comparing synthetic pendent hyperadrenocorticism, J Vet Intern
endocrinology and reproduction, ed 3, and compounded products, Vet Med Med 5:182, 1991.
St Louis, 2004, Saunders/Elsevier. February 134, 2004. Knighton EL: Congenital adrenal hyperplasia
Fossum TW, Birchard SJ: Lymphangiographic Hoerauf A, Reusch C: Ultrasonographic evalua- secondary to 11b-hydroxylase deficiency
evaluation of experimentally induced tion of the adrenal glands in six dogs with in a domestic cat, J Am Vet Med Assoc
chylothorax after ligation of the cranial hypoadrenocorticism, J Am Anim Hosp 225:238, 2004.
vena cava in dogs, Am J Vet Res 47:976, Assoc 35:214, 1999. Koch J, etal.: Duplex Doppler measurements
1986. Hughes AM, etal.: Clinical features and of renal blood flow in a dog with Addisons
Frank CB, etal.: Correlation of inflammation heritability of hypoadrenocorticism in disease, J Small Anim Pract 38:124, 1997.
with adrenocortical atrophy in canine adre- Nova Scotia Duck Tolling Retrievers: 25 Kooistra HS, etal.: Polyglandular deciency
nalitis, J Comp Path 149:268, 2013. cases (1994-2006), J Am Vet Med Assoc syndrome in a Boxer dog: thyroid hor-
Frank LA, Oliver JW: Comparison of serum 231:407, 2007. mone and glucocorticoid deciency, Vet Q
cortisol concentrations in clinically normal Hughes AM, etal.: Association of a dog 17:59, 1995.
dogs after administration of freshly recon- leucocyte antigen class II haplotype with Kook PH, etal.: Addisons disease due to bilat-
stituted versus reconstituted and stored hypoadrenocorticism in Nova Scotia Duck eral adrenal malignancy in a dog, J Small
frozen cosyntropin, J Am Vet Med Assoc Tolling Retrievers, Tissue Antigens 75:684, Anim Pract 51:333, 2010.
212:1569, 1998. 2010. Korth R, etal.: Hypoadrenocorticism due to a
Frank LA, etal.: Cortisol concentrations follow- Hughes AM, etal.: Examination of candidate bilateral abscessing inflammation of the
ing stimulation of healthy and adrenopath- genes for hypoadrenocorticism Nova Scotia adrenal cortex in a Rottweiler, Kleinier-
ic dogs with two doses of tetracosactrin, Duck Tolling Retrievers, Vet J 187:212, praxis 53:479, 2008.
J Small Anim Pract 41:308, 2000. 2011. Kreissler JJ, Langston CE: A case of hyporenin-
Frank LA, etal.: Serum concentrations of corti- Javadi S, etal.: Aldosterone-to-renin and emic hypoaldosteronism in the dog, J Vet
sol, sex hormones of adrenal origin, and ad- cortisol-to-adrenocorticotrophic hormone Intern Med 25:944, 2011.
renocortical steroid intermediates in healthy ratios in healthy dogs and dogs with Labelle P, De Cock HE: Metastatic tumors to
dogs following stimulation with two doses of primary hypoadrenocorticism, J Vet Intern the adrenal glands in domestic animals,
cosyntropin, Am J Vet Res 65:1631, 2004. Med 20:556, 2006. Vet Pathol 42:52, 2005.
|
Langlais-Burgess L, etal.: Concurrent hypo- Melin C, Peterson ME: Diagnosis and treat- Randolph JF, etal.: Use of the urine cortisol-
adrenocorticism and hypoalbuminemia in ment of naturally occurring hypoadreno- to-creatinine ratio for monitoring dogs
dogs: a retrospective study, J Am Anim corticism in 42 dogs, J Am Anim Pract with pituitary-dependent hyperadreno-
Hosp Assoc 31:307, 1995. 37:268, 1996. corticism during induction treatment
Lathan P, etal.: Use of a low dose ACTH Melin C, etal.: Radiographic findings in dogs with mitotane (op-DDD), Am J Vet Res
stimulation test for diagnosis of hypoad- with naturally-occurring primary hypoad- 59:258, 1998.
renocorticism in dogs, J Vet Intern Med renocorticism, J Am Anim Hosp Assoc Reid LE, etal.: Effect of trilostane and
22:1070, 2008. 35:208, 1999. mitotane on aldosterone secretory reserve
Lathan P, etal.: Use of the cortisol-to-ACTH Mitchell AL, Pearce SHS: Autoimmune Addison in dogs with pituitary-dependent hyperad-
ratio for diagnosis of primary hypoadre- disease: pathophysiology and genetic com- renocorticism, J Vet Intern Med 28:443,
nocorticism in dogs, J Vet Intern Med plexity, Nat Rev Endocrinol 8:306, 2012. 2014.
28:1546, 2014. Moore G, Hoenig M: Duration of pituitary and Reusch CE, etal.: Histological evaluation of
Lennon EM, etal.: Use of basal serum or adrenocortical suppression after long- the adrenal glands of seven dogs treated
plasma cortisol concentrations to rule out a term administration of antiinflammatory with trilostane, Vet Rec 160:219, 2007.
diagnosis of hypoadrenocorticism in dogs: doses of prednisone to dogs, Am J Vet Res Rich LJ, etal.: Elevated serum potassium as-
123 cases (2000-2005), J Am Vet Med 53:716, 1992. sociated with delayed separation of serum
Assoc 231:413, 2007. Moriello K, etal.: Adrenocortical suppression from clotted blood in dogs of the Akita
Levy JK: Hypoglycemic seizures attributable associated with topical administration of breed, Vet Clin Pathol 15:12, 1986.
to hypoadrenocorticism in a dog, J Am Vet glucocorticoids in dogs, J Am Vet Med Roberts S, etal.: Effect of ophthalmic pred-
Med Assoc 204:526, 1994. Assoc 193:329, 1988. nisolone acetate on the canine adrenal
Lifton SJ, etal.: Glucocorticoid-decient Murphy CJ, etal.: Iatrogenic Cushings syn- gland and hepatic function, Am J Vet Res
hypoadrenocorticism in dogs: 18 cases drome in a dog caused by topical ophthal- 45:1711, 1984.
(1986-1995), J Am Vet Med Assoc mic medications, J Am Anim Hosp Assoc Rockwell JL, etal.: Spontaneous hypoadre-
209:2076, 1996. 26:640, 1990. nocorticism in a dog after a diagnosis of
Lobetti RG: Hyperreninemic hypoaldosteronism Nielsen L, etal.: Low ratios of sodium to potas- hyperadrenocorticism, J Vet Intern Med
in a dog, J S Afr Vet Assoc 69:33, 1998. sium in the serum of 238 dogs, Vet Rec 19:255, 2005.
Lynn R, Feldman EC: Treatment of hypoadreno- 162:431, 2008. Rose BD, Post TW: Clinical physiology of acid-
corticism with microcrystalline desoxycor- Oberbauer AM, etal.: Inheritance of hypoadre- base disorders, ed 5., New York, 2001,
ticosterone pivalate, Br Vet J 147:478, nocorticism in Bearded Collies, Am J Vet McGraw-Hill. p. 178.
1991. Res 63:643, 2002. Roth L, Tyler RD: Evaluation of low
Lynn R, etal.: Efcacy of microcrystalline Oberbauer AM, etal.: Genetic evaluation of sodium:potassium ratios in dogs, J Vet
desoxycorticosterone pivalate for treatment Addisons disease in the Portuguese Water Diag Invest 11:60, 1999.
of hypoadrenocorticism in dogs, J Am Vet dog, BMC Vet Res 2:15, 2006. Rubin SI, etal.: Trimethoprim-induced exac-
Med Assoc 202:392, 1993. OBrien DP, etal.: Myelinolysis after correction erbation of hyperkalemia in a dog with
Martin LG: Critical illness-related corticosteroid of hyponatremia in two dogs, J Vet Intern hypoadrenocorticism, J Vet Intern Med
insufficiency in small animals, Vet Clin Med 8:40, 1994. 12:186, 1998.
Small Anim 41:767, 2011. Oelkers W, etal.: Diagnosis and therapy Russell NJ, etal.: Comparison of radioim-
Martin LG, etal.: Pituitary-adrenal function in surveillance in Addisons disease: rapid munoassay and chemiluminescent assay
dogs with acute critical illness, J Am Vet adrenocorticotrophin (ACTH) test and mea- methods to estimate canine blood cortisol
Med Assoc 233:87, 2008. surement of plasma ACTH, renin activity, concentrations, Aust Vet J 85:487, 2007.
Martin LG, etal.: Effects of low doses of co- and aldosterone, J Clin Endocrinol Metab Sadek D, Schaer M: Atypical Addisons disease
syntropin on serum cortisol concentrations 75:259, 1992. in the dog: a retrospective survey of 14
in clinically normal dogs, Am J Vet Res Olson PN, etal.: Effects of storage on con- cases, J Am Anim Hosp Assoc 32:159,
68:555, 2007. centration of hydrocortisone (cortisol) in 1996.
Massey J, etal.: MHC class II association study canine serum and plasma, Am J Vet Res Saito M, etal.: Muscle cramps in two standard
in eight breeds of dog with hypoadrenocor- 42:1618, 1981. poodles with hypoadrenocorticism, J Am
ticism, Immunogenetics 65:291, 2013. Owens SL, etal.: Congenital adrenal hyperpla- Anim Hosp Assoc 38:437, 2002.
McCabe M, etal.: Subcutaneous administra- sia associated with mutation in an 11beta- Schaer M, etal.: Autoimmunity and Addisons
tion of desoxycorticosterone pivalate for the hydroxylase-like gene in a cat, J Vet Intern disease in the dog, J Am Anim Hosp Assoc
treatment of canine hypoadrenocorticism, J Med 26:1221, 2012. 22:789, 1986.
Am Anim Hosp Assoc 31:151, 1995. Parnell NK, etal.: Hypoadrenocorticism as the Schaer M, etal.: Combined hyponatremia and
McGonigle KM, etal.: Mineralocorticoid before primary manifestation of lymphoma in two hyperkalemia mimicking an addisonian
glucocorticoid deficiency in a dog with cats, J Am Vet Med Assoc 214:1208, 1999. crisis in three near-term pregnant Grey-
primary hypoadrenocorticism and hypothy- Peterson ME, Feinman JM: Hypercalcemia hounds, J Vet Intern Med 14:121, 2000.
roidism, J Am Anim Hosp Assoc 49:54, associated with hypoadrenocorticism in 16 Schoeman JP, etal.: Serum cortisol and
2013. dogs, J Am Vet Med Assoc 181:802, 1982. thyroxine concentrations as predictors
Medinger TL, etal.: Severe gastrointestinal Peterson ME, etal.: Primary hypoadrenocorticism of death in critically ill puppies with
tract hemorrhage in three dogs with in ten cats, J Vet Intern Med 3:55, 1989. parvoviral diarrhea, J Am Vet Med Assoc
hypoadrenocorticism, J Am Vet Med Assoc Peterson ME, etal.: Pretreatment clinical and 231:1534, 2007.
202:1869, 1993. laboratory ndings in dogs with hypoadre- Scott-Moncrieff JCR, etal.: Validation of
Meij BP, etal.: Residual pituitary function nocorticism: 225 cases (1979-1993), chemiluminescent enzyme immunomet-
after transsphenoidal hypophysectomy in J Am Vet Med Assoc 208:85, 1996. ric assay for plasma adrenocorticotropic
dogs with pituitary dependent hyperadre- Platt SR, etal.: Secondary hypoadrenocorticism hormone in the dog, Vet Clin Pathol 32,
nocorticism, J Endocrinology 155:531, associated with craniocerebral trauma in a 2003.
1997. dog, J Am Anim Hosp Assoc 35:117, 1999. Seth M, etal.: White blood cell count and the
Melendez LD, etal.: Concurrent hypoadreno- Prittie JE, etal.: Pituitary ACTH and adreno- sodium to potassium ratio to screen for
corticism and hypothyroidism in 10 dogs, cortical secretion in critically ill dogs, J Am hypoadrenocorticism in dogs, J Vet Intern
J Vet Intern Med 10:182, 1996 (abstract). Vet Med Assoc 220:615, 2002. Med 25:1351, 2011.
Shaker E, etal.: Hypoadrenocorticism in a Thodou E, etal.: Lymphocytic hypophysitis: White PC: Aldosterone synthase deficiency
family of Standard Poodles, J Am Vet Med clinicopathological ndings, J Clin Endo- and related disorders, Mol Cell Endocrinol
Assoc 192:1091, 1988. crinol Metab 80:2302, 1995. 217:81, 2004.
Shiah CJ, etal.: Diagnostic value of plasma al- Thompson AL, etal.: Comparison of classic Whitley NT: Megaesophagus and glucocorticoid-
dosterone/potassium ratio in hypoaldoste- hypoadrenocorticism with glucocorticoid- decient hypoadrenocorticism in a dog,
ronism, J Formos Med Assoc 94:248254, deficient hypoadrenocorticism in dogs: J Am Anim Pract 36:132, 1995.
1995 46 cases (1985-2005), J Am Vet Med Willard MD: Disorders of potassium homeosta-
Sieber-Ruckstuhl NS, etal.: Cortisol, aldo- Assoc 230:1190, 2007. sis, Vet Clin North Am Small Anim Pract
sterone, cortisol precursor, androgen, Tsigos C, etal.: A novel mutation of the adre- 19:241, 1989.
andendogenous ACTH concentrations in nocorticotropin receptor (ACTH-R) gene Willard MD, etal.: Canine hypoadrenocorti-
dogs with pituitary-dependent hyperadre- in a family with the syndrome of isolated cism: report of 37 cases and review of 39
nocorticism treated with trilostane, Domest glucocorticoid deficiency, but no ACTH-R previously reported cases, J Am Vet Med
Anim Endocrinol 31:63, 2006. abnormalities in two families with the Assoc 180:59, 1982.
Short AD, etal.: A candidate gene analysis triple A syndrome, J Clin Endocrinol Metab Willard MD, etal.: Evaluation of plasma aldo-
of canine hypoadrenocorticism in 3 dog 80:2186, 1995. sterone concentrations before and after
breeds, J Heredity 104:807, 2013. Velardo A, etal.: Isolated adrenocorticotropic ACTH administration in clinically normal
Smallwood LJ, Barsanti J: Hypoadrenocorticism hormone deficiency secondary to hypotha- dogs and dogs with various diseases, Am J
in a family of Leonbergers, J Am Anim lamic deficit of corticotropin-releasing hor- Vet Res 48:713, 1987.
Hosp Assoc 31:301, 1995. mone, J Endocrinol Invest 15:53, 1992. Willard MD, etal.: Hyponatremia and hyperka-
Stewart PM, Krone NP: The adrenal cortex. In Weller RE, etal.: Hypoadrenocorticism in beagles lemia associated with idiopathic or experi-
Melmed S, etal.: Williams textbook for exposed to aerosols of plutonium-238 dioxide mentally induced chylothorax in four dogs,
endocrinology, ed 12, Philadelphia, 2011, by inhalation, Radiat Res 146:688, 1996. J Am Vet Med Assoc 199:353, 1991.
Saunders/Elsevier. Wenger M, etal.: Ultrasonographic evaluation Zenger E: Persistent hyperkalemia associated
Syme HM, Scott-Moncrieff JC: Chronic hypo- of adrenal glands in dogs with primary with nonchylous pleural effusion in a dog,
glycemia in a hunting dog due to second- hypoadrenocorticism and mimicking dis- J Am Anim Hosp Assoc 28:411, 1992.
ary hypoadrenocorticism, J Small Anim eases, Vet Rec 167:207, 2010.
Pract 39:348, 1998.
CHAPTER 13 Pheochromocytoma and Multiple
Endocrine Neoplasia
Claudia E. Reusch
CHAPTER CONTENTS offices, telephone directories, and the European-American Pheo-

History and Background, 521 chromocytoma Registry, several descendants were identified who
Definition, Embryology, Anatomy, and Etiology, 521 had developed pheochromocytomas between the age of 36 and
Physiology and Pathophysiology, 523 44 years. By molecular genetic testing, Neumann and colleagues were
Signalment, 527 able to demonstrate germ-line RET mutations and hence provided
Clinical Manifestations, 527 evidence that the pheochromocytomas of the original patient and
Clinical Pathology, 530 her family were in fact inherited as part of the multiple endocrine
Blood Pressure Measurement, 531 neoplasia type 2 (MEN-2) complex (Neumann etal, 2007).
Diagnostic Imaging, 531 The term pheochromocytoma was first proposed in 1912 by
Percutaneous Fine-Needle Aspiration and Biopsy of the Adrenal Glands, 535 Ludwig Pick, a pathologist from Berlin, Germany. It comes
Biochemical Testing, 536 from the Greek words phaios (dark), chroma (color), and cytoma
Establishing a Diagnosis, 541 (tumor), indicating the dark staining reaction caused by the oxi-
Surgical Treatment, 543 dation of catecholamines when exposed to chromium salts (Man-
Histopathology, 545 ger, 2006; Young, 2011). In 1926, the first pheochromocytomas
Medical Treatment, 545 were successfully surgically removed by Csar Roux in Switzer-
Prognosis, 546 land and Charles Mayo in the United States. In the following
Paraganglioma, 546 decades, epinephrine (in 1939) and norepinephrine (in 1949)
Incidental Discovered Adrenal Mass (Incidentaloma), 547 were isolated from pheochromocytoma tissue; and in 1950, it
Multiple Endocrine Neoplasia, 548 was shown that patients with pheochromocytomas have elevated
Multiple Endocrine Neoplasia in Human Medicine, 548 epinephrine and norepinephrine in plasma and urine (Manger,
Tumors of Multiple Endocrine Organs in Dogs and Cats, 549 2006; Young, 2011).
Approximately 80 years after Frnkels publication, the first two
cases of pheochromocytoma in dogs were described, interestingly
also in Germany (Mueller etal, 1955; Tamaschke, 1955). The first
pheochromocytoma in a cat was reported not until 1993 (Henry
HISTORY AND BACKGROUND
etal, 1993).
In 1884, an 18-year-old woman died at the University Hospital For many years pheochromocytoma in dogs and cats were usu-
of Freiburg, a town in southern Germany. She had been suffer- ally identified as an incidental finding at necropsy, and ante mor-
ing of recurrent episodes of palpitations, headaches, vomiting, tem diagnoses were extremely rare. This was due to several reasons:
pallor accompanied by a strong pulse, and retinitis (Manger, low index of suspicion by veterinarians; the fact that clinical signs
2006). At autopsy, bilateral adrenal tumors were found in addi- are highly variable, nonspecific, and often episodic; and lack of
tion to myocardial hypertrophy and arterial changes in the kid- appropriate screening tests. During the past decade, awareness
neys. The pathologists diagnosed sarcoma for one adrenal tumor of the potential presence of pheochromocytomas in sick animals
and angiosarcoma for the other. Felix Frnkel, a physician at the has increased, which is mainly due to the routine use of abdomi-
same hospital in which the woman had died, published the case nal ultrasonography and the frequent identification of adrenal
in 1886 and suggested, which was different to the opinion of the masses. Recently, biochemical testing (i.e., measurement of cat-
pathologists, that the tumors were of the same type and that they echolamines and their metabolites in urine or plasma) has been
had induced a generalized vasoactive disease (Frnkel, 1886). He introduced into veterinary medicine allowing specific diagnostic
did, however, not yet use the term pheochromocytoma. The original work-up.
article of Frnkel was written in German; in 1984, it was trans-
lated into English as a Classic in Oncology (Classics in oncology, DEFINITION, EMBRYOLOGY, ANATOMY,
1984). The case of the young woman was reconsidered by a AND ETIOLOGY
research group of the same hospital in Freiburg 120 years after
its publication (Neumann et al, 2007). The group hypothesized The World Health Organization (WHO) classification of endo-
that the patients pheochromocytoma had been an inherited con- crine tumors defines a pheochromocytoma as a tumor arising
dition because of her young age and the presence of bilateral dis- from catecholamine-producing chromaffin cells in the adrenal
ease. Because Frnkel had given the name and hometown of his medulla. Tumors of the extra-adrenal sympathetic and parasym-
patient in his paper (a fact which would be incompatible with pathetic paraganglia are classified as paragangliomas (Pacak etal,
todays regulations on data protection), they were able to start an 2007). This definition will also be followed in this chapter. Pheo-
extensive search for potential relatives. After contacting church chromocytoma (tumor of the adrenal medulla) is discussed in the
521
following sections, and paraganglioma will be covered thereafter. OH

The adrenal medulla, which comprises approximately one-fourth H C O
of the adrenal mass, develops during fetal life as part of the sym-
pathetic nervous system. The latter arises from the primitive cells HO C C NH2
of the neural crest; groups of these cells migrate along the cen-
tral vein and enter the adrenal cortex to form the adrenal medulla H H
(Galac etal, 2010; Sjaastad etal, 2010; Fitzgerald, 2011). The cells L-Tyrosine
of the adrenal medulla, called pheochromocytes or chromaffin cells,
Tyrosine
can be looked at as modified postganglionic sympathetic neurons hydroxylase
lacking axons. They are stimulated by sympathetic preganglionic
nerve fibers and secrete hormones into the bloodstream. OH
The adrenal medulla receives most of its blood through a HO
portal vascular system from the adrenal cortex; consequently, it H C O
receives high concentrations of glucocorticoids. Cortisol induces
HO C C NH2
the enzyme, phenylethanolamine-N-methyltransferase (PNMT),
which is responsible for the conversion of norepinephrine to H H
epinephrine (Fig. 13-1). Cells of the adrenal medulla, which L-DOPA
synthesize epinephrine, are exposed to higher concentrations of
glucocorticoids than cells that produce norepinephrine. The lat- DOPA
ter (i.e., cells that synthesize mostly norepinephrine) receive their decarboxylase
blood supply by arteries that bypass the adrenal cortex (Fitzger-
ald, 2011).
HO
In humans, pheochromocytoma is considered to be a rare H H
tumor. The incidence has long been estimated to be as low as 2 to
8 cases per million people annually (Beard etal, 1983; Stenstrm HO C C NH2
and Svrdsudd, 1986). More recent autopsy studies, however,
H H
suggest that the incidence may be higher and that many cases
remain undetected (McNeil etal, 2000). Many of the pheochro- Dopamine
mocytomas in humans develop sporadically, and their etiology Dopamine-
is not understood. Recently, genetic screening revealed that a -hydroxylase
substantial percentage (20% to 30%) of patients with pheochro-
mocytoma or paraganglioma have germline mutations in genes
associated with genetic disease. So far, 10 genes have been iden- HO H
tified, the three genes known best are: RET for MEN-2, VHL O H
for von Hippel-Lindau disease, and NF1 for neurofibromatosis
HO C C NH2
type 1 (Marini et al, 2006a; Maher et al, 2011; Fishbein and
Nathanson, 2012; Table 13-1). It is assumed that the majority of H H
human pheochromocytomas are benign; malignancy rates vary Norepinephrine
between 5% and 35% depending on the study. However, the
biological behavior of pheochromocytoma is unpredictable, and PNMT
reliable differentiation between benign and malignant tumors is
difficult. The traditional position of the WHO is to base the diag-
nosis of malignancy on the presence of metastasis (and not on
HO H
local invasion; Tischler etal, 2006; Carlsen etal, 2009). Because O H CH3
this approach requires life-long follow-up of patients, various
techniques and markers, including the multiparameter scoring HO C C NH2
system Pheochromocytoma of the Adrenal Scaled Score (PASS),
have been evaluated for their usefulness to predict malignancy. H H
Results of the various studies differ; it seems, however, that none Epinephrine
of the methods is 100% reliable (Carlsen et al, 2009; Agarwal FIGURE 13-1 Biosynthetic pathway of catecholamines. (Redrawn from Fitzgerald
et al, 2010; de Wailly et al, 2012; Eisenhofer et al, 2012). It PA: Adrenal medulla and paraganglia. In Gardner DA, Shoback D, editors: Greens-
may be interesting to follow future discussions on the criteria of pans Basic and Clinical Endocrinology, ed 9, New York, 2011, McGraw-Hill, p. 351.)
malignancy. Although the WHO approach is clear, some pathol- L-DOPA, L-dihydroxyphenylalanine; PNMT, phenylethanolamine-N-methyltransferase.
ogists challenge the definition because local invasion may also be
potentially lethal (Tischler etal, 2006).
As in humans, pheochromocytoma is considered to be a rare pheochromocytomas is unpredictable and may range from slow
tumor in dogs. According to currently available information they to quite rapid. The rate of malignant tumors seems to be much
account for 0.01% to 0.1% of all canine tumors (Bailey and Page, higher than in humans; however, those comparisons depend on
2007). However, due to the fact that comprehensive systemic how malignancy is perceived. As mentioned earlier, in human
evaluation has not been performed, it is possible that the true pheochromocytoma malignancy is currently defined by the pres-
prevalence is higher. In cats, pheochromocytomas are extremely ence of metastasis, not local invasion. In dogs, however, either local
rare, and knowledge is limited to a few case reports (Henry etal, invasion or distant metastasis usually qualifies for the definition
1993; Chun et al, 1997; Calsyn et al, 2010). Growth rate of of malignancy. Information concerning the matter of malignancy
|
CHAPTER 13 Pheochromocytoma and Multiple Endocrine Neoplasia 523
TABLE 13-1 T
HE THREE BEST-KNOWN GENETIC SYNDROMES ASSOCIATED WITH
PHEOCHROMOCYTOMA IN HUMANS*
OCCURRENCE OF
GENETIC SYNDROME INHERITANCE GENE CLINICAL FEATURES PHEOCHROMOCYTOMA
Multiple Endocrine Neoplasia Type 2
Subtype 2A Autosomal dominant RET MTC 50%
Hyperparathyroidism
Pheochromocytoma (often bilateral)
Cutaneous lichen amyloidosis
Hirschsprung disease
Subtype 2B Autosomal dominant RET MTC 50%
Mucocutaneous neuromas
Skeletal deformities, joint laxity
Marfanoid habitus
Myelinated corneal nerves
Intestinal ganglioneuromas
von Hippel-Lindau disease Autosomal dominant VHL CNS hemangioblastoma 10% to 20%
various subtypes Renal angioma
Renal cell carcinoma
Paraganglioma
Pancreatic NETs
Renal and pancreatic cysts
Endolymphatic sac tumors
Epididymal cystadenomas
Neurofibromatosis type 1 Autosomal dominant NF1 Cutaneous neurofibromas 5% to 7%
(von Recklinghausen disease) Multiple caf-au-lait spots
Axillary and inguinal freckling
Iris hamartomas
Pheochromocytoma (mostly unilateral)
Paraganglioma
Modified from Mackenzie IS, Brown MJ: Phaeochromocytomas, paragangliomas and neuroblastomas. In Wass JA, Stewart PM, Amiel SA, Davies MJ, editors: Oxford Textbook of Endocrinology
and Diabetes, ed 2, Oxford, 2011, Oxford University Press, p. 798.
CNS, Central nervous system; MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor.
*Please note that the occurrence rate of the disorders within the syndromes varies between patients, and only the approximate occurrence rate of pheochromocytoma is given. The syndromes
(in particular, neurofibromatosis type 1) may also occur with various additional diseases.
in dogs is based mainly on the three largest case series published adrenocorticotropic hormone (ACTH)-producing pituitary
so far, including 123 dogs with pheochromocytoma (Bouayad tumors, parathyroid tumor or hyperplasia, thyroid adenoma, or
etal, 1987; Gilson etal, 1994; Barthez etal, 1997). In 34% of carcinoma and insulinoma (Peterson et al, 1982; Gilson et al,
the dogs, local invasion of adjacent vessels, such as vena phren- 1994; Wright et al, 1995; Barthez et al, 1997; Thurczy et al,
icoabdominales, vena cava caudalis, renal vessels, adrenal vessels, 1998). These patients may be considered to suffer a multiple endo-
hepatic veins, and aorta or other tissue was found. Additionally, crine neoplasia (MEN)-like disorder. However, inherited MEN
20% of dogs had metastasis in regional lymph nodes, liver, spleen, syndromes, as they occur in humans, have thus far not been iden-
kidneys, pancreas, lung, heart, bone, and central nervous system tified in dogs (see later). Coexistence of non-endocrine tumors
(CNS). In sum, more than 50% of canine pheochromocytomas is also common. In two case series, 50% and 54% of dogs with
were considered malignant, a number often quoted today. It may, pheochromocytoma had additional endocrine or non-endocrine
however, be that small and potentially benign pheochromocyto- neoplasias (Gilson etal, 1994; Barthez etal, 1997).
mas go undetected, and therefore the overall malignancy may be
overestimated. In the three pheochromocytomas described in cats,
PHYSIOLOGY AND PATHOPHYSIOLOGY
so far invasion or metastasis was absent (Henry etal, 1993; Chun
etal, 1997; Calsyn etal, 2010). Catecholamines are molecules that contain a catechol struc-
The size of pheochromocytomas is extremely variable, and ture (ortho-dihydroxybenzene) and a side chain with an amino
their diameter ranges between a few millimeters and more than group. Catecholamines include epinephrine (adrenaline), nor-
15 centimeters. Most pheochromocytomas in dogs are unilat- epinephrine (noradrenaline), and dopamine (Young, 2011).
eral, less than 10% are bilateral. Dogs with pheochromocytoma They are synthesized from the amino acid tyrosine, which is
may have one or several additional endocrine neoplasias, such as derived from food or formed from phenylalanine in the liver
glucocorticoid-producing adrenocortical adenoma or carcinoma, (see Fig. 13-1). Tyrosine enters neurons and chromaffin cells
and is converted to L-dihydroxyphenylalanine (L-DOPA) by the measurement of metanephrines (which equals the sum of
the enzyme tyrosine hydroxylase. This conversion is the rate- metanephrine and normetanephrine) is superior to the measure-
limiting step in the catecholamine synthesis pathway; intra- ment of catecholamines in the diagnosis of pheochromocytoma
cellular catecholamine depletion rapidly increases the enzyme (Eisenhofer, 2001).
activity, whereas increased catecholamine levels lead to its Catecholamines act by binding to receptors located in the cell
down-regulation. Dopa is decarboxylated to dopamine, which membrane of the target cells. From there, signal transduction
is the final product in some neurons. In the adrenal medulla and to intracellular sites takes place via G-proteins (i.e., adrenergic
most sympathetic postganglionic neurons, dopamine is hydrox- receptors are so-called G-protein coupled receptors). They are
ylated to norepinephrine. In most sympathetic postganglionic present in most cells of the body and are responsible to mediate
neurons, norepinephrine is the final product. Hydroxylation of the bodys reaction to stress. The two broad categories of - and
dopamine to norepinephrine takes place after its active trans- -receptors have further expanded into nine receptor subtypes:
port into granulated vesicles. In the adrenal medulla, norepi- three 1 (1a, 1b, and 1d), three 2 (2A, 2B, and 2C), and
nephrine is released from the vesicles into the cytoplasms of the three (1, 2, and 3) (Cotecchia, 2010). Epinephrine and
chromaffin cells where the enzyme PNMT (see earlier) trans- norepinephrine both act on - and -adrenergic receptors. They
forms it to epinephrine. Epinephrine is then transported into have approximately the same potency to stimulate - and 1-
another vesicle (Cryer, 2001; Fitzgerald, 2011; Young, 2011). receptors. Epinephrine is much more potent to stimulate 2,
The expression of PNMT is enhanced by cortisol, which is pres- and norepinephrine is more potent to stimulate 3-receptors
ent in high concentrations in the adrenal medulla due to the (Fitzgerald, 2011). The effects of catecholamines depend on
blood supply from the adrenal cortex. Although the enzyme the density of the different receptors and their subtypes on spe-
PNMT is also found in other tissues than the adrenal medulla, cific organs and the relative concentrations of epinephrine and
the amount of epinephrine from extra-adrenal sources is small. norepinephrine. Additionally, the effects may be modulated by
This means that under physiological conditions, nearly all of the receptor dynamics (e.g., phenomena known as receptor desensi-
epinephrine in the circulation comes from the adrenal medulla, tization and resensitization; Tsujimoto etal, 1984; Garca-Sinz
whereas circulating norepinephrine is mostly derived from etal, 2011; Vasudevan etal, 2011). Norepinephrine causes vaso-
postganglionic sympathetic neurons (Fitzgerald, 2011; Young, constriction (1) and increase in cardiac contractility and rate
2011). Within the adrenal medulla, the amount of stored epi- (1). The effects are modulated by reflex mechanism (e.g., an
nephrine to norepinephrine varies between species. In the nor- increase in heart rate is limited by simultaneous vagal stimula-
mal human medulla, 80% of catecholamines are epinephrine tion). Epinephrine, through activation of 1 and 1 receptors,
and 20% are norepinephrine. In dogs, 70% is epinephrine and has the same effects as norepinephrine. However, epinephrine
30% is norepinephrine; in cats, the percentages are 60% and also stimulates 2 receptors, which causes vasodilation in skeletal
40% (Fitzgerald and Goldfien, 2004). Epinephrine and norepi- muscles. The effect of epinephrine on blood pressure is there-
nephrine are stored in intracellular vesicles together with many fore variable and depends on its plasma concentration: At low
other substances, such as chromogranins, adrenomedullin, neu- concentrations epinephrine mainly stimulates 2 receptors lead-
ropeptide Y, vasoactive intestinal peptide (VIP), enkephalins, ing to vasodilation, and at higher concentrations the effect on
pituitary adenylate cyclase activating polypeptide, and ACTH 1 receptors dominates causing vasoconstriction (Sjaastad etal,
(Thouennon etal, 2010; Fitzgerald, 2011). The question of the 2010; Fitzgerald, 2011). Table 13-2 gives an overview over the
physiological relevance of those peptides is an area of intensive physiologic effects of catecholamines. In short, those effects sup-
research. Chromogranin A (CGA) for instance, which is widely port the organisms in stressful events and mediate the fright,
used as diagnostic marker for tumors of neuroendocrine origin, flight, fight responseincrease in heart rate and contractility,
seems to have an important role for storage and release of cat- increase in blood pressure, increase in respiration rate, decrease
echolamines (Loh etal, 2004; Elias etal, 2010). in gastrointestinal motility, increase in blood glucose and fatty
Secretion of catecholamines takes place by exocytosis of the intra- acids, and increased alertness.
cellular vesicles as part of the activation of the sympathetic nervous The clinical signs in patients with a pheochromocytoma can
system. Catecholamine secretion increases with exercise, perceived be explained by the known actions of catecholamines or less fre-
danger, surgery, hypovolemia, hypotension, hypoglycemia, and quently by tumor size and invasiveness. Catecholamine secre-
many other stressful events (Galac etal, 2010; Fitzgerald, 2011). tion from pheochromocytomas is highly variable with regard
The plasma half-life of catecholamines is extremely short (1 to 3 to relative amounts and types of catecholamines as well as to
minutes). Metabolism of secreted catecholamines occurs mostly time of release (i.e., episodic versus continuous). In humans,
in the liver and kidney; they may also be inactivated by conjuga- these differences have been shown to be due to differences in
tion, which happens mainly in the gastrointestinal tract. Metabo- expression of genes responsible for the regulation of the cate-
lites of catecholamines, conjugates, and free catecholamines are cholamine synthesis pathway and differences in genes encoding
excreted in the urine; free catecholamines account for only a small the components of the complex secretory processes (Eisenhofer
amount (Fitzgerald, 2011). Two enzyme systems are involved in etal, 2011). Different to the normal medulla, the majority of
the catecholamine metabolism: catechol-O-methyltransferase pheochromocytomas in humans produce more norepinephrine
(COMT) and monoamine oxidase (MAO). In the normal adrenal than epinephrine, and many pheochromocytomas produce both
medulla and in pheochromocytoma, membrane-bound COMT catecholamines. Some tumors produce predominantly epineph-
metabolizes epinephrine to metanephrine and norepinephrine to rine (Fitzgerald, 2011). Recent studies have categorized human
normetanephrine (Fig. 13-2). It is important to understand that pheochromocytomas as with either noradrenergic or adrenergic
most metabolism of catecholamines happens in the same cells in phenotypes. The adrenergic phenotype represents a situation in
which they are produced (Eisenhofer et al, 2004a). In contrast which the enzyme PNMT (the enzyme that converts norepi-
to the catecholamines that are released only intermittently (by nephrine to epinephrine) is expressed, and the tumor secretes
means of exocytosis of storage vesicles), their metabolites are con- norepinephrine and epinephrine in various proportions. In the
stantly leaking into the circulation. This difference explains why noradrenergic phenotype, PNMT is lacking and tumors produce
|
OH OH
HO C HO C
HO CH2 HO CH2
NHCH3 NH2
Epinephrine Norepinephrine
MAO2
OH
HO C
COMT1,3 COMT1,3
HO CH2
OH
3,4-Dihydroxyphenylglycol
(DHPG)
OH COMT3 OH
AD3
CH3O CH CH3O CH
HO CH2 HO CH2
NHCH3 NH2
Metanephrine Normetanephrine
PST4 MAO3 MAO3 PST4
OH OH OH FIGURE 13-2Metabolism of catecholamines by catechol-

O-methyltransferase (COMT), monoamine oxidase (MAO),
CH3O CH CH3O CH CH3O CH
aldehyde dehydrogenase (AD), and phenol-sulfotransferase
O 4S CH2 HO C O O4S CH2 (PST). 1, adrenal medulla or pheochromocytoma; 2, sym-
pathetic nerves; 3, liver and kidneys; 4, gastrointestinal
NHCH3 OH NH2 tract, platelets, and lungs. (Modified from Fitzgerald PA:
Adrenal medulla and paraganglia. In Gardner DA, Sho-
Metanephrine-sulfate Normetanephrine-sulfate
back D, editors: Greenspans Basic and Clinical Endocri-
3-Methoxy-4-hydroxymandelic acid nology, ed 9, New York, 2011, McGraw-Hill, p. 351, with
(Vanillylmandelic acid, VMA) permission.)
predominantly norepinephrine (Eisenhofer etal, 2004b; 2008a; (Eisenhofer et al, 2005a). This is most likely due to the fact
2011; Pacak, 2011). In tumors with an adrenergic phenotype, that metanephrines are released continuously, whereas cat-
the epinephrine content may vary between 11% and 90% of echolamines are usually secreted episodically.
the combined epinephrine and norepinephrine content; in nor- Catecholamine release from pheochromocytoma happens
adrenergic phenotype tumors, epinephrine content is less than spontaneously and may be induced by various factors and drugs.
10% (Eisenhofer et al, 2005a). It was shown that the kind of The latter is a particular problematic issue in patients with an
mutation determines the phenotype: tumors due to RET, NF1, unrecognized tumor (Eisenhofer et al, 2007; Mannelli et al,
and the newly discovered TMEM127 mutations have an adren- 2012a; Box 13-1).
ergic phenotype, whereas tumors due to VHL mutations have In addition to catecholamines and metanephrines, pheochro-
a noradrenergic phenotype (Mannelli etal, 2012a). Metastasis mocytomas may secrete a multitude of other peptides. Those may
of pheochromocytoma usually produces predominantly norepi- add abnormalities to the clinical picture (e.g., hypercalcemia in
nephrine (Pacak, 2011). On very rare occasions pheochromocy- case of parathyroid hormonerelated peptide [PTHrp] secretion)
tomas may only produce dopamine (dopaminergic phenotype). and/or may counterbalance catecholamine effects (Box 13-2).
Those tumors are caused by a lack of expression of the enzyme Human pheochromocytomas may also produce inflammatory
dopamine -hydroxylase, which converts dopamine to norepi- cytokines, and several cases of systemic inflammatory syndrome
nephrine; typically they are not associated with hypertension have been described (Tokuda etal, 2009).
(Feldman etal, 1979; Mannelli etal, 2012a). Some human pheochromocytomas may present as clinically
In general, tumor size in humans is positively correlated with silent, termed subclinical pheochromocytomas. However, true
the amount of catecholamines and metanephrines released nonsecretory pheochromocytomas are very rare; they may some-
into the circulation (i.e., small tumors secrete less than large times be associated with certain mutations. Apparently subclinical
tumors). The relationship between size and released concen- pheochromocytomas may cause sudden hypertensive crisis and
tration is stronger for metanephrines than for catecholamines even death. There are various reasons why those tumors may
TABLE 13-2 CATECHOLAMINE RECEPTORS SUBTYPES, TISSUE LOCATIONS, AND ACTIONS
CATECHOLAMINE RECEPTOR TISSUE LOCATION ACTION FOLLOWING RECEPTOR ACTIVATION

1 Vascular smooth muscle Increases vasoconstriction (increases blood pressure)
Liver Increases glycogenolysis and gluconeogenesis
Eye Increases ciliary muscle contraction (pupil dilation)
Skin Increases pilomotor smooth muscle contraction (erects hairs)
Prostate Increases contraction and ejaculation
Uterus Increases gravid uterus contraction
Intestines Increases sphincter tone and relaxes smooth muscle
Spleen capsule Contracts spleen volume, expelling blood
2 Preganglionic nerves Decreases release of neurotransmitter
Vascular smooth muscle Increases vasoconstriction (increases blood pressure)
Pancreatic islet cells Decreases release of insulin and glucagon
Blood platelets Increases platelet aggregation
Adipose cells Decreases lipolysis
Brain Decreases norepinephrine release
1 Myocardium Increases force and rate of contraction
Kidney (juxtaglomerular apparatus) Increases secretion of renin
Adipose cells Increases lipolysis
Most tissues Increases calorigenesis
Nerves Increases conduction velocity
2 Vascular smooth muscle Decreases vasoconstriction (increases blood flow)
Bronchiolar smooth muscle Decreases contraction (bronchial dilation)
Liver Increases glycogenolysis and gluconeogenesis
Intestinal smooth muscle Decreases intestinal motility; increases sphincter tone
Pancreatic islet cells Increases release of insulin and glucagon
Adipose tissue Increases lipolysis
Muscles Increases muscle contraction speed and glycogenolysis
Liver and kidney Increases peripheral conversion of T4 to T3
Uterus smooth muscle Decreases nongravid uterine contraction (uterine relaxation)
3 Adipose cells Increases lipolysis
Intestinal smooth muscle Increases intestinal motility
Dopamine1 Vascular smooth muscle Decreases vasoconstriction (vasodilation)
Renal tubule Enhances natriuresis
Dopamine2 Sympathetic nerves Inhibits synaptic release of norepinephrine
Pituitary lactotrophs Inhibits prolactin release
Gastrointestinal tract Paracrine functions
Modified from Fitzgerald PA: Adrenal medulla and paraganglia. In Gardner DA, Shoback D, editors: Greenspans basic and clinical endocrinology, ed 9, New York, 2011, McGraw-Hill,
p. 353, with permission.
Dopamine1, Dopamine1-like family of receptors; dopamine2, dopamine2-like family of receptors; T3, triiodothyronine; T4, thyroxine.
appear silent, such as small tumor size in the early stages of devel- often an incidental finding than large tumors, and very serious
opment, large tumors with extensive tissue loss due to necrosis and clinical signs are more often associated with large than with small
hemorrhage, paroxysmal symptoms with long asymptomatic peri- tumors (Feldman and Nelson, 2004a). Investigation of catechol-
ods and low medical awareness, and counteraction of the effects amines and metanephrines in urine and plasma has only recently
of catecholamines by co-secreted peptides (Mannelli etal, 2012a). been started, and secretion patterns have not yet been established.
Information on pathophysiological aspects of pheochromocy- According to our preliminary results, norepinephrine concen-
toma in dogs is scarce. However, many of the findings in dogs trations are increased in most dogs with pheochromocytoma,
appear to be similar to those in humans. As in humans, clini- whereas a minority of dogs also reveals an increase in epinephrine
cal signs including hypertension occur paroxysmal in most dogs (Kook etal, 2007; 2010; Quante etal, 2010; Salesov etal, 2012).
with pheochromocytoma pointing to sporadic (and unpredict- Therefore, it is likely that also in canine pheochromocytoma,
able) catecholamine secretion. Some dogs reveal more constant norepinephrine is the predominant catecholamine. By means of
clinical signs, which is most likely associated with continuous immunohistochemical stainings, it has been shown that neoplas-
catecholamine release at a lower rate. There are also dogs that are tic cells also contain various peptides (e.g., somatostatin, CGA,
clinically asymptomatic (or have extremely mild signs), and the substance P, VIP, synaptophysin, galanin, leu-enkephalin, met-
pheochromocytoma is an incidental finding. As in humans, there enkephalin, and S 100 protein) (Wilson etal, 1986; Cuervo etal,
seems to be a correlation between severity and presence of clinical 1994; Sako etal, 2001). It is likely that those peptides contribute
signs and tumor size. Very small pheochromocytomas are more to the clinical picture.
|
BOX 13-1 F
actors that have been Reported to Induce BOX 13-2 S
ubstances that may be Co-Secreted with
Hypertensive Crisis in Human Patients with Catecholamines and Metanephrines in Human
Pheochromocytoma Patients with Pheochromocytoma
Mechanical/Physical Influences Peptide Correlated Signs

Palpation of abdomen Vasoactive intestinal peptide (VIP) Diarrhea, flushes
Physical exercise Substance P Flushes
Change of posture Somatostatin Constipation
Cough or sneezing Enkephalin Constipation
Defecation Motilin Diarrhea
Sexual intercourse Neuropeptide Y Vasoconstriction
Delivery Renin Hypertension
Surgery Corticotropin-releasing factor (CRF) Hypercortisolism
Invasive diagnostic procedures Adrenocorticotrophic hormone (ACTH) Hypercortisolism
Drugs Melanocyte-stimulating hormone (MSH) Melanodermia
Monoamine oxidase (MAO) inhibitors Parathyroid hormone (PTH) Hypercalcemia
Tricyclic antidepressants PTH-related peptide (PTHrp) Hypercalcemia
-blockers Endothelin Vasoconstriction
Metoclopramide Erythropoietin Polycythemia
Sympathomimetics Angiotensin converting enzyme (ACE) Hypertension
Decongestants Growth hormone-releasing hormone (GHRH) Acromegaly
Glucagon Interleukin-6 (IL-6) Fever
Glucocorticoids Neuron-specific enolase (NSE)
Adrenocorticotropic hormone (ACTH) Chromogranin A (CGA)
Opiates Insulin-like growth factor-2 (IGF-2) Hypoglycemia
Histamine Atrial natriuretic peptide (ANP) Polyuria, hypotension
Tyramine Calcitonin
Alcohol Calcitonin-related peptide (CGRP) Vasodilation
Nicotine Pituitary adenylate-cyclase activating peptide Vasodilation
Chlorpromazine Adrenomedullin Vasodilation
Chemotherapy
Modified from Mannelli M, etal.: Subclinical phaeochromocytoma, Best Pract Res
Others Clin Endocrinol Metab 26:507, 2012a, with permission; amended by Fukuda I, etal.:
Pain Clinical features of insulin-like growth factor-II producing non-islet-cell tumor
Emotional stress hypoglycemia, Growth Horm IGF Res 16:211, 2006.
Cold exposure
Food and drinks containing tyramine (e.g., aged cheese, meats, fish,
chocolate, bananas, beer, and wine)
(e.g., Golden Retriever, Labrador Retriever, Boxer, Doberman,
Modified from Fitzgerald PA: Adrenal medulla and paraganglia. In Gardner DA, German Shepherd, poodle, and terrier breeds) may just reflect
Shoback D, editors: Greenspans basic and clinical endocrinology, ed 9, New York, their popularity.
2011, McGraw-Hill; Mannelli M, etal.: Subclinical phaeochromocytoma, Best Pract The three cats described with pheochromocytoma so far were
Res Clin Endocrinol Metab 26:507, 2012a, with permission. 7, 11, and 15 years old, two were castrated males, and one was a
spayed female. All three were Domestic Short-Hair cats (Henry
Signalment etal, 1993; Chun etal, 1997; Calsyn etal, 2010).
Since the first description of pheochromocytoma in dogs in 1955

Clinical Manifestations
(Mueller et al, 1955; Tamaschke, 1955), a little more than 200
cases have been published. Of those, 123 are part of three large Clinical signs are most often the result of the secretion of excessive
case series (Bouayad etal, 1987; Gilson etal, 1994; Barthez etal, amounts of catecholamines by the pheochromocytoma. Less com-
1997); the others have been described either as single case reports monly, they are due to the space-occupying or invasive nature of
or small case series comprising fewer than 10 cases. the tumor or metastasis (Box 13-3). Pheochromocytoma should
Pheochromocytoma may be seen at any age; however, it occurs be considered a potentially life-threatening disease that may result
most commonly in older dogs. In the three case series, age ranged in collapse and sudden death due to massive catecholamine release
between 1 and 18 years with means between 11 and 12 years. In or tumor rupture.
the other case reports and small case series, most dogs were 7 years Hormone secretion from the tumors is highly variable, and
and older, only approximately 5% of dogs were younger. There is consequently, the clinical picture varies considerably. The triggers
no sex predilection because the relation between male and female for catecholamine secretion are usually unknown. Dogs may have
dogs is approximately 1:1. Neutering also does not seem to have some clinical signs at all times (e.g., lethargy, polydipsia/polyuria)
an obvious influence, because neutered as well as intact male and with paroxysmal episodes of additional signs (e.g., panting, tachy-
female dogs are affected. There also does not seem to be a breed cardia), and other dogs may be clinically unremarkable between
predilection: pheochromocytomas have been described in more episodes. The episodes may occur frequently, such as several times
than 40 breeds. The somewhat higher frequency in some breeds per day or several times per week, or they may only recur after
considered several times per day, because most sick dogs pre-
BOX 13-3 C
ategories of Clinical Signs in Dogs with sented to the veterinarian have one or several of the problems
Pheochromocytoma mentioned earlier. Of course, pheochromocytoma is still a rare
CLINICAL SIGNS SYMPTOMS disease; nevertheless, one should remember that many pheo-
Clinical signs and findings caused chromocytomas are still overlooked due to a low level of medi-
by catecholamine excess cal awareness.
The most frequent clinical signs are weakness, lethargy, tachy-
Nonspecific Anorexia, weight loss, lethargy pnea/panting, and collapse. Those signs often occur as intermittent
Related to cardiorespi- Tachypnea, dyspnea, panting, episodes associated with intermittent catecholamine release. They
ratory system and/or tachycardia, arrhythmias, col- may, however, also present as acute events (e.g., associated with
hypertension lapse, pale mucus membranes, tumor rupture, bleeding, and potential catecholamine surge). Other
hemorrhages, acute blindness frequent signs seen by owners or found by the veterinarian during
Related to neuromus- Weakness, anxiety, pacing, disori- physical examinations are anorexia, weight loss, cardiac arrhythmias,
cular system entation, muscle tremor, seizures tachycardia, polyuria/polydipsia, vomiting, and abdominal pain.
Miscellaneous Polyuria/polydipsia, vomiting, Cardiac arrhythmias are usually tachyarrhythmias (mostly
diarrhea, abdominal enlarge- supraventricular tachycardias, but ventricular premature com-
ment, abdominal pain plexes and ventricular tachycardia are also seen); so far only one
Clinical signs caused by large, Abdominal enlargement, ascites, case of pheochromocytoma-associated bradyarrhythmia (Mobitz
invasive tumor abdominal pain, hind limb edema type II atrioventricular [AV] block) has been described (Brown
etal, 2007a).
Clinical signs caused by tumor Acute severe lethargy, painful Box 13-4 gives an overview over clinical signs and findings in
rupture abdomen, tachypnea, weak- 105 dogs with pheochromocytoma that have been described dur-
ness, collapse, tachycardia, pale ing the past decades. The box only includes those dogs in which
mucus membranes, prolonged the clinical signs were specified. Because not all authors may have
capillary refill time listed all clinical signs and some of the signs may have been due to
Clinical signs caused by To brain: Seizures and other cen- concurrent diseases, there may be some overestimations or under-
metastasis tral nervous system (CNS) signs estimations. The signs and approximate percentages correspond
To vertebral canal or bone: Tetra- relatively well with a compilation of clinical signs and findings
paresis, paraparesis, lameness, in 40 dogs with pheochromocytoma with no other concurrent
swelling, local pain disorder. Those dogs had been seen at the University of California,
Davis, and were included in the previous edition of this textbook
(Tables 13-3 and 13-4). The pathophysiological mechanisms for
weeks to months. Their severity may range from very mild to life- some of the clinical signs are difficult to explain and may be multi-
threatening; severity of episodes may be similar each time or may factorial. For instance, polyuria/polydipsia may be due to excessive
progress over time (the latter is seen more often). The duration catecholamine release, release of other peptides from the tumor, or
of symptoms before presentation of the patient to the veterinar- may represent a form of tumor-induced, secondary nephrogenic
ian ranges from a few hours to several years. Many of the clinical diabetes insipidus. The presence of polyuria/polydipsia is particu-
signs may be explained by more common diseases and therefore larly challenging if it is the predominant sign. Together with the
the possibility of a pheochromocytoma may not be considered finding of an adrenal mass during work-up, it may be mistaken
by the clinician. Additional difficulties occur if the time intervals as evidence for adrenal-dependent hyperadrenocorticism, and the
between episodes are rather long and no link is made between possibility of a pheochromocytoma may not be considered. It is
them. Furthermore, the tumors often occur in conjunction with also important to be aware that seizures in a dog with pheochro-
other serious diseases that are often more obvious and draw away mocytoma may be due to different causes. They may be caused by
the attention from a concurrent pheochromocytoma. In the three catecholamine-induced vasospasms, catecholamine/hypertension
large case series, the percentage of dogs in which the presence of associated bleeding into the CNS, and also by brain metastasis
a pheochromocytoma was not considered and was an inciden- from the pheochromocytoma. It is therefore advisable to perform
tal finding (mostly at necropsy) ranged between 24% and 57% brain imaging in any dog with (suspected) pheochromocytoma
(Bouayad etal, 1987; Gilson etal, 1994; Barthez etal, 1997). and seizures. Interestingly, the percentage of dogs presented with
The clinical manifestations related to excessive catecholamine nasal bleeding, retinal bleeding, retinal detachment, and blind-
secretion may be categorized as follows (see Box 13-3):
ness is rather low. The reason is unclear. It may be that the pres-
Nonspecific: Anorexia, weight loss, and/or lethargy ence of pheochromocytoma goes unnoticed in some dogs with
Related to the cardiorespiratory system and/or hypertension: retinal detachment and blindness because no complete work-up
Tachypnea, dyspnea, panting, tachycardia, arrhythmias (mostly is performed. Alternatively, the catecholamine release and hyper-
tachyarrhythmias), collapse, pale mucus membranes, nasal tensive episodes may not be frequent enough to cause these kinds
hemorrhage, gingival hemorrhage, ocular hemorrhage, and/or of damage.
acute blindness Clinical signs may also be caused by large tumor size, inva-
Related to the neuromuscular system: Weakness, anxiety, pac- siveness into surrounding structures, and by metastasis. Invasion
ing, disorientation, muscle tremor, and/or seizures of adjacent structures most often affects the vena cava caudalis.
Miscellaneous: Polyuria/polydipsia, vomiting, diarrhea, abdom- Occlusion of the vena cava caudalis (partial or complete) is either
inal enlargement, and/or abdominal pain by tumor thrombosis within the lumen or by large tumor size
Those categories reflect the enormous variability of clinical both may cause ascites, hind limb edema, and distention of the
signs associated with pheochromocytoma, and it may be helpful caudal epigastric veins. However, clinical signs may also be absent
to memorize them. Theoretically, a pheochromocytoma may be although the vena cava is occluded, which is most likely due to
|
BOX 13-4 F
requency of Clinical Signs and Findings in TABLE 13-3 F
REQUENCY OF CLINICAL
Dogs with Pheochromocytoma* SIGNS IN 40 DOGS WITH
PHEOCHROMOCYTOMA AND
Clinical sign Percentage of Dogs IDENTIFICATION OF NO OTHER
Weakness 40% CONCURRENT DISEASE*
Tachypnea/panting 30%
Lethargy 24% PERCENTAGE
Collapse 21% CLINICAL SIGN NUMBER OF DOGS OF DOGS
Anorexia 19% Collapsing episodes 13 33%
Weight loss 19%
Cardiac arrhythmias 19% Weakness 12 30%
Polyuria/polydipsia 15% Panting/tachypnea 12 30%
Pale mucus membranes 14% Polyuria/polydipsia 10 25%
Tachycardia 13%
Lethargy 10 25%
Abdominal pain 13%
Abdominal distension (ascites and/or mass) 12% Vomiting 9 23%
Dyspnea 12% Inappetence 8 20%
Vomiting 12% Anxiety/agitation/pacing 6 15%
Hind limb lameness or paraparesis 10%
Diarrhea 4 10%
Cough 9%
Palpable abdominal mass 8% Abdominal distention 4 10%
Seizures 7% Hemorrhage (nasal, ocular, gingival) 4 10%
Ataxia 6% Acute blindness 3 8%
Weak pulse 4%
Cyanosis 3% Tremors 3 8%
Front leg lameness 3% Weight loss 3 8%
Nasal/ocular bleeding 3% Tachycardia/ pounding heart 2 5%
Congestive heart failure/cardiac arrest 3%
Rear limb edema 2 5%
Fever 2%
Injected mucus membranes 2% Tender or painful abdomen 2 5%
Restlessness/pacing 1% Adipsia 1 3%
Muscle tremor 1% No clinical signs 4 10%
Diarrhea 1%
Dilated pupils 1% *Those dogs had been seen at the University of California, Davis.
Usually reported to be intermittent by the owner.
Jugular distension 1%
Regurgitation 1%
Quadriparesis 1%
Distension of caudal epigastric veins 1%
presented with acute onset of lethargy, tachypnea, weakness or
collapse, tachycardia, pale mucus membranes, prolonged capil-
*The data are compiled from 105 dogs with pheochromocytoma that have been
described during the past decades in three larger case series and 25 case reports
lary refill time, and painful abdomen (Whittemore etal, 2001;
or small case series. Only dogs that had shown clinical signs were used (i.e., Williams and Hackner, 2001). Emergency work-up including
asymptomatic dogs were excluded). Dogs with additional other endocrine tumors ultrasonography, clinical pathology, and emergency treatment is
were also excluded. The given percentages should be considered as approximate required in those cases.
numbers, because history taking and physical examination were of course not Pheochromocytoma may metastasize into many organs, includ-
standardized between the studies. Some of the dogs had concurrent diseases, ing regional lymph nodes, liver, spleen, kidneys, pancreas, lung,
which may have contributed to the clinical signs. For comparison see heart, bone, and CNS. Metastasis into the brain may lead to sei-
Tables 13-3 and 13-4. zures and other CNS signs (Gilson etal, 1994). Metastasis to the
vertebral canal, causing tetraparesis or paraparesis depending on
the localization, and metastasis to bone (scapula, humerus, femur,
the development of collateral circulation (Bouayad et al, 1987; and/or tibia), causing lameness, swelling, and pain have been
Santamarina et al, 2003). Aortic thromboembolism with pain- reported several times (White and Cheyne, 1977; Stowater, 1979;
ful and weak hind limbs, paraparesis, absence of femoral pulse, Berzon, 1981; Platt et al, 1998; Head and Daniel, 2004; Boes
and cold distal extremities may occur in rare cases (Gilson etal, etal, 2009; Spall etal, 2011).
1994; Santamarina etal, 2003). Dorsal extension of a pheochro- As mentioned earlier, there seems to be a correlation between
mocytoma into the vertebral canal with paresis has been described tumor size and severity of clinical signs. Small tumors are often an
(Platt etal, 1998). incidental finding or associated with relatively mild signs. Large
Spontaneous tumor rupture with retroperitoneal hemorrhage tumors are often found in patients with serious clinical signs, inva-
may occur as a rare event, either as the only and first presenta- sion into the vena cava, and/or tumor rupture.
tion or in association with other clinical signs of pheochromo- Physical examination findings are variable and depend on the
cytoma during the course of the disease. This risk needs to be secretory activity of the tumor at the time of the examination, and
explained to owners of dogs with relatively large tumors who are they depend on tumor size and the presence or absence of clinically
reluctant to proceed to surgery. Dogs with tumor rupture are relevant metastasis or if the tumor has ruptured. In a substantial
TABLE 13-4 F
REQUENCY OF ABNORMAL results of dogs with pheochromocytoma that have been published
FINDINGS ON PHYSICAL during the last decades is given later. A little more than 100 dogs
EXAMINATION IN 40 DOGS WITH were included; dogs with concurrent endocrine neoplasia were not
PHEOCHROMOCYTOMA AND used. The reader should be aware that the percentages are approxi-
IDENTIFICATION OF NO OTHER mate numbers, because not all authors may have listed all abnor-
CONCURRENT DISEASE* malities, in particular if they were minor.

CBC: Mild to moderate anemia (45%), leucocytosis or stress

NUMBER PERCENTAGE
leukogram (37%), thrombocytopenia (8%), thrombocytosis
PHYSICAL FINDING OF DOGS OF DOGS
(6%). The anemia usually is nonregenerative and may be an
anemia associated with chronic disease; the latter may either
Panting, tachypnea 15 38% be the pheochromocytoma or another concurrent disease.
Weakness 9 23% Polycythemia may also be seen in a few cases, possibly due to
Tachycardia 7 18% hemoconcentration, release of erythropoietin from the kid-
neys associated with catecholamine-induced ischemia, or it
Thin, muscle wasting 6 15%
may result from erythropoietin release from the pheochro-
Cardiac arrhythmias 6 15% mocytoma (Mannelli etal, 2012a). Thrombocytosis has been
Hemorrhage (nasal, gingival, and/or ocular) 6 15% associated with chronically bleeding pheochromocytomas,
Weak pulses 4 10% whereas no association was found between bleeding from the
tumor and thrombocytopenia (Gilson et al, 1994; Feldman
Pale mucous membranes 4 10% and Nelson, 2004a).
Abdominal pain 4 10% Biochemistry panel: Increased alkaline phosphatase (ALP;
Ascites 4 10% 44%), increased alanine aminotransferase (ALT; 33%), in-
creased aspartate aminotransferase (AST; 27%), increased
Lethargy 3 8%
blood urea nitrogen (BUN; 25%), increased creatinine (21%),
Palpable abdominal mass 2 5% hypercholesterolemia (23%), hypoalbuminemia (21%), hy-
Shocky 2 5% perglycemia (8%), hyperphosphatemia (8%), hypokalemia
Blindness, retinal detachment 2 5% (7%), and hyponatremia (7%). Increase in liver enzymes is the
most frequent biochemical abnormality. There is no obvious
Rear limb edema 1 3% correlation of an increase in liver enzymes and the presence
Shaking, muscle tremors 1 3% of metastasis or tumor stage (Gilson etal, 1994; Feldman and
Lateral recumbency 1 3% Nelson, 2004a). Potential explanations are hypertension-in-
Anterior uveitis 1 3%
duced hepatopathy or concurrent disease (Barthez etal, 1997).
In humans, it is known that pheochromocytomas may release
Unremarkable 15 38% inflammatory cytokines (Kang etal, 2005); this would be an-
*Those dogs had been seen at the University of California, Davis.
other potential explanation for the increase in liver enzymes
Common geriatric findings, such as lipomas, dental disease, and incidental cardiac in dogs. Azotemia may be prerenal or renal due to volume-
murmurs are excluded. depletion and/or catecholamine induced vasoconstriction and
renal ischemia.
Hypercholesterolemia is most likely due to catecholamine-
induced lipolysis and the conversion of excess fatty acids to cho-
proportion of dogs, the physical examination is unremarkable lesterol and other lipids in the liver. Increased cholesterol levels
with regard to the pheochromocytoma. However, because the have been seen most often in advanced-stage tumors (Gilson
dogs usually are older, concurrent diseases are frequently pres- et al, 1994). Hyperglycemia is usually mild or moderate and
ent (in approximately 50% of cases). Because those diseases may most often does not require therapeutic intervention. Overt di-
have an impact on further work-up and prognosis, careful clinical abetes and diabetic ketoacidosis have been described in a small
evaluation of the patients is warranted. number of dogs with pheochromocytoma; however, it was not
Of the three cats with pheochromocytoma described so far, clear if the diabetes was caused by the catecholamine excess
one had no clinical signs (Chun et al, 1997). One of the two (Feldman and Nelson, 2004a). Catecholamines have various ef-
symptomatic cats just had polyuria/polydipsia; the other one fects on carbohydrate metabolism and insulin secretion. They
had polyuria/polydipsia, polyphagia, aggression, weight gain, stimulate gluconeogenesis and glycogenolysis and limit periph-
and an unkempt hair coat with areas of alopecia. Because the lateral glucose utilization. They both suppress (2) and stimulate
ter cat had a glucocorticoid-producing adrenocortical adenoma (2) insulin secretion, whereby the suppressive effect generally
in addition to the pheochromocytoma, the clinical signs were predominates (Cryer, 2001).
thought to be caused by the hypercortisolemia (Henry etal, 1993; Information on urinalysis is scarce in the literature. In our own
Calsyn etal, 2010). population of dogs with pheochromocytoma, urine specific grav-
ity ranged from 1.006 to 1.044 and was in the hyposthenuric or
CLINICAL PATHOLOGY isosthenuric range in about half of the dogs. Catecholamines, in
particular norepinephrine, suppress the release of antidiuretic hor-
There are no consistent changes in the complete blood count mone (ADH; Berl etal, 1974), which may, at least in part, explain
(CBC), serum biochemistry panel, and urinalysis, which would low urine specific gravity and the polyuria and polydipsia seen in
support the suspicion of a pheochromocytoma. Dogs with pheo- some of the dogs. Proteinuria may be present in approximately
chromocytoma may show one or several abnormalities; they may 30% of patients and may be caused by hypertension-induced kid-
also have normal laboratory results. A compilation of laboratory ney damage or concurrent diseases.
|
In human pheochromocytoma, hypertension occurs primarily

Blood Pressure Measurement
from the secretion of norepinephrine, whereas epinephrine has a
In humans, hypertension is one of the key features of pheochro- more variable influence on blood pressure. Additional factors that
mocytoma, which affects 80% to 90% of patients (Prejbisz etal, might contribute to hypertension are the co-secretion of neuro-
2011). Hypertension in humans is defined as systolic/diastolic peptide Y, a potent vasoconstrictor, or a compromised blood flow
blood pressure greater than or equal to 140/90 mm Hg; blood in the renal artery due to compression by a large tumor, caus-
pressure less than 120/80 mm Hg is considered normal. Accord- ing increased renin production (Fitzgerald, 2011). Various blood
ing to the latest (seventh) report of the Joint National Commit- pressure patterns are known to exist: (1) sustained but variable
tee on Prevention, Detection, Evaluation and Treatment of High hypertension with paroxysmal severe hypertensive peaks (approx-
Blood Pressure, values in between the two are allocated to the imately 50% of human patients), (2) normotension between
newly introduced category of prehypertension (Chobanian etal, paroxysmal hypertensive peaks, (3) sustained stable hyperten-
2003). Contrary to previous assumptions that an increase in dia- sion, and (4) normotension. Interestingly, in pheochromocyto-
stolic blood pressure is more worrisome than in systolic pressure, mas that exclusively produce epinephrine, hypotension is possible
it has been shown that hypertension-associated risks are more and even shock may occur. Other peptides, co-secreted with cat-
accurately attributed to systolic pressure (Black, 2004). echolamines, such as adrenomedullin, may also play a role in the
In dogs and cats, the importance of hypertension began to induction of hypotension. Tumors that predominantly produce
be recognized 20 to 25 years ago. Similar to the guidelines for dopamine are rare; they are usually associated with normoten-
humans, the American College of Veterinary Internal Medicine sion or hypotension (Fitzgerald, 2011; Kitamura et al, 2012).
provides a consensus statement for dogs and cats (Brown et al, Although pheochromocytoma is an uncommon cause for hyper-
2007b). There is some controversy with regard to the threshold tension because it affects approximately one in 1000 people with
values that should be considered as hypertension. The guidelines hypertension, it is associated with potentially fatal cardiovascu-
classify blood pressure in dogs and cats with regard to risk of lar complications. Lethal outcome is particularly common if the
target-organ damage into four categories. Minimal risk is present if tumor is undiagnosed, because a multitude of factors and drugs
systolic blood pressure is less than 150 mm Hg and diastolic pres- may provoke catecholamine release (Galetta etal, 2010; Prejbisz
sure is less than 95 mm Hg, and one may roughly say that these etal, 2011; see Box 13-1).
numbers represent normal blood pressure. Although studies have In dogs with pheochromocytoma, lesions attributed to
not determined if an increase in systolic pressure is more damag- hypertension were described decades ago. Main histological
ing than an increase in diastolic pressure, there has been emphasis changes were thickening and hyalinization of the Bowman cap-
in addressing systolic hypertension in dogs and cats (Reusch etal, sule; medial hypertrophy and sclerosis of pulmonary, splenic,
2010). Major causes of inaccurate blood pressure results are tech- and renal arteries; and hyaline degeneration of arterioles in the
nical errors associated with personnel inexperience. Therefore, to brain (Howard and Nielsen, 1965). Unfortunately, in many
obtain reliable results, the person making the measurement should dogs with pheochromocytoma, blood pressure was not mea-
be patient and skilled in the handling of animals, clients, and sured, and up until now no studies with regard to correlation
equipment (Brown etal, 2007b). Although direct blood pressure between the type of catecholamine released and any blood
measurement (by catheterizing a peripheral artery) is considered pressure pattern have been performed. Blood pressure measure-
the gold standard, veterinarians usually rely on indirect methods, ments are available in fewer than 50 dogs with pheochromocy-
including Doppler flow detection, oscillometry, or high definition toma; a little more than 50% had hypertension (Table 13-5).
oscillometry. Blood pressure is influenced by many physiologi- Similar to the situation in humans, the increase in blood pressure
cal factors (e.g., age, sex, and breed), and it decreases during rest in dogs may range from mild to severe; the maximum systolic
and sleep and increases during exercise. It can also increase due to pressure reported was 325 mm Hg. Hypotension was seen in
stress and anxiety; this so-called white coat effect may lead to the one dog (Reusch etal, 2010). As already mentioned, it is cur-
false assumption of hypertension. To minimize this risk and to rently not possible to determine blood pressure patterns as in
avoid mistakes, the veterinarian or the technician should follow a humans. However, repeated measurements in a small group
standardized protocol. Among various other issues, it is important of dogs with pheochromocytomas in our hospital suggest that
that the dog or cat is not subjected to any manipulation before there may be similar patterns as in humans. Two of five dogs
blood pressure is measured, that the patient is allowed to acclima- had multiple systolic blood pressure measurements constantly
tize in a quiet room, that several measurements are taken (in the below 160 mm Hg. One dog had variable paroxysmal hyper-
authors hospital the mean of 10 measurements is used), and that tensive peaks with maximal systolic values of 270 mm Hg, one
the first readings are discarded (Reusch etal, 2010). The reader dog had marked fluctuations between 55 and 175 mm Hg, and
is referred to the detailed protocol on how to organize a blood another dog had a single episode of an increased systolic pressure
pressure measurement session of the Consensus Statement of with 180 mm Hg (Kook etal, 2010).
the American College of Veterinary Internal Medicine (ACVIM; It is important to remember that hypertension is not pathog-
Brown etal, 2007b). nomonic for pheochromocytoma and is also frequently found in
Hypertension is classified as idiopathic (primary or essential) hyperadrenocorticism, which is one of the most important dif-
or secondary. Primary hypertension is thought to be rare in dogs ferential diagnoses.
and may account for up to 20% of cases in cats. Secondary hyper-
tension is subclassified into renal and endocrine hypertension. Diagnostic Imaging
Primary hyperaldosteronism, hyperadrenocorticism, pheochro-
mocytoma, hyperthyroidism, and diabetes mellitus are causes for Abdominal and Thoracic Radiographs
endocrine hypertension in dogs and cats. In humans, other endo- Survey abdominal radiographs play a limited role in the diagnostic
crine disorders (e.g., hypothyroidism, hyperparathyroidism, and work-up of dogs with pheochromocytoma.
acromegaly) have been associated with hypertension; there are no In a recent study on surgical outcome, 13% of canine pheo-
reports in dogs or cats. chromocytomas were small with a diameter less than 2.5 cm, 42%
TABLE 13-5 BLOOD PRESSURE MEASUREMENTS IN DOGS WITH PHEOCHROMOCYTOMA
NUMBER OF DOGS NUMBER OF DOGS NUMBER OF DOGS DEFINITION OF SYS- RANGE OF SYSTOLIC
WITH PHEOCHRO- WITH BLOOD PRES- CLASSIFIED AS BE- TOLIC HYPERTENSION BLOOD PRESSURE IN MEASURING
STUDY* MOCYTOMA SURE MEASUREMENT ING HYPERTENSIVE (mm Hg) ALL DOGS (mm Hg) TECHNIQUE
Gilson etal, 1994 50 7 6 > 160 164 to 325 Indirect, Doppler
Barthez etal, 1997 61 23 10 > 160 135 to 214 Indirect,
oscillometric
Williams and 1 1 1 Not given 200 to 240, continuous Indirect,
Hackner, 2001 monitoring oscillometric
Brown etal, 2007a 1 1 1 Not given 240, several Indirect, Doppler
measurements
Kook etal, 2007 7 5 3 > 160 55 to 270 (see text) Indirect,
Doppler, and
oscillometric
Bommarito etal, 2011 1 1 0 Not given Not given Indirect,
oscillometric
Guillaumot etal, 2012 1 1 1 Not given 160 Indirect,
oscillometric
*In some studies diastolic and mean pressures were recorded in addition to systolic pressures. To facilitate comparison, only systolic blood pressure results are given here.
were of moderate size with diameters between 2.6 and 4.9 cm,
and 45% were found to be large with diameters greater than or
equal to 5.0 cm. Sixty-two percent of the tumors were located
in the right adrenal gland (Herrera et al, 2008). The study was
not meant to investigate the role of radiology and does not give
details on radiological findings; it is mentioned here to give the
reader an impression on distribution of tumor sizes. By means of
plain radiographs, small and moderate sized tumors may not be
visiblein particular if located in the right adrenal gland. Detect-
able tumors display as a mass of soft tissue opacity adjacent to
the kidney, possibly with displacement of the kidney and other
abdominal organs. Mineralization is rare in pheochromocytoma,
further hampering their radiological visibility. Other potential
findings are distortion of renal shape or poor visualization of
kidneys, reduced serosal detail due to ascites, enlargement of the
vena cava caudalis, and hepatomegaly; the latter may or may not FIGURE 13-3 Abdominal radiograph of a Papillon (spayed, 10-year-old female).
be associated with pheochromocytoma. In case of tumor rupture, The dog was diagnosed with pheochromocytoma and invasion into the vena
diffuse retroperitoneal soft tissue opacity, reflecting retroperito- cava caudalis. The owner opted for medical treatment with phenoxybenzamine.
neal hemorrhage may be seen (Fig. 13-3). Thoracic radiography Fourteen months after the diagnosis, the dog was presented to the referring
currently still plays a role to search for pulmonary metastasis and veterinarian with acute collapse, pale mucus membranes, prolonged capillary
is therefore of particular importance if adrenalectomy is planned. refill time (CRT), tachycardia, abdominal pain, and a packed cell volume (PCV)
Pulmonary nodules (reflecting metastasis) have previously been of 28%. Diffuse retroperitoneal soft tissue opacity is seen, reflecting retroperi-
reported in approximately 10% of dogs with pheochromocytoma toneal hemorrhage due to rupture of the tumor. (Courtesy of Dr. Markus Haller,
(Gilson et al, 1994; Barthez et al, 1997). They may be missed Boniswil, Switzerland.)
by radiology, and it has been shown that computed tomogra-
phy (CT) is more sensitive for their detection (Armbrust et al,
2012). Most likely, thoracic radiographs will soon be replaced by Abdominal Ultrasonography
CT to search for metastasisat least in larger institutions. Other Abdominal ultrasonography has major advantages over radiogra-
radiological abnormalities, which have been reported in dogs phy for the imaging of the adrenal glands, such as higher resolu-
with pheochromocytoma, include generalized cardiomegaly, right tion to visualize small masses, potential to detect retroperitoneal
or left ventricular enlargement, and pulmonary edema. Those effusion and invasion of the tumor into surrounding vessels and
changes may be caused by the pheochromocytoma, although a tissues, and assessment of other abdominal organs for distant
cause and effect relationship has not been proven. In humans, metastasis (Figs. 13-4, 13-5, and 13-6). Often, a pheochromo-
left ventricular hypertrophy, hypertensive cardiomyopathy, myo- cytoma is only considered after detection of an abnormal adrenal
carditis, and dilated cardiomyopathy (including the relatively new gland on abdominal ultrasonography. Careful consideration of the
phenomenon of takotsubo cardiomyopathy) are known to occur patients history and physical examination is required. Areas of het-
either as a consequence of systemic hypertension and/or high lev- erogenous or hyperechoic parenchyma within the adrenal gland,
els of catecholamines (Prejbisz etal, 2011). adrenal nodules, or masses are frequent findings and are not always
|
5.00MR R5 0 G75 C11

Dist: 0.97cm
FIGURE 13-4Ultrasonographic image of a small pheochromocytoma in a
FIGURE 13-6 Ultrasonographic image of a tumor thrombus in the caudal vena
12-year-old, spayed female Fox Terrier. The tumor presented as hyperechoic nod-
cava (transverse plane) in an 11-year-old, castrated male Jack Russel Terrier. The
ular enlargement of the cranial pole of the left adrenal gland (sagittal plane).
thrombus originated from a pheochromocytoma in the right adrenal gland. Inva-
The maximum diameter of the tumor was 0.97 cm. (Courtesy of Dr. Matthias
sion of the tumor into the vena cava was confirmed by computed tomography (CT)
Dennler and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse
(see Fig. 13-8). Arrows, non-occluded lumen of caudal vena cava; arrowheads,
Faculty, University of Zurich, Zurich, Switzerland.)
tumor thrombus in lumen of caudal vena cava. (Courtesy of Dr. Matthias Dennler
and Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty,
MASS Left Adrenal Gland University of Zurich, Zurich, Switzerland.)
BOX 13-5 M
ain Important Differential Diagnosis of an
1
Incidentally Discovered Adrenal Mass
Hormonally Active Adrenal Nodule/Mass

Aldosterone-producing adenoma, carcinoma, or hyperplasia
Glucocorticoid-producing adenoma or carcinoma
Adrenocortical hyperplasia (ACTH-dependent or ACTH-independent)
Sex-hormone producing adenoma or carcinoma
Pheochromocytoma
Hormonally Inactive Adrenal Nodule/Mass
Hormonally silent adenoma, carcinoma, or hyperplasia
7.50M R9 0 G55 C11 Metastasis
1Dist: 5.26cm Dist: 4.36cm
Miscellaneous: Myelolipoma, lipoma, cyst, abscess hematoma,
FIGURE 13-5 Ultrasonographic image (dorsal plane) of a large pheochromocy- or granuloma
toma in a 13-year-old, spayed female Standard Schnauzer. The dog was ad-
mitted to the hospital as an emergency because of sudden onset of abdominal ACTH, Adrenocorticotropic hormone.
pain. Ultrasonographic evaluation of the abdomen revealed a large heterogenous
mass with irregular margins (maximum diameter of 5.3 cm) in the area of the
left adrenal gland. However, there was no evidence of tumor rupture or hemor- adrenal gland looks similar to a comma. The phrenicoabdominal
rhage. Because transducer pressure in the area of the mass aggravated abdomi- vein bisects the ventral surface of each gland and may serve as
nal pain, further evaluation by computed tomography (CT) was performed (see a marker (i.e., to differentiate the adrenal gland from a lymph
Fig. 13-7). The mass was confirmed to be a pheochromocytoma by histopathology node, which may look alike). Occasionally, a thin hyperechoic
after successful adrenalectomy. (Courtesy of Dr. Matthias Dennler and Prof. line, which is considered to be the corticomedullary junction,
Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty, University of can be seen. The adrenal glands are usually evaluated with 7.5
Zurich, Zurich, Switzerland.) to 10.0 MHz transducers. There are a number of techniques
for locating the adrenal glands either in dorsal or lateral recum-
bency, which is mainly a question of personal preference.
associated with disease. This is due to the fact that nowadays most Pheochromocytomas may present as nodules (focal increase in
sick animals undergo ultrasonography at some point during the thickness with normal global shape of the adrenal gland) or as
work-up; today, most sonographers are able to visualize the adrenal a mass (diffuse increase in thickness and/or length with distor-
glands, and the high-quality equipment allows detection of even tion of normal shape) (Besso et al, 1997). They may range in
small lesions. Finding an adrenal mass can create a diagnostic chal- size between a few millimeters to more than 10 centimeters in
lenge due to the many differential diagnosis (see Incidental Discov- diameter. The smallest pheochromocytoma seen by the author
ered Adrenal Mass (Incidentaloma) later; Box 13-5). was 2 mm in diameter in a dog with recurrent diarrhea. Echo-
The normal adrenal glands are hypoechoic to the surround- genicity is highly variable; nodules and masses may be hypo-,
ing fat. The left adrenal gland resembles a dumbbell; the right iso-, or hyperechoic (compared to the kidney); and echogenicity
may be homo- or heterogenous. Masses may have a multicystic

or multilobular architecture. Anechoic, non-far enhancing areas
may represent foci of necrosis and hemorrhage. No pattern of
echogenicity or architecture is specific for pheochromocytomas,
and other adrenal masses (e.g., cortisol-producing tumors) may
look alike (Besso etal, 1997; Rosenstein, 2000). The only differ-
ence is that mineralization is rare in pheochromocytoma and is
relatively common in cortisol-producing tumors. However, this
fact is not helpful to differentiate between the two tumor types
in an individual dog.
Ultrasonography is also helpful to detect metastasis into abdom-
inal organs and local invasion into surrounding structures, such as
veins and kidneys. Tumor thrombus is a term for a mass formed
by the extension of a nonvascular tumor into a blood vessel. In L R
dogs with pheochromocytoma, tumor thrombi are common
and may affect any of the surrounding vessels. Most commonly,
tumor thrombi involve the caudal vena cava, which has been
reported to occur in up to 56% of cases. They may originate from
thrombi that first invade the phrenicoabdominal vein and then
extend further into the vena cava. Tumor thrombi confined to the
phrenicoabdominal vein may represent early stages of thrombus FIGURE 13-7Transverse computed tomography (CT) image of the adrenal
formation (Kyles etal, 2003). Invasion of the vena cava has been tumor in the equilibrium phase after intravenous (IV) administration of iodinated
seen more often with right-sided pheochromocytoma; however, contrast medium in the 13-year-old Standard Schnauzer (see Fig. 13-5). The left
they also occur with left-sided pheochromocytoma. By means of adrenal gland is markedly enlarged and demonstrates heterogenous, moderate
ultrasonography (including Doppler) it may be difficult to dif- contrast enhancement (arrows). The irregular defined, large area between left
ferentiate compression of a vessel from vascular invasion (tumor adrenal and kidney without contrast enhancement was interpreted as hemor-
thrombus) and a blood clot (true thrombus). In a study on 40 rhage from the tumor (arrowheads). Adrenalectomy confirmed the CT findings,
dogs with various adrenal tumors, abdominal ultrasonography and the tumor was classified as pheochromocytoma by histopathology. This case
had a sensitivity of 80% and specificity of 90% for the diagnosis of nicely demonstrates the superior performance of CT compared to ultrasonogra-
a thrombus in the vena cava (Kyles etal, 2003). Due to the small phy with regard to a more precise and complete evaluation of tumor size, shape,
size of the vessel, detection of thrombi in the phrenicoabdominal and architecture. CT is also superior to detect hemorrhagein particular if the
vein is generally difficult. The question on a potential correlation amount of blood is only small to moderate. (Courtesy of Dr. Matthias Dennler and
between tumor size and invasiveness has not been addressed in a Prof. Patrick Kircher, Division of Diagnostic Imaging, Vetsuisse Faculty, University
large number of dogs. It is, however, likely, that invasion is rare as of Zurich, Zurich, Switzerland.)
long as the pheochromocytoma is small (maximum diameter less
than 2 cm).
Most pheochromocytomas are unilateral; in this case, the
contralateral adrenal has a normal shape and size. However,
Cran Caud
bilateral pheochromocytoma may occur, and pheochromo-
cytoma may also coexist with other types of nodule/mass in
the contralateral adrenal gland. In those cases, interpretation
of ultrasonographic (and clinical) findings is particularly dif-
ficult. The biggest challenge often is to differentiate between
a cortisol-producing adrenal tumor and a pheochromocytoma.
Unfortunately, this is not possible by means of ultrasonogra-
phy. In theory, the contralateral gland of a cortisol-producing
mass should be small due to atrophy, whereas it is normal in
the case of a pheochromocytoma. However, the atrophy of the
contralateral gland may not be apparent ultrasonographically
(Hoerauf and Reusch, 1999).
Computed Tomography and Magnetic Resonance Imaging
CT has several advantages over ultrasonography. It may be
particularly useful in patients where the adrenal gland is dif- FIGURE 13-8Sagittal reconstruction of the computed tomography (CT) angi-
ficult to visualize (e.g., in large breed or obese dogs) (Morandi, ography of the 11-year-old Jack Russell Terrier shown in Fig. 13-6 in the venous
2011). It also allows a more precise and complete evaluation phase after intravenous (IV) administration of iodinated contrast medium. The
of tumor size, shape, and architecture. Most importantly, tumor thrombus originated from a pheochromocytoma in the right adrenal gland
contrast-enhanced CT is superior to ultrasonography to detect and expanded into the lumen of the caudal vena cava. CT is superior to ultra-
vascular invasion (Figs. 13-7 and 13-8). In many cases, it sonography to detect vascular invasion of an adrenal tumor and also enables a
enables reliable differentiation between vascular invasion and precise determination of the exact extent of the thrombus. The arrows point to
mural compression of veins from the tumor, and also between the tumor and the arrowheads show the tumor invasion into caudal vena cava.
a tumor thrombus and a blood clot. On CT, pheochromocy- (Courtesy of Dr. Matthias Dennler and Prof. Patrick Kircher, Division of Diagnostic
tomas appear as soft-tissue masses in the mid-dorsal abdomen; Imaging, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.)
|
further findings include irregular margins, heterogenous a mass has been identified by the latter. It is now well accepted in
contrast-enhancement with regions of highly vascular paren- humans, however, that the presence of a pheochromocytoma/para-
chyma, and foci of low attenuation (Rosenstein, 2000). In one ganglioma has to be proven by biochemical tests first. The purpose
study, vascular invasion into the phrenicoabdominal vein, vena of functional imaging is to localize the primary tumor, to search for
cava, and renal vein was correctly identified in 11 of 12 cases. multiple primary tumors (which often occur in some genetic dis-
Invasion into the phrenicoabdominal vein was missed in only orders in humans), and to search for metastasis. The isotope most
one case, which was thought to be due to relatively thick image often used is 123iodine-metaiodobenzylguanidine (123I-MIBG).
collimation. Mural compression was also correctly differenti- 123I-MIBG is a norepinephrine analog that localizes first to presyn-
ated from vascular invasion. The sensitivity and specificity of aptic adrenergic nerves and sympathomedullary tissue and then
contrast-enhanced CT for vascular invasion compared to sur- into cytoplasmic storage vesicles. Its uptake is proportional to the
gery or pathology was 92% and 100%, respectively. CT also number of neurosecretory granules within the tumor (Leung etal,
correctly identified invasion into hypaxial and epaxial muscu- 2013). 123I-MIBG SPECT is preferred over 123I-MIBG scintigra-
lature (Schultz etal, 2009). phy due to higher sensitivity. Sensitivity and specificity have been
In humans, it is known that ionic (high osmolar) contrast reported to be 77% to 90% and 95% to 100% respectively (Leung
media used for contrast-enhanced CT may stimulate catechol- etal, 2013). Combining SPECT scanning with CT, which is now
amine release from a pheochromocytoma and may induce a possible on hybrid SPECT/CT machines, has the advantage of
hypertensive crisis. Non-ionic (low osmolar) contrast media simultaneous delivery of morphological and functional data and
do not have this side effect and are therefore considered to be has enhanced sensitivity (Fitzgerald, 2011; Timmers etal, 2012;
much safer (Baid etal, 2009; Chew, 2010). Although there are Leung etal, 2013). Because the sensitivity and resolution of PET
no reports on this side effect in dogs, it seems appropriate to use is superior to SPECT, PET imaging has grown rapidly together
non-ionic contrast media. with the development of new tracers (e.g., 18F-FDA, 18F-DOPA,
Magnetic resonance imaging (MRI) may be superior to CT to and 18F-FDG). Similar to SPECT/CT, PET is combined with CT
ascertain vascular invasion due to superior resolution and con- to produce very sensitive and accurate three-dimensional images
trast (Gavin and Holmes, 2009). It may also be more accurate (Fitzgerald, 2011; Timmers et al, 2012). Functional imaging is
to determine the exact extent of a tumor thrombus in the vena considered to be a very promising tool in human medicine, and
cava, as has been demonstrated in humans (Goldfarb etal, 1990; further development in this area will certainly allow an even more
Rosenstein, 2000). However, availability of MRI is currently more exact tumor characterization.
limited than that of CT; other disadvantages are longer scanning In dogs, knowledge on functional imaging is scarce. 123I-MIBG
time and higher costs. scintigraphy has been successfully used in one dog to demonstrate
For appropriate surgical planning (e.g., decision between mid- an area of focal intense uptake in the area of the right adrenal
line coeliotomy or laparoscopy) knowledge on invasion into vas- gland. After surgical excision, the mass was confirmed to be a
culature is important. Invasion into other tissue, such as hypaxial pheochromocytoma (Berry et al, 1993). PET scanning with
and epaxial musculature, has a profound impact on the feasibility 18F-fluorobenzylguanidine (18F-PFBG) has been investigated in
of tumor excision. Therefore, contrast-enhanced CT or MRI prior three dogs with adrenal masses. PET images showed increased
to surgery is indicated in any patient in whom invasiveness of the uptake in the right adrenal gland in two dogs in which histology
tumor is a concern. confirmed pheochromocytoma. In the third dog, no increased
In human medicine, attempts have been made to differenti- uptake was found, and exploratory laparotomy confirmed the
ate between the various tumor types of the adrenal gland and also absence of an adrenal mass (Berry et al, 2002). As in humans,
to differentiate primary adrenal tumors from metastasis. Findings functional imaging in dogs may have great potential in the future
previously considered to be characteristic included the following: for characterization of adrenal masses. Currently, costs and avail-
lower unenhanced CT density in adenomas compared to malignant ability are limiting factors.
tumors, very high contrast-enhanced CT density in pheochromo-
cytoma, slower wash-out of contrast in malignant tumors includ- Percutaneous Fine-Needle Aspiration and Biopsy
ing pheochromocytoma, and high signal intensity on T2-weighted of the Adrenal Glands
MRI images, a feature described as light-bulb signs in pheochro-
mocytoma. However, recent studies revealed large overlap between In human medicine, the question of whether adrenal masses
pheochromocytoma and other adrenal tumors, and therefore, CT should be biopsied has been discussed in a large number of pub-
and MRI cannot definitively identify an adrenal mass as a pheochro- lications. According to the North American Neuroendocrine
mocytoma (Blake etal, 2010; Fitzgerald, 2011; Leung etal, 2013). Tumor Society (NANETS) guidelines, diagnosis of pheochro-
In dogs, there are no studies so far on CT and MRI character- mocytoma (and paraganglioma) relies on biochemical evidence
istics of the various adrenal tumors. It is likely, however, that the of catecholamine production by the tumor. Biochemical test-
situation is similar to humans (i.e., diagnosis of a pheochromocy- ing should be performed in symptomatic patients, patients with
toma is most likely not possible by means of those two modalities). known hereditary risk for developing pheochromocytoma/
paraganglioma, and patients with an incidentaloma (Chen etal,
Functional Medical Imaging 2010). Those guidelines do not even mention biopsy as a diag-
Functional medical imaging provides information about the func- nostic tool. Other guidelines specifically state that fine-needle
tional characteristics of a tumor. Nuclear medicine scanning tech- aspiration of an incidentaloma is contraindicated if a pheo-
niques used for functional imaging are scintigraphy, single photon chromocytoma has not been excluded by biochemical testing
emission computed tomography (SPECT) and positron emission (National Institutes of Health, 2002; Terzolo etal, 2011). A high
tomography (PET). These modalities involve the application of rate of biopsy related complications including death have been
radiotracers, which are taken up by the tumor cells (Timmers etal, reported in human patients with pheochromocytoma. A study
2012). In human medicine, functional imaging is considered com- from the Mayo Clinic revealed problems in 70% of patients,
plimentary to anatomic imaging (CT, MRI) and usually used after including hematoma, severe hypertension, severe pain, delay in
surgical treatment, error in diagnosis, and difficulty in resecting period; rarely measurement is performed in spot urine samples,
the mass during surgery due to inflammation and retroperitoneal relating the concentrations to urinary creatinine.
fixation (Vanderveen etal, 2009). Reference laboratories usually perform analyses of catecholamines
In veterinary medicine, fine-needle aspiration of pheochromo- and metanephrines either by means of high-performance liquid
cytomas has been reported in a few dogs and a cat (Chun etal, chromatography with electrochemical detection (HPLC-ECD) or
1997; Rosenstein, 2000; Spall etal, 2011). In most cases, cyto- tandem mass spectroscopy (LC/MS/MS).
logical evaluation suggested the tumor to be of endocrine or neu- Understanding the biochemical tests also requires some knowl-
roendocrine origin. However, large studies would be needed to edge on the pathways for synthesis and metabolism of catechol-
evaluate the diagnostic accuracy of fine-needle aspiration of adre- amines. Comprehensive reviews of this complex matter have been
nal masses. So far, no complications have been reported. There published by Eisenhofer, et al. (2001b; 2008b), Pacak (2011),
is, however, no reason to believe, that complication rates would and others. The reader is also referred to the Physiology and
be less in dogs and cats than in humans. Therefore, before fine- Pathophysiology section at the beginning of this chapter and to
needle aspiration or core biopsy of adrenal masses in dogs and Figs. 13-1 and 13-2.
cats are performed, the risks should be weighed carefully against In humans, most pheochromocytomas are hormonally active
benefits. and produce catecholamines; however, there is large variation
depending on the expression of the biosynthetic pathway and
Biochemical Testing differences in the secretory processes (Eisenhofer et al, 2011).
The activities of the enzymes tyrosine hydroxylase, L-amino acid
Biochemical testing has been performed in humans for many decarboxylase and dopamine -hydroxylase are usually very high
years and various tests have been developed. In dogs, the same in pheochromocytomas, which is the basis of the overproduction
tests are used; however, their evaluation has only recently been of catecholamines (Pacak, 2011). Most human pheochromocyto-
initiated. Some important details of the tests routinely used in mas produce more norepinephrine than epinephrine, and many
humans today are discussed in the following section. produce both catecholamines. A few tumors produce predomi-
nantly epinephrine, and very rarely, pheochromocytomas only
Human Medicine produce dopamine.
Catecholamines and Metanephrines. In human medicine, there Pheochromocytomas (like normal chromaffin cells) express
is consensus that all patients with suspected pheochromocytoma COMT, which is responsible for catecholamine metabolism. It
should undergo biochemical testing and that the diagnosis relies converts norepinephrine to normetanephrine and epinephrine
on the demonstration of excessive production of catecholamines to metanephrine. Within the chromaffin cells, catecholamines
(Lenders etal, 2005; Pacak etal, 2007; Chen etal, 2010). Many permanently leak from storage vesicles into the cytoplasm where
products of the catecholamine pathway have been assessed as they are continuously metabolized to metanephrines. The release
potential markers for the disease, including urine catecholamines, of the parent catecholamines into the circulation is highly vari-
urine metanephrines, urine vanillylmandelic acid (VMA), plasma able, and it often occurs only intermittently or at low rates. In
catecholamines, and plasma metanephrines. contrast, metanephrines are continuously released into the circula-
In order to understand the various tests that are offered by the tion (Eisenhofer etal, 2004a; 2008b; Lenders etal, 2005; Pacak,
laboratories, knowledge of the current terminology is essential. 2011; Fig. 13-9). In humans with pheochromocytoma, more than
The term catecholamines includes dopamine, norepinephrine, and 94% of plasma metanephrines are derived from the metabolism
epinephrine. The term metanephrines in the plural form refers to
the sum of normetanephrine and metanephrine, which are the
major metabolites of norepinephrine and epinephrine. The term Tyrosine L-Dopa
does not include methoxytyramine, the metabolite of dopamine.
Previously, measuring techniques were only able to analyze the
Dopamine
two metabolites together (i.e., measurement of metanephrines).
Today, high-performance liquid chromatography (HPLC) assays
allow separate analysis of normetanephrine and metanephrine,
which is termed fractionated metanephrines (Eisenhofer, 2001).
Catecholamines as well as their metabolites (except VMA) are
converted to sulfate conjugates, mainly in gastrointestinal tissues.
The term total is used to describe the sum of free (unconjugated)
and conjugated parameters (Eisenhofer, 2001; Eisenhofer et al, Norepinephrine Normetanephrine
2001; 2008b; Grouzmann etal, 2010).
In plasma and urine, sulfate-conjugated metanephrines are
Epinephrine Metanephrine
present in much higher concentrations than the free forms.
Total metanephrines are determined after samples are subjected
to a deconjugation step so that both previously conjugated and
free forms are measured. This is sometimes termed deconjugated
metanephrines, which largely reflect the sulfate-conjugated
forms, due to their abundance. The measurement of total meta-
nephrines is analytically easier than the measurement of the free
forms (Grouzmann etal, 2010). In urine, total (deconjugated) FIGURE 13-9Main pathways of catecholamine synthesis, metabolism, and
metanephrines are measured; in plasma, measurement of both secretion in pheochromocytoma. (Graph redrawn and modified from Pacak, K:
free and total as separate tests is available. The standard procedure Pheochromocytoma: a catecholamine and oxidative stress disorder, Endocr Regul
for the urine test in humans is collecting urine over a 24-hour 45:65, 2011.)
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of catecholamines by COMT within the tumor and not by the An emerging challenge in human medicine is the detection
action of extra-adrenal COMT on catecholamines released into of small pheochromocytomas, which are increasingly found due
the circulation (Eisenhofer etal, 2004a). Therefore, there is con- to the frequent use of high-resolution imaging techniques. Bio-
sensus in human medicine that measurement of metanephrines chemical confirmation, however, may be difficult, because the
is superior to measurement of catecholamines for the diagnosis levels of the biochemical markers are generally lower in small
of pheochromocytoma (Pacak et al, 2007; Chen et al, 2010). than in large tumors. In a recent study, 50% of humans with
The relationship between synthesis, metabolism, and secretion small pheochromocytomas had only modestly elevated or even
of catecholamines and metanephrines may explain why there is normal test results (Yu etal, 2012).
a strong correlation between tumor size and urinary output of
metanephrines, whereas the correlation between tumor size and Other Tests
catecholamines is weak (Eisenhofer etal, 2005a). Today, the tests VMA is a catecholamine metabolite that is produced in the liver
with the highest sensitivity for the diagnosis of pheochromocy- and excreted in the urine. VMA in 24-hour urine has previously
toma in humans are measurements of fractionated metanephrines been an established biochemical test for pheochromocytoma;
in 24-hour urine samples and fractionated free metanephrines in however, its sensitivity has been shown to be low (64%; Lenders
plasma (Fitzgerald, 2011). There is some controversy as to which etal, 2005). Although the test is still offered by various laboratories,
test (urine or plasma) has the higher diagnostic accuracy. Several it is becoming less important.
authors have demonstrated higher sensitivity of plasma-free meta- CGA is a member of granins, which are a family of acid proteins
nephrines compared to 24-hour urine metanephrines (Lenders present in secretory granules of many endocrine and non-endocrine
etal, 2002; Kudva etal, 2003; Unger etal, 2006). Specificity has cells. In the adrenal medulla, CGA is stored with catecholamines
been claimed to be lower for the plasma test; however, the vari- in storage vesicles and is also co-secreted with them. It is secreted
ous studies are difficult to compare because their design differs. by various tumors, including pheochromocytoma, parathyroid
One recent study showed that the differences are in fact minor. adenoma, medullary thyroid carcinoma (MTC), carcinoids, pan-
Sensitivity of plasma-free metanephrines was 96% and for urinary creatic islet-cell tumors, and aortic-body tumors (Blek etal, 2008).
metanephrines 95%; specificity was 89% and 86%, respectively CGA is elevated in most patients with pheochromocytomas, and
(Grouzmann etal, 2010). The slightly superior performance of the the levels correlate with the tumor mass. The parameter, however,
plasma test may be explained by the fact, that the free metaneph- may also be elevated in other neuroendocrine and various non-
rines are direct products of the pheochromocytoma, whereas the endocrine diseases, as well as in renal failure, because of its excre-
urinary metanephrines largely reflect sulphate-conjugated metabo- tion by the kidney (Blek etal, 2008; Fitzgerald, 2011).
lites, which are formed in the gastrointestinal tissue. Plasma-free The clonidine suppression test is used as an aid to distinguish
normetanephrine was found to be the single best test, followed by between true and false positive measurement of metanephrines.
urinary normetanephrine, whereas plasma and urinary metaneph- Clonidine is a centrally-acting 2 adrenergic receptor agonist that
rine had lower diagnostic accuracy (Unger etal, 2006). The differ- suppresses the release of norepinephrine from sympathetic neu-
ence is most likely due to the fact that most pheochromocytomas rons but not its release from a pheochromocytoma. The test is
produce more norepinephrine than epinephrine. So far, there are performed by measuring plasma normetanephrine (and possibly
no official guidelines in humans as to which test (plasma or urine) plasma norepinephrine) before and 3 hours after the oral appli-
should be used preferentially. The recommendations from the cation of 0.3 mg clonidine. A positive response is defined as a
First International Symposium on Pheochromocytoma state that decrease in normetanephrine of less than 40%, or a decrease in
the initial testing for pheochromocytoma must include measure- norepinephrine of less than 50%. The test has a high diagnos-
ment of fractionated metanephrines in plasma, urine, or both, as tic accuracy, although false positive and false negative results may
available (Pacak etal, 2007). The same guidelines also address the occur (Eisenhofer et al, 2003). Clonidine may cause marked
problem of false-positive test results and advocate the use of a so- hypotension, and the test should only be performed under close
called continuous approach to test interpretation (e.g., the higher supervision (Mackenzie and Brown, 2011).
the test result, the more likely a pheochromocytoma is present). In order to identify the rare dopamine-secreting tumors, it has
An increase of plasma or urinary normetanephrine by more than been recommended to include the measurement of methoxy-
fourfold above the upper reference interval is associated with a tyramine (metabolite of dopamine) in the fractionated metaneph-
close to 100% probability of the presence of a pheochromocytoma rine assay (Barron, 2010).
(Pacak etal, 2007).
Many factors may lead to false positive results, including Dogs and Cats
drugs (e.g., phenoxybenzamine, -blocker), certain foods and Catecholamines and Metanephrines. Until recently, biochemi-
beverages, inadequate sampling conditions, exercise, emotional cal testing for pheochromocytoma had only infrequently been
stress, and stress of other diseases. Although measurements of performed in dogs due to low medical awareness of pheochromo-
metanephrines are superior to measurements of catecholamines, cytoma, limited availability of techniques, lack of reference ranges,
the latter may still be of some use. Human patients with pheo- and problems with 24-hour urine collection with regard to the
chromocytoma have larger increases in metanephrines than in urine test. During the last few years, a small number of studies
catecholamines, whereas patients with false-positive results due has investigated urinary and/or plasma catecholamines and meta-
to sympatho-adrenal activation usually have larger increases in nephrines (Kook etal, 2007; 2010; Cameron et al, 2010; Quante
catecholamines than in metanephrines (Eisenhofer etal, 2003). et al, 2010; Salesov etal, 2012; Gostelow etal, 2013). Our own
In patients with renal failure, total metanephrines are often studies initially focused on the measurement of the parameters in
severely elevated due to decreased renal elimination. Free meta- urine; more recently we started to compare the diagnostic perfor-
nephrines are less affected and therefore more suitable markers mance of the urine test with the plasma test. Due to the fact that
for pheochromocytoma in cases of renal failure (Eisenhofer etal, 24-hour urine collection is hardly feasible in client-owned dogs,
2005b). As a reminder, total metanephrines are measured in the the urine test was established by measuring the parameters in
urinary test. single-voided samples, and their concentrations were expressed as
ratios to the creatinine concentrations in the same urine samples ratios were significantly higher in samples taken in the hospital
(Kook etal, 2007). The objective of the first study was to evalu- compared to those taken 7 days after discharge. Urinary normeta-
ate if veterinary care and the stress of a hospital stay would lead nephrine ratios, however, did not differ between those two time
to an increase of catecholamines and metanephrines, which then points (Kook etal, 2007; Fig. 13-10).
would require urine sampling at home. Such an increase is known The question of when to take the urine samples is of importance
for the urinary corticoid-to-creatinine ratio (van Vonderen etal, mainly because of two reasons. First, urine has to be acidified to a
1998). Interestingly, in staff-owned healthy dogs (who were famil- pH less than or equal to 2 after sampling and chilled until analy-
iar with the environment), no differences were found between sis; those requirements may be difficult to fulfill for some own-
urine samples taken in the hospital or at home. In contrast, in ers. Second, in dogs with a high suspicion of pheochromocytoma,
healthy client-owned dogs (who were unfamiliar with the hospi- an immediate start of treatment with phenoxybenzamine (an
tal) epinephrine, norepinephrine, and metanephrine-to-creatinine adrenergic antagonist) may be desirable. However, it is known
*
*
* *
Norepinephrine-to-creatinine ratio
25
20
15
10
0
t7 t0 t1 t7
A Time points of urine collection
* * *
Normetanephrine-to-creatinine ratio
150
100
50
0
t7 t0 t1 t7
B Time points of urine collection
FIGURE 13-10 Urinary catecholamines (norepinephrine [A], epinephrine [C]) and metanephrines (normetaneph-
rine [B], metanephrine [D]) to creatinine ratios in healthy client-owned dogs (squares) and staff-owned dogs
(circles). Client-owned dogs had never been to the hospital before, whereas the staff-owned dogs were familiar
with the environment. Urine was sampled at various time points: t7 (7 days before hospital visit), t0 (hospital
visit), t1 and t7 (1 and 7 days after hospital visit). (Adopted and amended from Kook PH, etal.: Urinary cat-
echolamines and metanephrines to creatinine ratios in healthy dogs at home and in a hospital environment and
in 2 dogs with pheochromocytoma, J Vet Intern Med 21:388, 2007, with permission.) *, Significant difference;
horizontal line, median values.
|
*
* *
20
Epinephrine-to-creatinine ratio
15
10
0
t7 t0 t1 t7
C Time points of urine collection
*
*
*
* * *
300
Metanephrine-to-creatinine ratio
200
100
0
t7 t0 t1 t7
D Time points of urine collection
FIGURE 13-10, contd. See legend on previous page.
from humans that phenoxybenzamine may lead to false positive with pheochromocytoma. Interestingly, urinary normetanephrine
tests results, and it should be given only after samples for bio- ratios were the highest in two dogs with bilateral pheochromo-
chemical testing have been taken. Sending a dog home for a few cytomas (Kook et al, 2010). The superior performance of uri-
days before sampling would delay this treatment. The issue of time nary normetanephrine over urinary catecholamines and urinary
of urine sampling was therefore explored once more in a group metanephrine was also demonstrated in further studies (Quante
of dogs with hyperadrenocorticism (one of the most important etal, 2010; Salesov etal, 2012). As discussed earlier, this finding
differential diagnosis for pheochromocytoma). No difference was is similar to the situation in humans. It is very likely, that canine
found in any of the parameters between samples taken in the hos- pheochromocytomas (as human pheochromocytomas) produce
pital and samples taken at home 1 week after discharge (Quante predominantly norepinephrine, which is then metabolized into
etal, 2010). On the basis of this study and the fact that the dif- normetanephrine. The superior performance of the metabolite
ferences in the previous study were relatively small, we concluded over the parent catecholamine has been extensively shown in
that urine samples may be taken in the hospital, which became the humans (see the earlier paragraph about humans and Fig. 13-9).
standard procedure in our institution. Most of the urine samples Hyperadrenocorticism is one of the most important differential
in the following studies were taken in the hospital. It was then diagnoses for pheochromocytoma. Both diseases may present with
shown that dogs with pheochromocytoma had significantly higher similar clinical signs, such as weakness, tachypnea, panting, poly-
urinary norepinephrine, epinephrine, and normetanephrine ratios uria/polydipsia, and adrenal abnormalities detected by ultrasonog-
compared to healthy dogs. Urinary normetanephrine ratio dis- raphy. It is therefore important that biochemical tests established
criminated best with no overlap between healthy dogs and dogs for the diagnosis of pheochromocytoma enable differentiation
P0.01
P0.01 P0.001
P0.001
P0.05
100 1000
90 900
80 800
Normetanephrine-to-creatinine
Norepinephrine-to-creatinine
70 700
60 600
50 500
40 400
30 300
20 200
10 100
0 0
A Healthy HAC PHEO B Healthy HAC PHEO
P0.001
P0.05
75 375
70 350
65 325
60 300
55 Metanephrine-to-creatinine 275
Epinephrine-to-creatinine
50 250
45 225
40 200
FIGURE 13-11Urinary catecholamines
35 175
(norepinephrine [A], epinephrine [C]) and
metanephrines (normetanephrine [B], meta- 30 150
nephrine [D]) to creatinine ratios in healthy 25 125
dogs, dogs with hyperadrenocorticism (HAC), 20 100
and dogs with pheochromocytoma (PHEO).
15 75
(Modified from Quante S, etal.: Urinary cat-
echolamine and metanephrine to creatinine 10 50
ratios in dogs with hyperadrenocorticism or 5 25
pheochromocytoma, and in healthy dogs, J Vet 0 0
Intern Med 24:1093, 2010, with permission.) C Healthy HAC PHEO D Healthy HAC PHEO
between the two diseases. It was shown, however, that hyperad- of two to four times the upper limit of normal. By working with
renocorticism might be associated with increased catecholamine a cut-off value of four times the upper limit of normal, the prob-
production. Approximately 50% of dogs with hyperadrenocor- ability of a pheochromocytoma is nearly 100% in humans (Pacak
ticism had urinary norepinephrine, epinephrine, and normeta- etal, 2007). The same seems to apply for dogs: A cut-off urinary
nephrine ratios above those of healthy dogs, and the difference normetanephrine ratio of four times the highest level measured
was significant. Although urinary norepinephrine and epineph- in healthy dogs discriminates with no overlap between dogs with
rine did not differ between dogs with hyperadrenocorticism and hyperadrenocorticism and dogs with pheochromocytoma. How-
dogs with pheochromocytoma, urinary normetanephrine ratio ever, the diagnosis of a pheochromocytoma would have been
was the single parameter that was significantly higher in dogs with missed in three of seven dogs with pheochromocytoma. The use of
pheochromocytoma compared to dogs with hyperadrenocorti- lower cut-offs, such as two or three times normal, would increase
cism (Quante etal, 2010). As shown in Fig. 13-11, there was some sensitivity at the expense of specificity, which is a well-known phe-
overlap between the two groups. The problem that test results of nomenon. So far, we have seen urinary normetanephrine ratios
individuals with pheochromocytoma overlap to some extent with above four times normal only in dogs with pheochromocytoma.
those of individuals with other diseases also exists in human medi- Cameron, et al., (2010) found higher levels in a group of criti-
cine. There, it has led to the recommendation to use cut-off values cally ill dogs. The difference from our own results may be in part
|
P0.01 between groups was clearly superior for normetanephrine com-

pared to metanephrine. There was some difference between the
P0.001
urine and the plasma test. Unlike in the study of Gostelow, etal.,
P0.001 (2013), plasma-free normetanephrine levels overlapped to some
degree between dogs with pheochromocytoma and dogs with
200
hyperadrenocorticism or non-adrenal disease. In contrast, no
overlap was found with regard to the urinary normetanephrine
150
ratio (Fig. 13-13). The absence of overlap in the urine test is,
100 however, considered just to be a matter of coincidence, because
we have found overlap in previous series of dogs. Much larger
Normetanephrine concentration
numbers of dogs with pheochromocytoma have to be evaluated

60 before a more definitive statement about the performance of
50 the urine and plasma test can be made. It is likely, however,
40 that the differences will be small, as in human medicine. At the
30 moment, the veterinarian should choose between urine and
20 plasma test according to availability of techniques and availabil-
10
ity of species-specific reference ranges. Some laboratories still
only measure the parent catecholamines, which are of minor
8 importance for the diagnosis of canine pheochromocytoma.
Diagnosis should be based on metanephrines, the metabolites
6
of catecholamines, and it is highly recommended that normeta-
4
nephrine and metanephrine are measured as separate parameters
2 (in urine or plasma). Sampling conditions are critical, and the
0 user of any of the tests should discuss those with the laboratory
Healthy Non-adrenal Adrenal PHEO
beforehand. The protocols for urine sampling usually include
FIGURE 13-12 Plasma-free normetanephrine concentrations in healthy dogs, acidification of urine until pH is less than or equal to 2 and
dogs with non-adrenal diseases, dogs with adrenocortical tumors, and dogs with storage should be at 20o C; the protocols for plasma sampling
pheochromocytoma (PHEO). The horizontal lines represent the median values. include sampling into chilled tubes, immediate centrifugation,
(Adopted from Gostelow R, etal.: Plasma-free metanephrine and free normeta- and storage at 80 C. The shipping of both urine and plasma
nephrine measurement for the diagnosis of pheochromocytoma in dogs, J Vet samples has to be on dry ice.
Intern Med 27:83, 2013, with permission.) So far, only one study investigated metanephrines in cats.
Plasma-free normetanephrine was found to be markedly higher
due to methodological differences; another explanation would be in the one cat with suspected pheochromocytoma compared to
that the severity of illness in the dogs studied by Cameron, etal., healthy cats and cats with non-adrenal diseases. Plasma-free meta-
(2010) was higher than in our studies. In our hospital, we first nephrine was not different (Wimpole etal, 2010).
stabilize patients as much as possible before taking samples for the
biochemical tests. Other Tests
The plasma test (i.e., plasma-free normetanephrine and plasma- VMA, CGA and the clonidine test (see Other Tests earlier)
free metanephrine) was recently investigated by Gostelow, et al. have not been evaluated in dogs. Dopamine and its metabolite,
(2013). The two parameters were measured in healthy dogs, dogs methoxytyramine, have been measured so far in a small number
with non-adrenal disease, dogs with adrenocortical tumors, and of dogs with pheochromocytoma in our hospital; however, iso-
dogs with pheochromocytoma. Plasma-free normetanephrine was lated increases were not found. It is therefore not known whether
superior to plasma-free metanephrine, and it was significantly dopamine-secreting pheochromocytomas exist in dogs.
higher in dogs with pheochromocytoma compared to all other Measurement of serum inhibin concentration has recently been
groups with nearly no overlap (Fig. 13-12). Another finding was described as a valuable parameter to differentiate pheochromocyto-
that dogs have much higher free metanephrine and free normeta- mas from adrenocortical tumors in neutered dogs. Inhibin is a gly-
nephrine concentrations than humans. It is therefore important coprotein that is mainly synthesized in the gonads; however, it may
to use species-specific reference ranges (Gostelow etal, 2013). The also derive from the adrenal glands. In healthy neutered dogs and
same, of course, is true for the urinary parameters. With regard to in neutered dogs with pheochromocytoma, serum inhibin concen-
the latter, the laboratories usually provide human reference ranges trations were shown to be very low (i.e., below the detection limit
for parameters measured in 24-hour urine samples, which have to of the assay). Dogs with adrenocortical tumors had significantly
be ignored. higher inhibin concentrations. Therefore, an undetectable inhibin
In human medicine, the question of which of the tests, urine concentration in a neutered dog with an adrenal tumor is highly
or plasma, performs best is controversial. We recently compared supportive of a pheochromocytoma (Brmel etal, 2013).
the two tests in healthy dogs and dogs with pheochromocytoma,
hyperadrenocorticism, and non-adrenal diseases.
Establishing a Diagnosis
As expected from the previous studies, catecholamines (nor-
epinephrine and epinephrine) overlapped to a large degree The diagnosis of a pheochromocytoma is challenging, and a
between the groups and were of little diagnostic usefulness. This high index of suspicion is required. Most pheochromocytomas
was true for the urine as well as for the plasma test. The two are overlooked due to low medical awareness. Dogs with pheo-
metabolites, normetanephrine and metanephrine, were signifi- chromocytoma may present with a large variety of clinical signs.
cantly higher in dogs with pheochromocytoma than in the other The most frequent are weakness, lethargy, tachypnea or pant-
three groups in both urine and plasma. Again, the discrimination ing, and acute or episodic collapse. Hypertension may or may
*
* * *
* * *
* * * * * *
700
12,500 250
200
25 650
12,000 100
3500
3000
P-Total normetanephrine (nmol/L)

P-Free normetanephrine (nmol/L)
50
U-Normetanephrine:creatinine
2500 20 30
2000
1200 25
1000 15
20
800
10 15
600
10
400
5
200 5
0 0 0
Healthy PHEO HAC NAD Healthy PHEO HAC NAD Healthy PHEO HAC NAD
FIGURE 13-13Comparison of urinary normetanephrine-to-creatinine ratio, plasma-free and plasma-total
normetanephrine concentrations in healthy dogs, dogs with pheochromocytoma (PHEO), hyperadrenocorticism
(HAC), and non-adrenal diseases (NAD). Urinary normetanephrine-to-creatinine ratio showed less overlap than
plasma-free or plasma-total normetanephrine in dogs with pheochromocytoma compared to the other groups.
Plasma-total normetanephrine, which was measured for the first time in this study, performed in a similar way
to plasma-free normetanephrine and has therefore no advantage (Parts of the data are from Salesov E, etal.:
Urinary and plasma catecholamine and metanephrine in dogs with pheochromocytoma, hyperadrenocorticism and
in healthy dogs, J Vet Intern Med 26:1524 (abstract), 2012.) *, Significant difference; horizontal line, median value;
P-Free, plasma-free, P-Total, plasma-total; U, urinary.
not be present at the time of investigation. It is, however, not pheochromocytoma), hyperadrenocorticism should be ruled out
pathognomonic for pheochromocytoma and is often also seen in first by the appropriate screening tests. There are two points to
dogs with hyperadrenocorticism. The higher the systolic blood consider that demonstrate how difficult a correct approach may
pressure, the more likely a pheochromocytoma is present (e.g., be. First, screening tests for hyperadrenocorticism may be false-
systolic blood pressures > 300 mm Hg so far have only been positive in dogs with other diseases, and we have seen false-positive
seen in dogs with pheochromocytoma). CBC, chemistry pro- results in several of our dogs with pheochromocytoma. Of note,
file, and urinalysis are not helpful due to the lack of consistent both diseases may be present in the same dog, which then poses
abnormalities. It is important to remember that in some dogs an even bigger diagnostic challenge. The second point has so far
with pheochromocytoma, laboratory findings may be similar to only been described in humans with pheochromocytoma, namely
those in dogs with hyperadrenocorticism (e.g., increased ALP, that dexamethasone and ACTH may induce a hypertensive crisis
ALT, and cholesterol and urine specific gravity in the hypo (Rosas etal, 2008, Yi etal, 2010; see Box 13-1). So far, we have
sthenuric or isosthenuric range). Often, a pheochromocytoma is not seen problems after the low-dose dexamethasone test or
only considered after detection of an adrenal mass on abdominal the ACTH stimulation test in dogs with pheochromocytoma.
ultrasonography. Unfortunately, no pattern of echogenicity or However, close monitoring of the patients for approximately
architecture is specific for a pheochromocytoma, and therefore, 12 hours after the tests may be a valuable consideration.
all differential diagnosis for an adrenal mass have to be consid- In dogs in which hyperadrenocorticism has been ruled out
ered (see sections Abdominal Ultrasonography and Incidental or in which results of the screening tests are equivocal, bio-
Discovered Adrenal Mass). Ultrasonography is helpful to deter- chemical testing for pheochromocytoma is the next logical step.
mine the size and invasiveness of the mass. If the degree of the Some laboratories still offer the sole measurement of the par-
latter cannot be determined by ultrasonography (e.g., extent ent catecholamines (norepinephrine and epinephrine); however,
of vascular invasion), evaluation of the mass by CT or MRI their diagnostic accuracy is poor. It is important that the test-
is helpful. However, both modalities require anesthesia, which ing includes measurement of the catecholamine metabolites,
may be associated with hypertensive crisis and/or arrhythmias normetanephrine, and metanephrine. Discrimination between
in dogs with pheochromocytoma. Preferentially, CT/MRI dogs with pheochromocytoma and dogs with other diseases is
should be delayed either until a pheochromocytoma has been better for normetanephrine than for metanephrine. Measure-
ruled out or until a dog with confirmed pheochromocytoma has ment can be performed in urine (as ratio to urinary creatinine)
been pretreated with phenoxybenzamine and/or an experienced or in plasma. The probability of a pheochromocytoma is very
anesthetist is available. high if the urinary normetanephrine ratio or the plasma-free
Cortisol-producing adrenocortical tumors are much more com- normetanephrine concentration is greater than or equal to four
mon than pheochromocytomas. Therefore, in questionable cases times the upper limit of normal. In these patients, the diagno-
(i.e., all findings could be explained by hyperadrenocorticism or sis is straightforward. The major remaining problems are dogs
|
with smaller increases (e.g., two to three times normal). In those given for at least 2 days. Hypertension may become more severe
dogs, a pheochromocytoma may or may not be present. Further with -blockade alone, because 1 mediated vasoconstriction
steps will depend on the clinical situation and owner compli- is unopposed (Lenders et al, 2005; Pacak, 2007). Selective 1
ance. Usually, it is a decision between the search for another blockers (e.g., atenolol) are generally preferred over non-selec-
disease explaining the clinical signs, reevaluation of pheochro- tive -blockers (e.g., propranolol); however, at higher doses 1
mocytoma by biochemical testing after a few weeks, or surgical blockers also block 2 receptors (Fitzgerald, 2011).
removal of the adrenal tumor after a period of treatment with Another option for preoperative preparation of humans with
phenoxybenzamine. pheochromocytoma are calcium-channel blockers. They are
better tolerated than -blockers, but they may be less effective
(Pacak, 2007).
Surgical Treatment
The preoperative targets for humans differ slightly between
Pheochromocytomas should be considered malignant tumors in centers. Blood pressure should decrease to approximately 120 to
dogs. Tumor growth is unpredictable, and the risk of invasion into 130/80 mm Hg, and heart rate should decrease to approximately
vessels (most often into the vena cava) and into surrounding tis- 60 to 70 mm Hg.
sues is high. Adrenalectomy is the treatment of choice and should In dogs, the effect of preoperative treatment on anesthetic
be performed as soon as possible after diagnosis. The exceptions complications, surgical outcome, and survival has so far only
are very old and debilitated dogs, dogs in which the tumor is been investigated in a single study (Herrera etal, 2008). Twenty-
considered to be unresectable due to massive local invasion, and three of 48 dogs (48%) were treated with phenoxybenzamine for
dogs with serious concurrent diseases. It is currently not known a median of 20 days prior to adrenalectomy. The dose ranged
if adrenalectomy will prolong survival in dogs that have already between 0.1 to 2.5 mg/kg b.i.d. (twice a day; median 0.6 mg/
developed metastasis. In the rare case of bilateral pheochromocy- kg b.i.d.). Interestingly, there were no differences in anesthesia
toma, the owner has to be aware that lifelong mineralocorticoid time, surgical time, intraoperative and postoperative hyperten-
and glucocorticoid replacement will be required after bilateral sive and hypotensive episodes, and intraoperative arrhythmia
adrenalectomy. Adrenal cortexsparing surgery may in principle between treated and untreated dogs. However, all six untreated
be possible, however, has so far only been described in humans. dogs with intraoperative arrhythmias died, whereas only one of
Identification of a tumor thrombus in the vena cava is not an seven treated dogs with intraoperative arrhythmias died. The
absolute contraindication for surgery. Removal of tumor thrombi mortality rate was significantly lower in the treated group than
by adrenalectomy and thrombectomy without increased periop- in the untreated group (13% versus 48%). Dogs pretreated with
erative morbidity and mortality is possible. It requires, however, a phenoxybenzamine were six times more likely to survive adre-
surgeon experienced in appropriate techniques (Kyles etal, 2003). nalectomy. The results of the study strongly support the preop-
erative treatment with phenoxybenzamine. It should be realized,
Preoperative Medical Management however, that so far neither the dose nor the duration of preop-
In human medicine, careful consideration is given to the pre- erative treatment required to achieve the best effect have been
operative stabilization of the patient. The main goal is to keep defined.
catecholamine-induced complications during surgery to a mini- We are currently using phenoxybenzamine as a standard prepa-
mum. Complications may be life-threatening and include hyper- ration for adrenalectomy in dogs with pheochromocytoma. Treat-
tensive crisis, arrhythmias, pulmonary edema, and cardiac ischemia ment is performed in dogs with documented hypertension as
(Lenders etal, 2005). The traditional preoperative approach is to well as in dogs that are normotensive at the time of examination.
block the effects of catecholamines for at least 10 to 14 days prior In order to reduce side effects, dose is titrated similar to what is
to surgery in all patients with pheochromocytoma and paragangli- done in human medicine. Our starting dose is 0.25 mg/kg b.i.d.,
oma, including those with apparent normal catecholamine levels which is increased stepwise every 2 to 3 days until a final dose
(Chen etal, 2010). The most commonly used drug is phenoxy- of approximately 1 mg/kg b.i.d. is reached. Surgery is scheduled
benzamine, an oral, non-competitive, -adrenoreceptor blocker approximately 2 weeks after the start of treatment. The last dose
(Pacak, 2007; Fitzgerald, 2011). It is a non-selective blocker (act- of phenoxybenzamine is given in the evening prior to surgery. Ide-
ing on 1 and 2 receptors) that has irreversible and long lasting ally, blood pressure, heart rate, and heart rhythm are monitored
effects until de novo -receptor synthesis. Phenoxybenzamine regularly during the preparation phase, which would allow an
does not block the synthesis of catecholamines (in fact synthesis individualized dose titration. Often, however, dose adjustment is
increases) but blocks -adrenergic response to circulating norepi- done on the basis of owner feedback. If the dog shows signs of
nephrine and epinephrine. It decreases blood pressure, supports hypotension (e.g., lethargy, weakness, syncope) or other adverse
expansion of contracted blood volume, and decreases the fre- effects (e.g., tachycardia, vomiting), the dose should be reduced. It
quency of ventricular arrhythmias. In humans, the dose is usually is possible that by adding a calcium channel blocker (e.g., amlodip-
increased every 2 to 3 days; a dose titration is necessary to reduce ine), a lower dose of phenoxybenzamine would be sufficient, which
side effects, such as postural hypotension, dizziness, syncope, nasal would then improve tolerability. This has not yet been investigated.
congestion, and others (Pacak, 2007). In some human centers 1- In case tachycardia or tachyarrhythmia may occur during the
adrenoreceptor blockers (e.g., doxazosin, prazosin, terazosin, and preoperative period, a -blocker may be added to the treatment
urapidil) are preferred over phenoxybenzamine. They are competi- regimen. A selective 1 antagonist (e.g., atenolol 0.2 to 1.0 mg/kg
tive and short-acting antagonists that may have fewer side effects by mouth every 12 to 24 hours) is preferred over a non-selective
than phenoxybenzamine; however, there is no consensus as to -blocker. As mentioned earlier, -blockade should never be used
which drug is best. before the dog has received phenoxybenzamine for several days.
In human patients with catecholamine- or -blocker induced Otherwise, severe hypertension may result.
tachyarrhythmias, -adrenoreceptor blockers are often added Despite medical management, complications may still occur
to the preoperative treatment regimen. They should, however, during the preoperative period, and the owner should be advised
never be initiated before -adrenoreceptor blockers have been to closely monitor the dog (Feldman and Nelson, 2004a).
Anesthesia and Management of Intraoperative Complications Premedication is advisable to reduce stress before and during the
Surgical removal of a pheochromocytoma is a high-risk proce- induction of anesthesia, an opioid that is not considered to cause
dure and should only be performed by an experienced surgeon- histamine release (e.g., methadone or hydromorphone) may be a
anesthesiologist team. Close communication between the two suitable option. Induction of anesthesia with propofol, thiopental, or
before and during the procedure is mandatory. During the preop- etomidate has shown to be safe in humans with pheochromocytoma
erative period, blood pressure and heart rate should have been sta- (Kinney etal, 2002) and also seems to be safe in dogs. Propofol com-
bilized as much as possible, and the dog should be well-hydrated. bined with fentanyl, sufentanil, alfentanil, or remifentanil may be
Admission to the hospital at least 1 day prior to surgery and used for total intravenous anesthesia. If anesthesia is maintained by
administration of intravenous fluids (e.g., 0.9% NaCl) at main- inhalant anesthetics, isoflurane and sevoflurane are suitable agents.
tenance rates is recommended. The latter is also done in humans In humans with pheochromocytoma vecuronium is the safest agent
to further expand the intravascular volume and reduce the risk of to achieve muscle relaxation (Manelli etal, 2012b). Various drugs
intraoperative and postoperative hypotension (Pacak, 2007). The are considered to increase the risk of complications, such as atropine,
patient needs continuous monitoring throughout the procedure ketamine, acepromazine, chlorpromazine, morphine, meperidine,
and for approximately 24 to 48 hours thereafter. Monitoring droperidol, halothane, desflurane, succinylcholine, and atracurium.
should include electrocardiogram (ECG) and blood pressure (pref- Although no studies have been performed, it may be advisable to
erentially direct arterial pressure); a central venous pressure line avoid them in dogs with pheochromocytoma.
is helpful to optimize fluid therapy. Despite preoperative prepara- Intraoperative hypertension may often be successfully managed
tion, life-threatening complications may still occurin particu- by deepening the anesthesia. The most commonly used drug to
lar during induction of anesthesia, intubation, surgical incision, combat hypertension during pheochromocytoma surgery is phen-
and manipulation of the tumor (Fig. 13-14). The most worrisome tolamine, a short-acting -adrenergic antagonist. An intravenous
complications are severe hypertension, severe tachycardia, cardiac bolus dose of 0.02 to 0.1 mg/kg is followed by constant rate infu-
arrhythmias, hypotension, and hemorrhage. Systolic blood pressure sion to effect (Ware, 2009). In dogs with persistence of tachycardia
may reach levels above 300 mm Hg, and heart rate may increase and tachyarrhythmia esmolol, an ultra-short-acting 1 antagonist,
above 250 bpm. Cardiac arrhythmias most often are tachyarrhyth- can be given. The initial intravenous bolus of 50 to 500 g/kg
mias, such as supraventricular and ventricular tachycardia as well is followed by constant rate infusion of 50 to 200 g/kg/min
as atrial and ventricular premature contractions; bradyarrhythmias (Gordon, 2010). As mentioned earlier, a -blocker should not be
are rare. Hypotension with systolic blood pressure less than 80 given before -blockade. If 1-receptors are unopposed, severe
mm Hg may occur after tumor removal due to sudden decrease of hypertension may result. In cases of serious ventricular arrhyth-
catecholamine levels, hypovolemia, residual effect of preoperative mias, lidocaine is an appropriate choice. An initial bolus of 2 mg/
-blockers and desensitization of -receptors (Kinney etal, 2002; kg is followed by constant rate infusion of 20 to 80 g/kg/min
Fitzgerald, 2011). The anesthesiologist should be prepared to deal (Ettinger, 2010). In cases of intraoperative hypotension, the dose
with those complications immediately and should have all drugs of phentolamine (or other blood pressure reducing agents) should
ready to be administered. be decreased or its application discontinued; the next step is the
Many anesthetic drugs have been successfully used, and there expansion of the intravascular volume, preferentially with crystal-
is no widely accepted protocol for dogs with pheochromocytoma. loid. If those means remain ineffective, agents such as dobutamine
In humans it is believed that depth of anesthesia is generally more (to increase contractility) or phenylephrine, norepinephrine, vaso-
important than the particular drug (Kinney etal, 2002). pressin (to increase vascular tone) need to be considered.
320 320
Arterial blood pressure (mm Hg)
Arterial blood pressure (mm Hg)
280 280
240
*
240 *
200 200
160 160

120 120
80 80
40 40
140 140
(beats/min)
(beats/min)
Heart rate
Heart rate
120 120
100 100
80 80
60 60
Pre 0 15 30 45 60 75 90 Pre 0 15 30 45 60 75 90 105
A Time (minutes) B Time (minutes)
FIGURE 13-14 Direct arterial systolic and diastolic blood pressure measurements and heart rates prior to anesthe-
sia (Pre), during anesthetic induction (0), and during removal of a pheochromocytoma in a Border Collie (A) and a
West Highland White Terrier (B). Hypertension developed during anesthetic induction in the Border Collie and during
manual manipulation of the pheochromocytoma in both dogs. Hypertension ceased after tumor removal. *, Onset
of tumor manipulation by surgeon; +, completion of tumor excision.
|
Surgical and Postoperative Management stimulation test soon thereafter. Glucocorticoids are given until
The surgical techniques are described in detail in veterinary sur- the test results show normal function of the adrenal cortex (see
gical textbooks. Pheochromocytomas may be resected by an open Chapter 10 for further details). In dogs in which bilateral adrenal-
laparotomy (e.g., median celiotomy or flank laparotomy) or by ectomy is performed due to bilateral pheochromocytomas, life-
a laparoscopic approach. Selection of the technique is based on long supplementation of mineralocorticoids and glucocorticoids
tumor size and invasiveness and the surgeons preference and expe- is needed (see Chapter 12).
rience. In humans, laparoscopic adrenalectomy has become the
procedure of choice for non-invasive, solitary pheochromocytomas Histopathology
that are less than 6 to 8 cm in diameter (Fitzgerald, 2011; Young,
2011). In veterinary medicine, no official guidelines have yet been The definitive diagnosis of a pheochromocytoma is established
established, and complication rates and survival rates between the by histopathology and immunohistochemistry. Histologically,
two approaches have not been compared. Open laparotomy should pheochromocytoma cells are arranged in short cords, nests, or
definitely be performed in dogs with large tumors and tumors in lobules separated by a fine fibrovascular stroma. The cells are
which preoperative imaging techniques suggest invasion into the round to polyhedral with lightly eosinophilic to basophilic cyto-
vena cava (or other large vessels) and/or adhesion to surround- plasm. Nuclei are round to oval with coarsely granular chromatin.
ing tissue. The preoperative detection of tumor thrombi into the Mitotic activity is variable. Compression of the adrenal cortex or
vena cava is by itself not a contraindication for surgery. Successful disruption of its zonal architecture, disruption of the adrenal cap-
adrenalectomy and thrombectomy has been reported several times sule, as well as hemorrhage and necrosis may be seen. Invasion of
(Kyles etal, 2003; Louvet etal, 2005; Lang etal, 2011). During sur- small vessels and tumor thrombi may be present. Metastasis have
gery, close communication between the surgeon and the anesthesi- the same histological characteristics as the primary tumor (Wilson
ologist is critical, because any manipulation of the tumor may lead etal, 1986; Bouayad etal, 1987; Cuervo etal, 1994; Barthez etal,
to a catecholamine surge followed by hypertension, tachycardia, 1997; Sako etal, 2001; Santamarina etal, 2003; Boes etal, 2009;
and arrhythmias. Therefore, the area of the tumor and the tumor Guillaumot etal, 2012).
itself should only be touched after the anesthesiologist has been It may be difficult to differentiate a pheochromocytoma from
informed. The tumor has to be handled with extreme care. Because an adrenocortical tumor by its microscopic appearance, in par-
pheochromocytomas are considered potentially malignant tumors, ticular if the tumor is large and cells have a more atypical appear-
a thorough evaluation of all surrounding tissues and abdominal ance (Barthez etal, 1997; Herrera and Nelson, 2010). At times,
organs should be performed. Careful inspection may also help to differentiation from other tumor types may also be challenging.
detect additional tumors, which are relatively common in dogs In the pre-immunohistochemical era, so-called silver stains (e.g.,
with pheochromocytoma. The length of surgical time has a major Grimelius stain) were used as an aid to characterize the tumor as
influence on survival (i.e., the longer the procedure lasts, the poorer pheochromocytoma (Grimelius, 2004). Today, the use of immu-
the survival). According to a study, the odds of 10-day survival nohistochemical markers has widely replaced those traditional
decreased by 75% for every hour increase in surgery time (Herrera argyrophil methods. In humans, pheochromocytomas are posi-
etal, 2008). Removal of a pheochromocytoma is a demanding pro- tive for broad-spectrum neuroendocrine markers, such as CGA,
cedure and should only be performed by an experienced surgeon. synaptophysin, neuron-specific enolase (NSE), and protein gene
Postoperatively, the patient should be monitored closely for product 9.5 (PGP 9.5). However, adrenal cortical tumors may also
at least 48 hours, preferentially in an intensive care unit (ICU) show immunopositivity for synaptophysin as well as for PGP 9.5,
setting. Monitoring should at least include evaluation of clinical and NSE generally lacks specificity. In contrast, CGA is negative
parameters, continuous blood pressure measurement, continu- in adrenocortical tissue, rendering it a very useful marker to differ-
ous ECG, and measurement of the most important laboratory entiate between tumors of the adrenal medulla and tumors of the
parameters (packed cell volume [PCV], total protein, glucose, and adrenal cortex (Erickson and Lloyd, 2004). The same seems to be
electrolytes). Postoperative complications such as hypotension, true in dogs, although no comprehensive studies comparing sensi-
hypertension, and cardiac arrhythmias are common. Hypoten- tivity and specificity of the various immunohistochemical markers
sion may be due to the sudden decrease of catecholamine levels or have been performed so far. CGA is present in the adrenal medulla
residual effect of preoperative -blockers; however, the possibility and absent in the adrenal cortex of dogs and therefore suitable to
of massive bleeding from the surgical site also needs to be consid- confirm the presence of a pheochromocytoma (Doss etal, 1998).
ered. In theory, hypertension should no longer occur after tumor In most published cases of canine pheochromocytoma using
removal, and it may therefore raise concern for remnant tumor CGA, positive staining was demonstrated. Because staining relies
tissue and functional metastasis. In humans, however, hyperten- on a sufficient number of secretory granules, absence of CGA does
sion is commonly seen in the postoperative phase. Among other not exclude a pheochromocytoma (Doss etal, 1998). It may be
reasons, it is attributed to elevated catecholamine stores in adren- difficult to distinguish between benign and malignant pheochro-
ergic nerve endings, resetting of baroreceptors, and structural mocytomas by means of histology. Canine pheochromocytoma
changes of vessels (Kinney et al, 2002; Young, 2011). Manage- often invades surrounding vessels and tissue and metastasizes to
ment of postoperative complications follows the same principles distant sites. In veterinary medicine, usually both invasion and
as described earlier for intraoperative complications. metastasis are regarded as sign of malignancy. This is different to
In some dogs, it may not be clear prior to surgery if the adrenal humans, where the traditional position of the WHO is to base the
mass is a pheochromocytoma or a cortisol-producing adrenocorti- diagnosis of malignancy on the presence of metastasis and not on
cal tumor. Clinical signs often are alike, and results of the various local invasion (Tischler etal, 2006; Carlsen etal, 2009).
tests (low-dose dexamethasone suppression test [LDDST], uri-
nary, or plasma metanephrines) may be equivocal. It should also Medical Treatment
be remembered that both tumor types may occur together in the
same dog. In questionable cases, we therefore administer dexa- After the diagnosis of pheochromocytoma has been made,
methasone during the surgical procedure and perform an ACTH medical treatment should be started to prepare the dog for
surgery. We are currently using phenoxybenzamine, an oral, tumors secreting high amounts of catecholamines. Additional
non-competitive, non-selective -adrenoreceptor blocker in prognostic factors are age and general condition of the dog as well
dogs with hypertension as well as in dogs with normal blood as presence and severity of concurrent diseases.
pressure. Phenoxybenzamine does not block the synthesis of Adrenalectomy is the treatment of choice; it is, however, a
catecholamines but blocks -adrenergic response to circulat- demanding and high risk procedure. To decrease the risk of intra-
ing norepinephrine and epinephrine. A recent study showed operative and postoperative complications, it should only be
that perioperative mortality is significantly lower in pretreated performed by an experienced surgeon-anesthesiologist team. Peri-
than in untreated dogs (Herrera etal, 2008). Surgery may not operative mortality has been shown to be significantly lower in
be an option in dogs with large and invasive tumors, metasta- dogs pretreated with phenoxybenzamine compared to untreated
sis, serious concurrent disease, or in cases of financial or other dogs (18% versus 48%; Herrera et al, 2008). Dogs that survive
constraints of the owner. In those dogs, we suggest medical the immediate perioperative period and do not suffer from metas-
treatment according to the protocol used for preoperative prep- tasis or serious concurrent disease can live for several years. Tumor
aration. To limit side effects, the dose of phenoxybenzamine thrombus in the vena cava is by itself no contraindication for adre-
should be increased stepwise. Our starting dose is 0.25 mg/kg nalectomy. Dogs with and without tumor thrombus have similar
b.i.d., which is increased every few days until clinical signs are perioperative morbidity and mortality, provided that the surgeon
controlled or until a final dose of approximately 1 mg/kg b.i.d. is familiar with appropriate techniques (Kyles etal, 2003). Survival
is reached. If the dog shows signs of hypotension (e.g., leth- times of 20, 36, and 49 months have been reported after caval
argy, weakness, and/or syncope) or other adverse effects (e.g., venectomy or en bloc resection of the tumor and the invaded vena
tachycardia, and/or vomiting), the dose should be reduced. In cava (Kyles etal, 2003; Louvet etal, 2005; Guillaumot etal, 2012).
the case of tachycardia or tachyarrhythmia, a -blocker may be Dogs treated medically with phenoxybenzamine without subse-
added to the treatment regimen. A selective 1 antagonist (e.g., quent adrenalectomy can live for more than a year after diagnosis.
atenolol 0.2 to 1.0 mg/kg by mouth every 12 to 24 hours) is Most dogs die because of complications caused by catecholamine
preferred over a non-selective -blocker. As mentioned earlier, excess, tumor thrombosis, tumor invasion into surrounding tis-
-blockade should never be used before the dog has received the sue, tumor rupture, or metastasis.
-adrenoreceptor blocker for several days. There are no studies
investigating the effect of medical treatment on survival. However, Paraganglioma
several of our phenoxybenzamine treated dogs lived for more
than 1 year after diagnosis. The WHO classification of endocrine tumors defines paragan-
Metyrosine (Demser) is an inhibitor of tyrosine hydroxylase, gliomas as tumors of the extra-adrenal sympathetic and para-
the enzyme that catalyzes the rate-limiting step in the catechol- sympathetic paraganglia. The term pheochromocytoma is reserved
amine biosynthesis. It significantly reduces catecholamine stores for tumors arising from catecholamine-producing chromaffin
and excretion. In some human centers, it is used as preoperative cells in the adrenal medulla (Pacak etal, 2007). Paragangliomas
treatment in conjunction with - and -blocker or in case of are a diverse group of neuroendocrine tumors (NETs) that may
metastatic disease. It has no effect on tumor progression. Serious develop at many body sites, such as the head, neck, thorax, and
side effects are common and include sedation, depression, anxi- abdomen. They originate from paraganglia, which in turn derive
ety, extrapyramidal signs, galactorrhea, diarrhea, crystalluria, and from primitive cells of the neural crest, and are associated with
urolithiasis, and it has to be administered with caution in patients autonomic ganglia throughout the body. At a microscopic and
with hepatic and renal impairment (Pacak, 2007; Fitzgerald, cellular level, both types (sympathetic and parasympathetic)
2011). In humans with advanced metastatic pheochromocytoma, paraganglia are similar, and both contain catecholamines, how-
chemotherapy with a combination of cyclophosphamide, vincris- ever, there are quantitative differences. In humans, clinical signs
tine, and dacarbazine has been used; however, treatment success due to catecholamine secretion are usually only seen in tumors
is limited. Complete tumor response was seen in 11% and partial of sympathetic paraganglia (Tischler, 2007). Sympathetic para-
response in 44% of patients; median duration of response was 20 ganglioma (also called non-head-neck paragangliomas) account for
months (Huang etal, 2008). about 10% of all pheochromocytomas/paragangliomas in adult
Sunitinib (Sutent), an antiangiogenic drug, has also been used so humans. About 75% of them are intra-abdominal, and 25% are
far with limited success. There are no studies on the use of metyro- found in the thorax (Fitzgerald, 2011). Typical locations are the
sine, chemotherapy, or sunitinib in dogs with pheochromocytoma. Zuckerkandl body (a sympathetic ganglion at the root of the cau-
In humans with advanced disease, radioisotope therapy with dal mesenteric artery), the sympathetic plexus of the urinary blad-
131I-MIBG or somatostatin analog is used with some success; der, the kidneys, and the heart, as well as the sympathetic ganglia
however, complete remission is rare. Recently, radioisotope ther- or the aortopulmonary body in the mediastinum (Timmers etal,
apy with 131I-MIBG has been reported in one dog with a large, 2012). Up to 60% are hormonally active and secrete norepineph-
invasive pheochromocytoma. The dog improved and had clinically rine and normetanephrine. They do not secrete epinephrine and
stable disease for 4 months. Tumor progression led to a second metanephrine. They can be locally invasive with destruction of
treatment after 5 months; however, the dog died 3 weeks thereafter vertebrae and compression of nerve roots and spinal cord; metas-
(Bommarito etal, 2011). tasis occurs in 30% to 50% of human patients (Fitzgerald, 2011).
Paragangliomas arising from parasympathetic paraganglia are
Prognosis also called glomus tumors or head-and-neck paraganglia. Most of
them do not secrete relevant amounts of catecholamines (Lenders
The prognosis depends on various factors such as size, malignant etal, 2005; Fitzgerald, 2011; Timmers etal, 2012). A substantial
potential, and endocrine activity of the tumor. Dogs with small percentage of humans have a genetic basis for the development
tumors (maximum diameter less than 2 to 3 cm) without invasion of paraganglia (e.g., familial paraganglioma/pheochromocytoma
and metastasis and low endocrine activity have better prognosis syndromes due to succinate dehydrogenase gene mutations;
than dogs with large, invasive tumors; tumor metastasis; and with Fishbein and Nathanson, 2012).
|
In dogs and cats, paragangliomas are very rare NETs. Parasym- to the routine use of abdominal ultrasonography in sick animals,
pathetic paragangliomas are the most common type in dogs and the frequency of detection of adrenal lesions has increased tre-
usually arise from the aortic or carotic body. They are also known mendously. It is very common to identify an adrenal nodule or
as glomus tumors, chemoreceptor tumors, or chemodectomas. They mass during work-up of a problem that is not considered to be
are considered nonfunctional, and clinical signs result from space- endocrine-related. The important questions thereafter are:
occupying effects, local invasion, and metastasis (Capen, 2007). Is the nodule/mass hormonally active or inactive?
Other paragangliomas that may have originated from sympathetic Is the nodule/mass benign or malignant or is it a metastasis?

paraganglia have only been described in a few dogs and cats. They Unfortunately, ultrasonography is not helpful to differentiate
were associated with posterior mediastinal, abdominal, or pelvic between the different types of nodules/masses.
masses (Patnaik etal, 1990; Mascort and Pumarola, 1995; Davis So far, no data are available with regard to the prevalence of
etal, 1997). So far, endocrine activity (i.e., catecholamine secre- the different adrenal lesions (see Box 13-5). In dogs, cortisol-
tion) has not been demonstrated, and therefore it is currently producing adrenal tumors are by far the most common, followed
unclear if sympathetic paragangliomas secrete relevant amounts by pheochromocytoma; aldosterone and sex-hormone produc-
of catecholamines. Due to the fact that the mass-related signs ing lesions are rare. In cats, the prevalence of adrenal tumors is
predominate, endocrine work-up in dogs and cats with paragan- generally much lower than in dogs. Cortisol-producing and
glioma is usually not considered. aldosterone-producing lesions are the most common among the
functional adrenal tumors, followed by sex-hormone producing
Incidental Discovered Adrenal Mass (Incidentaloma) tumors; pheochromocytomas are extremely rare in cats.
Due to the similarities, it seems reasonable to use the guidelines
The NIH State-of-the-Science Statement (National Institutes of for humans with some amendments in the management of canine
Health, 2002) defines the term incidentaloma for human medi- and feline adrenal incidentaloma. The work-up should be done
cine as follows: according to the following considerations:

Incidentalomas are clinically inapparent adrenal masses that are dis-

1. Rule out adrenal metastasis by searching for a primary tumor:
covered inadvertently in the course of diagnostic testing for other
Adrenal involvement in case of metastatic disease is common
clinical conditions that are not related to suspicion of adrenal dis-
and was found in 21% of dogs and 14.8% of cats (Labelle and
ease. The definition of incidentaloma excludes patients who undergo
De Cock, 2005).
imaging procedures as part of staging and work-up for cancer.
2. Rule out hormonally active tumors: Careful review of the his-
tory, physical examination, and laboratory findings as well as
To be regarded as incidentaloma, the mass should have a diam- blood pressure measurements should be performed. If poten-
eter of 1 cm or more (Young, 2007). The topic has become a chal- tially endocrine-related abnormalities are detected, hormonal
lenging clinical problem due to the increased discovery of masses by evaluations are the next logical steps. See Chapters 10 and 11
the widespread use of diagnostic imaging techniques. In radiologi- for details on the different diseases and the various tests. The
cal studies, prevalence of incidentalomas in middle-aged people is latter include low-dose dexamethasone test, urinary corticoid-
found to be approximately 2% to 4% and increases with increasing to-creatinine ratio, and measurement of endogenous ACTH
age (Arnaldi and Boscaro, 2012). Most adrenal incidentalomas in to investigate for cortisol-producing adrenal lesions, urinary,
humans are benign adenomas, which are nonfunctional. However, or plasma metanephrines for pheochromocytoma and plasma
in 20% to 30%, the tumors are hormonally active; because the hor- renin and aldosterone for primary hyperaldosteronism.
mone excess is often only mild, the disease is either subclinical or The sequence of testing depends on clinical findings and
associated with very subtle symptoms. Cortisol-producing tumors likelihood. For instance, if clinical findings are equivocal in
are the most frequent, followed by pheochromocytoma and aldo- a dog, we usually rule out hyperadrenocorticism before per-
steronoma. Larger tumors (> 6 cm) are more likely to be malignant forming tests for pheochromocytoma. In a cat in which hy-
than smaller ones (Terzolo etal, 2011; Aron etal, 2012). The big pertension is the predominant sign, we first test for primary
challenge is to identify those adrenal incidentaloma that pose the hyperaldosteronism. Sex-hormone producing adrenal tumors
patient at risk, either because of their hormonal activity or because usually are associated with obvious clinical signs, such as ag-
of their malignant potential, while leaving the others alone. A gressive male-type or estrus-like behavior or signs similar to
pheochromocytoma has to be excluded before fine-needle aspira- those of hypercortisolism. Strictly speaking, adrenal masses in
tion (Aron etal, 2012). There is agreement that human patients patients with obvious signs of an endocrinopathy should not
with an adrenal incidentaloma should be screened for hypercorti- be considered to be an incidentaloma.
solism, pheochromocytoma, and if hypertension is present, also 3. If the presence of a hormonally active tumor is confirmed, med-
for hyperaldosteronism. Routine screening for excess androgens or ical and surgical treatment options should be discussed with
estrogens is not indicated, unless the patient has obvious clinical the owner. In most situations, adrenalectomy is the modality
signs (Young, 2007; Zeiger et al, 2009). Adrenal biopsy is con- of choice. Knowledge of functional status prior to surgery is
sidered to be of low discriminant value and should not be done essential for appropriate perioperative care (e.g., pretreatment
unless it is part of staging of a known malignant disease (Aron with phenoxybenzamine in the case of pheochromocytoma,
et al, 2012). Surgery is usually recommended for all functional or intraoperative and postoperative steroid replacement in the
masses, although there is some controversy as to which removal of case of a cortisol-producing tumor).
small tumors is useful in human patients with subclinical hyper- 4. In large nonfunctional masses, adrenalectomy should be con-
cortisolism. Adrenalectomy is recommended in all nonfunctional sidered. The likelihood that a mass is malignant increases with
masses more than 4 to 6 cm in diameter, due to the likelihood of size, and masses larger than 4 cm in diameters are almost al-
malignancy (Young, 2007; Zeiger etal, 2009; Terzolo etal, 2011; ways malignant (Besso etal, 1997).
Arnaldi and Boscaro, 2012; Aron etal, 2012). 5. Small nodules/masses (less than 2 to 3 cm) that are thought
In dogs and cats, the situation with regard to incidentally dis- to be nonfunctional should be monitored by ultrasonography
covered adrenal masses shows many similarities to humans. Due for growth. Initially, intervals should be quite short (e.g., every
2 to 3 months). If the disease is stable, intervals may be in- TABLE 13-6 MULTIPLE ENDOCRINE
creased to every 4 to 6 months. If size increases, adrenalec- NEOPLASIA SYNDROMES AND
tomy should be performed. It is possible that a mass initially ESTIMATED PENETRANCE OF
considered to be nonfunctional will become hormonally active THE VARIOUS TUMORS
with time. Therefore, it may be necessary to perform or repeat
hormonal evaluation later in the course of the disease. GENETIC INHERITANCE TUMORS AND OTHER ABNORMALITIES
SYNDROME GENE AND ESTIMATED PENETRANCE
MULTIPLE ENDOCRINE NEOPLASIA MEN-1 Autosomal Parathyroid hyperplasia or ad-
dominant enoma (90%)
Multiple Endocrine Neoplasia in Human Medicine MEN 1 Enteropancreatic tumor
The first published case consistent with MEN can be attributed (30% to 70%)
to Jakob Erdheim, a pathologist working in Vienna, Austria, little Gastrinoma (40%)
more than 100 years ago (Erdheim, 1903). The syndrome was Insulinoma (10%)
later classified into the two major forms, MEN-1 and MEN-2. Glucagonoma (< 1%)
Each form is characterized by the development of tumors within VIPoma (< 1%)
specific endocrine organs. The tumors may be functional or non- Nonfunctioning tumor
functional, and each form may also be associated with neoplasias (20% to 55%)
in non-endocrine tissue (Gardner, 2011; Marx and Wells, 2011; Pituitary adenoma (30% to 40%)
Thakker etal, 2012). Prolactin-producing tumor (20%)
Usually, MEN-1 and MEN-2 occur as distinct clinical syn- GH-producing tumor (10%)
dromes; some patients, however, have some kind of overlapping ACTH-producing tumor (< 5%)
syndrome and develop tumors of both forms (Thakker, 2011). All Nonfunctioning tumors (< 5%)
forms of MEN may be either inherited as autosomal dominant Associated tumors and lesions
disease or may occur sporadically without a family history. The Adrenocortical tumor (40%)
distinction between hereditary and sporadic disease may, however, Pheochromocytoma (< 1%)
be difficult in some cases due to death of family members before NETs in various organs (14%)
manifestation of symptoms or due to lack of symptoms in others Lipoma (30%)
(Thakker etal, 2012). The main genes, whose mutations are respon- Angiofibroma (85%)
sible for the MEN syndromes, have been identified. MEN-1 is Collagenoma (70%)
caused by inactivation mutations of a growth suppressor gene, and Meningioma (8%)
MEN-2 is caused by activating mutations of a growth promoter MEN-2 Autosomal
gene (Marx and Wells, 2011). In humans and their families at risk, dominant
screening programs are available, including tumor screening by a RET
combination of clinical, biochemical, and diagnostic imaging pro- Subtype 2A MTC (90%)
cedures as well as germline mutation testing (Brandi etal 2001, Pheochromocytoma (50%)
Marini etal, 2006a; 2006b; Thakker etal, 2012). Parathyroid hyperplasia or ad-
enoma (20% to 30%)
Multiple Endocrine Neoplasia Type 1
Associated lesions
MEN-1, which is also known as Wermer syndrome, has an esti- Cutaneous lichen amyloidosis
mated prevalence of 2 to 20 per 100,000 in the general human Hirschsprung disease
population (Gardner, 2011). MEN-1 occurs as early as 5 years of
Subtype 2B MTC (> 90%)
age, and due to the high degree of penetrance, 80% of individuals
Pheochromocytoma (40% - 50%)
display clinical manifestations by the fifth decade (Thakker etal,
Associated lesions (40% - 50%)
2012). It is an autosomal dominant disease, which is due to muta-
Mucocutaneous neuromas
tions in the tumor suppressor gene MEN-1 that encodes a 610-
Skeletal deformities,
amino acid protein named menin. Menin is primarily a nuclear
joint laxity
protein and is involved in the regulation of transcription, genome
Marfanoid habitus
stability, cell division, and proliferation. So far, more than 1300
Myelinated corneal nerves
mutations have been described, and most of them are predicted
Intestinal ganglioneuromas
to lead to a truncated form of menin (Lemos and Thakker, 2008).
Inheritance of a germline MEN-1 mutation predisposes to tumor FMTC Autosomal MTC (100%)
development after a somatic mutation, which may be a deletion dominant
leading to loss of heterozygosity (Thakker etal, 2012). Addition- RET
ally to the autosomal dominant disease, a nonfamilial, sporadic
Modified from Thakker RV, etal.: Clinical practice guidelines for multiple endocrine
form may occur and genetic studies revealed de novo mutations neoplasia type 1 (MEN 1), J Clin Endocrinol Metab 97:2990, 2012.
of the MEN-1 gene in approximately 10% of patients (Thakker, ACTH, Adrenocorticotropic hormone; FMTC, familial medullary thyroid carcinoma; GH,
2010; 2011). growth hormone; MEN-1, multiple endocrine neoplasia type 1; MEN-2, multiple endocrine
The three major components of MEN-1 are parathyroid, pan- neoplasia type 2; MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor; VIP,
creatic, and pituitary tumors. Some patients have additional vasoactive intestinal peptide.
tumors, such as adrenocortical tumors, lipomas, carcinoids, facial
angiofibromas, collagenomas, and others (Table 13-6). A diagno-
sis of MEN-1 is made if the patient has at least two of the three
|
main MEN-1associated tumors (parathyroid, pancreas, and/ and primary hyperparathyroidism (20% to 30% of cases). Some
or pituitary). Familial MEN-1 is present if such a patient has at patients may develop additional problems, such as cutaneous
least one first degree relative with at least one of the three tumors lichen amyloidosis and Hirschsprung disease (congenital megaco-
(Brandi etal, 2001). lon). The subtype MEN-2B is more aggressive than the subtype
Primary hyperparathyroidism is the most common endocrine MEN-2A and FMTC. It is characterized by MTC (more than
tumor in MEN-1 and occurs in approximately 90% of patients. 90% of cases) and pheochromocytoma (40% to 50% of cases).
It is also typically the first clinical manifestation of MEN-1. In 40% to 50% of cases, additional abnormalities such as muco-
Usually three or all four parathyroid glands are enlarged due to sal neuromas, ganglioneuromas of the gastrointestinal tract, skel-
either hyperplasia or multiple adenomas; carcinomas are rare. The etal deformities, joint laxity, marfanoid habitus, and myelinated
increase in size is highly asymmetric. Clinical signs vary, depend- corneal nerves are present (Marini et al, 2006b; Thakker et al,
ing on the degree of hypercalcemia. Patients may be asymptomatic 2012; see Table 13-6). MTC is the most common manifestation
or display the multiple problems associated with hypercalcemia, of MEN-2. It is the main cause of morbidity and mortality, and
such as lethargy, confusion, polyuria/polydipsia, nephrocalcino- it often is also the abnormality occurring first. It originates from
sis, increased bone resorption, anorexia, constipation, and oth- multifocal C-cell hyperplasia as a precursor lesion and progresses
ers (Marini et al, 2006a; Thakker et al, 2012). Pancreatic islet to carcinoma. The progression from initial hyperplasia to benign
tumors, also called pancreatic NETs, are the second most com- or malignant tumors is a phenomenon also seen in other MEN-
mon manifestation of MEN-1 and are present in 30% to 70% of associated tumors. MTC metastasizes locally and to distant sites,
patients. They comprise gastrinomas, insulinomas, glucagonomas, such as lung, liver, and bone. Clinical manifestations are neck
VIP-secreting tumors, and nonfunctional tumors. Because gastri- mass, neck pain, and diarrhea associated with excessive secretion
nomas are often located in the duodenal mucosa, this group of of calcitonin (Brandi etal, 2001; Marini etal, 2006b).
tumors is also called pancreatico-duodenal NETs. Gastrinomas are
the major cause of morbidity and mortality in MEN-1 patients. Familial Medullary Thyroid Carcinoma
They are often malignant and metastasize, and they may manifest FMTC is defined by the isolated occurrence of MTC without
as Zollinger-Ellison syndrome. The latter is due to hypersecretion other manifestations of MEN in at least four members of the same
of gastrin and is associated with upper abdominal pain, oesopha- family. The clinical course is more benign than in MEN-2A and
geale reflux, diarrhea, and ulcers that may perforate (Marini etal, MEN-2B (Marini etal, 2006b).
2006a; Gardner, 2011; Marx and Wells, 2011). Patients with insu-
linoma may display hypoglycemic symptoms: those with gluca- Tumors of Multiple Endocrine Organs in Dogs and Cats
gonomas skin rash, weight loss, anemia, and stomatitis; those with
VIPomas watery diarrhea, hypocalcemia, and achlorhydria. Pitu- In dogs and cats, it is well known that tumors in several endo-
itary tumors occur in 30% to 40% of MEN-1 patients. Compared crine organs may be present in the same patient. Oftentimes,
to nonMEN-1 tumors, they tend to be larger, show more inva- the tumors are diagnosed simultaneously or within a short time
sive behavior to surrounding pituitary tissue, and respond less to period; however, it is possible that a second or third endocrine
therapy. The clinical manifestations are associated with either the tumor arises months to several years after the diagnosis of the first
mass effect, such as vision field defects or headaches, and/or with or second ones. The tumors may be hormonally active or inac-
the excessive secretion of hormones. Most pituitary tumors are tive. In the case of hormonally active tumors, each tumor may
prolactin-secreting tumors inducing galactorrhea, amenorrhea, express its own clinical picture and biochemical abnormalities. As
and infertility in woman and hypogonadism, sexual dysfunction, seen in humans, it is possible that one tumor and its secretory
and gynecomastia in man. The next common pituitary tumors product predominates the clinical manifestation. Tumors may also
secrete growth hormone (GH) and cause acromegaly; ACTH-probe hormonally silent and incidentally found by ultrasonography
ducing tumors causing Cushings syndrome are the least common or at necropsy. A family of Alaskan Malamute-mixed breed dogs
(Marini etal 2006a; Thakker etal, 2012). with MTC has been described. The father, as well as three female
offspring, was presented at 8 to 9 years of age with neck masses
Multiple Endocrine Neoplasia Type 2 and clinical signs consistent with hypothyroidism. The pattern
MEN-2 has an estimated prevalence of 1 to 10 per 100,000 in was suggesting a dominant inheritance of autosomal or X-linked
the general human population. In individuals with the defective type and resembled FMTC in humans. RET mutational screen-
gene, penetrance of MEN-2 is greater than 80% (Gardner, 2011). ing was performed; however, no mutation could be demonstrated.
MEN-2 occurs in three clinical variants, named MEN-2A, MEN- The authors hypothesized that there may be RET mutations out-
2B, and familial medullary thyroid carcinoma (FMTC). MEN-2A side the human hotspots or mutations in other genes (Lee etal,
accounts for 75%, FMTC for 20%, and MEN-2B for 5% of all 2006). All other studies published so far describe single, sporadic
MEN-2 cases (Martin etal, 2011). Sporadic and familial forms cases. However, different from human medicine where family
occur, and the latter are more common. MEN-2 is defined as the members are screened after the diagnosis of a MEN disorder in
presence of at least two of the main MEN-2-related endocrine an individual, family histories of our canine and feline patients
tumors. Familial MEN-2 is defined as a MEN-2 case plus a first are usually unknown or are not investigated. A further limitation
degree relative with at least one MEN-2-related endocrine tumor in veterinary medicine is that work-up oftentimes is incomplete.
(Marini et al, 2006b). MEN-2 is an autosomal dominant dis- For instance, pituitary-dependent hyperadrenocorticism is often
ease, and 98% of MEN-2 patients have activating germline point diagnosed by endocrine testing without the verification of the
mutations of the RET protooncogene. Different from MEN-1, a presence of a pituitary mass by diagnostic imaging, or a thyroid
strong genotype-phenotype correlation exists, and a specific RET mass is not investigated by immunohistochemistry to define if
mutation may be responsible for a more or less aggressive clinical it is a MTC. Table 13-7 provides an overview of the published
course (Marini etal, 2006b; Romei etal, 2012). MEN-2A (Sipple canine cases harboring several endocrine tumors. In addition
syndrome) is characterized by MTC (in approximately 90% of to the aforementioned family with a FMTC-like disease, only
cases), unilateral or bilateral pheochromocytoma (50% of cases), two dogs revealed similarity with the human MEN syndromes.
550
TABLE 13-7 CASE REPORTS AND CASE SERIES OF DOGS WITH MULTIPLE ENDOCRINE TUMORS
SECTION 4 THE ADRENAL GLAND

PITUITARY
TUMOR OR PITUITARY PARATHYROID ADRENO-
PREDOMINANT CLINICAL DEPENDENT HYPER- HYPERPLASIA/ THYROID PHEOCHRO- CORTICAL PANCREATIC TESTICULAR
DOGS SIGNS ADRENOCORTICISM TUMOR TUMOR MOCYTOMA TUMOR TUMOR TUMOR COMMENT STUDY*
Fox Terrier, male, 15 years old PU/PD, + + (MTC) + + (ICT) compares to Peterson etal,
weakness MEN-2A 1982
Yorkshire Terrier, spayed, female, PU/PD, + + Wright etal,
13 years old weakness, 1995
disorientation
Six dogs (four different breeds, Clinical signs consistent ++++ ++++ Von Dehn
two mixed), four males (two with HAC etal, 1995
castrated males), two spayed
females, 7- to 16 years old ++ ++
Australian Cattle dog, spayed PU/PD + + Bennet and
female, 11 years old Norman,
1998
Standard Schnauzer, spayed Clinical signs consistent + + + Thurczy etal,
female, 10 years old with HAC 1998
Mixed breed, male, 12 years old PU/PD, polyphagia + + compares to Walker
MEN-1 etal, 2000
Mixed breed, spayed female, PU/PD, anorexia, weight (+) (Paragan- + + (Ins) Kiupel
12 years old loss, vomiting, diarrhea glioma) etal, 2000
Mixed breed, male, 15 years old Mass in perianal region + + + (Sem) Unterer
etal, 2002
Portuguese Water dog, spayed Weight loss ++ Hoenerhoff
female, 10 years old (Somatostati- and Kiupel,
noma and 2004
gastrinoma)
Family of Alaskan Malamute- Clinical signs consistent +++ compares to Lee etal, 2006
mixed breed with hypothyroidism, (MTC) FMTC
neck mass
Mixed breed, male, 14 years old PU/PD, polyphagia, ab- + + + (ICT) Proverbio
dominal enlargement etal, 2012
FMTC, Familial medullary thyroid carcinoma; HAC, hyperadrenocorticism; ICT, interstitial cell tumor; Ins, insulinoma; MEN-1, multiple endocrine neoplasia type 1; MEN-2A, multiple endocrine neoplasia subtype 2A; MTC, medullary thyroid
carcinoma; PU/PD, polyuria and polydipsia; Sem, seminoma.
*The table only contains the major abnormalities; see the publications for details.
Gastrinoma was found in mesenteric lymph nodes and liver.
+Presence of tumor in individual dog
|
Peterson, etal., (1982) described a 15-year-old Fox Terrier with lethargy, exercise intolerance, and cervical ventriflexion, an aldo-
MTC, parathyroid hyperplasia, and pheochromocytoma, resem- sterone-secreting adrenal tumor, an insulinoma, and a functional
bling MEN-2A in humans. Walker, etal., (2000) found a simulta- parathyroid adenoma were diagnosed simultaneously (Reimer
neous presence of parathyroid adenoma and pituitary-dependent et al, 2005). Roccabianca, et al., (2006) described two male
hyperadrenocorticism, resembling MEN-1. Additional cases have Domestic Short-Hair cats aged 12 and 13 years with a combina-
been described in textbooks and epidemiological studies. Feldman tion of tumors resembling human MEN-1. Both cats had pituitary
and Nelson (2004b) mention seven dogs with MTC, parathyroid dependent hyperadrenocorticism due to a pituitary corticotroph
tumor, and pheochromocytoma, which is similar to the case of adenoma, thyroid C-cell and parathyroid hyperplasia, and pancre-
Peterson, etal. (1982). In another four dogs, MTC was combined atic -cell carcinoma.
with pituitary tumor and pheochromocytoma. Thyroid adenoma So far, it is unknown if hereditary syndromes comparable
or thyroid carcinoma (follicular or compact-follicular) in combi- to MEN in humans exist in dogs and cats. It may well be that
nation with various other endocrine tumors was seen in an addi- the combination of endocrine tumors is different in dogs from
tional 52 dogs. Many different breeds were affected, rendering in humans and that a different classification scheme has to be
familial syndromes unlikely in these cases. Hayes and Fraumeni established.
(1975) investigated 144 dogs with thyroid tumors and found four However, it is important to realize that multiple endocrine
dogs with concurrent adrenal adenoma. tumors can occur in the same animal, underscoring the impor-
In cats, tumors in multiple endocrine organs have only rarely tance of a thorough evaluation in a patient in which an endocrine
been described. In a 13-year-old, Domestic Long-Hair cat with tumor is diagnosed.
REFERENCES
Agarwal A, etal.: Size of the tumor and pheo- Berry CR, etal.: Imaging of pheochromocytoma Calsyn JDR, etal.: Adrenal pheochromocy-
chromocytoma of the adrenal gland scaled in 2 dogs using p-[18F] fluorobenzylgua- toma with contralateral adrenocortical
score (PASS): can they predict malignan- nidine, Vet Radiol Ultrasound 43:183, adenoma in a cat, J Am Anim Hosp Assoc
cy? World J Surg 34:3022, 2010. 2002. 46:36, 2010.
Armbrust LJ, etal.: Comparison of three-view Berzon JL: A metastatic pheochromocytoma Cameron KN, etal.: The effects of illness on
thoracic radiography and computed tomog- causing progressive paraparesis in a dog, urinary catecholamines and their metabo-
raphy for detection of pulmonary nodules Vet Med Small Anim Clin 76:675, 1981. lites in dogs, J Vet Intern Med 24:1329,
in dogs with neoplasia, J Am Vet Med Besso JG, etal.: Retrospective ultrasonograph- 2010.
Assoc 240:1088, 2012. ic evaluation of adrenal lesions in 26 dogs, Capen CC: Endocrine glands. In ed 5, Maxie
Arnaldi G, Boscaro M: Adrenal incidentaloma, Vet Radiol Ultrasound 38:448, 1997. MG, editor: Jubb, Kennedy, and Palmers
Best Pract Res Clin Endocrinol Metab Blek R, etal.: Chromogranin A, a member of pathology of domestic animals, vol. 3.
26:405, 2012. neuroendocrine secretory proteins as a Philadelphia, 2007, Elsevier.
Aron D, etal.: Adrenal incidentalomas, Best selective marker for laboratory diagnosis of Carlsen E, etal.: Pheochromocytomas, PASS,
Pract Res Clin Endocrinol Metab 26:69, pheochromocytoma, Physiol Res 57(Suppl and immunohistochemistry, Horm Metab
2012. 1):171, 2008. Epub. Res 41:715, 2009.
Baid SK, etal.: Brief communication: radio- Black HR: The paradigm has shifted to Chen H, etal.: The NANETS Consensus Guide-
graphic contrast infusion and catechol- systolic blood pressure, J Hum Hypertens line for the diagnosis and management of
amine release in patients with pheochro- 18(Suppl 2):3, 2004. neuroendocrine tumors: pheochromocy-
mocytoma, Ann Intern Med 150:27, 2009. Blake MA, etal.: Adrenal imaging, Am J Roent- toma, paraganglioma & medullary thyroid
Bailey DB, Page RL: Tumors of the endocrine genol 194:1450, 2010. cancer, Pancreas 39:775, 2010.
system. In Withrow SJ, Vail DM, edi- Boes K, etal.: What is your diagnosis? Shoul- Chew SL: Diagnosis: imaging of pheochromo-
tors: Withrow & MacEwens small animal der mass in a dog with lameness, Vet Clin cytomas and paragangliomas, Nat Rev
clinical oncology, ed 4, St Louis, 2007, Pathol 38:511, 2009. Endocrinol 6:193, 2010.
Saunders/Elsevier. Bommarito DA, etal.: Treatment of a malignant Chobanian AV, etal.: The seventh report of the
Barron J: Phaeochromocytoma: diagnostic pheochromocytoma in a dog using 131I me- joint national committee on prevention,
challenges for biochemical screening and taiodobenzylguanidine, J Am Anim Hosp detection, evaluation, and treatment of
diagnosis, J Clin Pathol 63:669, 2010. Assoc 47:188, 2011. high blood pressure: the JNC 7 report,
Barthez PY, etal.: Pheochromocytoma in dogs: Bouayad H, etal.: Pheochromocytoma in dogs: J Am Med Assoc 289:2560, 2003.
61 cases (1984-1995), J Vet Intern Med 13 cases (1980-1985), J Am Vet Med As- Chun R, etal.: Apocrine gland adenocarcinoma
11:272, 1997. soc 191:1610, 1987. and pheochromocytoma in a cat, J Am
Beard CM, etal.: Occurrence of pheochromocy- Brandi ML, etal.: Consensus. Guidelines for Anim Hosp Assoc 33:33, 1997.
toma in Rochester, Minnesota, 1950 through diagnosis and therapy of MEN type 1 and Classics in oncology: a case of bilateral
1979, Mayo Clin Proc 58:802, 1983. type 2, J Clin Endocrinol Metab 86:5658, completely latent adrenal tumor and
Bennett PF, Norman EJ: Mitotane (op-DDD) 2001. concurrent nephritis with changes in the
resistance in a dog with pituitary-depen- Brmel C, etal.: Serum inhibin concentration circulatory system and retinitis: Felix
dent hyperadrenocorticism and phaeochro- in dogs with adrenal gland disease and Frnkel, 1886, CA Cancer J Clin 34:93,
mocytoma, Aust Vet 76:101, 1998. in healthy dogs, J Vet Intern Med 27:76, 1984.
Berl T, etal.: Mechanism of suppression of 2013. Cotecchia S: The 1-adrenergic receptors: di-
vasopressin during alpha-adrenergic stimu- Brown AJ, etal.: Malignant pheochromocytoma versity of signaling networks and regulation,
lation with norepinephrine, J Clin Invest presenting as a bradyarrhythmia in a dog, J Recept Signal Transduct Res 30:410,
53:219, 1974. J Vet Emerg Crit Care 17:164, 2007a. 2010.
Berry CR, etal.: Use of 123iodine metaiodoben- Brown S, etal.: Guidelines for the identifica- Cryer PE: Diseases of the sympathochromaffin
zylguanidine scintigraphy for the diagnosis tion, evaluation, and management of system. In Felig P, Frohman LA, editors:
of a pheochromocytoma in a dog, Vet systemic hypertension in dogs and cats, Endocrinology and metabolism, ed 4, New
Radiol Ultrasound 34:52, 1993. J Vet Intern Med 21:542, 2007b. York, 2001, McGraw-Hill.
Cuervo L, etal.: Immunoreactivity to chromo- Erdheim J: Zur normalen und pathologischen Goldfarb DA, etal.: Magnetic resonance imag-
granin and to vasoactive intestinal peptide Histologie der Glandula thyreoidea, Para- ing for assessment of vena caval tumor
in a canine phaeochromocytoma, J Comp thyreoidea und Hypophysis, Beitr Pathol thrombi: a comparative study with vena-
Path 111:327, 1994. Anat 33,158, 1903. cavography and computerized tomography
Davis WP, etal.: Malignant cauda equina para- Erickson LA, Lloyd RV: Practical markers used scanning, J Urol 144:1100, 1990.
ganglioma in a cat, Vet Pathol 34:243, in the diagnosis of endocrine tumors, Adv Gordon SG: Beta blocking agents. In ed 7,
1997. Anat Pathol 11:175, 2004. Ettinger SJ, Feldman EC, editors: Textbook
de Wailly P, etal.: Malignant pheochromocyto- Ettinger SJ: Therapy of arrhythmias. In ed 7, of veterinary internal medicine, vol. 2. St
ma: new malignancy criteria, Langenbecks Ettinger SJ, Feldman EC, editors: Textbook Louis, 2010, Saunders/Elsevier.
Arch Surg 397:239, 2012. of veterinary internal medicine, vol. 2. St Gostelow R, etal.: Plasma-free metanephrine
Doss JC, etal.: Immunohistochemical local- Louis, 2010, Saunders/Elsevier. and free normetanephrine measurement
ization of chromogranin A in endocrine Feldman JM, etal.: Deficiency of dopamine- for the diagnosis of pheochromocytoma in
tissues and endocrine tumors of dogs, Vet beta-hydroxylase: a new mechanism for dogs, J Vet Intern Med 27:83, 2013.
Pathol Online 35:312, 1998. normotensive pheochromocytomas, Am J Grimelius L: Silver stains demonstrating
Eisenhofer G: Free or total metanephrines for Clin Pathol 72:175, 1979. neuroendocrine cells, Biotech Histochem
diagnosis of pheochromocytoma: what is Feldman EC, Nelson RW: Pheochromocytoma 79:37, 2004.
the difference? Clin Chem 47:988, 2001. and multiple endocrine neoplasia. In Feld- Grouzmann E, etal.: Diagnostic accuracy of
Eisenhofer G, etal.: Understanding catechol- man EC, Nelson RW, editors: Canine and free and total metanephrines in plasma
amine metabolism as a guide to the bio- feline endocrinology and reproduction, ed and fractionated metanephrines in urine
chemical diagnosis of pheochromocytoma, 3, St Louis, 2004a, of patients with pheochromocytoma, Eur J
Rev Endocr Metab Disord 2:297, 2001. Saunders/Elsevier. Endocrinol 162:951, 2010.
Eisenhofer G, etal.: Biochemical diagnosis of Feldman EC, Nelson RW: Canine thyroid Guillaumot PJ, etal.: 49-month survival follow-
pheochromocytoma: how to distinguish tumors and hyperthyroidism. In Feldman ing caval venectomy without nephrectomy
true- from false-positive test results, J Clin EC, Nelson RW, editors: Canine and feline in a dog with a pheochromocytoma, J Am
Endocrinol 88:2656, 2003. endocrinology and reproduction, ed 3, St Anim Hosp Assoc 48:352, 2012.
Eisenhofer G, etal.: Catecholamine metabo- Louis, 2004b, Saunders/Elsevier. Hayes HM, Fraumeni JF: Canine thyroid neo-
lism: a contemporary view with implica- Fishbein L, Nathanson KL: Pheochromocytoma plasms: epidemiologic features (abstract),
tions for physiology and medicine, Pharma- and paraganglioma: understanding the J Natl Cancer Inst 55:931, 1975.
col Rev 56:331, 2004a. complexities of the genetic background, Head LL, Daniel GB: Scintigraphic diagnosis
Eisenhofer G, etal.: Distinct gene expres- Cancer Genet 205:1, 2012. an unusual presentation of metastatic
sion profiles in norepinephrine- and Fitzgerald PA, Goldfien A: Adrenal medulla. In pheochromocytoma in a dog, Vet Radiol
epinephrine-producing hereditary and Greenspan FS, Gardner DG, editors: Basic Ultrasound 45:574, 2004.
sporadic pheochromocytomas: activation and clinical endocrinology, ed 7, New York, Henry CJ, etal.: Clinical vignette: adrenal
of hypoxia-driven angiogenic pathways in 2004, Lang Medical Books/McGraw-Hill. pheochromocytoma, J Vet Intern Med
von Hippel-Lindau syndrome, Endocr Relat Fitzgerald PA: Adrenal medulla and paragan- 7:199, 1993.
Cancer 11:897, 2004b. glia. In Gardner DA, Shoback D, editors: Herrera MA, etal.: Predictive factors and the
Eisenhofer G, etal.: Pheochromocytoma cat- Greenspans basic and clinical endocrinol- effect of phenoxybenzamine on outcome in
echolamine phenotypes and prediction of ogy, ed 9, New York, 2011, McGraw-Hill. dogs undergoing adrenalectomy for pheo-
tumor size and location by use of plasma free Frnkel F: Ein Fall von doppelseitigem, vllig chromocytoma, J Vet Intern Med 22:1333,
metanephrines, Clin Chem 51:735, 2005a. latent verlaufenen Nebennierentumor und 2008.
Eisenhofer G, etal.: Plasma metanephrines in gleichzeitiger Nephritis mit Vernderungen Herrera M, Nelson RW: Pheochromocytoma.
renal failure, Kidney Int 67:668, 2005b. am Circulationsapparat und Retinitis, Arch In ed 7, Ettinger SJ, Feldman EC, editors:
Eisenhofer G, etal.: Adverse drug reactions in Pathol Anat Physiol Klin Med 103:244, Textbook of veterinary internal medicine,
patients with phaeochromocytoma: inci- 1886. vol. 2. St Louis, 2010, Saunders/Elsevier.
dence, prevention and management, Drug Fukuda I, etal.: Clinical features of insulin-like Hoenerhoff M, Kiupel M: Concurrent gastri-
Saf 30:1031, 2007. growth factor-II producing non-islet-cell noma and somatostatinoma in a 10-year-
Eisenhofer G, etal.: Differential expression tumor hypoglycemia, Growth Horm IGF Res old Portuguese water dog, J Comp Path
of the regulated catecholamine secretory 16:211, 2006. 130:313, 2004.
pathway in different hereditary forms of Galac S, etal.: Adrenals. In Rijnberk A, Koo- Hoerauf A, Reusch C: Ultrasonographic charac-
pheochromocytoma, Am J Physiol Endo- istra HS, editors: Clinical endocrinology teristics of both adrenal glands in 15 dogs
crinol Metab 295:1223, 2008a. of dogs and cats, ed 2, Hannover, 2010, with functional adrenocortical tumors,
Eisenhofer G, etal.: Current progress and Schltersche Verlagsgesellschaft. J Am Anim Hosp Assoc 35:193, 1999.
future challenges in the biochemical Galetta F, etal.: Cardiovascular complica- Howard EB, Nielsen SW: Pheochromocytomas
diagnosis and treatment of pheochromocy- tions in patients with pheochromocytoma: associated with hypertensive lesions in
tomas and paragangliomas, Horm Metab a mini-review, Biomed Pharmacother dogs, J Am Vet Med Assoc 147:245, 1965.
Res 40:329, 2008b. 64:505, 2010. Huang H, etal.: Treatment of malignant
Eisenhofer G, etal.: Catecholamine metabo- Garca-Sinz JA, etal.: Mechanisms involved in pheochromocytoma/paraganglioma with
lomic and secretory phenotypes in pha- 1B-adrenoceptor desensitization, IUBMB cyclophosphamide, vincristine, and
eochromocytoma, Endocr Relat Cancer Life 63:811, 2011. dacarbazine: recommendation from a
18:97, 2011. Gardner DG: Multiple endocrine neoplasia. In 22-year follow-up of 18 patients, Cancer
Eisenhofer G, etal.: Diagnostic tests and Gardner DG, Shoback D, editors: Greens- 113:2020, 2008.
biomarkers for pheochromocytoma and pans basic and clinical endocrinology, ed Kang JM, etal.: Systemic inflammatory
extra-adrenal paraganglioma: from routine 9, New York, 2011, McGraw-Hill. syndrome and hepatic inflammatory cell
laboratory methods to disease stratifica- Gavin PR, Holmes SP: Magnetic resonance im- infiltration caused by an interleukin-6
tion, Endocr Pathol 23:4, 2012. aging of abdominal disease. In Gavin PR, producing pheochromocytoma, Endocr J
Elias S, etal.: Chromogranin as a crucial Bagley RS, editors: Practical small animal 52:193, 2005.
factor in the sorting of peptide hormones MRI, Iowa, 2009, Wiley-Blackwell. Kinney MA, etal.: Perioperative management
to secretory granules, Cell Mol Neurobiol Gilson SD, etal.: Pheochromocytoma in 50 of pheochromocytoma, J Cardiothorac Vasc
30:1189, 2010. dogs, J Vet Intern Med 8:228, 1994. Anesth 16:359, 2002.
|
Kitamura K, etal.: Adrenomedullin: a novel Mannelli M, etal.: Subclinical phaeochromo- Quante S, etal.: Urinary catecholamine and
hypotensive peptide isolated from human cytoma, Best Pract Res Clin Endocrinol metanephrine to creatinine ratios in dogs
pheochromocytoma, Biochem Biophys Res Metab 26:507, 2012a. with hyperadrenocorticism or pheochromo-
Commun 425:548, 2012. Mannelli M, etal.: Perioperative management cytoma, and in healthy dogs, J Vet Intern
Kiupel M, etal.: Multiple endocrine neoplasia of pheochromocytoma/paraganglioma: is Med 24:1093, 2010.
in a dog, J Comp Path 123:210, 2000. there a state of the art? Horm Metab Res Reimer SB, etal.: Multiple endocrine neoplasia
Kook PH, etal.: Urinary catecholamine and 44:373, 2012b. type I in a cat, J Am Vet Med Assoc
metanephrine to creatinine ratios in Marini F, etal.: Multiple endocrine neoplasia 227:101, 2005.
healthy dogs at home and in a hospital en- type 2, Orphanet J Rare Dis 1:45, 2006a. Reusch CE, etal.: Endocrine hypertension in
vironment and in 2 dogs with pheochromo- Marini F, etal.: Multiple endocrine neoplasia small animals, Vet Clin North Am Small
cytoma, J Vet Intern Med 21:388, 2007. type I, Orphanet J Rare Dis 1:38, 2006b. Anim Pract 40:335, 2010.
Kook PH, etal.: Urinary catecholamine and Martin NM, etal.: Multiple endocrine neoplasia Roccabianca P, etal.: Multiple endocrine
metadrenaline to creatinine ratios in type 2. In Wass JAH, Stwart PM, Amiel neoplasia type-I-like syndrome in two cats,
dogs with a phaeochromocytoma, Vet Rec SA, Davies MJ, editors: Oxford textbook of Vet Pathol 43:345, 2006.
166:169, 2010. endocrinology and diabetes, ed 2, Oxford, Romei C, etal.: Genetic and clinical features
Kudva YC, etal.: The laboratory diagnosis of 2011, Oxford University Press. of multiple endocrine neoplasia types 1
adrenal pheochromocytoma: the Mayo Marx SJ, Wells SA: Multiple endocrine neo- and 2 (abstract), J Oncol, 2012.
Clinic experience, J Clin Endocrinol Metab plasia. In Melmed S, Polonsky KS, Larsen Epub.
88:4533, 2003. PR, Kronenberg HM, editors: Williams Rosas AL, etal.: Pheochromocytoma crisis
Kyles AE, etal.: Surgical management of textbook of endocrinology, ed 12, Phila- induced by glucocorticoids: a report of four
adrenal gland tumors with and without delphia, 2011, Elsevier/Saunders. cases and review of the literature, Eur J
associated tumor thrombi in dogs: 40 Mascort J, Pumarola M: Posterior mediastinal Endocrinol 158:423, 2008.
cases (1994-2001), J Am Vet Med Assoc paraganglioma involving the spinal cord of Rosenstein DS: Diagnostic imaging in canine
223:654, 2003. a dog, J Small Anim Pract 36:274, 1995. pheochromocytoma, Vet Radiol Ultrasound
Labelle P, De Cock HE: Metastatic tumors to McNeil AR, etal.: Phaeochromocytomas 41:499, 2000.
the adrenal glands in domestic animals, discovered during coronial autopsies in Sako T, etal.: Immunohistochemical evalua-
Vet Pathol 42:52, 2005. Sydney, Melbourne and Auckland, Aust N tion of a malignant pheochromocytoma in
Lang, etal.: Elective and emergency surgical Z J Med 30:648, 2000. a wolfdog, Vet Pathol 38:447, 2001.
management of adrenal gland tumors: Morandi F: Adrenal glands. In Schwarz T, Salesov E, etal.: Urinary and plasma catechol-
60 cases (1999-2006), J Am Anim Hosp Saunders J, editors: Veterinary computed amine and metanephrine in dogs with
Assoc 47(6):428, 2011. tomography, Iowa, Wiley-Blackwell, 2011. pheochromocytoma, hyperadrenocorticism
Lee JJ, etal.: A dog pedigree with familial Mueller B, etal.: Innersekretorisch wirksame and in healthy dogs (abstract), J Vet Intern
medullary thyroid cancer, Int J Oncol Nebennierenmarksgeschwulst (Phochro- Med 26:1524, 2012.
29:1173, 2006. mocytom) bei einem Hund, Zentralblatt fr Santamarina G, etal.: Aortic thromboembolism
Lemos MC, Thakker RV: Multiple endocrine Veterinrmedizin 2:289, 1955. and retroperitoneal hemorrhage associated
neoplasia type 1 (MEN1): analysis of 1336 National Institutes of Health: NIH state-of- with a pheochromocytoma in a dog, J Vet
mutations reported in the first decade the-science statement on management Intern Med 17:917, 2003.
following identification of the gene, Hum of the clinically inapparent adrenal mass Schultz RM, etal.: Contrast-enhanced comput-
Mutat 29:22, 2008. (incidentaloma), NIH Consens State Sci ed tomography as a preoperative indicator
Lenders JWM, etal.: Biochemical diagnosis Statements 19(2):1, 2002. of vascular invasion from adrenal masses
of pheochromocytoma, J Am Med Assoc Neumann HP, etal.: Evidence of MEN-2 in the in dogs, Vet Radiol Ultrasound 50:625,
287:1427, 2002. original description of classic pheochromo- 2009.
Lenders JWM, etal.: Phaeochromocytoma, cytoma, N Engl J Med 357:1311, 2007. Sjaastad V, etal.: The endocrine system. In
Lancet 366:665, 2005. Pacak K: Approach to the patient: preoperative Sjaastad V, Hove K, Sand O, editors:
Leung K, etal.: Pheochromocytoma: the range management of the pheochromocytoma Physiology of domestic animals, Norway,
of appearances on ultrasound, CT, MRI, patient, J Clin Endocrinol Metab 92:4069, 2010, Scandinavian Veterinary Press.
and functional imaging, AJR Am J Roent- 2007. Spall B, etal.: Imaging diagnosismetastatic
genol 200:370, 2013. Pacak K: Pheochromocytoma: a catecholamine adrenal pheochromocytoma in a dog, Vet
Loh YP, etal.: Secretory granule biogenesis and oxidative stress disorder, Endocr Regul Radiol Ultrasound 52:534, 2011.
and neuropeptide sorting to the regulated 45:65, 2011. Stenstrm G, Svrdsudd K: Pheochromocytoma
secretory pathway in neuroendocrine cells, Pacak, etal.: Pheochromocytoma: recommen- in Sweden 1958-1981: an analysis of the
J Mol Neurosci 22:63, 2004. dations for clinical practice from the First national cancer registry data, Acta Med
Louvet A, etal.: Phaeochromocytoma treated International Symposium, Nat Clin Pract Scand 220:225, 1986.
by en bloc resection including the supra- Endocrinol Metab 3:92, 2007. Stowater JL: Pheochromocytoma metastatic to
renal caudal vena cava in a dog, J Small Patnaik AK, etal.: Extra-adrenal pheochromo- bone in a dog, Vet Med Small Anim Clin
Anim Pract 46:591, 2005. cytoma (paraganglioma) in a cat, J Am Vet 74:343, 1979.
Mackenzie IS, Brown MJ: Phaeochromocyto- Med Assoc 197:104, 1990. Tamaschke C: Adrenal tumors of the dog,
mas, paragangliomas and neuroblastomas. Peterson ME, etal.: Multiple endocrine Virchows Arch 327:480, 1955.
In Wass JA, Stewart PM, Amiel SA, Davies neoplasia in a dog, J Am Vet Med Assoc Terzolo M, etal.: AME position statement on
MJ, editors: Oxford textbook of endocrinol- 180:1476, 1982. adrenal incidentaloma, Eur J Endocrinol
ogy and diabetes, ed 2, Oxford, 2011, Platt SR, etal.: Pheochromocytoma in the ver- 164:851, 2011.
Oxford University Press. tebral canal of two dogs, J Am Anim Hosp Thakker RV: Multiple endocrine neoplasia type
Maher ER, etal.: von Hippel-Lindau disease: Assoc 34:365, 1998. 1 (MEN1), Best Pract Res Clin Endocrinol
a clinical and scientific review, Eur J Hum Prejbisz A, etal.: Cardiovascular manifesta- Metab 24:355, 2010.
Genet 19:617, 2011. tions of phaeochromocytoma, J Hypertens Thakker RV: Multiple endocrine neoplasia type 1.
Manger WM: An overview of pheochromocy- 29:2049, 2011. In Wass JA, Stewart PM, Amiel SA, Davies
toma: history, current concepts, vagaries, Proverbio D, etal.: Potential variant of multiple MJ, editors: Oxford textbook of endocrinology
and diagnostic challenges, Ann N Y Acad endocrine neoplasia in a dog, J Am Anim and diabetes, ed 2, Oxford, 2011, Oxford
Sci 1073:1, 2006. Hosp Assoc 48:132, 2012. University Press.
Thakker RV, etal.: Clinical practice guide- Unterer S, etal.: Ein Fallbericht ber einen Williams JE, Hackner SG: Pheochromocy-
lines for multiple endocrine neoplasia Hund mit multiplen endokrinen Neoplasien toma presenting as acute retroperitoneal
type 1 (MEN1), J Clin Endocrinol Metab (MEN): Nebenschilddrsenadenom, hemorrhage in a dog, J Vet Emerg Crit Care
97:2990, 2012. Schilddrsenkarzinom, Seminom und 11:221, 2001.
Thouennon E, etal.: Expression of trophic perianale Adenome, Kleintierpraxis Wilson RB, etal.: Leu-enkephalin and soma-
peptides and their receptors in chromaf- 10:615, 2002. tostatin immunoreactivities in canine and
fin cells and pheochromocytoma, Cell Mol Vanderveen KA, etal.: Biopsy of pheochromo- equine pheochromocytomas, Vet Pathol
Neurobiol 30:1383, 2010. cytomas and paragangliomas: potential for 23:96, 1986.
Thurczy J, etal.: Multiple endocrine neopla- disaster, Surgery 146:1158, 2009. Wimpole JA, etal.: Plasma free metanephrines
sias in a dog: corticotrophic tumour, bilat- van Vonderen IK, etal.: Influence of veterinary in healthy cats, cats with non-adrenal
eral adrenocortical tumours, and pheochro- care on the urinary corticoid:creatinine disease and a cat with suspected phaeo-
mocytoma, Vet Quart 20:56, 1998. ratio in dogs, J Vet Intern Med 12:431, chromocytoma, J Feline Med Surg 12:435,
Timmers HJ, etal.: Current and future ana- 1998. 2010.
tomical and functional imaging approaches Vasudevan NT, etal.: Regulation of - Wright KN, etal.: Diagnostic and therapeutic
to pheochromocytoma and paraganglioma, adrenergic receptor function: an emphasis considerations in a hypercalcemic dog with
Horm Metab Res 44:367, 2012. on receptor resensitization, Cell Cycle multiple endocrine neoplasia, J Am Anim
Tischler AS: Paraganglia. In Mills SE, editor: 10:3684, 2011. Hosp Assoc 31:156, 1995.
Histology for pathologists, ed 3, Philadel- Von Dehn BJ, etal.: Pheochromocytoma Yi DW, etal.: Pheochromocytoma crisis after a
phia, 2007, Lippincott Williams & Wilkins. and hyperadrenocorticism in dogs: six dexamethasone suppression test for adre-
Tischler AS, etal.: Pathology of pheochromo- cases (1982-1992), J Am Vet Med Assoc nal incidentaloma, Endocr 37:213, 2010.
cytoma and extra-adrenal paraganglioma, 207:322, 1995. Young WF: The incidentally discovered adrenal
Ann N Y Acad Sci 1073:557, 2006. Walker MC, etal.: Multiple endocrine neoplasia mass, N Engl J Med 356:601, 2007.
Tokuda H, etal.: Overexpression of protein type 1 in a crossbred dog, J Small Anim Young WF: Endocrine hypertension. In Melmed
kinase C-delta plays a crucial role in Pract 41:67, 2000. S, Polonsky KS, Larsen PR, Kronenberg
interleukin-6-producing pheochromocy- Ware WA: Systemic arterial hypertension. In HM, editors: Williams textbook of endocri-
toma presenting with acute inflammatory Nelson RW, Couto CG, editors: Small nology, ed 12, St Louis, 2011, Saunders/
syndrome: a case report, Horm Metab Res animal internal medicine, ed 4, St Louis, Elsevier.
41:333, 2009. 2009, Mosby/Elsevier. Yu Run, etal.: Small pheochromocytomas:
Tsujimoto G, etal.: Desensitization of beta-ad- White RAS, Cheyne IA: Bone metastases from significance, diagnosis, and outcome, J
renergic receptors by pheochromocytoma, a phaeochromocytoma in the dog, J Small Clin Hypertens 14:307, 2012.
Endocrinology 114:1272, 1984. Anim Pract 18:579, 1977. Zeiger MA, etal.: The American Association
Unger N, etal.: Diagnostic value of various Whittemore JC, etal.: Nontraumatic rupture of Clinical Endocrinologists and American
biochemical parameters for the diagnosis of an adrenal gland tumor causing intra- Association of Endocrine Surgeons medical
of pheochromocytoma in patients with abdominal or retroperitoneal hemorrhage in guidelines for the management of adrenal
adrenal mass, Eur J Endocrinol 154:409, four dogs, J Am Vet Med Assoc 219:329, incidentalomas, Endocr Pract 15(Suppl 1):
2006. 2001. 1, 2009.
CHAPTER 14 Glucocorticoid Therapy
Claudia E. Reusch
CHAPTER CONTENTS The initial discovery was followed by the development of synthetic
Chemistry of Glucocorticoids and Structure-Activity Relationship, 555 steroids mainly for use in inflammatory and immune-mediated
Molecular Mechanism of Action, 556 diseases. However, it soon became obvious that their efficacy is
Genomic Effects, 556 not without costs in terms of potentially serious adverse effects
Nongenomic Effects, 558 (Goulding and Flower, 2000b).
Biologic Effects of Glucocorticoids, 559 Currently, glucocorticoids are among the most frequently used
Effects on Carbohydrate, Protein, and Lipid Metabolism, 559 (and misused) drugs in veterinary medicine. Despite the wide-
Effects on Other Tissues, 559 spread use of glucocorticoids, scientifically based information on
Anti-Inflammatory and Immunosuppressive Effects, 562 optimal dose, dose interval, and physiological and pharmacologi-
Pharmacokinetics and Clinical Pharmacology, 563 cal effects in dogs and cats is scarce. Therefore, treatment protocols
Duration of Action, 563 are often extrapolated from human medicine or rodent studies or
Route of Administration, 563 are the result of clinical experience (Ferguson etal, 2009; Boothe
Distribution, Metabolism, and Excretion, 565 and Mealey, 2012). Knowledge on effects, different potencies of
Dose Equivalents of Glucocorticoids, 565 synthetic glucocorticoids, adverse effects, and contraindications
Galenic Formulations and Steroid Esters, 566 will help the veterinarian to make informed decisions and to avoid
Combination Products, 567 serious complications as much as possible.
Therapeutic Application and Classes of Glucocorticoid Usage, 567
Goals and General Guidelines, 567 CHEMISTRY OF GLUCOCORTICOIDS AND
Physiological Replacement Therapy, 568 STRUCTURE-ACTIVITY RELATIONSHIP
Anti-Inflammatory Therapy, 568
Immunosuppressive Therapy, 569 All hormones of the adrenal cortex are derivatives of cholesterol
Antineoplastic Therapy, 569 and contain the cyclopentanoperhydrophenanthrene nucleus
Shock, 569 (Fig. 14-1). The main products of the adrenal cortex are C21
Neurological Diseases, 570 and C19 steroids. The C19 steroids have a keto or hydroxyl
Adverse Effects, 570 group at position 17 and display androgenic activity. The C21
Iatrogenic Hyperadrenocorticism, 570 steroids have a two-carbon side chain at position 17 and are
Alteration of the Hypothalamic Pituitary Adrenal Axis, 571 classified as mineralocorticoids and glucocorticoids. Those C21
Diabetes Mellitus, 572 steroids that have an additional hydroxyl group at position 17
Gastrointestinal Hemorrhage and Ulceration, 572 are often called 17-hydroxycorticoids or 17-hydroxycorticosteroids
Laboratory Abnormalities, 573 (Barrett etal, 2012).
Pancreatitis, 573 Cortisol (hydrocortisone) has glucocorticoid as well as miner-
Miscellaneous, 573 alocorticoid properties due to its ability to stimulate both gluco-
Glucocorticoid Reduction Protocol, 574 corticoid and mineralocorticoid receptors (Parente, 2000). Certain
structures and groups on the steroid base, as well as the orientation
of the groups in the ring system, are essential for the biological
In 1949, Hench and colleagues reported on the first therapeutic activity. The groups lying below the plane of the steroid ring are
use of a glucocorticoid in nine patients with rheumatoid arthritis. indicated by and a dashed line (.... OH), the groups lying above
The substance had been known under the term compound E the ring are indicated by and a solid line ( OH) (Parente, 2000;
and was then named cortisone. Later it was found that the true Barrett etal, 2012). The important features for biological activity
hormone is in fact cortisol, which is reversibly converted to its are: a ketone group at C-3 and C-20, a double bond between C-4
inactive metabolite cortisone. In 1950, Edward Kendall, a bio- and C-5, a hydroxyl group in -orientation at C-11, a two-carbon
chemist at the Graduate School of the Mayo Foundation, the chain in -orientation, a hydroxyl group in -orientation at C-17,
Swiss chemist, Tadeus Reichstein, and a Mayo Clinic physician, and a methyl group in -orientation at C-18 and C-19 (Parente,
Philip Hench, were awarded the Nobel Prize for their work on 2000) (Fig. 14-2).
the adrenal gland hormones. The Noble Lecture held by Kendall Chemical modifications of the cortisol molecule have generated
on December 11, 1950, was titled, The Development of Cor- compounds with higher glucocorticoid activity and less mineralo-
tisone as a Therapeutic Agent (Kendall, 1950). The finding of corticoid activity (Fig. 14-3). Modifications of the molecular struc-
Hench and colleagues (1949) introduced the world to a new type ture also alter the protein binding and hepatic metabolism thereby
of therapy and there was a saying, Therapy was now dated BC prolonging duration of action. High anti-inflammatory properties
(before cortisone) or after (AC) (Goulding and Flower, 2000a). are unfortunately also associated with higher glucocorticoid activity
555
12 17 (i.e., effects on carbohydrate and protein metabolism) (Boothe and

13 Mealey, 2012). Introduction of a double bond between C-1 and
11 C-2 resulted in prednisone and prednisolone, revealing increased
C D 16 anti-inflammatory and reduced mineralocorticoid activity com-
1 9 pared with cortisone and cortisol. Of note, cortisone and predni-
10 14
sone are inactive compounds (or prodrugs) until the 11-keto group
2 is converted into a hydroxyl group in the liver by the enzyme 11-
8 15
B
hydroxysteroid dehydrogenase (11-HSD) type 1 (Parente, 2000;
A
Ferguson etal, 2009). The addition of a methyl group in position
3 7 C-6 resulted in methylprednisolone, which has slightly higher anti-
5
inflammatory and less mineralocorticoid effect than prednisolone.
4 6 The insertion of a 16-hydroxy group decreases mineralocorticoid
FIGURE 14-1 Basic chemical structure of the glucocorticoids (steroid nucleus). activity and leads to the synthesis of triamcinolone (which also has
a 9-fluoro group). The most potent anti-inflammatory glucocorti-
coids, dexamethasone and betamethasone, were designed by adding
a fluorine atom at C-9, which increases glucocorticoid activity, and
a methyl group at C-16, reducing mineralocorticoid effects (add-
ing was in -orientation for dexamethasone and -orientation for
betamethasone) (Parente, 2000). The effects of glucocorticoids are
21
dose dependent, and they are classified according to their potency
CH2 OH
in relation to the potency of cortisol (Table 14-1). There is an ongo-
ing search to identify compounds or mechanism by which adverse
20 effects can be minimized (McMaster and Ray, 2007; Vandevyver
C=O
18 etal, 2013). One mechanism is the topical administration of drugs,
12
CH3 which are rapidly metabolized if absorbed into the systemic circu-
17 lation. This goal is mainly reached by manipulation of chemical
HO OH
11 13
groups of the D ring of the steroid base (Ferguson et al, 2009).
19 Examples of those so-called soft glucocorticoids include beclo-
CH3 16 methasone, budesonide, fluticasone propionate, ciclesonide, and
1 9 loteprednol etabonate (Ferguson etal, 2009; Boothe and Mealey,
10 14 2012). In particular the use of budesonide as an oral drug for the
2
8 15 treatment of inflammatory bowel disease and budesonide and fluti-
casone propionate as inhaled medications for chronic inflammatory
3 airway disease has recently gained popularity in dogs and cats (Bex-
5 7 field etal, 2006; Padrid, 2006; Dye etal, 2013; Galler etal, 2013;
0
4 6
Pietra etal, 2013).
Cortisol (hydrocortisone) MOLECULAR MECHANISM OF ACTION

A
Genomic Effects
CH2 OH Glucocorticoid activities can roughly be divided into genomic
and nongenomic effects. The classical genomic effect is medi-
ated by a cytoplasmic glucocorticoid receptor (GR) that belongs
C=O to the nuclear receptor superfamily, which includes all of the
steroid receptors. GRs are widely distributed throughout the
CH3 body: every cell appears to have GRs (Boothe and Mealey,
O OH 2012). The GRs consist of three domains with different func-
tions: a poorly conserved N-terminal domain, a highly con-
served DNA-binding domain, and a well-conserved C-terminal
CH3 glucocorticoid-binding domain. Several splice variants of the
GR exist, of which GR is the most widely expressed and is the
variant exerting most of the glucocorticoid actions. The vari-
ant GR is unable to bind glucocorticoids, but it may act as an
inhibitor of GR. The variant may play a role in glucocorti-
coid resistance and possibly in autoimmune and inflammatory
0 disorders (Ferguson etal, 2009; Nixon etal, 2013). In the rest-
ing (ligand-free) state, GR is located in the cytoplasm, where it
Cortisone exists as a multiprotein complex containing several heat-shock
proteins (Hsp90, Hsp70, Hsp56, Hsp40); there is also interac-
B tion with other molecules, such as immunophilins and several
FIGURE 14-2Structure of (A) cortisol (hydrocortisone) and its inactive additional factors (Stahn etal, 2007; Vandevyver etal, 2013).
metabolite cortisone (B). The GR is inactive until bound to a glucocorticoid ligand.
|
CHAPTER 14 Glucocorticoid Therapy 557
Glucocorticoids enter the cell by passive diffusion through the a high-affinity GR (Nixon et al, 2013). The best character-
cell membrane, although there may also be an active trans- ized mechanism of transcriptional activation is the binding of
port mechanism. After binding of the glucocorticoid, the heat the GR/glucocorticoid complex to specific DNA binding-sites
shock proteins dissociate from the GR, resulting in confor- (glucocorticoid response elements [GREs]) in the promoter
mational changes that unmask nuclear localization sequences. regions of target genes after entering the nucleus (Vandevyver
Thereafter, the GR/glucocorticoid complex is translocated et al, 2013). Binding to positive GRE induces synthesis of
into the nucleus, where it activates or represses target gene anti-inflammatory proteins as well as regulator proteins that
transcription (Nixon etal, 2013). Although the main actions are important for metabolism (e.g., enzymes involved in glu-
of glucocorticoids are mediated through the GR, some effects coneogenesis). The process mediated through positive GRE
are also mediated through another nuclear receptor, the min- is also called transactivation and is considered to be respon-
eralocorticoid receptor (MR). The MR has a high affinity for sible for numerous side effects of glucocorticoids. Binding
endogenous glucocorticoids, which are generally present in to negative GRE leads to inhibition of gene transcription
much higher concentrations than mineralocorticoids. One of (transrepression) of the pro-opiomelanocortin (the precursor
the major mechanism by which the body limits the access of of adrenocorticotropic hormoneACTH), -fetoprotein,
endogenous glucocorticoids to the MR is through the activ- and prolactin gene, as well as suppression of inflammatory
ity of the enzyme 11-HSD type 2 that converts cortisol to genes, such as interleukin-1 (IL-1) and interleukin-2 (IL-
inactive cortisone. Therefore, when the MR is co-expressed 2) Lwenberg etal, 2007; Stahn etal, 2007). Besides binding
with 11-HSD type 2, its activation results in mineralocor- to GRE, other mechanisms for the upregulation and down-
ticoid activity; in the absence of 11-HSD type 2, the MR is regulation of genes exist. For instance, suppressed target gene
CH2 OH
CH2 OH
C=O
C=O
CH3
CH3 OH
OH O
HO
CH3
CH3
0
0
Prednisolone Prednisone
CH2 OH CH2 OH
C=O C=O
CH3 CH3
HO OH OH
HO
OH
CH3 CH3
0 0
CH3 Triamcinolone
Methylprednisolone
FIGURE 14-3 Structure of selected synthetic glucocorticoids.
CH2 OH
CH2 OH
C=O
C=O
CH3
CH3
HO OH
OH
HO
CH3
CH3 CH3
CH3
F
F
0
0
Dexamethasone Betamethasone
CH2 OH
C=O
O
CH3
CH3
HO
CH3
O
Budenoside
FIGURE 14-3, contd
expression can be achieved through direct protein-protein essential for the anti-inflammatory actions (Nixon etal, 2013;
interaction with pro-inflammatory transcription factors, Vandevyver etal, 2013).
such as activator protein-1 (AP-1), nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-B), nuclear Nongenomic Effects
factor of activated T-cells (NFAT), or signal transducers and
activator of transcription (STAT; Lwenberg et al, 2007). It In addition to the classic genomic mode of action, glucocorticoids
takes approximately 30 minutes for the activation of the GR, may exert effects through nongenomic mechanisms. It has been
nuclear transportation of the GR/glucocorticoid complex, recognized that some of the immunosuppressive, anti-inflamma-
binding to promoter regions, and initiation of transcription tory, anti-allergic effects, and effects when used during shock occur
and translation. Hours to days are required until changes on too fast to be regulated via transcription. Rapid clinical effects may
cellular, tissue or organism level become obvious (Stahn etal, be seen when glucocorticoids are administered intravenously or
2007). For many years, it was thought that the undesirable intra-articularly at high doses. Various underlying mechanisms for
side effects of glucocorticoid therapy are due to dimer-medi- the nongenomic effects have been described, such as nonspecific
ated transactivation, whereas its beneficial anti-inflammatory interactions of glucocorticoids with cellular membranes, nonge-
activity is mainly caused by monomer-mediated transrepres- nomic effects that are mediated by the cytosolic GR, and specific
sive effects. Research was therefore focused on the develop- interactions with a membrane-bound GR (Lwenberg etal, 2007;
ment of dissociated compounds that only exhibit those actions Stahn etal, 2007).
of glucocorticoids that are monomer-dependent. The dimer/ It has been shown that glucocorticoids at high concentrations
monomer dogma has recently been challenged, because it was intercalate into membranes, thereby changing their physiological
demonstrated that the GR dimer-dependent transactivation is properties and the activities of membrane-associated proteins. For
|
TABLE 14-1 COMPARISON OF THE CHARACTERISTICS OF THE MAJOR GLUCOCORTICOID PREPARATIONS
GLUCOCORTICOID/ANTI- MINERALOCORTICOID
DRUG INFLAMMATORY POTENCY POTENCY EQUIVALENT ORAL DOSE (mg) BIOLOGIC HALF-LIFE (h)
Short-Acting
Cortisol (hydrocortisone) 1 1 20 8-12
Cortisone 0.8 0.8 25 8-12
Intermediate-Acting
Prednisolone/Prednisone 4 0.8 5 12-36
Methylprednisolone 5 0.5 4 12-36
Triamcinolone 5 0 4 12-36
Long-Acting
Betamethasone 25-30 0 0.7-0.8 36-72
Dexamethasone 25-30 0 0.7-0.8 36-72
Mineralocorticoids
Aldosterone 0 200-1000
Fludrocortisone 10 125-200
Data from Parente L: The development of synthetic glucocorticoids. In Goulding NJ, Flower RJ, editors: Glucocorticoids, Basel, 2000, Springer Basel AG; and Boothe DM, Mealey KA:
Glucocorticoids and mineralocorticoids. In Boothe DM, editor: Small animal clinical pharmacology and therapeutics, ed 2, St Louis, 2012, Saunders/Elsevier.
instance, this results in reduced calcium and sodium cycling across metabolism), decreased protein synthesis, and increased release of
the cell membrane of immune cells, which contributes to rapid amino acids, providing precursors for gluconeogenesis in the liver.
immunosuppression and reduction of the inflammatory process. In adipose tissue, glucocorticoids stimulate lipolysis, which gener-
Binding of glucocorticoids to the cytosolic GR leads to dissociation ates free fatty acids and glycerol, thereby providing energy and
of signaling molecules, which mediate rapid responses; the cyto- substrate for gluconeogenesis (Carroll etal, 2011; Hall, 2011).
solic GR is also involved in inhibition of the release of arachidonic In healthy individuals, the increase in blood glucose is coun-
acid, an essential mediator for cell growth and various metabolic/ terbalanced by an increase in insulin secretion. High levels of
inflammatory reactions. Binding of glucocorticoids to a membrane- glucocorticoids (endogenous or exogenous) reduce the sensibility
bound GR, which may be a variant of the cytosolic GR, seems to be of many tissues, in particular muscle and fat, to the stimulatory
involved in apoptosis and T cell receptormediated signal transduc- effects of insulin on glucose uptake and utilization (i.e., lead to
tion (Stahn etal, 2007). The physiological significance of the non- insulin resistance). In this way, glucocorticoids may induce glu-
genomic effects is not totally clear. It is assumed that they play an cose intolerance and diabetes mellitus or worsen glycemic control
important role during stress when the concentration of endogenous in an individual with pre-existing diabetes. Glucocorticoid excess
glucocorticoids is high (Jiang et al, 2014). Fig. 14-4 summarizes also leads to increased breakdown of protein, clinically seen as
genomic and nongenomic mechanisms of glucocorticoids. muscle wasting, thinning of the skin, and delayed wound healing
(Boothe and Mealey, 2012). Although glucocorticoids stimulate
BIOLOGIC EFFECTS OF GLUCOCORTICOIDS lipolysis, increased fat deposition is a common clinical sign. The
paradox has been explained by steroid-induced stimulation of
The name glucocorticoid is derived from the words glucose and appetite and the lipogenic effect of hyperinsulinemia. The reason
cortex, and it relates to the role of glucocorticoids in glucose for the abnormal fat distribution is unknown (Carroll etal, 2011).
metabolism and their origin from the adrenal cortex. Glucocorti-
coids, however, have a much broader spectrum of function, they
Effects on Other Tissues
influence most cells in the body, and without them an individual
will not survive a stressful event. Growth and Development
Glucocorticoids play an important role in normal fetal development.
They stimulate lung maturation through synthesis of surfactant pro-
Effects on Carbohydrate, Protein, and Lipid Metabolism
teins in the near-term fetus, allowing adaption to air breathing. In
The physiological effects of glucocorticoids in the fed state are physiological concentrations, glucocorticoids stimulate gene tran-
small; however, during fasting, they contribute to the mainte- scription of growth hormone (GH); glucocorticoid excess, however,
nance of blood glucose levels by increasing hepatic gluconeogen- inhibits skeletal growth by catabolic effects on bone, muscle, and
esis and decreasing uptake of glucose in peripheral tissues (muscle, connective tissue and inhibition of insulin-like growth factor-1
fat). These effects protect glucose-dependent organs (e.g., brain (IGF-1) effects (Ferguson etal, 2009).
and heart) from starvation. Glucocorticoids stimulate glycogen
deposition and inhibit glycogen-mobilizing enzymes. This allows Bone, Cartilage, and Calcium
other hormones (e.g., glucagon and epinephrine) to mobilize glu- The effects of glucocorticoids on bone are complex and include
cose when needed (e.g., between meals). Glucocorticoids exert direct and indirect effects. Under physiological circumstances,
catabolic effects on muscle (i.e., decreased glucose uptake and bone formation and bone resorption are tightly coupled; in cases of
FIGURE 14-4 Genomic and nongenomic immunoregulation by glucocorticoids (GCs). GCs passively diffuse into
cells and bind to the cytoplasmic glucocorticoid receptor (GR), after which the GC-GR complex translocates into
the nucleus for gene regulation. Left: Ligated GR directly inhibits pro-inflammatory transcription factors (i.e.,
activator protein-1 [AP-1], nuclear factor of activated T-cells [NFAT], nuclear factor kappa-light-chain-enhancer
of activated B cells [NF-B], and signal transducers and activator of transcription [STAT]) (a) or actively sup-
presses transcription (transrepression) of inflammatory genes (i.e., interleukin-1 [IL-1] and IL-2) through
binding to negative glucocorticoid response elements (nGRE) (b). Activated GR induces transcription (transacti-
vation) of immunosuppressive genes (i.e., IB, annexin-1, IL-10, mitogen-activated protein kinase [MAPK] phos-
phatase-1, lipocortin-1, and annexin-1) via positive GREs (pGRE) (c). GC-induced biological responses, which are
based on transrepression, are slow because some time is required before RNA and protein levels of target genes
are fully degraded (a,b). GC-dependent transactivation of genes that encode regulator proteins is less slow (me-
dium slow) compared with transrepression (c). Right: GCs induce rapid effects (occurring within minutes) on
transmembrane currents, signal transduction (e.g., T-cell receptor [TCR] and MAPK signaling pathways), second-
messenger cascades or intracellular Ca2+ mobilization. It is currently assumed that nongenomic GC effects
are mediated by cytosolic or membrane-bound GRs, or via nonspecific interactions with cell membranes. In this
simplified scheme, no GR-chaperones are depicted. (Reproduced with permission from Loewenberg M, Verhaar
AP, van den Brink GR, etal.: Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression,
Trends Mol Med 13:158, 2007.) cGR, Cytosolic glucocorticoid receptor; mGR, membrane-bound glucocorticoid
receptor; TF, transcription factor.
glucocorticoid excess, those processes are uncoupled (van Brussel the study by Costa and colleagues (2010) and also do not occur in
etal, 2009). Glucocorticoid excess decreases number and function dogs with long-standing glucocorticoid excess (e.g., in dogs with
of osteoblasts, induces apoptosis of osteocytes, and increases the endogenous hyperadrenocorticism).
formation of osteoclasts. Indirect effects include disturbed calcium At physiological concentrations, glucocorticoids stimulate col-
metabolism, muscle weakening, and decrease of GH and gonado- lagen; glucocorticoid excess results in inhibition of collagen syn-
tropin secretion (Canalis etal, 2007; van Brussel etal, 2009). In thesis, depression of chondrocyte metabolism, and decrease of the
humans, glucocorticoid-induced osteoporosis belongs to the most proteoglycan content of cartilage (Boothe and Mealey, 2012).
devastating side effects of long-term glucocorticoid therapy (van Glucocorticoids inhibit calcium absorption from the intesti-
Brussel etal, 2009). In dogs and cats, effects of glucocorticoids are nal tract by antagonizing the effect of active vitamin D3 and by
rarely described. Recently, the effect of glucocorticoids on mineral decreasing the expression of specific calcium channels in the
density of the vertebral spine was investigated. Application of duodenum. The inhibition is not due to decreased levels of
2 mg/kg prednisone over 30 days led to a significant loss of bone vitamin D3, as those are normal, or even increased in the pres-
mass (Costa etal, 2010). Pathological fractures were not seen in ence of glucocorticoid excess. Glucocorticoids also increase renal
|
calcium excretion as well as the excretion of phosphorous. Serum aldosterone revealed conflicting results (Goy-Thollot etal, 2002;
phosphate concentrations are reduced, whereas calcium concentra- Javadi etal, 2003; Wenger etal, 2004). Martinez and colleagues
tions are usually maintained normal (Canalis etal, 2007; Carroll (2005) demonstrated increased vascular reactivity to increasing
etal, 2011). Theoretically, the reduced absorption and increased doses of norepinephrine in dogs with experimentally induced
secretion of calcium would promote secondary hyperparathyroid- hypercortisolism.
ism. In humans on glucocorticoid therapy, however, increased Glucocorticoids increase the number and affinity of 2 recep-
parathyroid hormone (PTH) levels have not been consistently tors, thus promoting bronchodilatation (Boothe and Mealey,
demonstrated. Glucocorticoids may alter the secretory dynamics 2012).
of PTH with a decrease in its tonic release and an increase in pul-
satile bursts. Additionally, they may enhance sensitivity of skeletal Gastrointestinal Tract
cells to PTH by increasing the number and affinity of PTH recep- Glucocorticoids are involved in normal function and integrity of
tors (Canalis etal, 2007). So far, no detailed studies on calcium the gastrointestinal tract. Glucocorticoid excess is associated with
balance in dogs and cats with endogenous or exogenous glucocor- reduced gastric mucosal cell growth and renewal and decreased
ticoid excess have been performed. In dogs, the administration of mucus production, resulting in impairment of the protective bar-
approximately 1 mg/kg prednisolone every other day for 6 weeks rier of the gastric mucosa (Boothe and Mealey, 2012). Gluco-
did not result in significant changes in concentrations of total corticoid therapy in dogs with neurological disease may result
and ionized calcium, phosphate, vitamin D metabolites (25(OH) in gastrointestinal hemorrhage, ulcers, and colonic perforations.
D and 1,25(OH)2D3), and PTH in blood and urinary fractional Gastric hemorrhage has also been described in healthy dogs given
excretion of calcium and phosphate (Kovalik et al, 2012). The high doses of methylprednisolone sodium succinate (Rohrer
results contrast in part those of Ramsey, etal., (2005) who assessed etal, 1999a).
parameters of calcium metabolism in dogs with endogenous
hyperadrenocorticism. Total and ionized calcium concentrations Central Nervous System Function
were not different to a matched control group. Different from Glucocorticoids are involved in maintaining adequate blood glu-
humans and the study of Kovalik, et al, (2012), phosphate and cose concentrations for cerebral functions, maintaining cerebral
PTH concentrations were significantly higher. Approximately one blood flow, and influencing electrolyte balance in the central
third of the dogs had PTH concentrations greater than three times nervous system (CNS). They also decrease formation of cerebro-
the reference range. No explanation for the increased phosphate spinal fluid, appear to regulate neuronal excitation, and appear
concentrations could be given; it was assumed to play a role in the to have neuroprotective effects (Boothe and Mealey, 2012). In
increase in PTH concentrations (Ramsey etal, 2005). humans, glucocorticoid excess initially causes euphoria, and pro-
longed exposure may result in various psychologic abnormalities,
Renal Function including irritability, emotional lability, and depression; impair-
Glucocorticoids increase the glomerular filtration rate, sodium ment in cognitive functions is also common (Carroll etal, 2011).
transport in the proximal tubule, and free water clearance. They In dogs treated with glucocorticoids, euphoric effects are also
have an inhibitory effect on antidiuretic hormone (ADH) and commonly seen.
may decrease permeability of the distal tubules to water through a
direct effect (Boothe and Mealey, 2012). Cortisol and several syn- Blood Cells
thetic glucocorticoids have mineralocorticoid activity. Depending Glucocorticoids have only little effects on erythrocytes, although
on the concentration or dose and the activity of the 11-HSD mild polycythemia may be seen. The underlying mechanism may
type 2, they act on the MR and cause sodium retention and potas- be glucocorticoid-induced enhancement of erythroid progenitor
sium loss. The polyuria and polydipsia commonly seen in dogs proliferation (von Lindern etal, 1999).
(infrequently in non-diabetic cats treated with glucocorticoids) is Endogenous or exogenous glucocorticoid excess may induce
considered to be mainly due to inhibition of ADH release and leukocytosis in dogs and cats. The leukogram (stress leukogram)
action. is characterized by mature neutrophilia, lymphopenia, and eosin-
openia. In dogs, monocytosis may be an additional finding, which
Cardiovascular and Respiratory Functions is usually not present in cats. The mature neutrophilia is due to
Glucocorticoids have positive inotrope and positive chronotropic several factors, such as increased release of neutrophils from bone
actions on the heart. Because glucocorticoids are necessary for marrow, shift of marginated neutrophils in the circulating neutro-
maximal catecholamine sensitivity, they contribute to the main- phil pool, and decreased movement of neutrophils from blood into
tenance of normal vascular tone. They decrease capillary perme- tissue. Lymphopenia is the result of a redistribution of circulating
ability through inhibition of the activity of kinins and bacterial lymphocytes; lysis of lymphocytes may occur with high doses of
endotoxins and by decreasing the amount of histamine released glucocorticoids. Eosinopenia is caused by inhibition of eosinophil
by basophils (Ferguson etal, 2009). Refractory shock may occur release from the bone marrow and sequestration of eosinophils
when individuals deficient in glucocorticoids are exposed to stress within tissues (Schultze, 2010; Valenciano etal, 2010). In dogs,
(Carroll etal, 2011). glucocorticoid excess may provoke thrombocytosis (Neel et al,
Glucocorticoid excess may lead to hypertension through vari- 2012); knowledge on potential glucocorticoid-induced thrombo-
ous mechanisms, such as their intrinsic mineralocorticoid activity, cytosis in cats is scarce.
activation of the renin-angiotensin-aldosterone system; enhance-
ment of cardiovascular inotropic and pressor activity of vasoactive Hypothalamic Pituitary Adrenal Axis
substances, including catecholamines, vasopressin and angioten- Glucocorticoids inhibit synthesis and secretion of ACTH from the
sin II; and suppression of the vasodilatory system, including the corticotropic cells in the anterior pituitary and of corticotropin-
nitric oxide (NO) synthase, prostacyclin and kinin-kallikrein sys- releasing hormone (CRH) and ADH from neurons in the hypo-
tems. The exact mechanisms in dogs and cats have not been elu- thalamus in a negative feedback fashion. Exogenous glucocorticoids
cidated (Reusch etal, 2010). The studies on the potential role of have profound effects on the hypothalamic pituitary adrenal
(HPA) axis. Even physiological doses of glucocorticoids (0.22

Anti-Inflammatory and Immunosuppressive Effects
mg/kg prednisolone once daily) may result in suppression of
the HPA axis, which is reflected by reduced increase of cortisol Glucocorticoids suppress inflammatory and immune-mediated
after ACTH stimulation and lead to a reduction of the zona fas- responses of the body, and this fact has been the stimulus for the
ciculate and reticularis to the zona glomerulosa in the adrenal development of potent glucocorticoid preparations. The anti-
gland (Ferguson etal, 2009). Generally, the degree and dura- inflammatory and immunosuppressive effects only occur when
tion of suppression of the HPA axis depends on dose, potency, supraphysiological doses (i.e., pharmacological doses) are given.
half-life, and duration of administration of the glucocorticoid Both effects are closely related, and which of the two predomi-
preparation. HPA axis suppression can occur with any form of nates in a clinical situation is a question of the dose given. Many
glucocorticoid. Glucocorticoids possessing anti-inflammatory hundreds of glucocorticoid response genes have been identified.
effects but no suppressive effects on the HPA axis have not Additional to the genomic effects, rapid actions of glucocorti-
yet been identified (Ferguson etal, 2009). For more details on coids on inflammation are mediated by nongenomic mechanisms
HPA axis suppression, see the Adverse Effects section. (Rhen and Cidlowski, 2005). It is important to remember that
the encompassing properties render glucocorticoid therapy dan-
Thyroid Function gerous, because it can mask severity and progression of the disease
Glucocorticoids have a major impact on the hypothalamic pitu- and serious side effects may occur. Glucocorticoids limit early and
itary thyroid axis and also influence peripheral metabolism of thy- late manifestations of inflammation, including edema formation,
roid hormones. Main proposed mechanisms include inhibition of fibrin deposition, leukocyte migration, phagocytic activity, colla-
synthesis and release of thyroid-stimulating hormone (also known gen deposition, and capillary and fibroblast proliferation. Many of
as thyrotropin; TSH), decrease in thyroxine (T4) binding proteins, these processes involve lymphokines, and other soluble mediators
and impairment of peripheral 5-deiodination. Studies in dogs do of inflammation and glucocorticoids exert their anti-inflamma-
not point as clearly to a suppressive effect on TSH secretion in tory effects through those mediators (Boothe and Mealey, 2012).
dogs as compared to humans. In dogs with hyperadrenocorticism, Generally, due to the fact that GR expression is ubiquitous, gluco-
reduced T4 and triiodothyronine (T3) concentrations were found corticoids can affect nearly all cells of the immune system. Glucocor-
in more than 50% of cases. The concentrations of both hormones ticoids inhibit proliferation, growth and differentiation, adhesion,
normalized during treatment of the hyperadrenocorticism. The migration, and chemotaxis of monocytes/macrophages, neutro-
T4 response after TSH administration was also reduced (Peter- phils, and T cells (Box 14-1). Antigen processing by monocytes/
son etal, 1984). TSH concentrations in dogs with hyperadreno- macrophages is suppressed, and antibody production by B cells may
corticism were not different from that of control dogs in another be impaired; apoptosis of monocytes/macrophages, T cells, and B
study (Meij etal, 1997). The effect of exogenous glucocorticoids cells is increased (Vollmar and Dingermann, 2005). Of note, B
on thyroid hormones has been evaluated in various studies. The
duration and extent of thyroid hormone suppression varies with
type, dose, and route of administration, and duration of therapy BOX 14-1 S
elected Effects of Glucocorticoids
and is certainly also influenced by individual sensitivity. In dogs, on the Immune System
the application of immunosuppressive doses of prednisone/pred-
nisolone (1.1 to 2.0 mg/kg twice a day) for 3 weeks significantly Neutrophils
decreased T4; it also decreased free T4, albeit to a lesser extent. Neutrophilia
The effect on T4 was seen as early as 1 day after start of therapy. Depressed chemotaxis
Endogenous TSH concentrations were not affected (Torres etal, Depressed margination
1991; Daminet etal, 1999; Daminet and Ferguson, 2003). See Depressed phagocytosis
Chapter 3 for more details. Depressed antibody-dependent cellular cytotoxicity
Depressed bactericidal activity
Growth Hormone and Gonadotropins Stabilization of membranes
Glucocorticoids decrease GH secretion, most likely by increas- Inhibition of phospholipase A2
ing somatostatin release. Dogs with hyperadrenocorticism have
Macrophages
decreased response of GH after stimulation with xylazine, clonidine,
Depressed chemotaxis
and growth hormone-releasing hormone (GHRH) (Frank, 2005).
Depressed phagocytosis
Exogenous glucocorticoid excess presumably has the same effect.
Depressed bactericidal activity
Hyperadrenocorticism is also frequently associated with repro-
Depressed IL-1 and IL-6 production
ductive disturbances, such as testicular atrophy, reduced libido,
Depressed antigen processing
and persistent anestrus. Similarly, exogenous glucocorticoid
(prednisone) leads to a decrease in circulating testosterone con- Lymphocytes
centrations in male dogs. Prednisone treatment also resulted in a Depressed proliferation
reduction of basal luteinizing hormone (LH) concentration, which Depressed T-cell responses
suggested that glucocorticoids inhibit the gonadal axis at the hypo- Impaired T-cell mediated cytotoxicity
thalamic or pituitary level (Kemppainen etal, 1983; Kemppainen, Depressed IL-2 production
1984). Interestingly, however, basal LH concentrations in dogs Depressed lymphokine production
with hyperadrenocorticism were not different from controls. It was Immunoglobulins
hypothesized that glucocorticoids have a direct inhibitory effect Decreased antibody synthesis only after high dose, long-term therapy
on gonads and/or on transport and metabolism of their secretory Interference with antibody function
products and influence the sensitivity of the feedback control at
the hypothalamic/pituitary level (Meij etal, 1997). Glucocorticoid Modified from Tizard IR, Veterinary immunology, ed 9, St Louis, 2013, Elsevier.
administration to pregnant dogs may lead to abortion. IL, Interleukin.
|
cells are thought to have greater resistance to the effects of gluco- from plasma, whereas the biological half-life refers to the dura-
corticoids, although the inhibition of T-cell help will have indirect tion of effect. The biologic half-life of glucocorticoids is dispa-
consequences for B-cell activation. Glucocorticoids may inhibit the rate, because many of the biological effects are due to alterations
action of complement molecules and interfere with the function in genetic regulation of protein production; biological effects are
of immunoglobulins by down-regulation of Fc receptor expression delayed and prolonged compared to the drug concentration in
(Day, 2011). Usually, high doses of glucocorticoid are required to plasma (Cohn, 2010). It is the biological half-life that needs to
suppress antibody production, and therapeutic doses do not signifi- be considered when a treatment protocol is established. Gluco-
cantly decrease the antibody response to an antigenic challenge (e.g., corticoids are usually divided into three groups according to the
vaccinations; Boothe and Mealey, 2012; Tizard, 2013). duration of HPA axis suppression. Cortisol (hydrocortisone)
Inflammatory and immunologic reactions are mediated by various and cortisone are considered short-acting (biologic half-life < 12
signaling pathways. The pathways that are associated with the activa- hours); prednisolone, prednisone, methylprednisolone, and tri-
tion of NF-B are of particular importance (Fig. 14-5). In its inactive amcinolone are intermediate-acting (biologic half-life 12 to
state, NF-B is sequestered in the cytoplasm by the inhibitory factor 36 hours); and dexamethasone and betamethasone are long-acting
IB-. Tumor necrosis factor alpha (TNF), interleukin-1 (IL-1), drugs (biologic half-life 36 to 72 hours) (see Table 14-1). Duration
microbial pathogens, viral infections, and other inflammatory signals of action is influenced by factors such as route of administration,
trigger signaling cascades that activate IB- kinases, resulting in libe the preparation used (e.g., soluble or insoluble steroid ester), and
ration and translocation of NF-B into the nucleus. NF-B stimu- other variables, such as health of the patient and concurrent use
lates the transcription of cytokines (e.g., IL-1, IL-2, IL-6, and TNF), of other drugs.
chemokines (e.g., IL-8, monocyte chemotactic protein-1 [MCP-1]),
cell-adhesion molecules, complement factors, and receptors for these
Route of Administration
molecules. After binding to its receptor, glucocorticoids inhibit NF-B
by direct protein-protein interaction; glucocorticoids also induce the Glucocorticoids of varying potency are available in oral, paren-
synthesis of IB-, thereby inhibiting translocation of NF-B into the teral, and topical formulations.
nucleus (Rhen and Cidlowksi, 2005; Steinfelder and Oetjen, 2009;
see also http://www.bu.edu/nf-kb/gene-resources/target-genes/). Oral
Similar to NF-B, the transcription factor AP-1 is one of the Cortisol (hydrocortisone) and synthetic glucocorticoids are
key mediators of the inflammatory response; AP-1 is inhibited by orally effective, and oral administration is the preferred route
glucocorticoids as well (Busillo and Cidlowski, 2013). NF-B also for systemic application (except in emergency situations). It is
induces the transcription of cyclooxygenase 2 (COX2), an enzyme the safest, most convenient, and most economical route. The
that is essential for prostaglandin production; glucocorticoids main disadvantages and limitations of the oral route include
inhibit COX2 through inhibition of NF-B. Other mechanisms vomiting as a result of irritation of the gastric mucosa, variable
by which glucocorticoids inhibit prostaglandin synthesis are medi- absorption due to many factors (gastrointestinal disease, local
ated through induction and activation of annexin I (also called blood flow, and/or presence of food or other drugs), and the
lipocortin-1) and through induction of mitogen-activated protein need for cooperation of the pet. The oral bioavailability differs
kinase (MAPK) phosphatase 1. Annexin I is an anti-inflammatory between glucocorticoids; it is generally highest for cortisol,
protein that inhibits phospholipase A2, thereby blocking the release prednisolone, and methylprednisolone and lower for dexa-
of arachidonic acid and its subsequent conversion to eicosanoids. methasone. Triamcinolone and budesonide have a very low oral
Phospholipase A2 is also inhibited by MAPK phosphatase 1. bioavailability; in the case of budesonide, the low bioavailability
MAPKs are pivotal in the regulation of immune responses; they are is a desired effect because it is designed for local application
involved in the production of inflammatory mediators (e.g., TNF, (e.g., for treatment of inflammatory bowel disease [IBD]).
IL-1, IL-6, prostaglandin, NO, and inducible nitric-oxide synthase) Previously, it had been thought that prednisolone and the pro-
and in T-cell development and function. Removal of the phospha- drug prednisone are equivalent in terms of dosing when used as
tases (which is induced by glucocorticoids) renders MAPK inac- oral drugs. However, this belief does not seem to be correct. It
tive (Rhen and Cidlowski, 2005; Liu etal, 2007). Glucocorticoids was shown in cats that only 21% of orally-administered predni-
reduce local inflammation by preventing the actions of histamine sone appeared in the blood as active prednisolone. It is not clear if
and plasminogen activators (Stewart and Krone, 2011). In summary, the differences are due to decreased gastrointestinal absorption or
the anti-inflammatory and immunosuppressive effects of gluco- to decreased hepatic conversion of prednisone to prednisolone
corticoids are attributed to partial or complete suppression of an (Graham-Mize and Rosser, 2004). According to these data, the
extremely complex interplay of cells and cell mediators. The potent dose of prednisone must be three- to fivefold higher than that of
effects of glucocorticoids on leukocytes are responsible for most of prednisolone to achieve equivalent activity (Boothe and Mealey,
the anti-inflammatory activity. These effects are also immunosup- 2012). Because prednisone is commonly used in cats, its poor
pressive, which explains their efficacy in immune-mediated disease. absorption (or poor conversion) may contribute to the perceived
It should be remembered, however, that glucocorticoids can lead to glucocorticoid resistance in cats (Lowe etal, 2008a). Also in dogs,
an increased susceptibility to infection (Papich and Davis, 1989). oral administration of prednisone may not result in systemic predni
solone concentrations, which are achieved with oral prednisolone.
The relative bioavailability of prednisolone was only 65% when
PHARMACOKINETICS AND CLINICAL
prednisone was administered compared to the administration of
PHARMACOLOGY
prednisolone (Boothe and Mealey, 2012). These data suggest that
prednisolone should be preferred over prednisone.
Duration of Action
A distinction has to be made between plasma half-life and bio- Parenteral
logical half-life of glucocorticoids. Plasma half-life is the amount Most glucocorticoids for parenteral use are synthesized as glu-
of time required for 50% of a drugs concentration to disappear cocorticoid esters, which either improves solubility or increases
Cytokine
Glucocorticoid
Proinflammatory
proteins
Cell membrane
Cytokine receptor
Protein
Cytoplasm
P
IKBa Glucocorticoid
IKBa receptor
p50 p65
NF-KB p50 p65
IKBa mRNA
Nucleus
mRNA
Direct
interaction
p50 p65
Glucocorticoid Coding
response element sequence
IKBa-gene Proinflammatory
gene
FIGURE 14-5 Inhibition of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-B) by glucocorticoids. NF-B is a dimer and consists of two subunits (p50, p65). In its inactive state, it is
sequestered in the cytoplasm by the inhibitory factor IB-. Upon stimulation by, for example, cytokines NF-B is
released and translocates into the nucleus. After binding to specific DNA sites, NF-B increases the transcription
of target genes, which include genes of cytokines, chemokines, growth factors, cell adhesion molecules, comple-
ment factors, immunoreceptors, and cyclooxygenase 2 (COX2). Glucocorticoids inhibit NF-B after their binding to
the glucocorticoid receptor (GR) through direct protein-protein interaction between the GR and the p65 subunit.
Glucocorticoids can also stimulate the transcription of the IB- gen, thereby augmenting the inhibition of NF-B.
Inhibition of NF-B is one of the major mechanisms of the anti-inflammatory and immunosuppressive effect of
glucocorticoids. (Redrawn from Steinfelder HJ, Oetjen E: Nebennierenrindenhormone. In Aktories K, Foerstermann U,
Hofmann F, Starke K, editors: Allgemeine und Spezielle Pharmakologie und Toxikologie, ed 10, 2009, Elsevier Urban
& Fischer.) mRNA, Messenger ribonucleic acid.
|
TABLE 14-2 SOME CHARACTERISTICS OF COMMON ROUTES OF DRUG ADMINISTRATION
ROUTE ABSORPTION PATTERN SPECIAL UTILITY LIMITATIONS AND PRECAUTIONS

Intravenous (IV) Absorption circumvented Valuable for emergency use Increased risk of adverse effects
Potentially immediate effects Permits titration of dosage Must inject solutions slowly as a rule
Suitable for large volumes and for Not suitable for oily solutions or insoluble substances
irritating substances when diluted
Subcutaneous (SC) Prompt, from aqueous solution Suitable for some insoluble suspensions Not suitable for large volumes
Slow and sustained, from repository and for implantation of solid pellets Possible pain or necrosis from irritating substances
preparations
Intramuscular (IM) Prompt, from aqueous solution Suitable for moderate volumes, oily Precluded during anticoagulant medication
Slow and sustained, from repository vehicles, and some irritating substances May interfere with interpretation of certain diagnostic
preparations tests (e.g., creatine phosphokinase)
Oral ingestion Variable, depends upon many Most convenient and economical; Requires patient cooperation
factors (see text) usually safer than other routes Absorption potentially erratic and incomplete for drugs
that are poorly soluble, slowly absorbed, or unstable
duration of action. Water-soluble esters of cortisol and synthetic binding capacity. Albumin, on the other hand, has a low affinity but
glucocorticoids can be given intravenously to achieve high con- large binding capacity. Glucocorticoids compete with one another
centrations rapidly. Prolonged effects are obtained by intramus- for binding sites and will displace one another at high concentra-
cular (IM) injection of water-insoluble esters (suspensions) of tions (Boothe and Mealey, 2012). Compared to cortisol, binding
cortisol and its synthetic derivatives (see later). Injection of drugs to CBP is less for synthetic glucocorticoids; they are mainly bound
has certain advantages over oral administration. Absorption is to albumin or circulate as free hormones, thereby diffusing more
usually more predictable than oral application, and therefore, the readily into tissues. Glucocorticoids distribute widely in all tissues
effective dose can be accurately selected. In particular, intravenous of the body, and they pass the blood brain and placental barrier.
(IV) administration circumvents absorption issues and permits Glucocorticoids are metabolized in the liver and to a lesser extent
titration of dose. It also allows the administration of large vol- in the kidney; synthetic drugs are metabolized slower than cortisol.
umes. Disadvantages include the need for asepsis, possible pain Metabolism is by oxidation or reduction followed by glucuronida-
and necrosis, and costs. See Table 14-2 for some characteristics of tion or sulfation, and excretion of the metabolites is mainly via the
the major routes of glucocorticoids. kidney. Only small amounts of glucocorticoids are excreted in the
unmodified form. Biliary and fecal elimination do not appear to
Topical be significant; enterohepatic cycling takes place to a small extent
Topical steroids for dermatological indications are available in (Ungemach, 2010; Boothe and Mealey, 2012).
ointments, creams, gels, solutions, shampoos, and rinses. Glu- Synthetic steroids with an 11-ketogroup, such as cortisone and
cocorticoids for ophthalmological indications come as eye drops prednisolone, must be enzymatically reduced to the 11--hydroxy
(aqueous solutions and suspensions) and ointments; intra-articular derivative before they become biologically active. The enzyme 11-
application is usually in form of crystal suspensions. Glucocor- HSD type 1, which catalyzes this reaction, is expressed mainly in
ticoids are also used as inhalants in patients with lung disease. the liver but also in other tissues, including adipose tissue, immune
Topical therapy can provide high concentrations of a potent glu- system cells, and brain tissue. Similarly, also in natural situations, this
cocorticoid at a specific site while reducing systemic side effects. enzyme generates active (endogenous) cortisol from inactive (endog-
However, topical glucocorticoids can be absorbed to a certain enous) cortisone. The isoform 11-HSD type 2 is predominantly
extent, exerting the same adverse reaction as systemically admin- expressed in classic mineralocorticoid targets, such as distal nephron,
istered steroids. The extent of percutaneous absorption depends salivary glands, colon, and placenta. It inactivates cortisol by mediat-
on various factors, including the preparation vehicle, ester form of ing the conversion to inactive cortisone and thereby ensures that only
the steroid (greater lipid solubility enhances percutaneous absorp- aldosterone binds to the MR (Chapman etal, 2013; Fig. 14-6).
tion), integrity of epidermal barriers (e.g., absorption is increased
in case of inflammation), size of treated area, and duration of treat- Dose Equivalents of Glucocorticoids
ment. Absorption is enhanced by use of occlusive wraps and possi-
bly by clipping the skin (Behrend and Kemppainen, 1997; Boothe The glucocorticoid activity is closely related to the anti-inflam-
and Mealey, 2012). Systemic effects (e.g., suppression of the HPA matory activity, and the effective anti-inflammatory time usually
axis) may also occur with inhaled glucocorticoids and in conjunc- equals the time of HPA axis suppression (Ferguson etal, 2009).
tion with intra-articular, intra-lesional, or ocular application. The anti-inflammatory and mineralocorticoid activities of corti-
sol (hydrocortisone) are used as a baseline for comparison with
Distribution, Metabolism, and Excretion the synthetic glucocorticoids and are arbitrarily assigned as being
1. Chemical modifications have generated glucocorticoids with
After absorption, cortisol and synthetic glucocorticoids are bound greater glucocorticoid/anti-inflammatory activity and less miner-
to corticosteroid binding protein (CBP, also called transcortin) and alocorticoid activity. Some derivatives (e.g., triamcinolone, dexa-
albumin. Only the unbound, free fraction of glucocorticoids is methasone) have no or negligible mineralocorticoid effects even
active and can enter cells. CBP is -globulin secreted by the liver, at high doses. Increased anti-inflammatory potency is also associ-
which has a high affinity for glucocorticoids but a relatively low ated with longer duration of action. The latter can be prolonged
FIGURE 14-6Interconversion of cortisol and

cortisone by 11-hydroxysteroid dehydrogenase
(11-HSD) type 1 and 2. Similar to the conver-
sion of cortisone to cortisol, prednisone has
to be converted to prednisolone to be able to
bind to the glucocorticoid receptor (GR). NAD+,
Nicotinamide adenine dinucleotide; NADH, nico-
tinamide adenine dinucleotide plus hydrogen;
NADP+, nicotinamide adenine dinucleotide
phosphate; NADPH, nicotinamide adenine di-
nucleotide phosphate plus hydrogen.
substantially by esterification. See the Chemistry of Glucocorti- kind of ester at C-21 of the glucocorticoid base determine to a
coids and Structure-Activity Relationship section and Box 14-1 large extent the lipid/water solubility ratio and the duration of
for more details; the effects of esterification are discussed later. action (Ferguson etal, 2009). The ester moiety also determines if
There is a general belief that there are no relevant qualitative dif- the drug can be given intravenously, intramuscularly, or topically
ferences between the various glucocorticoid preparations because (Fig. 14-7; Table 14-3). Glucocorticoid preparations for oral use
they all bind to the GR. Equipotent amounts of any glucocorticoid are either free alcohols or they are esterified; however, in this case,
exert similar effects, meaning that a higher dose of a less potent esterification does not impair bioavailability.
glucocorticoid can achieve the same effect as a lower dose of a more For parenteral application, three galenic formulations are
potent preparation (Cohn, 2010). When choosing a treatment available.
protocol, the veterinarian has to be aware of the equivalent doses
of glucocorticoids. Failure to make dose adjustments for different Water-Soluble Ester (Aqueous Solutions)
glucocorticoids will result in the administration of inadequate or The most commonly used esters are succinate, hemisuccinate,
excessive doses, leading to either inefficacy or dangerous overdose. and phosphate; common formulations are hydrocortisone sodium
For instance, a dose of 1 mg/kg prednisolone in a dog is a reason- succinate, prednisolone sodium succinate, prednisolone sodium
able anti-inflammatory dose; the equivalent dose of dexamethasone phosphate, methylprednisolone sodium phosphate, and dexa-
is only approximately 0.14 mg/kg (Calvert and Cornelius, 1990a). methasone sodium phosphate. Those esters are hydrolyzed within
Generally, the anti-inflammatory dose is considered to be approxi- minutes, resulting in immediate availability of the glucocorticoid.
mately 10 times the physiological dose, and immunosuppressive They can be administered intravenously, as well as intramuscularly
doses are roughly twice the anti-inflammatory dose. In contrast to and subcutaneously. These characteristics render them ideal for
the aforementioned belief of equal effects, it is possible that there emergency situations. The duration of action of these esterified
are indeed some qualitative differences between the various syn- glucocorticoids is equivalent to that of the unmodified glucocor-
thetic steroids. In an invitro model, it was shown that dexametha- ticoid (Cohn, 2010).
sone was more effective than prednisone and cortisol in inhibiting
the clearance of immunoglobulin G (IgG)-coated cells by its effect Free Alcohol Solutions
on Fc receptors of splenic macrophages (Ruiz et al, 1991). In These preparations are unique to veterinary medicine as dexa-
healthy cats, dexamethasone showed a greater diabetogenic effect methasone solutions. Dexamethasone is poorly soluble in water,
than equipotent doses of prednisolone (Lowe etal, 2009). but it is available as an injectable preparation in solution with
polyethylene glycol. The glucocorticoid is released within minutes
to a few hours. Free alcohol solutions can be administered intra-
Galenic Formulations and Steroid Esters
muscularly as well as intravenously. IV application, however, may
Water solubility of glucocorticoids is generally low and can be be associated with CNS side effects. If IV application of larger
altered by pharmaceutical manipulations. Esterification and the doses is required, water soluble esters should be used.
|
O O
C CH2 CH2 C O Na Sodium succinate
O
P O Na
Sodium phosphate
O
CH2O Na
C O O
CH3 Acetate
OH OH C CH3
CH3
CH3 O CH3
Acetonide FIGURE 14-7Esters of glucocorticoids. Gluco-
C CH2 C CH3
corticoid structure illustrating various esters that
O CH3
may bind to C-21.
TABLE 14-3 D
URATION OF ACTION OF VARIOUS STEROID ESTERS AFTER
INTRAMUSCULAR ADMINISTRATION
ABSORPTION FOLLOWING
STEROID ESTER INTRAMUSCULAR APPLICATION DURATION OF ACTION MOST COMMONLY USED GLUCOCORTICOID BASES
Sodium succinate Minutes to hours Hours Hydrocortisone, prednisolone, prednisone, methylprednisolone,
dexamethasone, betamethasone
Sodium phosphate
Acetate Days to weeks Days to weeks Methylprednisolone, triamcinolone, betamethasone
Diacetate
Acetonide Weeks Weeks Triamcinolone
Dipropionate
Pivalate
Insoluble Steroid Ester (Suspensions) cats and cats that live outdoors and are only seen occasion-
Suspensions can be administered intramuscularly, intra-articu- ally by their owners. The same anti-inflammatory effects can
larly, and intralesionally. They are not to be given intravenously. be achieved with much shorter acting oral preparations. Use
They are used as depot preparation because of their slow release of short-acting drugs allows the dose to be altered as needed
of the active glucocorticoid from the site of administration. and helps to minimize HPA axis suppression and other adverse
They provide long-term, low level therapy and are not indi- effects (Feldman and Nelson, 2004).
cated in situations in which a quick effect and high blood lev-
els are needed (Feldman and Nelson, 2004). The duration of
Combination Products
action depends on the extent of water-solubility. Water solubil-
ity of acetate and diacetate esters is moderate and duration of Combination products between glucocorticoids and other phar-
action ranges from days to weeks. Pivalate, dipropionate, and maceutical products (e.g., antibiotics) are available. However, their
acetonide esters are the least water soluble and have duration use is associated with various problems, such as dose discrepancies
of actions of several weeks. It is of utmost importance to real- and variable duration of effects of the constituent drugs. Dose
ize that glucocorticoid preparations esterified with those esters discrepancy means that administrations based on recommended
do not compare with the native base with regard to duration dose for one of the drugs may result in underdosing or overdos-
of effect. For instance, the duration of effect of methylpred- ing of the other drug in the product. The use of those drugs is
nisolone is 12 to 36 hours; the duration of methylprednisolone discouraged.
acetate, however, is 3 to 6 weeks (Cohn etal, 2010). The major
advantage of the suspensions is convenience of administration.
THERAPEUTIC APPLICATION AND CLASSES OF
However, they have major disadvantages, such as unpredictabil-
GLUCOCORTICOID USAGE
ity of blood concentrations, long-term suppression of the HPA
axis (may be up to several months after a single dose), pos-
Goals and General Guidelines
sible induction of glucocorticoid resistance, and the fact that
the drug cannot be withdrawn in case adverse reactions occur Except in case of physiological replacement, therapy with gluco-
(Boothe and Mealey, 2012). Steroid suspensions should be corticoids is not directed at the inciting agent. Glucocorticoids
handled with care, and the guidelines of the manufacturer with are used to reduce the processes that are activated in response to
regard to storage temperature and shelf life should be followed. a disease (Boothe and Mealey, 2012). Oftentimes, glucocorti-
The steroid suspensions represent some of the most abused and coids are applied, although there is no indication or even a clear
overused drugs in veterinary medicine. Other than for intra- contraindication in higher than recommended doses and/or as
lesional and intra-articular therapy, those long-acting prepa- depot preparations that lead to long-term suppression of the
rations are hardly ever needed. The exceptions are fractious HPA axis. The goal is to bring the disease process under control
with the lowest dose necessary. In serious conditions, initial IV increased two to five times in case of moderate stress, and five
application may be required. For this purpose, water-soluble to twenty times in case of severe stress (e.g., surgery) (Ferguson
ester preparations should be used. Thereafter, treatment should etal, 2009). See Chapter 12 for more details.
be continued with oral glucocorticoids (e.g., prednisolone). Par-
enteral use of depot preparations (insoluble steroid esters) should
Anti-Inflammatory Therapy
only be used in exceptional cases (i.e., if application of shorter
acting steroids is not possible [fractious cats]). After achieving Inflammatory and allergic disorders are the most common rea-
disease remission, the latter should be maintained with the low- sons for the use of glucocorticoids. If no specific treatment can
est possible dose; alternate-day regimens using oral predniso- be initiated or is insufficient, glucocorticoids can help to com-
lone should be used whenever indicated. Cats have fewer GRs bat the clinical signs. However, there is a great potential for
than dogs and require higher doses. For the discussion on the misuse in this category. If an infectious disease goes unnoticed,
preferred use of prednisolone over prednisone, see the Route of the use of glucocorticoids may have deleterious effects because
Administration section. the disease can progress and the outcome can potentially be
Generally, given dose ranges should be regarded as approxi- fatal. Due to the general effects of glucocorticoids (e.g., reduc-
mate guidelines, because glucocorticoid sensitivity differs tion of fever, stimulation of appetite, feeling of euphoria, and
between individuals. Frequent reevaluations of patients treated suppression of the clinical signs of inflammation), the clini-
with glucocorticoids are of utmost importance. It is the predom- cian may have the impression of improvement, while in fact
inant opinion that cats require higher doses of glucocorticoids the disease is worsening (Cohn, 2010). Calvert and Cornelius
than dogs. This belief is supported by a study demonstrating (1990b) described this as, When glucocorticoids are mis-
that cats have approximately half the density of GRs in skin used, the patient may walk all the way to the necropsy labora-
and liver as compared to dogs, and the receptors have lower tory. There are a few exceptions, as in some infectious diseases
binding affinity (van den Broek and Stafford, 1992; Lowe etal, (e.g., bacterial or Malassezia-induced otitis externa or severe
2008a). Physiological effects of glucocorticoids occur at much ehrlichiosis), the concurrent administration of glucocorticoids
lower doses than do anti-inflammatory and immunosuppressive may have beneficial effects. It is understood that in the latter
doses (see Dose Equivalents of Glucocorticoids). Before initiat- disease the application should be limited to a few days (2 to 7
ing glucocorticoid therapy, the clinician should identify the goal days) (Cohn, 2003; Rougier etal, 2005; Bensignor and Gran-
(e.g., physiological replacement, suppression of inflammation, demange, 2006). Generally, before using glucocorticoids for
suppression of the immune system, or other actions like in neu- their anti-inflammatory effects, information regarding specific
rological or neoplastic disorders) (Cohn, 2010). Other questions conditions should be reviewed.
that should be answered prior to glucocorticoid therapy are (Fer- Except in emergency cases (e.g., acute bronchial disease)
guson etal, 2009):
in which IV administration of sodium succinate or sodium
Has an exact diagnosis been made and specific treatment been phosphate esters of prednisolone or methylprednisolone is
initiated? indicated, oral prednisolone is usually the treatment of choice.
Have other types of treatment been explored to minimize glu- In dogs, the anti-inflammatory dose of prednisolone is 0.5 to
cocorticoid dose and side effects? 1.0 mg/kg per day. In cats, it is usually recommended to give
Are there contraindications or known risk factors? twice the dose of dogs (e.g., 1.0 to 2.0 mg/kg) (Lowe et al,
How serious is the disease? 2008a; Cohn, 2010). As soon as clinical signs of inflammation
What is the anticipated length of glucocorticoid therapy? are under control, the dose should be reduced to the lowest
necessary concentration. The induction period usually ranges
Physiological Replacement Therapy between 5 and 7 days (Behrend and Kemppainen, 1997). Pred-
nisolone (or methylprednisolone) enables accurate dose titra-
Animals with primary or secondary adrenocortical insufficiency tion and the possibility of withdrawal in case of adverse effect.
require replacement of glucocorticoids. In case of primary It is also the glucocorticoid that can be most appropriately used
disease (Addison's disease), the majority of patients also need every other day after remission is achieved, thereby allowing
mineralocorticoid replacement. Replacement means to provide the HPA axis to recover to a certain extent (Boothe and Mealey,
glucocorticoids in amounts similar to those of the naturally 2012). There is some controversy as to whether the daily dose
produced glucocorticoids (mainly cortisol). Ideal replacement of prednisolone should be given at once or divided twice daily.
mimics the hormonal output of the adrenal gland under basal As studies supporting either frequency are lacking, once-daily
conditions, which is roughly 1 mg/kg cortisol per day in dogs dosing seems reasonablein particular in animals that are dif-
and cats. Dose increase is needed in times of stress (Ferguson ficult to medicate (Lowe etal, 2008a).
etal, 2009). A perfect replacement is difficult to reach because Topical instead of systemic glucocorticoids may be use-
of the dynamic function of the adrenal gland with minute-to- ful in inflammatory conditions of the eye, skin, respiratory
minute adaption of cortisol secretion according to the actual tract, gastrointestinal tract, and joints. Topical steroids reduce
requirement. Prednisolone is the glucocorticoid preparation inflammation by their local activity while minimizing systemic
most commonly used for replacement therapy in a dose of effects. Newer generation glucocorticoids (also called soft
0.1 to 0.25 mg/kg once daily. Glucocorticoid sensitivity varies glucocorticoids) were designed specifically for topical use in
widely between individuals, and therefore, replacement doses humans, and some of them have also been investigated in small
have to be curtailed to the patient's need. In some dogs in animals. Inhalant glucocorticoids are used in nebulizers or
which the mineralocorticoid deficiency is replaced by fludro- metered dose inhaler (MDI) in patients with chronic inflam-
cortisone (which also has glucocorticoid activity), additional matory airway inflammation. They have relatively low systemic
prednisolone may not be required under normal conditions. bioavailability because of their poor absorption and extensive
During times of stress, the need for glucocorticoid activity first-pass metabolism in the liver into inactive metabolites.
increases. As a rough guideline, the replacement dose should be Examples are fluticasone and budesonide; their local potencies
|
are extremely high. In the case of budesonide, the potency immunosuppressive agents may have steroid-sparing effects and
compared to cortisol is 60, that of fluticasone is 540 (Viviano, may allow disease control at lower glucocorticoid doses and faster
2013). Both have been successfully used as inhaled glucocor- tapering of the dose (Cohn, 2010).
ticoids in dogs and cats (Bexfield et al, 2006; Padrid, 2006;
Cohn etal, 2010; Galler etal, 2013). Budesonide is also avail-
Antineoplastic Therapy
able as an oral drug and exerts its inflammatory action locally
in the intestinal tract. It is mainly used to treat IBD in dogs Prednisolone is often included in combination chemotherapy
(Dye etal, 2013; Pietra etal, 2013). Mometasone is a potent protocols for their cytotoxic activity. Additional desired effects
topical glucocorticoid with low systemic effects designed for of prednisolone are reduction of edema and inflammation,
use in dermatological diseases; it is 25 times more potent than appetite-stimulations, and decrease of nausea and vomiting.
cortisol (Mendelsohn, 2009). Oral prednisolone is also used for alleviation of chronic cancer
pain; the recommended dose in dogs is 0.25 to 1.0 mg/kg, and
Immunosuppressive Therapy for cats it is 0.5 to 1.0 mg/kg (Mealey et al, 2003; Lascelles,
2013). Interestingly, in dogs with multicentric lymphoma
Glucocorticoids are considered the initial first-line therapy in using a multidrug protocol, the benefit of prednisolone with
various immune-mediated diseases, including immune-medi- regard to outcome was recently questioned (Zandvliet et al,
ated hemolytic anemia, immune-mediated thrombocytopenia, 2013). In case of financial or other restrictions, prednisone/
immune-mediated polyarthritis, systemic lupus erythematosus, prednisolone (initial dose, 2 mg/kg) is sometimes used as a
and pemphigus complex. They are also used to prevent organ single agent in lymphoma cases with a possible tumor control
rejection after transplantation and to reduce immunological of 1 to 2 months. Besides the short remission period, other dis-
reactions associated with some infectious diseases, such as feline advantages include serious side effects and the potential induc-
infectious peritonitis (FIP) and ehrlichiosis (Cohn, 2003; Greg- tion of multidrug resistance. The latter would limit the success
ory etal, 2006; Case etal, 2007; Addie etal, 2009; Hopper etal, of more aggressive drug therapy in case the owner changes his
2012). It should be noted, however, that treatment protocols for or her mind (Chun, 2009; Vail etal, 2013). Besides the poten-
small animals are mostly empirical and adapted from human tial risk of decreased response to later chemotherapy, glucocor-
medicine. Rigorous evaluations by randomized double-blinded ticoids induce apoptosis of neoplastic lymphocytes and may
placebo-controlled trials have not been performed (Whitley and interfere with the diagnosis; they should therefore only be used
Day, 2011). after the diagnosis has been made.
The goal of immune-suppressive therapy is to achieve disease Glucocorticoids may also be used in patients with hypercalce-
remission quickly, which usually requires high doses; thereafter, mia of malignancy (see Chapter 15) and to increase blood glucose
the dose is tapered slowly to the lowest level that will maintain concentrations in cases with insulinoma (see Chapter 9).
remission. Oral application of prednisolone is the preferred
modality. In acute or emergency situations, IV application of Shock
water-soluble esters of prednisolone or methylprednisolone may
be indicated. Depot preparations do not allow dose adjustments The use of high-dose glucocorticoid therapy for shock has fallen
and should not be used. The initial oral dose of prednisolone repeatedly in and out of favor (Cohn, 2010). Different from the
typically is 2 to 4 mg/kg in dogs and 2 to 8 mg/kg in cats per past, high-dose glucocorticoids are nowadays mentioned only in
day (Cohn, 1997; 2010; Lowe et al, 2008a). The dose is usu- the treatment protocols of anaphylactic shock. In humans, epi-
ally divided twice daily, based on the belief that this division nephrine is the first line treatment with a rapid onset of action;
will decrease gastrointestinal side effects. Generally, larger dogs and although glucocorticoids are often used, their onset of action
should be treated with the lower end of the dose range (Cohn, is considered quite slow (Lieberman, 2014). A systemic review
2010). In the opinion of the author, the high-end dose in cats of databases failed to identify adequately designed studies, and
should be used with great caution. The recommendation may no relevant evidence for the use of glucocorticoids was found.
in part be based on the frequent use of prednisone instead of The authors were therefore unable to make any recommenda-
prednisolone. As mentioned earlier, it is now known that only tions for the use of glucocorticoids in the treatment of anaphy-
a small part of oral prednisone appears as prednisolone in the laxis in humans (Choo etal, 2013). Similarly, in dogs and cats,
systemic circulation in cats (Graham-Mize and Rosser, 2004). epinephrine is the drug of choice for treatment of anaphylaxis
Some clinicians prefer to use dexamethasone for the first few (Shmuel and Cortes, 2013). Glucocorticoids continue to be fre-
doses and thereafter switch to oral prednisolone. There are no quently used in small animals with anaphylaxis; however, as in
controlled clinical studies to confirm any advantage of this humans, no studies support their benefit. Of note, glucocorticoids
approach. In one experimental study, dexamethasone was more themselves may cause allergic reaction and even anaphylaxis. The
effective than prednisone and cortisol in inhibiting the clearance application of methylprednisolone sodium succinate 30 mg/kg
of IgG-coated cells (Ruiz etal, 1991) (see Dose Equivalents of intravenously is commonly mentioned for cases with anaphylactic
Glucocorticoids). shock (Dowling, 2009).
If dexamethasone is used, equipotent doses have to be calcu- In humans with septic shock, relative adrenal insufficiency
lated (e.g., 2 mg/kg prednisolone equals approximately 0.3 mg/kg may be present and low-dose glucocorticoid therapy for a few
dexamethasone). High doses of prednisolone are continued for days appeared to be safe and may have some benefit for shock
several days after remission is achieved; usually, high doses are reversal and short-term survival (Annane etal, 2009; Sligl etal,
needed for 1 to 4 weeks. 2009). Although relative adrenal insufficiency may also exist in
Thereafter, the dose should be tapered slowly over many weeks dogs and cats, no clinical studies have investigated the use of low-
to months (see Glucocorticoid Reduction Protocol). Adverse dose glucocorticoid therapy in cases with septic shock. The results
effects are commonly seen with immunosuppressive doses, and of one experimental study using low-dose corticosteroids showed
the owner has to be warned about them. The addition of other beneficial effects in dogs with severe sepsis; however, results also
pointed to reduced bacterial clearance even with short term treat- TABLE 14-4 POTENTIAL DRUG
ment (Hicks etal, 2012). Therefore, no recommendation can be INTERACTIONS OF
made for the application of glucocorticoids in septic shock. They GLUCOCORTICOIDS
should only be used at low doses, if at all, under close monitoring
of the patient. DRUG POTENTIAL INTERACTION
Antacids Reduced oral glucocorticoid absorption
Neurological Diseases Anticholinesterase agents Muscle weakness
Previously, glucocorticoids were advocated for the treatment of Aspirin (salicylates) Reduced salicylate blood levels
traumatic brain injury on the basis that they decreased brain Cyclophosphamide Inhibition of hepatic metabolism of
edema. However, in humans, high-dose methylprednisolone was cyclophosphamide
associated with an increase in mortality. Their use in humans
as well as in small animals with brain injury is no longer rec- Cyclosporine Increase blood levels of each, by inhibiting
ommended (DiFazio and Fletcher, 2013). In acute spinal cord hepatic metabolism of each other
injury, methylprednisolone is considered to reveal free radical- Digoxin Secondary to hypokalemia, increased risk
scavenging effects, which other glucocorticoids are lacking. It is for arrhythmias
suggested that methylprednisolone has a positive effect if admin- Diuretics (furosemide, Increased risk of hypokalemia
istered within 8 hours of the time of insult. Suggested initial thiazides)
dose of methylprednisolone sodium succinate is 30 mg/kg fol-
Ephedrine Increased metabolism of glucocorticoids
lowed by repeated boluses of 15 mg/kg at 2 and 6 hours, then
every 8 hours up to 48 hours after the trauma (Park etal, 2012). Estrogens Potentiation of glucocorticoid effect
However, these doses are enormous and have the potential of Insulin Decreased insulin effect
serious side effects (e.g., gastrointestinal ulceration, immuno- Ketoconazole Decreased metabolism of glucocorticoids
suppression, and impaired wound healing). Sound data to sup-
port the use of this protocol is lacking in small animals, and its Macrolide antibiotics (eryth- Decreased metabolism of glucocorticoids
use in acute spinal cord injury is currently controversial (Park romycin, clarithromycin)
etal, 2012). Nonsteroidal anti- Increased risk of gastric ulceration
inflammatory drugs
(NSAIDs)
ADVERSE EFFECTS
Phenobarbital Increased metabolism of glucocorticoids
Adverse effects are common with glucocorticoid therapy, in
Phenytoin Increased metabolism of glucocorticoids
particular if the protocol includes high doses and/or long-term
application. Severely reduced quality of life and even fatal out- Rifampin Increased metabolism of glucocorticoids
comes are possible. On the other hand, glucocorticoids may be Vaccines Immunosuppressive doses of glucocorti-
life-saving and have major therapeutic benefits when used ade- coids may augment virus replication,
quately. As with any therapy, benefits must be weighed against avoid live-attenuated vaccines
potential adverse effects. Glucocorticoids can also alter the effec-
tiveness or toxicity of other drugs. One of the most important Modified from Plumb DC, editor: Plumbs veterinary drug handbook, ed 7, Ames, IA, 2011,
Wiley-Blackwell.
examples is the substantially increased risk of gastric ulceration
when glucocorticoids are co-administered with non-steroidal
anti-inflammatory agents (Table 14-4). Numerous adverse effects be seen either as a short- or long-term effect. Resolution of
may occur; the most important ones are discussed in the follow- those signs takes considerably longer than cessation of polyuria,
ing section. polydipsia, polyphagia, and panting. Improvement may be seen
within a few weeks; however, depending on severity, resolution
Iatrogenic Hyperadrenocorticism may take up to 6 months or longer. Resolution may not always
be complete; for instance, persistence of calcinosis cutis and of
In a significant percentage of dogs with hyperadrenocorticism, pulmonary mineralization has been reported, and there may be
the disease is in fact caused by exogenous glucocorticoids. Clini- color change in new hair growth (Huang etal, 1999; Blois etal,
cal signs and laboratory abnormalities of iatrogenic hyperadre- 2009). Exogenous glucocorticoids lead to atrophy of the adrenal
nocorticism are identical to those of the endogenous form of the glands, which may be seen ultrasonographically as reduction in
disease. Polyuria, polydipsia, polyphagia, and panting usually length and height of the cranial and caudal pole. The decrease in
manifest within the first 1 to 2 weeks of therapy in dogs (e.g., size is progressive during therapy and percentage change varies
with oral prednisolone in anti-inflammatory or immunosup- between dogs (Pey etal, 2012). Generally, there is a large indi-
pressive doses). These signs may even occur within hours after vidual variation with regard to glucocorticoid sensitivity. The
the first dose. They dissipate as the dose is tapered or discon- same dose may be tolerated well in one dog, whereas substantial
tinued (Feldman and Nelson, 2004). More severe signs such side effects are seen in another dog. Even low doses (e.g., sug-
as cutaneous lesions (thin hair coat, alopecia, hyperpigmenta- gested for physiological replacement) may induce side effects in
tion, pyoderma, calcinosis cutis, and thin skin), poor wound sensitive dogs. In particular, large breed dogs may develop pro-
healing, muscle weakness and atrophy, hepatomegaly due to found weakness and paraparesis when treated with high doses of
steroid hepatopathy, pendulous abdomen, urinary tract infec- glucocorticoids.
tion, and myotonia usually require a longer time and develop Cats are considered to be more resistant than dogs toward the
within weeks to months (Behrend and Kemppainen, 1997; development of iatrogenic hyperadrenocorticism. Associated
Huang etal, 1999; Feldman and Nelson, 2004). Lethargy may signs occur most often after repeated injections of long-acting
|
glucocorticoid preparations; however, occurrence of signs (e.g., dose of prednisone (2.2 mg/kg IM) did not result in adre-
polyphagia and weight gain) have also been reported after a nocortical suppression (Kemppainen et al, 1982). How-
single injection of methylprednisolone acetate (Ferasin, 2001). ever, even prednisone/prednisolone given at physiological
It is often assumed that polyuria and polydipsia do not occur doses can suppress the HPA axis when given for some
in cats until diabetes mellitus is induced by exogenous glu- time. Oral application of 0.22 mg/kg (physiological dose) or
cocorticoids. Although this may be true for the majority of 0.55 mg/kg per day led to a significantly depressed cortisol after
cases, polyuria and polydipsia have also been reported in cats ACTH stimulation after 1 week. Administration of 1 mg/kg
without diabetes (Lien etal, 2006; Lowe etal, 2008a). Other prednisone daily resulted in HPA axis suppression within 2
signs of iatrogenic hyperadrenocorticism are similar to those weeks; administration of 1 mg/kg prednisolone every other
seen in dogs. Unique to the cat is the development of spon- day was associated with HPA axis suppression after 3 weeks
taneous tearing and sloughing of the skin and, in rare cases, (Chastain and Graham, 1979; Moore and Hoenig, 1992). Cats
medial curling of the pinnae (Scott et al, 1982; Lowe et al, are more resistant to the development of clinical signs of iat-
2008a; 2008b). Steroid hepatopathy does occur in cats, but is rogenic hyperadrenocorticism; however, they experience HPA
considered to be less common than in dogs (Schaer and Ginn, suppression similar to dogs (Behrend and Kemppainen, 1997).
1999). Of note, signs of iatrogenic hyperadrenocorticism may The application of a single dose of methylprednisolone acetate
not only occur with oral or parenteral application but also with (20 mg IM) to healthy cats led to a reduced cortisol response
topical treatment. Exceptions are the newer generations of top- after ACTH within 1 week (Scott etal, 1979). In a cat treated
ical glucocorticoids (budesonide, fluticasone), which seem to with subcutaneous (SC) methylprednisolone acetate (20 mg)
have minimal side effects. There is no treatment for iatrogenic weekly for 4 weeks, complete suppression of the HPA axis was
hyperadrenocorticism. The only measure consists in cessation still seen 1 month after the last injection (Ferasin, 2001). Daily
of glucocorticoid therapy. Because the HPA axis is usually sup- oral administration of prednisolone (2 mg/kg) resulted in HPA
pressed, adrenocortical insufficiency may develop if therapy is axis suppression after 1 week and was more pronounced after 2
abruptly stopped (see later and Glucocorticoid Reduction Pro- weeks of daily therapy (Middleton etal, 1987). Similarly, daily
tocol section). oral methylprednisolone (4 mg/kg) was associated with HPA
axis suppression within 1 week (Crager etal, 1994).
Any topically applied glucocorticoid can suppress the HPA
Alteration of the Hypothalamic Pituitary Adrenal Axis
axis. Application of triamcinolone, fluocinonide, and beta-
Closely related to the development of clinical signs of gluco- methasone valerate on the skin of healthy dogs (once daily for
corticoid excess is the suppression of the HPA axis. Of note, 5 days) resulted in decreased cortisol after stimulation with
however, suppression of the HPA axis may be present without ACTH within 5 days. The HPA axis remained suppressed for 3
the animal displaying clinical signs of hyperadrenocorticism. to 4 weeks after the last treatment (Zenoble and Kemppainen,
All synthetic glucocorticoids suppress CRH and ACTH secre- 1987). Ophthalmic instillation of 1% prednisolone acetate or
tion, but their effects are not equivalent. Generally, the greater 0.1% dexamethasone four times daily in both eyes resulted in
the anti-inflammatory potency, the greater is the capacity to HPA axis suppression within 2 weeks, intensifying throughout
suppress the HPA axis. Over time, the glucocorticoid-produc- the treatment period (Roberts et al, 1984; Glaze et al, 1988).
ing cells of the two inner zones of the adrenal cortex atrophy Ototopical administration of therapeutic doses of dexametha-
and the responsiveness of the HPA axis decrease progressively sone-containing ointment daily to healthy dogs resulted in HPA
(Behrend and Kemppainen, 1997). Animals with suppression axis suppression within 11 days (Abraham etal, 2005). The new
of the HPA lack the ability to secrete cortisol sufficiently in generation of topical steroids cause minimal signs of iatrogenic
response to stress and may develop signs of acute adrenocortical hyperadrenocorticism but are associated with HPA axis sup-
insufficiency. The zona glomerulosa and its function are pre- pression. Oral budesonide in dogs with IBD resulted in signifi-
served, and therefore, electrolyte abnormalities associated with cantly lower post-ACTH cortisol concentrations after 30 days
mineralocorticoid deficiency are not seen. Suppression of the of therapy (Tumulty et al, 2004). Inhalant budesonide in cats
HPA axis may occur quite soon after the onset of glucocorticoid with chronic bronchial disease resulted in HPA axis suppression
therapy. in three of 15 cases (Galler etal, 2013). Inhaled fluticasone in
Oral, parenteral, and topical administration all lead to healthy dogs and inhaled flunisolide in healthy cats suppressed
HPA axis suppression, which is most serious and prolonged the HPA axis within 2 to 3 weeks (Reinero et al, 2006; Cohn
after repeated injection of long-acting preparations (water- etal, 2008).
insoluble esters). In experimental dogs, a single dose of Diagnosis of HPA axis suppression is made by performing an
methylprednisolone acetate (2.5 mg/kg IM) suppressed the ACTH stimulation test. Depending on the severity, post-ACTH
HPA axis, as demonstrated by reduced response of cortisol cortisol concentrations can be below the detection limit of the
after ACTH, for at least 5 weeks (Kemppainen et al, 1981). cortisol assay, low (e.g., 2 to 5 g/dL, 55 to 138 nmol/L) or low-
A dog that was treated for pruritus with a similar single dose normal. Animals with undetectable or low concentrations are at
of methylprednisolone acetate experienced HPA axis sup- risk for signs of adrenal insufficiency, in particular when encoun-
pression for 7 weeks (Meyer, 1982). A single dose of triam- tering a stressful situation. Potentially lethal situations may arise.
cinolone acetonide (0.22 mg/kg IM) suppressed the HPA axis If clinical signs (e.g., lethargy, anorexia, or vomiting) develop
for 2 to 4 weeks (Kemppainen et al, 1982). Single IV doses after cessation of steroids, prednisolone administrations should be
of 0.01 mg/kg and 0.1 mg/kg dexamethasone (as free alco- instituted. The dose is somewhat arbitrary and depends on the
hol) resulted in reduced cortisol response after ACTH for clinical situation. If severity of signs and extent of stress are mod-
16 to 24 hours and 32 hours, respectively. Dexametha- erate, prednisolone doses between 0.5 to 1 mg/kg/day may be suf-
sone sodium phosphate was associated with a somewhat ficient; doses up to 2 to 4 mg/kg/day may be needed temporarily
shorter suppression compared with the free alcohol with in life-threatening situations. The prednisolone dose should then
the 0.01 mg/kg dose (Kemppainen and Sartin, 1984). A single be tapered slowly. Generally, glucocorticoids should be reduced
slowly after a longer period of glucocorticoid administration (e.g., Diagnosis of steroid-induced diabetes should result in cessation
> 2 weeks). Suppression of the HPA axis is usually reversible. The of glucocorticoid therapy whenever possible; depending on the dis-
length of time required for full axis recovery depends on duration, ease, alternative drugs (e.g., cyclosporine) or topical use of the new
dose, preparation, and frequency of application of the steroid. generation of glucocorticoids should be considered. In cats, steroid-
Single doses of triamcinolone acetonide or methylprednisolone induced diabetes often goes into remission, provided that the glu-
acetate can suppress adrenal responsiveness for up to 5 weeks (see cocorticoid application is ceased immediately and insulin treatment
earlier). Multiple injections of long-acting preparations will aggra- is initiated. In dogs, diabetic remission has been seen; however, too
vate the suppressive effect, and HPA axis malfunction may persist few data have been published to make a general statement. In a
for months. Oral administration of shorter-acting or less-potent dog or cat with known diabetes, glycemic control usually worsens
preparations may result in quicker normalization (Behrend and when glucocorticoids are administered. Diabetes mellitus should
Kemppainen, 1997). not be regarded as an absolute contraindication for glucocorticoids,
Abrupt cessation of glucocorticoids may result in a so-called because in some diseases they may be life-saving. The glucocorti-
glucocorticoid withdrawal syndrome (Greco and Behrend, coid dose should be as low as possible to control the disease. In
1995). Several subgroups are known in humans; one of them short-term glucocorticoid therapy (1 to 2 weeks), the insulin dose
is attributed to the sudden lack of the high concentration of may be maintained while awaiting the withdrawal of the drug. If
steroids. In this situation, the body perceives the glucocorticoid long-term glucocorticoid therapy is needed, an increase in the daily
withdrawal as a relative deficiency. The signs are vague and can insulin doses is usually necessary to maintain control over the dia-
easily be mistaken with those of true adrenal insufficiency. The betic state. The amount of increase is variable and should follow
syndrome has been poorly characterized in dogs and cats. In the guidelines discussed in Chapters 6 and 7. Careful monitoring
questionable cases, an ACTH stimulation test should be per- of blood glucose levels is important. After the effect of the gluco-
formed to differentiate between absolute or relative adrenal corticoid on insulin sensitivity wears off, the insulin requirement
insufficiency. Prednisolone administration may be needed in decreases, resulting in the need to also decrease the insulin dose.
either situation. Remission may fail to appear if treatment is inadequate or if the cat
has substantial islet pathology. If glucocorticoid therapy cannot be
Diabetes Mellitus terminated and no alternative drug can be used, the insulin dose
has to be adjusted based on the severity of the insulin resistance. In
Glucocorticoids may exert diabetogenic properties thereby induc- those cases, glycemic control oftentimes remains difficult.
ing hyperglycemia in previously normoglycemic patients, as well
as worsening glycemic control in patients already known to have
Gastrointestinal Hemorrhage and Ulceration
diabetes mellitus. Glucocorticoids increase insulin resistance in
peripheral tissues (muscle, fat) and increase hepatic glucose produc- In the physiological state, glucocorticoids exert protective effects for
tion, and they may also inhibit insulin release from the cells. In the gastrointestinal integrity by various mechanisms. The adminis-
humans, overt diabetes or impaired glucose tolerance is seen in 14% tration of glucocorticoids in pharmacological doses may alter muco-
to 28% of individuals receiving long-term glucocorticoids. Preva- sal defense mechanisms in many ways (e.g., by decreasing mucus
lence of diabetes induced by exogenous glucocorticoids has not been production, altering the biochemical structure of mucus, decreas-
systematically studied in dogs and cats. It is well known that cats ing mucosal cell turnover, increasing acid output, and impairing
are more susceptible to the diabetogenic effects of glucocorticoids mucosal blood flow). Other mechanisms are decreased healing rate
than dogs. Approximately 80% of cats with endogenous hyperad- and promotion of bacterial colonization of ulcers (Hanson et al,
renocorticism are diabetic, whereas in dogs, the prevalence is only 1997; Rohrer etal, 1999a; Feldman and Nelson, 2004). In most
about 10%. Steroid diabetes can occur after oral or parenteral, as situations, it is unlikely that glucocorticoids are the sole factor for
well as after topical administration of any of the traditional gluco- gastrointestinal problems. The exception may be when extremely
corticoids, but it has not been reported with the newer class of topi- high doses of steroids are used. The application of methylpredniso-
cal drugs (budesonide, fluticasone). Glucocorticoid sensitivity varies lone sodium succinate (30 mg/kg initially, and then 15 mg/kg 2
between individuals and therefore dose, duration, and frequency of and 6 hours later and every 6 hours thereafter for 48 hours) was
application that will ultimately lead to hyperglycemia cannot be associated with gastric hemorrhage in all of the 10 dogs and was
predicted. Experimental studies have shown that abnormalities may severe in nine of them (Rohrer etal, 1999a). Similarly, the applica-
already become apparent after short-term therapy. Administration tion of extremely high doses of dexamethasone (4.4 mg/kg/day for
of 2 mg/kg prednisolone once daily for 8 days resulted in reduced 8 days) or prednisone (8.8 mg/kg/day for 7 days) to experimental
glucose tolerance after an IV glucose load in all six cats, and three dogs did result in endoscopic evidence of hemorrhage but not in
of the six cats developed hyperglycemia (Middleton and Watson, ulcers (Sorjonen etal, 1983; Behrend and Kemppainen, 1997).
1985). Weekly injections of 20 mg methylprednisolone subcutane- In clinical patients, the most striking gastrointestinal side effects
ously lead to hyperglycemia within 4 weeks in the two cats stud- have been reported in dogs with neurological disease. However,
ied (Scott etal, 1982). Within 1 month of daily administration of because a neurological problem can result in gastrointestinal
immunosuppressive doses of prednisolone or dexamethasone, 29% lesions itself, it is difficult to say how much glucocorticoids con-
and 71% of cats developed glucosuria (Lowe etal, 2009). The later tributed to the development of the problems. In one study, 23
study points to a greater diabetogenic effect of dexamethasone than of 155 dogs with intervertebral disk herniation had gastrointes-
equipotent doses of prednisolone. Steroid-induced diabetes is also tinal problems, and 10 of them had not received glucocorticoids
seen in dogs but with much lower frequency than in cats (Camp- (Moore and Withrow, 1982). More than 75% of dogs with acute
bell and Latimer, 1984; Jeffers etal, 1991). Administration of anti- intervertebral disc disease treated with glucocorticoids had gastric
inflammatory/immunosuppressive doses of prednisone (1.1 mg/kg/ mucosal lesions as detected by endoscopy. In 8% of dogs, gastric
day) or prednisolone (1 to 2 mg/kg/day) for 28 days to normal dogs ulcers developed during the treatment period. Only 24% of the
has not produced hyperglycemia, glucose intolerance, or insulin dogs had clinical signs such as vomiting or melena (Neiger etal,
resistance (Wolfsheimer etal, 1986; Moore and Hoenig, 1993). 2000). The most catastrophic of the gastrointestinal complications
|
is colon perforation. Colonic perforation in 13 dogs treated with may also be seen with the new generation of glucocorticoids. A
glucocorticoids was uniformly fatal (Toombs etal, 1986). Ten of short term (30 days) oral application of budesonide was associated
the 13 dogs were neurosurgical patients, one was treated for head- with an increase in ALP activity in dogs, but the difference to pre-
trauma and non-ambulatory paresis, and two others had under- treatment levels was not significant (Tumulty etal, 2004). Cats are
gone major surgery for other reasons. Dexamethasone was the generally considered more resistant to the effects of glucocorticoids
most frequently used steroid and was given in a mean cumulative and do not have a glucocorticoid induced isoenzyme. Increases in
dose of 6.4 mg/kg/day over a period of 5 days. The most com- liver enzyme activities after administration of glucocorticoids do
mon clinical signs were depression, anorexia, and vomiting. Signs occur, and the most consistent increase is seen in ALT activity.
became evident 3 to 8 days after surgery and preceded death by an The ALP activity may also increase; however, it often still remains
average of 22 hours (Toombs etal, 1986). within the normal range (Scott etal, 1982; Sharkey etal, 2007;
Because of the potential association between glucocorticoids Lowe etal, 2008b). As in dogs, glucocorticoid administration in
and gastrointestinal side effects, certain precautions should be cats may result in steroid (vacuolar) hepatopathy, although the fre-
taken, in particular in patients with neurological disease. Non- quency is lower (Schaer and Ginn, 1999). Increase in serum lipids
ambulatory patients certainly have an increased risk (Behrend and (cholesterol, triglycerides) may be seen in both species.
Kemppainen, 1997). The following recommendations have been Glucocorticoids also affect hematological parameters. In dogs
made: to use prednisolone or methylprednisolone instead of the with iatrogenic hyperadrenocorticism, eosinopenia was seen in 18
more potent dexamethasone, limit treatment to the lowest pos- out of 28 dogs and was the most frequent finding. Other constitu-
sible dose and duration, avoid concurrent or successive use of ents of the stress leukogram were also found, but to a lesser extent
other drugs with known ulcerogenic potential (in particular non- (Huang etal, 1999). In 14 cats treated with glucocorticoids (4.4
steroidal anti-inflammatory drugs), avoid urinary retention by mg/kg prednisolone or 0.55 mg/kg dexamethasone for 56 days),
closed urine drainage, and correct fecal retention problems prior neutrophils were significantly higher, and lymphocytes and eosino-
to surgery (Toombs etal, 1986). phils were significantly lower after treatment (Lowe etal, 2008b).
Misoprostol, cimetidine, or sucralfate were evaluated for their In this study, monocytes were also increased, which is usually con-
potential preventative role for gastrointestinal hemorrhage but did sidered not a typical finding in steroid-treated cats.
not show any effect (Hanson etal, 1997; Rohrer etal, 1999b).
Pancreatitis
Laboratory Abnormalities
More than 500 drugs have been reported to the World Health
The most common biochemical abnormalities in dogs receiving Organization (WHO) because they were suspected to induce
exogenous glucocorticoids are elevation of liver enzymes. Any glu- pancreatitis in humans. In many of them, evidence of causal-
cocorticoid and any form of application (oral, parenteral, or topi- ity is weak, and for only 31 of those drugs a definitive causality
cal) can lead to an increase of alkaline phosphatase (ALP), alanine has been established. Among them are steroids, but they do not
aminotransferase (ALT), and gamma glutamyl transferase (GGT). belong to the group of high risk drugs (Nitsche etal, 2010). Previ-
However, there is a tremendous amount of variation between indi- ously, glucocorticoids were also assumed to cause pancreatitis in
vidual dogs; in some, the elevation may reach several-fold of nor- small animals. Much of the evidence regarding this association,
mal, whereas others only have minor increase or even no change. however, is related to an increased viscosity of pancreatic secretion
In part, the changes may be dose-related. The administration of shown in rabbits. In dogs, increased viscosity of pancreatic secre-
1.1 mg/kg/day prednisone by mouth for 35 days did not result in tions has been shown only when isolated pancreases were perfused
a significant increase of ALP and the glucocorticoid-induced ALP with a huge dose of methylprednisolone (400 mg); a lower dose
isoenzyme. Only five of the 18 healthy dogs had ALP activities (200 mg) did not change the viscosity (Kimura etal, 1979; Beh-
above the reference range (Moore etal, 1992). A prednisone dose rend and Kemppainen, 1997). Pancreatitis has also been seen in
of 4.4 mg/kg/day IM for 14 days was associated with a significant dogs treated with glucocorticoids. However, these were sporadic
increase in ALP activity within 2 days, in ALT activity within cases, and the dogs suffered from intervertebral disc disease, which
3 days, and in GGT activity within 6 days. Six weeks after the end may alone be a risk factor (Behrend and Kemppainen, 1997). The
of the study, the enzyme activities were still slightly to moderately administration of dexamethasone to healthy dogs in various doses
increased (Badylak and Van Vleet, 1981). for up to 3 weeks did not cause pancreatitis. However, it increased
The application of other glucocorticoids, such as dexametha- lipase activity without any histological damage to the pancreas
sone, methylprednisolone (acetate), and triamcinolone, has simi- (Parent, 1982). In a more recent study, evaluating the canine pan-
lar effects. The contributory role of the glucocorticoid induced creatic lipase immunoreactivity (cPLI), immunosuppressive doses
isoenzyme of ALP to the increase of total ALP activity seems to of prednisone (2.2 mg/kg once daily) given for 6 weeks did not
be inconsistent. In the study of Moore and colleagues (1992), it result in an increase in cPLI (Steiner etal, 2009).
contributed only to a small extent to the total ALP activity. In a In dogs and cats, the early concerns that glucocorticoids could
study by Solter and colleagues (1994), the initial increase of ALP cause pancreatitis have now largely been dismissed. Steroids are
was mainly due to the liver ALP isoenzyme, followed by the gluco- no longer included in the list of drugs suspected of being associ-
corticoid and bone isoenzyme 7 and 10 days after initiating treat- ated with pancreatitis (Armstrong and Williams, 2012; Mansfield,
ment with prednisone. Serum bile acids may also increase during 2012). It is possible, however, that glucocorticoids are a contrib-
glucocorticoid therapy, whereas ammonia tolerance test does not uting factor in sick animals or that only a subset of patients is
seem to be affected (Meyer, 1982; DeNovo and Prasse, 1983; susceptible for steroid-induced pancreatitis.
Solter etal, 1994). For effects on blood glucose and lipase activity,
see the Diabetes Mellitus section and the Pancreatitis section. Otic Miscellaneous
medications containing triamcinolone or dexamethasone were also
associated with an increase in ALP, ALT, and GGT (Meyer etal, Glucocorticoids may have numerous other adverse effects, includ-
1990; Abraham et al, 2005). Increase in liver enzyme activities ing growth retardation in young animals, induction or worsening
of hypertension, disposing the animal to infections due to immu- latter should allow the HPA axis to recover on the off-days and
nosuppression (e.g., urinary tract infection), interference with fer- is assumed to provide greater safety than if therapy is suddenly
tility, induction of abortion, and behavior changes. discontinued. Successful alternate-day therapy depends upon the
therapeutic effects lasting longer than the suppressive effects on
GLUCOCORTICOID REDUCTION PROTOCOL the HPA axis (Ferguson etal, 2009). Alternate-day therapy should
not be applied during the initial phase of glucocorticoid therapy
There are various ways to taper an animal from glucocorticoids, because it will not be effective to bring the disease under con-
and there are no studies demonstrating that one way is better than trol. Prednisolone is the preferred glucocorticoid for alternate-day
the other. Several principles, however, are widely accepted. Taper- therapy; the action of cortisol (hydrocortisone) is too short and
ing of the glucocorticoid dose should always be done if therapy that of dexamethasone is too long for this approach. When chang-
was longer than or equal to 2 weeks, or if high doses have been ing to alternate-dose therapy, the same daily dose of prednisolone
used (> 1 mg/kg prednisolone/day or its equivalent) (Ferguson can be given every other day (e.g., change from 5 mg every day to
etal, 2009). In the latter case (i.e., short duration of high dose), 5 mg every other day), which results in a 50% reduction of dose.
tapering can be done quickly over a few days. Tapering of the ste- Alternatively, the same dose can be maintained by doubling the
roid dose should be started after the disease being addressed is dose on the on-days (e.g., change from 5 mg every day to 10 mg
in remission (e.g., normalized hematocrit in immune-mediated every other day) (Behrend and Kemppainen, 1997). In case of
anemia, and/or absence of gastrointestinal signs in IBD). Inflam- serious immune-mediated diseases, this latter approach for mov-
matory diseases usually require 5 to 7 days of induction therapy, ing from daily to alternate-day therapy is preferred. If alternate-
whereas immunosuppressive diseases may need 10 to 28 days dose therapy is successful to maintain the disease in remission,
(Behrend and Kemppainen, 1997). Worsening of the disease soon further reduction to every third day can be attempted (Behrend
after the start of tapering suggests that the tapering was done too and Kemppainen, 1997).
fast. If an immune-mediated disease recrudesces, a second remis- Tapering of oral prednisolone used for immune-mediated dis-
sion is more difficult to obtain than previously. If recrudescence ease in dogs could be done as follows (Behrend and Kemppainen,
occurs, the glucocorticoid dose should be increased immediately 1997):
to a dose equivalent even higher than the initial dose. If remission Induction: 2.0 mg/kg divided b.i.d. for 10 to 28 days
is lost in an inflammatory disease, the dose should be increased to
Tapering: 1.5 mg/kg divided b.i.d. or once daily for
the last dose that kept the animal disease free (Behrend and Kemp-
10 to 28 days
painen, 1997). In general, the longer the induction phase and/or
1.0 mg/kg divided b.i.d. or once daily for
the greater the induction dose, the more stepwise and longer the
10 to 28 days
period between dose reductions has to be. Glucocorticoids used
0.5 mg/kg divided b.i.d. or once daily for
for life-threatening diseases should be tapered more slowly than
10 to 28 days
glucocorticoids used for other diseases (Cohn, 2010). Tapering
0.25 mg/kg once daily for 10 to 28 days
for immune-mediated disease can take several months; some cases
0.25 mg/kg every other day, for 21 days or more
may even need life-long therapy.
The initial dose reduction step may be done by consolidating
the dose, thereby achieving longer dosing intervals; this might It should be understood that the animal should be reevaluated
spare the HPA axis suppression while the desired effects are main- before every reduction step to ensure that the disease is still in
tained. For instance, if prednisolone is administered twice daily, remission. The glucocorticoid dose used for induction in inflam-
the daily dose is given at once (e.g., 10 mg prednisolone once matory diseases is substantially lower (0.5 to 1.0 mg/kg/day in
daily instead of 5 mg prednisolone twice daily). The daily dose dogs) and the induction period is shorter (5 to 7 days). Tapering,
is then reduced incrementally (Cohn, 2010). Usually, when the therefore, can be done faster, usually within 10 to 14 days. Taper-
daily prednisolone dose has been reduced to 0.25 to 0.5 mg/kg/ ing of the higher anti-inflammatory and immune-suppressive
day, the dose interval is switched to alternate-day therapy. The doses in cats should be done accordingly.
REFERENCES
Abraham G, etal.: Evidence for ototopical Barrett KE, etal.: The adrenal medulla and Blois SL, etal.: Diagnosis and outcome of a
glucocorticoid-induced decrease in hypotha- adrenal cortex. In Barrett KE, Barman SM, dog with iatrogenic hyperadrenocorticism
lamic-pituitary-adrenal axis response and Boitano S, Brooks HL, editors: Ganongs and secondary pulmonary mineralization,
liver function, Endocrinol 146:3163, 2005. review of medical physiology, ed 24, New Can Vet 50:397, 2009.
Addie D, etal.: Feline infectious peritonitis: York, 2012, McGraw-Hill Lange. Boothe DM, Mealey KA: Glucocorticoids and
ABCD guidelines on prevention and man- Behrend EN, Kemppainen RJ: Glucocorticoid mineralocorticoids. In Boothe DM, editor:
agement, J Feline Med Surg 11:594, 2009. therapy: pharmacology, indications, and Small animal clinical pharmacology and
Annane D, etal.: Corticosteroids in the treat- complications, Vet Clin North Am Small therapeutics, ed 2, St Louis, 2012, Saun-
ment of severe sepsis and septic shock Anim Pract 27:187, 1997. ders/Elsevier.
in adults: a systematic review, J Am Med Bensignor E, Grandemange E: Comparison of an Busillo JM, Cidlowski JA: The five Rs of
Assoc 301:2362, 2009. antifungal agent with a mixture of antifun- glucocorticoid action during inflamma-
Armstrong PJ, Williams DA: Pancreatitis in cats, gal, antibiotic and corticosteroid agents for tion: ready, reinforce, repress, resolve, and
Top Companion Anim Med 27:140, 2012. the treatment of Malassezia species otitis in restore, Trends Endocrinol Metab 24:109,
Badylak SF, Van Vleet JF: Sequential mor- dogs, Vet Rec 158:193, 2006. 2013.
phologic and clinicopathologic alterations Bexfield NH, etal.: Management of 13 cases Calvert CA, Cornelius LM: The pharmacody-
in dogs with experimentally induced of canine respiratory disease using inhaled namic differences among glucocorticoid
glucocorticoid hepatopathy, Am J Vet Res corticosteroids, J Small Anim Pract 47:377, preparations, Vet Med 85:860,
42:1310, 1981. 2006. 1990a.
|
Calvert CA, Cornelius LM: Corticosteroid DeNovo RC, Prasse KW: Comparison of serum Hall JE: Adrenocortical hormones. In Hall JE,
hormones: endogenous regulation and the biochemical and hepatic functional altera- editor: Guyton and Hall textbook of medi-
effects of exogenous administration, Vet tions in dogs treated with corticosteroids cal physiology, ed 12, Philadelphia, 2011,
Med 85:810, 1990b. and hepatic duct ligation, Am J Vet Res Saunders/Elsevier.
Campbell KL, Latimer KS: Transient diabe- 44:1703, 1983. Hanson SM, etal.: Clinical evaluation of
tes mellitus associated with prednisone DiFazio J, Fletcher DJ: Update in the manage- cimetidine, sucralfate, and misoprostol for
therapy in a dog, J Am Vet Med Assoc ment of the small animal patient with prevention of gastrointestinal tract bleed-
185:299, 1984. neurologic trauma, Vet Clin Small Anim ing in dogs undergoing spinal surgery, Am
Canalis E, etal.: Glucocorticoid-induced 43:915, 2013. J Vet Res 58:1320, 1997.
osteoporosis: pathophysiology and therapy, Dowling PM: Anaphylaxis. In Silverstein DC, Hench P, etal.: The effects of a hormone of
Osteoporos Int 18:1319, 2007. Hopper K, editors: Small animal critical the adrenal cortex (17-hydroxy-11-dehy-
Carroll TB, etal.: Glucocorticoids and adrenal an- care medicine, St Louis, 2009, Saunders/ drocorticosterone; compound E) and of
drogens. In Gardner DG, Shoback D, editors: Elsevier. pituitary adrenocorticotropic hormone on
Greenspans basic and clinical endocrinol- Dye TL, etal.: Randomized, controlled trial rheumatoid arthritis, Proc Staff Meet Mayo
ogy, ed 9, New York, 2011, McGraw-Hill. of budesonide and prednisone for the Clin 24:181, 1949.
Case JB, etal.: Incidence of and risk factors treatment of idiopathic inflammatory Hicks CW, etal.: Beneficial effects of stress-
for diabetes mellitus in cats that have bowel disease in dogs, J Vet Intern Med dose corticosteroid therapy in canines
undergone renal transplantation: 187 27:1385, 2013. depend on the severity of staphylococcal
cases (1986-2005), J Am Vet Med Assoc Feldman EC, Nelson RW: Glucocorticoid pneumonia, Intensive Care Med 38:2063,
230:880, 2007. therapy. In Feldman EC, Nelson RW, 2012.
Chapman K, etal.: 11-hydroxysteroid dehy- editors: Canine and feline endocrinology Hopper K, etal.: Outcome after renal trans-
drogenases: intracellular gate-keepers of and reproduction, ed 3, St Louis, 2004, plantation in 26 dogs, Vet Surg 41:316,
tissue glucocorticoid action, Physiol Rev Saunders/Elsevier. 2012.
93:1139, 2013. Ferasin L: Iatrogenic hyperadrenocorticism in a Huang HP, etal.: Iatrogenic hyperadrenocorti-
Chastain CB, Graham CL: Adrenocortical sup- cat following a short therapeutic course of cism in 28 dogs, J Am Anim Hosp Assoc
pression in dogs on daily and alternate-day methylprednisolone acetate, J Feline Med 35:200, 1999.
prednisone administration, Am J Vet Res Surg 3:87, 2001. Javadi S, etal.: Plasma aldosterone concentra-
40:936, 1979. Ferguson DC, etal.: Glucocorticoids, mineralo- tions and plasma renin activity in healthy
Choo KJ, etal.: Glucocorticoids for the treat- corticoids and adrenolytic drugs. In Riviere dogs and dogs with hyperadrenocorticism,
ment of anaphylaxis, Cochrane Database JE, Papich MG, editors: Veterinary pharma- Vet Rec 153:521, 2003.
Syst Rev 18:1276, 2013. cology and therapeutics, ed 9, Ames, IA, Jeffers JG, etal.: Diabetes mellitus induced
Chun R: Lymphoma: Which chemotherapy 2009, Wiley-Blackwell. in a dog after administration of cortico-
protocol and why? Top Companion Anim Frank LA: Growth hormone-responsive alopecia steroids and methylprednisolone pulse
Med 24:157, 2009. in dogs, J Am Vet Med Assoc 226:1494, therapy, J Am Vet Med Assoc 199:77,
Cohn LA: Glucocorticosteroids as immunosup- 2005. 1991.
pressive agents, Semin Vet Med Surg Galler A, etal.: Inhaled budesonide therapy in Jiang CL, etal.: Why do we need nongenomic
(Small Anim) 12:150, 1997. cats with naturally occurring chronic bron- glucocorticoid mechanisms? Front Neuro-
Cohn LA: Ehrlichiosis and related infections, chial disease (feline asthma and chronic endocrinol 35:72, 2014.
Vet Clin Small Anim 33:863, 2003. bronchitis), J Small Anim Pract 54:531, Kemppainen RJ: Effects of glucocorticoids on
Cohn LA: Glucocorticoid therapy. In Ettinger 2013. endocrine function in the dog, Vet Clin
SJ, Feldman EC, editors: Textbook of vet- Glaze MB, etal.: Ophthalmic corticosteroid North Am Small Anim Pract 14:721,
erinary internal medicine, ed 7, St Louis, therapy: systemic effects in the dog, J Am 1984.
2010, Saunders/Elsevier. Vet Med Assoc 192:73, 1988. Kemppainen RJ, Sartin JL: Effects of single
Cohn LA, etal.: Endocrine and immunologic Goulding NJ, Flower RJ: Preface. In Goulding intravenous doses of dexamethasone
effects of inhaled fluticasone propionate in NJ, Flower RJ, editors: Glucocorticoids, on baseline plasma cortisol concentra-
healthy dogs, J Vet Intern Med 22:37, 2008. Basel, 2000a, Springer Basel AG. tions and responses to synthetic ACTH
Cohn LA, etal.: Effects of fluticasone propionate Goulding NJ, Flower RJ: Glucocorticoid in healthy dogs, Am J Vet Res 45:742,
dosage in an experimental model of feline biologya molecular maze and clinical 1984.
asthma, J Feline Med Surg 12:91, 2010. challenge. In Goulding NJ, Flower RJ, Kemppainen RJ, etal.: Adrenocortical sup-
Costa LAVS, etal.: Bone demineralization editors: Glucocorticoids, Basel, 2000b, pression in the dog after a single dose of
in the lumbar spine of dogs submitted Springer Basel AG. methylprednisolone acetate, Am J Vet Res
to prednisone therapy, J Vet Pharmacol Goy-Thollot I, etal.: Investigation of the role 42:822, 1981.
Therap 33:583, 2010. of aldosterone in hypertension associated Kemppainen RJ, etal.: Adrenocortical suppres-
Crager CS, etal.: Adrenocorticotropic hormone with spontaneous pituitary-dependent hy- sion in the dog given a single intramus-
and cortisol concentrations after corticotro- peradrenocorticism in dogs, J Small Anim cular dose of prednisone or triamcinolone
pin-releasing hormone stimulation testing Pract 43:489, 2002. acetonide, Am J Vet Res 42:204, 1982.
in cats administered methylprednisolone, Graham-Mize CA, Rosser EJ: Bioavailability Kemppainen RJ, etal.: Effects of prednisone
Am J Vet Res 55:704, 1994. and activity of prednisone and predniso- on thyroid and gonadal endocrine function
Daminet S, Ferguson DC: Influence of drugs on lone in the feline patient, Plenary Session in dogs, J Endocrinol 96:293, 1983.
thyroid function in dogs, J Vet Intern Med Abstracts, Vet Dermatol 15(Suppl. 1):9, Kendall EC: The development of cortisone
17:463, 2003. 2004. as a therapeutic agent, Nobel Lecture,
Daminet S, etal.: Short-term influence of December 11, 1950. Nobelprize.org: (PDF
Greco CS, Behrend EN: Corticosteroid with-
prednisone and phenobarbital on thyroid online): http://www.nobelprize.org/nobel_
drawal syndrome. In Bonagura JD, editor:
function in euthyroid dogs, Can Vet J prizes/medicine/laureates/1950/kendall-
Kirks current veterinary therapy XII, Phila-
40:411, 1999. lecture.pdf. Accessed June 19, 2014.
delphia, 1995, Saunders/Elsevier.
Day MJ: Immunotherapy. In Day MJ, Schultz Kimura T, etal.: Steroid administration and
Gregory CR, etal.: Results of clinical renal
RD, editors: Veterinary immunology, acute pancreatitis: studies with an iso-
transplantation in 15 dogs using triple
principles and practice, London, 2011, lated, perfused canine pancreas, Surgery
drug immunosuppressive therapy, Vet Surg
Manson Publishing Ltd. 85:520, 1979.
35:105, 2006.
Kovalik M, etal.: Short-term prednisolone Middleton DJ, Watson AD: Glucose intoler- Peterson ME, etal.: Effects of spontaneous
therapy has minimal impact on calcium ance in cats given short-term therapies of hyperadrenocorticism on serum thyroid
metabolism in dogs with atopic dermatitis, prednisolone and megestrol acetate, Am J hormone concentrations in the dog, Am J
Vet J 193:439, 2012. Vet Res 46:2623, 1985. Vet Res 45:2034, 1984.
Lascelles BDX: Supportive care for the cancer Middleton DJ, etal.: Suppression of cortisol Pey P, etal.: Effect of glucocorticoid adminis-
patient. In Withrow SJ, Vail DM, Page responses to exogenous adrenocortico- tration on adrenal gland size and sono-
RL, editors: Withrow & MacEwens small trophic hormone, and the occurrence of graphic appearance in beagle dogs, Vet
animal clinical oncology, ed 5, St Louis, side effects attributable to glucocorti- Radiol Ultrasound 53:204, 2012.
2013, Elsevier/Saunders. coid excess, in cats during therapy with Pietra M, etal.: Plasma concentrations and
Lieberman PL: Recognition and first-line treat- megestrol acetate and prednisolone, Can therapeutic effects of budesonide in dogs
ment of anaphylaxis, Am J Med 127:S6, J Vet Res 51:60, 1987. with inflammatory bowel disease, Am J Vet
2014. Moore GE, Hoenig M: Duration of pituitary and Res 74:78, 2013.
Lien YH, etal.: Iatrogenic hyperadrenocorti- adrenocortical suppression after long- Plumb DC, editor: Plumbs veterinary drug
cism in 12 cats, J Am Anim Hosp Assoc term administration of anti-inflammatory handbook, ed 7, Ames, IA, 2011, Wiley-
42:414, 2006. doses of prednisone in dogs, Am J Vet Res Blackwell.
Liu Y, etal.: MAPK phosphatasesregulating 53:716, 1992. Ramsey IK, etal.: Hyperparathyroidism in dogs
the immune response, Nat Rev Immunol Moore GE, Hoenig M: Effects of orally adminis- with hyperadrenocorticism, J Small Anim
7:202, 2007. tered prednisone on glucose tolerance and Pract 46:531, 2005.
Lowe AD, etal.: Glucocorticoids in the cat, Vet insulin secretion in clinically normal dogs, Reinero CR, etal.: Inhaled flunisolide sup-
Dermatol 19:340, 2008a. Am J Vet Res 54:126, 1993. presses the hypothalamic-pituitary-adre-
Lowe AD, etal.: Clinical, clinicopathological Moore GE, etal.: Hematologic and serum nocortical axis, but has minimal systemic
and histological changes observed in 14 biochemical effects of long-term adminis- immune effects in healthy cats, J Vet
cats treated with glucocorticoids, Vet Rec tration of anti-inflammatory doses of pred- Intern Med 20:57, 2006.
162:777, 2008b. nisone in dogs, Am J Vet Res 53:1033, Reusch CE, etal.: Endocrine hypertension in
Lowe AD, etal.: A pilot study comparing the 1992. small animals, Vet Clin North Am Small
diabetogenic effects of dexamethasone Moore GE, etal.: Effects of oral administration Anim Pract 40:335, 2010.
and prednisolone in cats, J Am Anim Hosp of anti-inflammatory doses of prednisone Rhen T, Cidlowski JA: Antiinflammatory action
Assoc 45:215, 2009. on thyroid hormone response to thyrotro- of glucocorticoidsnew mechanisms for
Lwenberg M, etal.: Glucocorticoid signaling: pin-releasing hormone and thyrotropin old drugs, N Engl J Med 353:1711, 2005.
a nongenomic mechanism for T-cell immu- in clinically normal dogs, Am J Vet Res Roberts SM, etal.: Effect of ophthalmic
nosuppression, Trends Mol Med 13:158, 54:130, 1993. prednisolone acetate on the canine adrenal
2007. Moore RW, Withrow SJ: Gastrointestinal hemor- gland and hepatic function, Am J Vet Res
Mansfield C: Acute pancreatitis in dogs: rhage and pancreatitis associated with 45:1711, 1984.
advances in understanding, diagnostics, intervertebral disk disease in the dog, J Am Rohrer CR, etal.: Gastric hemorrhage in dogs giv-
and treatment, Top Companion Anim Med Vet Med Assoc 180:1443, 1982. en high doses of methylprednisolone sodium
27:123, 2012. Neel JA, etal.: Thrombocytosis: a retrospec- succinate, Am J Vet Res 60:977, 1999a.
Martinez NI, etal.: Evaluation of pressor tive study of 165 dogs, Vet Clin Pathol Rohrer CR, etal.: Efficacy of misoprostol in
sensitivity to norepinephrine infusion in 41:216, 2012. prevention of gastric hemorrhage in dogs
dogs with iatrogenic hyperadrenocorticism. Neiger R, etal.: Gastric mucosal lesions in treated with high doses of methylpred-
Pressor sensitivity in dogs with hyperadre- dogs with acute intervertebral disc disease: nisolone sodium succinate, Am J Vet Res
nocorticism, Res Vet Sci 78:25, 2005. characterization and effects of omeprazole 60:982, 1999b.
McMaster A, Ray DW: Modelling the glucocor- or misoprostol, J Vet Intern Med 14:33, Rougier S, etal.: A comparative study of two
ticoid receptor and producing therapeutic 2000. antimicrobial/anti-inflammatory formula-
agents with anti-inflammatory effects but Nitsche CJ, etal.: Drug induced pancreatitis, tions in the treatment of canine otitis
reduced side-effects, Exp Physiol 92:299, Best Pract Res Clin Gastroenterol 24:143, externa, Vet Dermatol 16:299, 2005.
2007. 2010. Ruiz P, etal.: Invivo glucocorticoid modula-
Mealey KL, etal.: Dexamethasone treatment of Nixon M, etal.: It takes two to tango: dimerisa- tion of guinea pig splenic macrophage Fc
a canine, but not human, tumour cell line tion of glucocorticoid receptor and its anti- gamma receptors, J Clin Invest 88:149,
increases chemoresistance independent of inflammatory functions, Steroids 78:59, 1991.
P-glycoprotein and multidrug resistance- 2013. Schaer M, Ginn PE: Iatrogenic Cushings syn-
related protein expression, Vet Comp Oncol Padrid P: Use of inhaled medications to treat drome and steroid hepatopathy in a cat, J
1:67, 2003. respiratory diseases in dogs and cats, J Am Am Anim Hosp Assoc 35:48, 1999.
Meij BP, etal.: Alterations in anterior pituitary Anim Hosp Assoc 42:165, 2006. Schultze AE: Interpretation of canine leukocyte
function of dogs with pituitary-dependent Papich MG, Davis LE: Glucocorticoid therapy. responses. Interpretation of feline leuko-
hyperadrenocorticism, J Endocrinol In Kirk RW, editor: Current veterinary cyte response. In Weiss DJ, Wardrop KJ,
154:505, 1997. therapy X: small animal practice, Philadel- editors: Schalms veterinary hematology,
Mendelsohn C: Topical therapy for otitis ex- phia, 1989, Saunders/Elsevier. ed 6, Ames, IA, 2010, Wiley-Blackwell.
terna. In Bonagura JD, Twedt DC, editors: Parent J: Effects of dexamethasone on pan- Scott DW, etal.: Some effects of short-term
Kirks current veterinary therapy, ed 14, St creatic tissue and on serum amylase and methylprednisolone therapy in normal cats,
Louis, 2009, Saunders/Elsevier. lipase activities in dogs, J Am Vet Med Cornell Vet 69:104, 1979.
Meyer DJ: Prolonged liver test abnormalities Assoc 180:743, 1982. Scott DW, etal.: Iatrogenic Cushings syn-
and adrenocortical suppression in a dog Parente L: The development of synthetic drome in the cat, Feline Pract 12:30,
following a single intramuscular glucocorti- glucocorticoids. In Goulding NJ, Flower 1982.
coid dose, J Am Anim Hosp Assoc 18:725, RJ, editors: Glucocorticoids, Basel, 2000, Sharkey LC, etal.: Effects of a single injection
1982. Springer Basel AG. of methylprednisolone acetate on serum
Meyer DJ, etal.: Effect of otic medications Park EH, etal.: Mechanisms of injury and biochemical parameters in 11 cats, Vet
containing glucocorticoids on liver function emergency care of acute spinal cord injury Clin Pathol 36:184, 2007.
test results in healthy dogs, J Am Vet Med in dogs and cats, J Vet Emerg Crit Care Shmuel DL, Cortes Y: Anaphylaxis in dogs and
Assoc 196:743, 1990. 22:160, 2012. cats, J Vet Emerg Crit Care 23:377, 2013.
|
Sligl WI, etal.: Safety and efficacy of cortico- Toombs JP, etal.: Colonic perforation in Vollmar A, Dingermann T: Immunosuppres-
steroids for the treatment of septic shock: corticosteroid-treated dogs, J Am Vet Med siva. In Vollmar A, Dingermann T, editors:
a systematic review and meta-analysis, Assoc 188:145, 1986. Immunologie, Grundlagen und Wirkstoffe,
Clin Infect Dis 49:93, 2009. Torres SM, etal.: Effect of oral administra- Stuttgart, 2005, Wissenschaftliche Ver-
Solter PF, etal.: Hepatic total 3-hydroxy bile tion of prednisolone on thyroid function in lagsgesellschaft.
acids concentration and enzyme activities dogs, Am J Vet Res 52:416, 1991. von Lindern M, etal.: The glucocorticoid
in prednisone-treated dogs, Am J Vet Res Tumulty JW, etal.: Clinical effects of short- receptor cooperates with the erythropoietin
55:1086, 1994. term oral budesonide on the hypothalamic- receptor and c-Kit to enhance and sustain
Sorjonen DC, etal.: Effects of dexamethasone pituitary-adrenal axis in dogs with inflam- proliferation of erythroid progenitors invi-
and surgical hypotension on the stomach matory bowel disease, J Am Anim Hosp tro, Blood 94:550, 1999.
of dogs: clinical, endoscopic, and patho- Assoc 40:120, 2004. Wenger M, etal.: Effect of trilostane on serum
logic evaluations, Am J Vet Res 44:1233, Ungemach FR: Pharmaka zur Beeinflussung concentrations of aldosterone, cortisol, and
1983. von Entzndungen. In Loescher W, Un- potassium in dogs with pituitary-depen-
Stahn C, etal.: Molecular mechanisms of glu- gemach FR, Kroker R, editors: Pharmako- dent hyperadrenocorticism, Am J Vet Res
cocorticoid action and selective glucocorti- therapie bei Haus- und Nutztieren, ed 8, 65:1245, 2004.
coid receptor agonists, Mol Cell Endocrinol Stuttgart, 2010, Enke Verlag. Whitley NT, Day MJ: Immunomodulatory drugs
275:71, 2007. Vail DM, etal.: Hematopoietic tumors. In With- and their application to the management
Steiner JM, etal.: Stability of canine pancre- row SJ, Vail DM, Page RL, editors: Withrow of canine immune-mediated disease, J
atic lipase immunoreactivity concentration & MacEwens small animal clinical oncology, Small Anim Pract 52:670, 2011.
in serum samples and effects of long-term ed 5, St Louis, 2013, Elsevier/Saunders. Wolfsheimer KJ, etal.: Effects of prednisolone
administration of prednisone to dogs on Valenciano AC, etal.: Interpretation of feline on glucose tolerance and insulin secretion
serum canine pancreatic lipase immuno- leukocyte response. In Weiss DJ, Wardrop in the dog, Am J Vet Res 47:1011, 1986.
reactivity concentrations, Am J Vet Res KJ, editors: Schalms veterinary hematolo- Zandvliet M, etal.: Prednisolone inclusion in a
70:1001, 2009. gy, ed 6, Ames, IA, 2010, Wiley-Blackwell. first-line multidrug cytostatic protocol for
Steinfelder HJ, Oetjen E: Nebennierenrinden- van Brussel MS, etal.: Prevention of glucocor- the treatment of canine lymphoma does
hormone. In Aktories K, Foerstermann U, ticoid-induced osteoporosis, Expert Opin not affect therapy results, Vet J 197:656,
Hofmann F, Starke K, editors: Allgemeine Pharmacother 10:997, 2009. 2013.
und spezielle Pharmakologie und Toxikolo- van den Broek AH, Stafford WL: Epidermal and Zenoble RD, Kemppainen RJ: Adrenocortical
gie, ed 10, 2009, Elsevier Urban & Fischer. hepatic glucocorticoid receptors in cats suppression by topically applied corticoste-
Stewart PM, Krone NP: The adrenal cortex. In and dogs, Res Vet Sci 52:312, 1992. roids in healthy dogs, J Am Vet Med Assoc
Melmed S, Polonsky K, Larsen PR, Kro- Vandevyver S, etal.: New insights into the 191:685, 1987.
nenberger HM, editors: Williams textbook anti-inflammatory mechanisms of glucocorti-
of endocrinology, ed 12, Philadelphia, coids: an emerging role for glucocorticoid-
2011, Elsevier/Saunders. receptor-mediated transactivation, Endocri-
Tizard IR: Drugs and other agents that affect nol 154:993, 2013.
the immune system. In Tizard IR, editor: Viviano KR: Update on immunosuppressive
Veterinary immunology, ed 9, St Louis, therapies for dogs and cats, Vet Clin Small
2013, Elsevier/Saunders. Anim 43:1149, 2013.

SECTION 5 PARATHYROID GLAND
CHAPTER 15 Hypercalcemia and Primary Hyperparathyroidism

Edward C. Feldman
CHAPTER CONTENTS Anamnesis: Clinical Signs, 594

CALCIUM REGULATION AND HYPERCALCEMIA, 580 Overview, 594
Calcium Function and Control, 580 Polydipsia and/or Polyuria, 595
Overview, 580 Urinary Tract Calculi and Infections, 595
Parathyroid Hormone, 580 Chronic Kidney Disease or Acute Kidney Injury, 595
Parathyroid HormoneRelated Protein, 582 Lethargy, Weakness, Shivering, and Muscle Atrophy, 595
Vitamin D, 582 Inappetence, Weight Loss, and Abdominal or Nonspecific Pain, 595
Pathophysiology of Primary Hyperparathyroidism, 583 Stiff Gait, Fractures, and Skeletal Pain, 596
Introduction: Extensive Effects of Excess PTH, 583 Physical Examination, 596
Kidney, 583 General Observations, 596
Bone, 583 Common Abnormalities, 596
Uroliths and Urinary Tract Infections, 583 Ophthalmologic Changes, 596
Calcitonin, 583 Palpable Parathyroid Masses, 596
Assays, 584 Importance of a Thorough Physical Examination, 596
Total Calcium, 584 Clinical Pathology, 596
Ionized Calcium, 584 Hemogram, 596
Parathyroid Hormone, 584 Biochemical Prole, 597
Vitamin D, 584 Urinalysis, 600
Parathyroid HormoneRelated Protein, 585 Electrocardiography, 601
Differential Diagnosis of Hypercalcemia, 585 Imaging, 601
Primary Hyperparathyroidism, 585 Radiography, 601
Hypercalcemia of Malignancy, 585 Ultrasonography, 601
Hypervitaminosis D, 590 Use of Parathyroid Hormone and Parathyroid HormoneRelated
Hypoadrenocorticism, 591 Protein assays, 603
Chronic Kidney Disease (CKD), 592 Diagnostic Approach to the Hypercalcemic Patient, 604
Acute Kidney Injury (AKI), 592 General Comments, 604
Raisin/Grape Toxicity, 592 Review of the History and Physical Examination, 604
Nutritional Secondary Hyperparathyroidism, 593 Initial Database, 604
Septic Bone Disease, Sepsis, Schistosomiasis, and Systemic Mycoses, 593 Lymph Node and Bone Marrow Evaluations, 607
Disuse Osteoporosis/Tumors Metastasizing to Bone, 593 Specic Assays: Parathyroid Hormone, Parathyroid HormoneRelated Protein,
Hemoconcentration, Sodium Bicarbonate Infusion, and Plasma Transfusion, 593 and Calcitriol, 607
Hypothermia, Fetal Retention, and Endometritis, 593 Trial TherapyWhy This Approach Is Strongly Discouraged, 607
Age, 593 Nonspecific Medical Treatment for Hypercalcemia, 608
Laboratory Error, 593 Exploratory SurgeryNo Longer Necessary?, 608
PRIMARY HYPERPARATHYROIDISM IN DOGS, 593 Spontaneous Resolution of Primary Hyperparathyroidism, 608
Signalment, 593 Acute Medical Therapy for Hypercalcemia (Not Primary
Age, Gender, and Weight, 593 Hyperparathyroidism), 608
Breed, 594 Primary Hyperparathyroidism Versus Other Disorders, 608
Indications and Alternatives for Acute Therapy in Hypercalcemia, 608
579
580 SECTION 5 PARATHYROID GLAND
Surgical Therapy for Primary Hyperparathyroidism, 609 Timing of Posttreatment Hypocalcemia and Recommendations Regarding
Introduction, 609 Vitamin D, 616
Surgical Observations, 609 The Tapering Process, 617
Cervical Imaging, 609 Prophylactic Vitamin D (Calcitriol) Therapy in All Dogs Treated for Primary
New Methylene Blue Infusions, 611 Hyperparathyroidism, 617
Solitary Adenoma, Hyperplastic Nodule, or Carcinoma?, 611 Vitamin D Resistance/Time Until an Effect Is Documented, 617
Enlargement of Multiple Parathyroid Glands, 611 Pathology, 617
Recurrence of Primary Hyperparathyroidism, 612 Subjectivity of Histologic Interpretation, 617
Absence of a Parathyroid Mass at Surgery, 612 Solitary Parathyroid Mass, 618
Percutaneous Therapies for Primary Hyperparathyroidism Mediastinal Parathyroid Tissue, 618
in Dogs, 612 Multiple Endocrine Neoplasia and Adrenal Secondary Hyperparathyroidism, 619
Percutaneous Ultrasound-Guided Ethanol Ablation, 612 Hereditary Neonatal Primary Hyperparathyroidism, 619
Percutaneous Ultrasound-Guided Radio Frequency Heat Prognosis: Dogs with Primary Hyperparathyroidism, 619
Ablation, 612 HYPERCALCEMIA IN CATS, 619
Posttreatment Management of Potential Hypocalcemia, 614 Background, 619
Background, 614 Idiopathic Hypercalcemia of Cats, 619
Protocol Based on the Pretreatment Total Calcium Concentration, 615 Primary Hyperparathyroidism in Cats, 620
CALCIUM REGULATION AND HYPERCALCEMIA lesser extent, complexed with anions, such as citrate or sulfate. The
remaining 50% is in the ionized biologically active form (Fig. 15-1).
The concentration of serum ionized calcium (iCa) and the
CALCIUM FUNCTION AND CONTROL calcium content of skeleton is maintained within narrow limits
by a complicated homeostatic system involving multiple organs
Overview and several hormones. The organs involved in the regulation of
calcium metabolism are the parathyroid glands, kidneys, skel-
Calcium serves two principal physiologic functions. First, insolu- eton, and gut (Fig. 15-2). The hormones include parathyroid
ble calcium salts (primarily hydroxyapatite) provide the structural hormone (PTH), vitamin D, and PTH-related protein (PTHrP).
characteristics that allow bones to protect internal organs and bear The actions of PTH on bone resorption, renal calcium excretion,
weight. Second, soluble calcium ions in the extracellular fluid and metabolism of vitamin D are responsible for maintaining
(ECF) and cytosol are critically important for a myriad of biochemi- homeostasis (Fig. 15-3; Table 15-1). Abnormalities in any of these
cal intracellular and extracellular functions. For example, calcium is organs, hormones, or receptors may cause disturbances in calcium
necessary for various enzymatic reactions, transport of substances metabolism that can lead to hypercalcemia or hypocalcemia.
across membranes and membrane stability, blood coagulation,
nerve conduction, neuromuscular transmission, muscle contrac-
Parathyroid Hormone
tion, smooth muscle tone, hormone secretion, bone formation,
hepatic glycogen metabolism, cell growth, and cell division (Ras- PTH is an 84amino acid, single-chain polypeptide, synthesized,
mussen, 1989; Brown etal, 1995; Rosol etal, 2000; Wysolmerski stored, and secreted by chief cells in the four parathyroid glands
and Insogna, 2012). Approximately 1% of total body calcium is (Fig. 15-4). PTH is synthesized initially as a single-chain, prepro-
contained within the ECF and soft tissue, 99% is found in bone. parathyroid peptide. The 25 residue presequence is cleaved twice
The skeleton, therefore, is a reservoir of available calcium when to generate the biologically active full-length protein (PTH 1-84).
ECF concentrations decline, and it acts as a storehouse for excess PTH has a half-life of minutes in circulation and is degraded in
calcium. About 50% of circulating calcium (0.5% of total body the liver and kidneys. The degradative process releases carboxy-
calcium) is bound to serum proteins, primarily albumin, and to a terminal (C-terminal) fragments of PTH into the circulation. In
Ionized
calcium
50%
Ca2+
FIGURE 15-1 Skeletal calcium acts as a res-

ervoir so that calcium can be stored or mo- 50% Protein-
bilized, depending on need. (From Skelly BJ: or
Hyperparathyroidism. In Mooney CT, Peterson complex-
bound
ME, editors: BSAVA manual of canine and
feline endocrinology, ed 4, Gloucester, Eng-
land, 2012, British Small Animal Veterinary
Association; used with permission.)
|
CHAPTER 15 Hypercalcemia and Primary Hyperparathyroidism 581
response to subtle hypercalcemia, proteases found within para- binding to the CaR activates downstream signaling pathways, pri-
thyroid secretory granules digest the amino-terminal portions of marily induction of phospholipases, and intracellular calcium tran-
PTH, leaving the inactive C-terminal fragments to be secreted. sients (Stewart, 2004). This, in turn, suppresses PTH secretion. In
Thus, biologically inactive C-terminal fragments, known to accu- addition to parathyroid cells, the CaR is prominently expressed in
mulate in the circulation of patients with chronic kidney disease kidneys, where they regulate the calcium handling by renal tubules.
(CKD), are a product of both parathyroid secretion and peripheral Subtle hypercalcemia activates the CaR, suppressing renal calcium
metabolism of full-length PTH (Wysolmerski and Insogna, 2012). reabsorption. In this manner, hypercalcemia directly promotes cal-
PTH secretion is regulated by the extracellular iCa concentration. cium excretion in urine, and hypocalcemia directly enhances its
A steep inverse sigmoidal relationship exists between PTH secre- reabsorption (Wysolmerski and Insogna, 2012; see Fig. 15-2).
tion and calcium concentration. The steep portion of this curve The actions of PTH are mediated by the type 1 PTH/PTHrP
encompasses the normal physiologic range for extracellular calcium, receptor (PTH1R). The calcium-regulating effects of the receptor
over which small changes in serum concentrations of iCa elicit large appear to be primarily the result of activating adenylyl cyclase.
changes in the rate of PTH secretion. Increased serum calcium con- During usual conditions, this receptor is activated equally well by
centrations inhibit secretion of PTH and decreased concentrations the amino-terminal portions of PTH and PTHrP (see later). The
stimulate PTH synthesis and secretion (Aurbach etal, 1985; Brown PTH1P is most abundant in bone and kidney, where it medi-
etal, 1999; see Fig. 15-3). For parathyroid cells to regulate PTH ates the systemic functions of PTH. However, PTH1P is also
secretion, they must sense changes in extracellular calcium concen- expressed in cells throughout the body, where it serves as a PTHrP
tration. This is accomplished through a G protein-coupled recep- receptor. In this capacity, PTH1P has important functions during
tor (GPCR) known as the calcium-sensing receptor (CaR). Calcium bone development, and it mediates many of PTHrPs effects on
Extracellular ionized
calcium
Renal
tubule
Calcium-
sensing 2+
receptor Ca
Parathyroid cell PTH

receptor
Ca2+
PTH
Bone
1,25(OH)2D3
Calcium- Ca2+
Endocrine
sensing PTHrP
mechanism
receptor
Duodenal
lumen
PTHrP Blood and other

extracellular fluid
Autocrineparacrine PTH receptor Cartilage and PTHrP

mechanism target cells in many
other tissues
FIGURE 15-2 The parathyroid axis. The synthesis of parathyroid hormone (PTH) and parathyroid hormonerelated
protein (PTHrP) is shown on the left and the target sites on the right. Both act by means of the same receptor
(also called the type 1 receptor). Negative feedback of 1,25-dihydroxyvitamin D31,25(OH)2D3 is not shown.
(Modified from Marx SJ: Hyperparathyroid and hypoparathyroid disorders, N Engl J Med 343:1863, 2000.)
Blood calcium increases Larynx

PTH
Renal
+ uptake Gut uptake
Skeletal
mobilization
Trachea
Left external
parathyroid
Right lobe
Kidney Gut Skeleton gland
of thyroid
Renal loss Gut loss Skeletal Isthmus Left lobe

+ storage of thyroid of thyroid
(not always
present) Left internal
Calcitonin
Blood calcium decreases parathyroid
gland
FIGURE 15-3 Calcium homeostasis. The release of parathyroid hormone (PTH)
causes increased uptake of calcium in the kidney and gut and mobilization from
the skeleton. (From Skelly BJ: Hyperparathyroidism. In Mooney CT, Peterson ME, ed- Common carotid
artery
itors: BSAVA manual of canine and feline endocrinology, ed 4, Gloucester, E ngland,
2012, British Small Animal Veterinary Association; used with permission.) Vagosympathetic
trunk
TABLE 15-1 APPROXIMATE REFERENCE

INTERVALS FOR SERUM FIGURE 15-4Schematic representation of the anatomical position of the
CONCENTRATIONS OF TOTAL parathyroid glands. (From Skelly BJ: Hyperparathyroidism. In Mooney CT, Peterson
CALCIUM, IONIZED CALCIUM, ME, editors: BSAVA manual of canine and feline endocrinology, ed 4, Gloucester,
PARATHYROID HORMONE, England, 2012, British Small Animal Veterinary Association; used with permission.)
PARATHYROID HORMONE
RELATED PROTEIN, AND terminus is thought to serve only as a guide for PTH through the
CALCITRIOL cellular secretory pathway (Orloff and Stewart, 1995). A synthetic
1-34 amino-terminal fragment is biologically active, but relatively
DOG CAT
minor modications, especially at the rst two residues, can com-
pletely abolish this effect (Marx, 2000).
Total calcium (TCa)
(mg/dL) 9.0-11.7 8.0-10.5
Parathyroid HormoneRelated Protein
(mmol/L) 2.2-2.9 2.0-2.6
PTHrP was discovered in the course of exploring the pathogen-
Ionized calcium (iCa)
esis of humoral hypercalcemia of malignancy (HHM). PTH and
(mg/dL) 4.6-5.6 4.5-5.5 PTHrP share structural features suggesting that they arose from a
(mmol/L) 1.1-1.4 1.1-1.4 common ancestor: in people eight of the first 13 amino-terminal
Parathyroid hormone (PTH) amino acids are identical. This amino-terminal homology allows
(variability among laboratories) both PTH and PTHrP to bind to the receptor PTH1P with equal
affinity, thereby activating the same pathways. PTH is made only
(pmol/L) 0.5-5.8 0-4 in parathyroid glands and is secreted into the circulation. PTHrP
(pg/mL) 6-16* is synthesized in many cells, is secreted locally, and acts in a para-
Parathyroid hormonerelated crine or autocrine fashion to activate PTH1P on neighboring
protein (PTHrP) cells. In veterinary medicine, PTHrP is best r ecognized as having
a central role in the pathogenesis of HHM and is used as a tumor
(pmol/L) <2 <2
marker in both dogs and cats (Williams et al, 2003; Henry,
1,25-Dihydroxyvitamin D3 2010). Since its discovery in the early 1980s, assay of PTHrP has
(calcitriol) (pg/mL) been used in the evaluation of hypercalcemic patients in whom
Adults 20-50 20-40 cancer is a possibility (Philbrick etal, 1996).
10 to 12 weeks old (pg/mL) 60-120 20-80
Vitamin D
*From Pineda etal.: Feline parathyroid hormone: validation of hormonal assays and
dynamics of secretion, Domest Anim Endocrinol 42:256, 2012. Inactive vitamin D is produced in skin and is available in some
From Rosol etal.: Disorders of calcium. In DiBartola SP, editor: Fluid therapy in small
foods. It appears that dogs are less able to synthesize vitamin D
animal practice, ed 2, Philadelphia, 2000, WB Saunders, pp. 108-162. in the skin than are other mammals (Gross etal, 2000; Mellanby
et al, 2005). Thus, dogs have a greater requirement for dietary
cellular proliferation, apoptosis, and differentiation (Wysolmerski vitamin D. PTH stimulates activity of renal enzymes responsible
and Insogna, 2012). for synthesizing biologically-active 1,25- dihydroxyvitamin D3
The amino acid sequence of PTH is known for humans, dogs, (1,25[OH]2D3), also known as calcitriol. The main function of
cows, pigs, rats, chickens, and cats. Based on immunologic reac- vitamin D is to support circulating calcium concentrations. Vita-
tivities, most mammals appear to have similar amino-terminal min D stimulates calcium (and phosphorus) absorption from the
portions of the molecule (Toribio etal, 2002). It is recognized that gut lumen by enterocytes, and it stimulates bone resorption via
the amino terminal of PTH binds to CaR, whereas the carboxyl osteoblastic release of cytokines (see Figs. 15-2 and 15-3).
|
surfaces, increased numbers of osteoclasts, osteocytic osteolysis,

PATHOPHYSIOLOGY OF PRIMARY
and marrow brosis. Bone histomorphometric ndings in dogs
HYPERPARATHYROIDISM
with PHPTH were similar to those reported in humans (i.e., par-
allel increases in osteoblastic and osteoclastic activity) (Meuten
Introduction: Extensive Effects of Excess PTH
etal, 1983a; Weir etal, 1986). Excessive absorption of calcium
Hypercalcemia in primary hyperparathyroidism (PHPTH) is the from the gastrointestinal tract is not usually an important cause of
result of PTH inducing osteoclast-mediated bone resorption, hypercalcemia, although it is a contributor to the hypercalcemia
stimulating intestinal absorption of calcium, and stimulating resulting from vitamin D toxicosis.
renal tubular resorption of calcium (Mundy, 1988; Hruska and
Teitelbaum, 1995). Uroliths and Urinary Tract Infections
Hypercalciuria resulting from PHPTH is a cause of the uro-
Kidney
lithiasis and urinary tract infections that are common with
In the setting of accelerated bone resorption, the kidneys become this disorder. The incidence of urinary tract infection is about
the principal defense against hypercalcemia (Bilezikian, 1992a; 20% to 30% of afflicted dogs and about 25% to 40% have uri-
Hruska and Teitelbaum, 1995). In the kidney, PTH has three nary calculi (Berger and Feldman, 1987; Klausner etal, 1987).
principal effects. First, PTH acts on proximal tubules to inhibit Hypercalciuria from increased glomerular ltration of calcium
reabsorption of phosphate. Second, it stimulates the activity of predisposes individuals to urolithiasis. Additional factors may
renal 1-hydroxylase in proximal tubular cells leading to for- play a role in urolith formation or urinary solute saturation,
mation of biologically active 1,25(OH)2D3 from its circulating including pH, ionic strength, and crystal aggregation inhibitors.
precursor 25-hydroxyvitamin D (25[OH]D) (also known as cal- Calcium phosphate, for example, is markedly less soluble in alka-
cidiol) while inhibiting synthesis of inactive vitamin D forms. line urine than in acidic urine. Other hypercalcemic conditions
Third, PTH increases kidney calcium reabsorption. Most calcium are not usually associated with urolithiasis. This discrepancy may
is reclaimed from glomerular filtrate in the proximal tubules via be explained, perhaps, by the chronic nature of the hypercalce-
a PTH-independent process. The primary target of PTHs action mia in dogs with PHPTH as opposed to the short-term nature of
to promote calcium reabsorption is in distal tubules, where it hypercalcemia in dogs with neoplasia, toxin exposure, and other
stimulates directional, transcellular calcium transport from the such conditions. In these other conditions, dogs tend to develop
tubule lumen, across the cell, and into the ECF. Early in the their clinical signs quickly, which either resolve or worsen in the
course of PHPTH, when hypercalcemia is mild, urinary cal- short-term.
cium excretion is relatively low. PTH action, at the renal level, In PHPTH, hypercalcemia is aggravated by increased pro-
enhances tubular resorption of calcium. When serum calcium duction of vitamin D and decreased amount of serum phos-
concentrations are greater than 12 to 14 mg/dL, the renal tubu- phate available to form complexes with serum iCa. The result is
lar mechanism for reabsorbing calcium becomes overwhelmed. decreased tubular resorption of phosphate, hyperphosphaturia,
Here, the kidneys adaptive mechanism for correcting hyper- and hypophosphatemia. These actions are responsible for the
calcemia becomes operative despite excessive concentrations of development of the biochemical triad classic for PHPTH: hyper-
PTH. This hypercalciuria, however, is not sufcient to correct calcemia, hypophosphatemia, and hyperphosphaturia. Vitamin
the hypercalcemia but can lead to nephrocalcinosis. Nephro- D deciency, after chronic PTH-stimulated use of vitamin D
calcinosis may be mild and reversible or severe and progressive, stores, is a possible natural adaptive mechanism to PHPTH in
leading to continued renal damage and uremia. Most dogs with people. People with vitamin D deciency caused by PHPTH
PHPTH have normal blood urea nitrogen (BUN) and serum may develop osteomalacia, a problem considered uncommon or
creatinine concentrations. As has been described in people with not clinically relevant in animals (Meuten et al, 1983a; Weir
PHPTH untreated for as many as 10 years, virtually no changes etal, 1986).
in serum renal or other biochemical proles (aside from increas-
ing calcium and decreasing phosphate concentrations) are noted Calcitonin
(Silverberg etal, 1999).
Calcitonin, a 32amino acid polypeptide hormone produced by
parafollicular or C cells located in the thyroid, is secreted in
Bone
response to increases in serum calcium (Mol et al, 1991). This
In the skeleton, PTH activates bone turnover and liberates stored hormone has the primary responsibility of limiting postprandial
calcium. The immediate action of PTH is to stimulate the trans- hypercalcemia in normal mammals. Calcitonin decreases bone
port of calcium across bone lining cells from an easily mobilized resorption by reducing the size of osteoclast brush borders, the
pool of calcium at the bone surface (Attie, 1989). The activity of number of osteoclasts, and osteoclast motility. Calcitonin does not
these cells, caused by PTH or PTHrP, is the foundation for virtu- affect the kidney or intestine. It may, however, influence the sati-
ally all cases of marked hypercalcemia. Associated with accelerated ety center, decreasing appetite. The role of calcitonin in dogs with
osteocytic and osteoclastic bone resorption, mineral is removed PHPTH is not known. Increased calcitonin secretion in response
and replaced by immature brous connective tissue. The bone to hypercalcemia seems a reasonable physiologic response. Para-
lesion of brous osteodystrophy in afflicted dogs is reported to follicular cells are markedly hyperplastic and appear as small
be generalized throughout the skeleton but accentuated in cer- white foci in the thyroid gland of dogs with PHPTH (Capen and
tain areas, such as the cancellous bone of the skull (Capen and Martin, 1983). Hyperplastic parafollicular cells may displace col-
Martin, 1983). Iliac crest bone biopsies from virtually all humans loid-containing follicles lined by thyroid follicular cells, implying
with PHPTH reveal histomorphometric evidence of the effects of the presence of an adaptive response by the parafollicular cells.
excess PTH (Arnaud and Kolb, 1991; Hruska and Teitelbaum, Studies in humans suggest that this adaptive mechanism is incon-
1995). These ndings may include increased bone resorption sistent (Arnaud and Kolb, 1991).
both antibodies, with a sandwich comprised of the N-terminal

ASSAYS
antibody plus the patients intact hormone plus the 39-84 anti-
body. Only these sandwiches are detected by the assay system,
Total Calcium
eliminating interference by midregion or C-terminal fragments,
Serum or heparinized plasma samples are suitable for routine anal- even if present in large concentrations. These assays usually require
ysis of total calcium (TCa). Fasted blood samples may reduce prob- several days to receive results.
lems with lipemia. Mean serum TCa concentrations in healthy Two-site immunochemiluminometric assays for intact PTH in
mature dogs is about 10.5 mg/dL (reference interval of about 9.6 humans use similar antibodies and a similar range of applicabil-
to 11.6 mg/dL; 2.4 to 2.9 mmol/L). Results from healthy cats are ity to animal sera (Michelangeli etal, 1997; Estepa etal, 2003).
usually slightly lower. Dogs younger than 3 months of age have One chemiluminescent PTH assay system required only about
slightly higher results than dogs older than 1 year (Schenck and 20 minutes to perform, making this method potentially of use
Chew, 2012). Oxalate, citrate, and ethylenediaminetetraacetic during surgery (Bilezikian et al, 2001; Ham et al, 2009; Cort-
acid (EDTA) anticoagulants should not be used because they bind adellas et al, 2010). As can be appreciated, assay systems often
calcium. Calcium status of dogs and cats is often initially based on become unavailable for various reasons. A whole intact molecule
the total concentration because this is the result provided in most PTH assay system is now being used that has lower reference val-
general biochemistry profiles. Estimation of iCa based on the ues, but good correlation with previously-used systems (Refsal
TCa is not a perfect science. For example, when estimating the iCa and Nachreiner, 2012). Currently, enzyme-linked immunosor-
based on the TCa in dogs, there is a tendency to overestimate the bent assay (ELISA) is the most common assay used to measure
number of normocalcemic patients and underestimate those with PTH in the Great Britain and Europe. A canine-specific intact
hypocalcemia. In cats, using the TCa to estimate the iCa tends to ELISA, which is also validated for cats, is available (Skelly, 2012).
underestimate normocalcemia and hypercalcemia, overestimating Reference intervals and units used in reporting results vary among
hypocalcemia (Schenck and Chew, 2005a; 2005b). Adjustment laboratories, necessitating good communication to avoid confu-
formulas previously used to predict the iCa are not recommended sion. Assay of 1-84 amino acid PTH is now considered to be most
(Schenck and Chew, 2012). Because iCa is available to most vet- reliable (Gao etal, 2001).
erinary clinicians, it is wise to assess the iCa directly whenever Determination of the serum PTH concentration is a useful
there is suspicion of a calcium imbalance. diagnostic aid in the evaluation of dogs and cats suspected of hav-
ing parathyroid disease. As with most hormone assays, evaluation
of the serum hormone concentration out of context is not as
Ionized Calcium
consistently informative as evaluation in the proper context is.
Typically, serum is analyzed for iCa measurement, but heparinized With this in mind, the serum PTH concentration must be evalu-
plasma or whole blood can be used. Results from heparinized whole ated relative to the total and, ideally, ionized serum calcium con-
blood samples tend to be lower than results using serum (Schenck centrations. Decreases in the serum calcium concentration are
and Chew, 2008). The analysis of serum eliminates potential inter- normally associated with increases in the serum PTH concentra-
ference by heparin and allows longer storage periods. Silicone sepa- tion. Increases in the serum calcium concentration are normally
rator tubes should not be used. Analysis utilizing an ion-selective associated with decreases in the PTH concentration (Fig. 15-5).
electrode allows easy and accurate measurement. Serum iCa concen- As with any laboratory value, a single PTH result may not be
tration in healthy adult dogs and cats is about 1.1 to 1.4 mmol/L. the expected value. Therefore practitioners are encouraged to
Young dogs and cats have slightly higher values. Accurate determi- complete a thorough evaluation of hypercalcemic dogs or cats. If
nation of iCa requires that samples be collected and processed cor- any test result does not seem logical, it may need to be repeated.
rectly. Therefore, adhering to laboratory protocol is imperative. Serum hormone concentrations may fluctuate significantly.
Parathyroid Hormone Vitamin D

The development of an assay for serum PTH in 1963 by Ber- Measurement of vitamin D metabolites, although not com-
son and colleagues was a major breakthrough in the diagnosis of monly used in veterinary medicine, would occasionally be helpful
human parathyroid disorders. It is now appreciated that complete in the diagnosis of calcium disorders. 25(OH)D (calcidiol) and
(84amino acid) molecules of PTH and numerous incomplete 1,25(OH)2D3 (calcitriol) are the metabolites of greatest clinical
pieces of PTH are found in the circulation of all animals. Pri- interest for detection of hypovitaminosis or hypervitaminosis D
mary bioactivity resides in the intact molecule, the major secre- syndromes and in CKD (Carothers etal, 1994). These metabolites
tory product of parathyroid glands (see Fig. 15-4). Excellent valid are stable during refrigeration and freezing, but samples should
assays are available for PTH in dogs and cats. It is imperative for not be exposed to light for any length of time. Both metabolites
clinicians to follow their laboratories protocols regarding sample are chemically identical among species, therefore receptor-binding
collection and processing, usually including shipping samples on assays or radioimmunoassays (RIAs) used for people may be sat-
ice (Torrance and Nachreiner, 1989a; 1989b). Development of the isfactory for dogs and cats (Hollis et al, 1996). Young growing
two-site PTH assay system used by many laboratories depended individuals have higher calcitriol concentrations than adults.
on production of two different polyclonal antibodies. The two- Calcitriol assays have demonstrated genetic errors of vitamin D
site immunoradiometric assay (IRMA) system for intact human metabolism and normal-to-increased concentrations in PHPTH,
PTH was demonstrated to be valid for measurement of dog and whereas patients with hypercalcemia of malignancy have levels
cat PTH (Torrance and Nachreiner, 1989a; Flanders and Reimers, that may be low, normal, or high. Dogs and cats with possible
1991; Barber etal, 1993). One antibody binds only the midre- exposure to rat and mouse poisons containing vitamin D may
gion and C-terminal 39-84 amino acids of human PTH. The present challenging diagnostic problems. Serum concentrations
other antibody binds only the N-terminal amino acids of human of vitamin D have been increased in these animals (Dougherty
PTH. Samples being assayed are incubated simultaneously with etal, 1990).
|
Primary Chronic Apocrine Hypo-

hyperpara- Lympho- renal gland tumors Hyper- para-
thyroidism sarcoma failure of the anal sac vitaminosis D thyroidism
Severe
Mild
[PTH]
Normal
Mild
Severe
Severe
Mild
[PTHrP]
Normal ?
Mild
Severe
Severe
Ionized calcium
Mild
Normal
Mild
Severe
Severe
Mild
FIGURE 15-5Graph showing the serum
Vitamin D
Normal parathyroid hormone (PTH), parathyroid hor-

monerelated protein (PTHrP), ionized cal-
Mild cium (iCa), and vitamin D concentrations in
the most common causes for hypercalcemia
Severe of dogs.
Parathyroid HormoneRelated Protein reliable, noninvasive, and inexpensive aide in distinguishing

HHM from nonmalignant hypercalcemia. Animals with renal
PTHrP resembles PTH not only in terms of its genetic sequence insufciency may also have increased concentrations of PTHrP
but also in terms of structure (Fig. 15-6); thus, PTHrP is a (see Fig. 15-5).
second member of the PTH family of hormones (Broadus
and Stewart, 1994). In marked contrast to PTH, found only
DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA
in parathyroid glands, PTHrP is found in many tissues (Table
15-2; Fig. 15-7) (Strewler, 2000). Two-site IRMA and N-termi- See Box 15-1.
nal RIAs are available for the measurement of human PTHrP,
and these same assay systems have been validated for the dog
Primary Hyperparathyroidism
(Brown etal, 1987; B urtis, 1992). Because PTHrP is suscepti-
ble to degradation by serum proteases, assays should use fresh or See the next section.
frozen plasma using EDTA as anticoagulant. The EDTA com-
plexes with plasma calcium, limiting the action of most prote-
Hypercalcemia of Malignancy
ases. The addition of protease inhibitors, such as aprotinin, may
provide further protection. Use of serum is not recommended General Overview
(Budayr etal, 1989; Henderson etal, 1990; Rosol etal, 2000). Malignancies are the most common causes of hypercalcemia in
Valid assays for dog and cat PTHrP can be used to screen for dogs and cats (Messinger etal, 2009). Neoplasms can cause hyper-
certain cancers. Simultaneously assaying PTH and PTHrP in calcemia by several recognized physiologic processes (Fig. 15-8):
hypercalcemic dogs and cats has the potential to be a quick, HHM is caused by secretion of PTHrP, while some lymphomas
IA TABLE 15-2 S
ITES AND PROPOSED ACTIONS
0
1 Sequence OF PARATHYROID HORMONE
~PTH IB
Functional ~PTH
RELATED PROTEIN (PTHrP)
II
Unique
IIB SITE PROPOSED ACTIONS
Processing Mesenchymal Tissues
III
Divergent Cartilage Promotes proliferation of chondrocytes; inhib-
(species) its terminal differentiation and apoptosis
of chondrocytes
1 13 34 88 108-111 141 Bone Stimulates or inhibits bone resorption
Smooth muscle Released in response to stretching; relaxes
PTH-like PTH-unlike
smooth muscle in the vascular system,
FIGURE 15-6Structural and functional domains of parathyroid hormone myometrium, and urinary bladder
related protein (PTHrP). The 1 to 13 region of PTHrP is 70% homologous with the Cardiac muscle Positive chronotropic stimulus; indirect posi-
corresponding region of parathyroid hormone (PTH) and is believed to be involved tive inotropic stimulus
in activation of adenylate cyclase and other second-messenger systems in target
tissues. The 14 to 34 region shares no homology with the 14 to 34 region of PTH Skeletal muscle Unknown
but has been shown to bind effectively to the PTH receptor. The 35 to 108 r egion Epithelial Tissues
of PTHrP is unique, sharing no homology with any other known peptide. This Mammary Induces branching morphogenesis; secreted
region is extraordinarily highly conserved among species, which suggests that in milk; possible roles in lactation
it has a crucial but as yet unknown function or functions. The 88 to 108 region
of the peptide is rich in potential proteolytic cleavage sites and contains several Epidermis Unknown
amidation signals and is therefore presumed to be the site of posttranslational Hair follicle Inhibits anagen
processing, at least in some tissues. The 112 to 141 region of the peptide is Intestine Unknown
poorly conserved among species. Preliminary evidence suggests that at least in
Tooth enamel Induces osteoclastic resorption of
some situations, C-terminal fragments derived from this region enter the circula-
overlying bone
tion. The functional consequences of this are unknown. (From Broadus AE, etal.:
Humoral hypercalcemia of cancer: identification of a novel parathyroid hormone- Endocrine Tissues
like peptide, N Engl J Med 319:556, 1988.) Parathyroid glands Stimulates placental transport of calcium (?)
Pancreatic islets Stimulates insulin secretion and somatic
synthesize vitamin D in addition to PTHrP. Hypercalcemia is growth
then induced by marked increase in osteoclastic bone resorption Pituitary Unknown
in areas surrounding the malignant cells within the marrow (Rosol Placenta Calcium transport (?)
etal, 2000; Stewart, 2005). Ectopic PTH synthesis and secretion Central Nervous Released from cerebellar granular neurons in
is a rare cause of hypercalcemia in people (Stewart, 2005). Some System (CNS) response to activation of L-type calcium
dogs with lymphosarcoma, apocrine gland carcinomas of the anal
channels; receptors in cerebellum, hip-
sac, or multiple myeloma are hypercalcemic. Some tumors that
pocampus, hypothalamus
metastasize to bone can cause hypercalcemia through the induc-
tion of local bone resorption. These include malignancies of mam- From Strewler GL: The physiology of parathyroid hormonerelated protein, N Engl J Med
mary tissue, prostate, liver, and lung. Primary bone tumors do not 342:177, 2000.
typically cause hypercalcemia. Hypercalcemia has been associated
with nasal adenocarcinomas, thyroid carcinoma, thymoma, squa-
mous cell carcinoma of the gastrointestinal system or vagina, and
melanoma (Pressler etal, 2002; Schenck and Chew, 2012).
2000). Identification of PTHrP provides an explanation of why
Humoral Hypercalcemia of Malignancy some tumors (those that do not synthesize PTHrP) are not asso-
Humoral Factors, Including Parathyroid HormoneRelated ciated with hypercalcemia. PTHrP concentrations are abnormal
Protein.Tumor tissue at a site distant from bone may synthe- usually only in individuals with malignancies and renal failure (see
size and secrete PTHrP, stimulating bone resorption, leading to Fig. 15-5). Serum PTH concentrations in dogs with malignancy-
hypercalcemia. Excessive secretion of biologically active PTHrP associated hypercalcemia are typically low or undetectable. This
plays a central role in the pathogenesis of hypercalcemia in most should be seen as a normal response by the parathyroid glands to
forms of HHM. Cytokines, such as interleukin-1 (IL-1), tumor hypercalcemia. Assay of PTH and PTHrP concentrations should
necrosis factor alpha (TNF), transforming growth factor-a not be viewed as a replacement for a complete physical exami-
(TGF-a), transforming growth factor-b (TGF-b), or calcitriol, can nation, thoracic radiography, abdominal ultrasonography, or any
have synergistic or cooperative actions with PTHrP (Fig. 15-9) other key parameter used to identify neoplasia. These assay results
(Rosol et al, 2000). PTHrP binds to the PTH1R, as described are as integral as other components of an evaluation.
earlier. PTHrP, via interaction with PTH1R, stimulates osteo- Hematopoietic Neoplasia. T cell lymphoma is the most com-
clastic bone resorption, increases renal tubular calcium resorp- mon cause of hypercalcemia in dogs, accounting for almost 60%
tion, and decreases renal tubular phosphate resorption. IL-1 and of dogs with hypercalcemia and almost 80% of dogs with hyper-
the transforming growth factors (TGFs) also have the potential calcemia due to cancer (Messinger etal, 2009). Lymphoma afflicts
to stimulate bone resorption (McCauley etal, 1991; Rosol etal, dogs of any age and either sex. Approximately 20% to 40% of
|
PTHrP ACTIONS
Normal/ Normal/ Abnormal/

endocrine paracrine endocrine
Fetal Skin Humoral

parathyroid Mammary gland hypercalcemia
glands Endocrine organs of malignancy
Placenta Muscle
Lymphoid organs
FIGURE 15-7Actions of parathyroid hormonerelated protein
Kidney (PTHrP). (From Rosol TJ, etal.: Disorders of calcium. In DiBartola SP,
Bone editor: Fluid therapy in small animal practice, ed 2, Philadelphia,
Brain 2000, WB Saunders, pp. 108-162.)
BOX 15-1 Differential Diagnoses for Hypercalcemia Cancer-Associated

Hypercalcemia
Non-Pathologic Humoral Forms Local Forms
Spurious, laboratory error
Young growing animal
Solid tumors
Common or
Lymphosarcoma Ca++ Ca++
multiple myeloma
Hypoadrenocorticism
Primary hyperparathyroidism (PHPTH)
Chronic kidney disease (CKD) Humoral
Tumor
Idiopathic hypercalcemia of cats (IHC) factors Hematologic
Ca++ Ca++ tumors
Less Common
Apocrine gland carcinoma of the anal sac
Multiple myeloma FIGURE 15-8 Pathogenesis of cancer-associated hypercalcemia. Humoral and
Vitamin D toxicosis local forms of cancer-associated hypercalcemia increase circulating concen-
Overzealous dietary supplementation trations of calcium by stimulating osteoclastic bone resorption and increased
Plants (calcitriol glycosides) renal tubular resorption of calcium. (From Rosol TJ, etal.: Disorders of calcium.
Rodenticides (cholecalciferol) In DiBartola SP, editor: Fluid therapy in small animal practice, ed 2, Philadelphia,
Anti-psoriasis creams (calcipotriol or calcipotriene) 2000, WB Saunders, pp. 108-162.)
Uncommon to Rare
Hemoconcentration, hyperproteinemia
Carcinomas dogs with lymphosarcoma are hypercalcemic (Weller etal, 1982;
Lung Matus etal, 1986; Rosol etal, 2000). Clinical signs may be subtle,
Mammary moderate, or severe. About one-third of cats with lymphoma are
Nasal hypercalcemic (Savary etal, 2000). Studies on affected dogs have
Pancreas demonstrated parameters consistent with influence by PTHrP,
Testicular including increased fractional excretion of phosphorus, increased
Thymus nephrogenous cyclic adenosine monophosphate (cAMP), and
Thyroid increased osteoclastic bone resorption. PTHrP appears to differ
Vaginal from natural PTH in its inability to stimulate renal formation of
Adrenal medullary 1,25(OH)2D3 and its lack of cross-reactivity with specic, two-
Melanoma site, intact PTH assays. A signicant percentage of these dogs
Acute kidney injury (AKI) have increased serum concentrations of PTHrP (Fig. 15-10) (Weir
Hyperthyroidism etal, 1988a; 1988b; 1988c). Studies in cats have revealed similar
Nutritional secondary hyperparathyroidism findings (i.e., some cats with cancer have hypercalcemia secondary
(Serum calcium concentrations usually within reference intervals) to tumor-synthesis and secretion of PTHrP). In seven cats with
Granulomatous disease HHM and increases in serum or plasma PTHrP, one had lym-
Blastomycosis phoma, four had lung carcinomas, one had a thyroid carcinoma,
Histoplasmosis and one had an undifferentiated carcinoma. These authors dem-
Schistosomiasis onstrated that IRMA assays for human 1-84 PTHrP can be used
Hypervitaminosis A to measure PTHrP in cats and that malignancies in cats, particu-
Raisin/grape toxicity larly carcinomas, may secrete PTHrP and induce HHM in cats
(Bollinger etal, 2002).
Humoral Factor and HHM
Humoral factors ++
Ca
(ILs, TNFs, TGFs, etc.)
Synergy
or
additivity
Ca++
Tumor
PTHrP Ca++
FIGURE 15-9 Humoral factors, such as parathyroid hormonerelated protein (PTHrP), interleukin-1 (IL-1), tumor necrosis factors (TNFs), and transforming growth fac-
tors (TGFs) produced by tumors induce humoral hypercalcemia of malignancy (HHM) by acting as systemic hormones and stimulating osteoclastic bone resorption or by
increasing tubular resorption of calcium. (From Rosol TJ, etal.: Disorders of calcium. In DiBartola SP, editor: Fluid therapy in small animal practice, ed 2, Philadelphia,
2000, WB Saunders, pp. 108-162.)
100
N-terminal PTHrP (pM)
10
Detectability = 1.8 pM
1
Control ASA ASA Lymphoma Lymphoma Misc Misc
normo- hyper- normo- hyper- normo- tumor tumor
calcemia calcemia calcemia calcemia calcemia hyper- normo-
calcemia calcemia
FIGURE 15-10 Circulating N-terminal parathyroid hormonerelated protein (PTHrP) concentrations in normal dogs
(control); dogs with hypercalcemia (>12 mg/dL) and anal sac adenocarcinoma (ASA), lymphoma, or miscellaneous
tumors (misc tumor); and dogs with normocalcemia (< 12 mg/dL) and anal sac adenocarcinoma, lymphoma, or
miscellaneous tumors. (From Rosol TJ, etal.: Disorders of calcium. In DiBartola SP, editor: Fluid therapy in small
animal practice, ed 2, Philadelphia, 2000, WB Saunders, pp. 108-162.)
|
Lymphomas can synthesize vitamin D in addition to PTHrP, In affected dogs, rectal examination usually demonstrates a space-
in which case afflicted patients would not only have the expected occupying mass that may be invasive and occasionally ulcerated.
increases in serum PTHrP but also would have increased vitamin Careful digital rectal palpation is necessary to identify the pres-
D concentrations (Seymour and Gagel, 1993). Some lymphocytes ence of sublumbar lymph node enlargement. Although radiogra-
contain the 1-hydroxylase (similar to that found in renal tubules) phy may also be used to evaluate the sublumbar area, abdominal
that converts 25(OH)D to the active metabolite, 1,25(OH)2D3 ultrasonography has been a sensitive diagnostic aid. Radiography
(Rosol etal, 2000). Therefore lymphomas that retain this capabil- of the thorax and abdomen can be used in searching for pulmo-
ity may synthesize excessive amounts of calcitriol, which would nary metastases and/or bony metastases (lytic areas).
increase calcium absorption from the intestinal tract and exacer- Other Nonneoplastic and Solid Tumors That May Synthesize
bate the hypercalcemia resulting from PTHrP synthesis and secre- Parathyroid HormoneRelated Protein.Thymoma, melanoma,
tion (see Figs. 15-1 and 15-5). carcinomas of the lung, pancreas, thyroid, skin, mammary gland,
Although the clinical signs associated with lymphoma are vari- nasal cavity, adrenal medulla, and interstitial cell tumors of the tes-
able, a dog with lymphoma and HHM is typically far more ill ticle are less commonly encountered solid tumors that cause hyper-
than dogs with PHPTH. Lymphoma must remain a possible calcemia without bone metastasis (Grain and Walder, 1982; Meuten
explanation for hypercalcemia in any dog or cat until a different etal, 1983a; Pressler etal, 2002; Williams etal, 2003). Dogs or cats
cause has been confirmed. Lymphosarcoma may or may not be with any of these neoplastic conditions are not usually hypercalcemic,
apparent to the veterinarian during the physical examination. At but when present, the value of a randomly collected serum or plasma
least 40% of dogs with both lymphoma and HHM do not have sample for PTHrP measurement can be quite informative. In people,
peripheral lymph node, liver, spleen, or renal enlargement. Most a small percentage of bronchogenic nonsmall-cell carcinomas, breast
of these dogs have a mediastinal mass, usually obvious on tho- cancers, squamous cell carcinomas of the esophagus, renal-cell carci-
racic radiographs. The nding of a mediastinal mass in a dog with nomas, and hepatomas have synthesized and secreted PTHrP (Harris
hypercalcemia should suggest a diagnosis of lymphoma, although etal, 2002). PTHrP has also been associated with hypercalcemia in
other forms of neoplasia (e.g., thymoma) may account for both nonneoplastic diseases, such as schistosomiasis (Fradkin etal, 2001).
the mass and the hypercalcemia (Foley etal, 2000). In addition
to lymphoma and thymoma, hypercalcemia due to HHM can Hematologic Malignancies of the Bone Marrow: Osteolytic
be caused by melanoma, myeloma, or by carcinomas of the lung, Hypercalcemia
pancreas, thyroid, skin, mammary gland, nasal cavity, or adre- Background.Some types of hematologic malignancies present
nal medulla. Concentrations of PTHrP are highest in dogs with in bone (e.g., lymphoma and multiple myeloma) produce hyper-
apocrine gland carcinomas of the anal sac (Pressler et al, 2002; calcemia by inducing bone resorption locally (Rosol etal, 2000).
Williams etal, 2003; Schenck and Chew, 2012). In humans, metastatic breast cancer is another example, although
Apocrine Gland Adenocarcinoma of the Anal Sac.Adeno- this association is not common in dogs or cats. A number of para-
carcinomas of the anal sac represent a classic example of cancer crine factors may be responsible for the stimulation of local bone
associated hypercalcemia. Like lymphosarcoma, this neoplasm is resorption in dogs or cats with such tumors, such as the previously
known to synthesize PTHrP (Matus and Weir, 1989; Williams discussed cytokines and PTHrP (see Humoral Hypercalcemia
et al, 2003). This is a well-dened but relatively uncommon of Malignancy; Black and Mundy, 1994). Production of small
tumor of older dogs; their mean age at presentation is 10 to 11 amounts of PTHrP by a tumor in bone may stimulate local bone
years (range, 3 to 17 years) (Bennett etal, 2002). Slightly more resorption without inducing a systemic response. Prostaglandins
than half of the dogs with this cancer were female. Dogs of almost (especially prostaglandin E2) may also contribute to local stimula-
any breed and mixed breed dogs can develop this condition (Ross tion of bone resorption (Rosol etal, 2000). Together, these cyto-
etal, 1991; Goldschmidt and Shofer, 1992; Bennett etal, 2002; kines and prostaglandins comprise the osteoclast-activating factors.
Williams etal, 2003). In one study, the serum calcium concen- Multiple Myeloma.Multiple myeloma is a tumor of B-lym-
trations (upper reference value of 12.6 mg/dL) at the time of phocytes or plasma cell lines that may be associated with the devel-
diagnosis ranged from 12.7 to 21.7 mg/dL (Bennett etal, 2002). opment of osteolytic bone lesions and, occasionally, hypercalcemia.
Clinical signs associated with this condition include (among many The hypercalcemia develops secondary to production of the pre-
owner observations) recognition of a mass near the rectum, tenes- viously described interleukin-1 (IL-1; previously described as
mus, poor appetite or anorexia, polyuria/polydipsia, and lethargy. osteoclast-activating factor), plus transforming growth factor-
HHM is reported in about 25% of dogs with apocrine gland car- (TGF-), and the receptor activator of nuclear factor k-B ligand
cinoma of the anal sac (Ross etal, 1991; Williams etal, 2003). (RAN kL). The latter is a membrane-associated protein that stim-
Local reappearance of the cancer or metastasis causes recurrence ulates osteoclast activity by binding to surface receptors (Henry,
of hypercalcemia if surgery resulted in transient resolution. Dogs 2010). There is correlation between extent of bone destruction,
afflicted with this form of cancer have increases in urinary cAMP tumor cell burden, and the amount of IL-1 produced by myeloma
and fractional phosphorus excretion. Serum PTH concentrations cell cultures (Durie etal, 1981; Wysolmerski and Insogna, 2012).
are suppressed, PTHrP concentrations are excessive, bone histo- Approximately 17% of dogs afflicted with this cancer are hypercal-
morphometry reveals increased bone resorption, and there is no cemic and 50% of dogs with multiple myeloma have radiographic
compensatory increase in formation. These changes are consistent evidence of bone lysis (Matus etal, 1986; Henry, 2010).
with excesses in PTH or PTHrP (Meuten etal, 1983b). Apocrine Bone pain may be associated with the lytic areas. The initial
gland adenocarcinoma cell lines established in mice have also database from afflicted dogs often reveals abnormal increases in
demonstrated potential factors responsible for HHM, although the total serum globulin concentration as a result of a monoclo-
only PTHrP is increased in the serum (Grone etal, 1998). This nal spike. A monoclonal gammopathy can be demonstrated
form of malignancy carries a guarded prognosis (Rosol et al, via serum protein electrophoresis. Bone marrow aspiration may
1992a; 1992b; Williams etal, 2003). aid in conrming the diagnosis. Analysis of urine for light chains
With recognition of hypercalcemia in any dog, a rectal examina- of myeloma protein (Bence Jones protein) has not been of value
tion and careful palpation of the anal sac areas should be routine. (Matus etal, 1986; Henry, 2010).
Hypercalcemia Induced by Metastases of Solid

Tumors to Bone Hypervitaminosis D
Certain malignant neoplasms with osseous metastasis may cause Background
hypercalcemia and hypercalciuria. Primary bone tumors, by Vitamin D can be cumulative in its toxic action if a dog or cat consumes
contrast, do not typically induce hypercalcemia. For example, excess quantities in food, for example, and may require weeks before
hypercalcemia would be rare in a dog with osteosarcoma, whereas effects on mineral metabolism become clinically obvious. However,
malignant mammary adenocarcinoma or squamous cell carcinoma acute toxicity after massive ingestion of cholecalciferol appears to be
are (albeit infrequently) associated with both bone metastasis and the more commonly reported cause of vitamin D toxicosis in dogs.
hypercalcemia. Several different types of cells may be involved Hypercalcemia and hyperphosphatemia are the anticipated electro-
in the actual destruction of bone at sites of metastasis, including lyte abnormalities in vitamin D toxicity, although normophospha-
osteoclasts, tumor cells, lymphocytes, and monocytes. Lympho- temia and transient periods of normocalcemia have been reported
cytes and monocytes may accumulate as part of the cell-mediated (Harrington and Page, 1983; Mellanby etal, 2005; Figs. 15-11 and
immune response to a tumor (Mundy etal, 1984). Osteolysis is 15-12). Hypercalcemia begins as soon as 12 to 18 hours after mas-
a result of the physical disruption of bone by proliferating neo- sive ingestion, and peak concentrations are usually demonstrated by
plastic cells, but it also can be caused by secretion of cytokines 48 to 72 hours, coinciding with increases in BUN and creatinine
or prostaglandins that stimulate local bone resorption (Garrett, (Rumbeiha, 2000). Increased resorption from bone, coupled with
1993; Henry, 2010). increased gastrointestinal absorption of calcium and phosphorus,
Epithelial tumors, especially squamous cell carcinomas, are the are responsible for these abnormalities. Skeletal disease is usually not
most likely neoplasms to metastasize to bone in dogs and cats detectable radiographically, probably because of the acute nature of
(Quigley and Leedale, 1983). Common metastatic bone sites in the toxicosis. The osteoclastic phase of bone resorption occurs early
the dog include the humerus, femur, and vertebrae, whereas in the and is followed by osteoid deposition and hyperosteoidosis (Boyce
cat, local invasion of bone rather than distant metastasis is more and Weisbrode, 1983). Extensive soft tissue mineralization of the
common. Although reported, these tumors are not commonly endocardium, blood vessels, tendons, kidney, and lung is frequently
associated with hypercalcemia (Grain and Walder, 1982). associated with vitamin D toxicity (Meuten, 1984).
20
18
16
Serum calcium (mg/dL)
14
12
10
8
6
4
2
6 12 18 24 30 36 42 48 54 60 66 72 78
Time (days)
A
12
10
Serum phosphorus (mg/dL)
FIGURE 15-11 Serum calcium (A) and phosphorus (B) concentrations

of dogs given vitamin D3 at a dosage of 10 mg/kg (circles) and 20 mg/kg 6 12 18 24 30 36 42 48 54 60 66 72 78
(triangles). (From Gunther R, etal.: Toxicity of a vitamin D3 rodenticide B Time (days)
to dogs, J Am Vet Med Assoc 193:211, 1988.)
|
Rodenticide Toxicosis Lilies and Cestrum diurnum (day-blooming jessamine) are popu-
Hypercalcemia that develops secondary to cholecalciferol roden- lar houseplants that should be considered sources of vitamin D
ticide toxicosis in dogs and cats is a recognized concern (Gun- toxicity in pets because they contain active metabolite of vitamin
ther etal, 1988; Moore etal, 1988; Bahri, 1990; Dougherty etal, D. Jasmine, an indoor climbing plant without active vitamin D
1990; Fooshee and Forrester, 1990; Rumbeiha etal, 1999; Mur- metabolites, should not be confused with day-blooming jessa-
phy, 2002). A variety of rat bait products contain cholecalciferol mine. Other plants containing glycosides of vitamin D include
(Nicholson, 2000; Rumbeiha, 2000; Morrow, 2001). Dogs stud- Solanum malacoxylon and Trisetum flavescens.
ied after being given this type of poison became weak, lethargic,
and anorexic within 48 hours. Within 60 to 70 hours of consump- Diagnosis
tion, all dogs became recumbent, exhibited hematemesis, and The diagnosis of vitamin D toxicosis is based on a history of
progressed into shock before dying or being euthanized (Gunther exposure. In acute cases, one may see dark or bloody feces, azote-
etal, 1988). Although the median lethal dose of cholecalciferol in mia, oliguria or polyuria, proteinuria, and sometimes glucosuria.
dogs is widely reported to be 43 to 88 mg/kg, studies have shown An additional clue in diagnosing chronic hypervitaminosis D,
that as little as 10 mg/kg given once orally can be lethal. Dogs such as with a dietary excess, would be hyperphosphatemia in a
that ingest as little as 4 to 6 mg/kg, once, can become ill. Clini- hypercalcemic dog or cat. Most other causes of hypercalcemia are
cally healthy dogs that ingest single doses of 2 mg/kg may develop associated with hypophosphatemia or normal serum phosphate
hypercalcemia (Rumbeiha, 2000). concentrations. The history and signs of vitamin D toxicosis can
Most dogs and cats exposed to these toxins have had rapid be strikingly similar to those seen in dogs with hypoadrenocor-
increases in the serum calcium and phosphate concentrations ticism, acute kidney injury (AKI), and CKD. Various assays are
(see Fig. 15-11). Diffuse gastrointestinal hemorrhage was obvi- available as diagnostic aides. Calcidiol (25[OH]D) concentration
ous. Histologic lesions consisting of hemorrhage or mineral- is a good indicator of vitamin D ingestion and can be used to
ization or both were identied in the gastrointestinal tract, help identify hypervitaminosis D, because vitamin D metabo-
kidneys, myocardium, and in the blood vessels of many organs lites resulting from rodenticides will be measured. The vitamin D
(Gunther et al, 1988). The incidence of acute and/or severe analog found in skin creams is not measured with this assay but
renal failure was variable. Three exposed cats survived (Moore should be detectable with a calcitriol assay (Peterson, 2012).
etal, 1988).
Other Causes of Vitamin D Toxicosis (Creams, Plants, Hypoadrenocorticism

and Dietary Supplements) Hypoadrenocorticism (Addisons disease) is one of the more com-
Since 1997, perhaps the most common accidental cause of vita- mon causes of hypercalcemia in dogs, accounting for approxi-
min D toxicosis in pets has been ingestion of human psoriasis mately 10% to 50% of cases (Uehlinger et al, 1998; Rosol
medications containing the vitamin D analogs calcipotriol or et al, 2000). Serum calcium concentrations have been reported
calcipotriene. Excess dietary supplementation and overzealous to be increased in as many as 33% of dogs with adrenocortical
administration of vitamin D by veterinarians to dogs or cats with insufciency (hypoadrenocorticism) (Peterson and Feinman,
hypoparathyroidism have been reported (Mellanby etal, 2005). 1982; Peterson etal, 1996; Scott-Moncrieff, 2010) as well as in
Vitamin D given after removal of a parathyroid tumor when a smaller percentage of hypoadrenal cats (Johnessee etal, 1982;
hypocalcemia is recognized or anticipated can be overdosed. Peterson et al, 1989). A correlation has been noted between
Severe
Serum calcium
Mild
Normal range
Mild
Severe
Primary Hyper- CKD Vitamin D Nutritional Addison's
HP calcemia toxicity 2 HP disease
of malignancy
Severe
Serum phosphorus
Mild
Normal Range
Mild
Severe FIGURE 15-12 The range in serum calcium and phosphorus con-
Primary Hyper- CKD Vitamin D Nutritional Addison's centrations for the more common causes of hypercalcemia and/
HP calcemia toxicity 2 HP disease or hyperparathyroidism in the dog. CKD, Chronic kidney disease;
of malignancy HP, hyperparathyroidism; 2 HP, secondary hyperparathyroidism.
the degree of hyperkalemia and the level of hypercalcemia (see evaluation. Measurement of serum iCa concentrations should
Chapter 12). If the serum potassium concentration exceeds 6.0 help distinguish primary kidney disease (normal or low) from a
to 6.5 mEq/L, a large percentage of these animals have serum cal- primary parathyroid problem (increased) (see Fig. 15-5). Cervical
cium concentrations of 12 to 13.5 mg/dL. Hypercalcemia is not ultrasonography may aid in distinguishing enlargement of more
restricted to the extremely ill hypoadrenal dog. It is not common, than one gland (consistent with renal secondary hyperparathy-
however, for the serum calcium concentration to exceed 13.5 mg/ roidism) versus identifying one parathyroid nodule (consistent
dL, and it rarely exceeds 15 to 16 mg/dL. Despite the increased with PHPTH). If the underlying disease process is still uncertain,
serum TCa concentrations, serum iCa concentrations usually the results of PTH and PTHrP assays may be helpful (Schenck
remain in the reference range. Serum phosphate concentrations and Chew, 2012).
also correlate with serum calcium concentrations, with the hyper-
phosphatemic animal more likely to exhibit hypercalcemia (see
Acute Kidney Injury (AKI)
Fig. 15-12).
Clinical signs and laboratory abnormalities associated with Dogs with acute and severe hyperphosphatemia as a component
hypoaldosteronism (a primary component of Addisons disease) are of AKI usually have normal or low serum calcium concentrations.
often striking and overshadow concerns related to hypercalcemia Mild hypercalcemia is occasionally seen. As with hypercalcemia
(see Chapter 12). Most dogs and cats with hypoadrenocorticism associated with CKD, the pathogenesis of hypercalcemia induced
have hyperkalemia, hyponatremia, azotemia, hyperphosphate- by AKI is multifactorial. In the oliguric phase of acute failure,
mia, and may be severely ill. The only differential diagnoses for deposition of calcium and phosphorus in soft tissues may occur.
this combination of clinical and serum abnormalities are hypoad- During the polyuric phase, as kidney function improves, this min-
renocorticism, significant (acute?) kidney injury, and vitamin D eral may be mobilized, and hypercalcemia and hyperphosphatemia
(rodenticide) toxicosis. Hypercalcemia rapidly resolves after saline may develop (Llach etal, 1981). Alternatively, rapid improvement
fluid therapy for adrenal insufciency, but does not respond as in both renal function and serum phosphate concentrations may
quickly or at all in dogs with vitamin D toxicosis or primary renal lead to transient hypercalcemia as a result of changing mass law
disease. interactions.
The pathogenesis of the hypercalcemia associated with hypo-
adrenocorticism is probably multifactorial. Any combination of
Raisin/Grape Toxicity
the following may be involved: volume contraction, decreased
glomerular ltration rate (GFR), increased intestinal absorption Of 132 dogs reported to have had raisin or grape ingestion, 33 had
of calcium, hyperproteinemia resulting from dehydration and no adverse effects, 14 became ill but did not have azotemia, and
hemoconcentration, increased plasma protein binding afnity for 43 had clinical signs and AKI. More than 90% of dogs with grape
calcium, increased concentrations of calcium-citrate complexes, or raisin ingestion associated AKI have had increases in both
and increased renal tubular resorption of calcium (Peterson and serum TCa and phosphate concentrations. Ingestion of even small
Feinman, 1982; Scott-Moncrieff, 2010). quantities can lead to acute life threatening kidney failure. Any
dog suspected of ingesting raisins or grapes should be induced to
Chronic Kidney Disease (CKD) vomit while gastric lavage and administration of activated charcoal
are considered. Intravenous (IV) fluid therapy is recommended
A majority of dogs and cats with CKD have normal serum TCa for at least 48 hours. Pathogenesis of the kidney injury and of
concentrations, a small minority have hypocalcemia, and a larger the hypercalcemia is multifactorial (Gwaltney-Brant etal, 2001;
minority (14% of dogs and 38% of cats) have increases in TCa, Morrow etal, 2001; Eubig etal, 2005; Schenck and Chew, 2012).
making CKD the second or third most common cause of hyper- As many as 50% of these dogs do not survive, whereas many of
calcemia (Schenck and Chew, 2012). The prevalence of hypercal- those who have survived required days or even weeks of fluid ther-
cemia increases with CKD severity. The finding of hypercalcemia apy or dialysis. Higher serum TCa and TCa x phosphate products
and renal azotemia presents a diagnostic dilemma because hyper- are associated with poorer prognosis.
calcemia can lead to renal failure or develop as a consequence
of it. Deleterious effects of hypercalcemia only follow increases
in serum iCa concentrations, making assessment of this param- Chronic Kidney Disease
eter of particular importance. About 10% of dogs and almost
Calcium and Phosphorus
11 2.75
30% of cats with CKD have increases in serum iCa concentra-
tions. The pathogenesis of hypercalcemia associated with CKD 9 2.25
(mmol/L)
usually involves diffuse hyperplasia of the parathyroid glands Calcium

(mg/dL)
(Fig. 15-13). The actual presence or incidence of a syndrome

involving autonomously functioning parathyroid glands that are 5 1.6
the result of chronic stimulation due to CKD (i.e., tertiary hyper-
parathyroidism) is not known. Tertiary hyperparathyroidism is the 2.5 0.8
name given to the syndrome of chronic renal secondary hyper- Phosphorus
parathyroidism, in which one or more of the parathyroid glands
begin to autonomously secrete PTH (tertiary disease). Dogs or Time
cats with no or minimal clinical signs, persistent hypercalcemia FIGURE 15-13 Diagrammatic illustration of progressive renal failure with time.
of a magnitude greater than 13.0 mg/dL, and a serum phosphate Note the progressive loss in the ability to excrete phosphate, the small fluctua-
that is normal or low usually do not have CKD. Those with serum tions in the serum calcium concentration until late in the disease, and the pro-
calcium concentrations less than 12.5 mg/dL and hyperphospha- gressive enlargement of all four parathyroids secondary to the progressive renal
temia are more likely to have CKD. The dog or cat for which the failure. Open circles, Parathyroid gland size over time, illustrating renal second-
diagnosis remains vague despite these guidelines may need further ary hyperparathyroidism.
|
Nutritional Secondary Hyperparathyroidism Hemoconcentration, Sodium Bicarbonate Infusion, and

Plasma Transfusion
Increased secretion of PTH associated with nutritional second-
ary hyperparathyroidism represents a normal compensatory Hypercalcemia occasionally may develop in severely dehydrated
response to nutritionally induced hypocalcemia. Dietary mineral animals. Hypercalcemia is usually mild, perhaps resulting from
imbalances capable of inducing this syndrome include diets low volume contraction and secondary hyperproteinemia. Hyper-
in calcium or vitamin D or diets containing excessive amounts calcemia should resolve with fluid therapy. Sodium bicarbon-
of phosphorus with normal or low calcium levels (Crager and ate infusions have been demonstrated to decrease the TCa and
Nachreiner, 1993). Nutritional secondary hyperparathyroidism iCa concentrations (Chew et al, 1989). Increases in the serum
most commonly develops after the exclusive ingestion of all-meat TCa concentration and decreases in the iCa concentration can
diets, classically diets consisting solely of liver or beef heart (Capen transiently follow plasma transfusion, presumably secondary to
and Martin, 1983). excesses in citratecalcium ion complexes (Mischke etal, 1996).
Subtle and chronic decreases in the serum calcium concen-
tration (usually not below normal reference concentrations) Hypothermia, Fetal Retention, and Endometritis
develop in animals fed these diets. Subtle decreases in serum
iCa concentration stimulate the parathyroid glands to secrete A dog and a cat have been described with severe, environmentally
PTH. With prolonged stimulation, chief cell hyperplasia and induced hypothermia and hypercalcemia (Ross and Goldstein,
secondary hyperparathyroidism develop. Depletion of skeletal 1981). Hypercalcemia rapidly resolved after rewarming and fluid
calcium leads to clinical signs in these animals. Pathologic therapy. The pathogenesis is not known. Similarly, one dog with
bone fractures are common. Acute lameness is the most com- a retained fetus and concurrent endometritis had hypercalcemia
mon owner observation. Because renal function is normal, (Hirt etal, 2000). It remains to be demonstrated whether or not
hyperparathyroidism diminishes renal tubular resorption of these conditions warrant being included in differential diagnosis
phosphate (hyperphosphaturia) and increases resorption of lists for hypercalcemia.
calcium. These dogs and cats usually have a low-normal serum
calcium concentration and a normal serum phosphorus con- Age
centration (Schenck and Chew, 2012).
See Serum Total Calcium Concentration.
Septic Bone Disease, Sepsis, Schistosomiasis, and
Systemic Mycoses Laboratory Error
Bacterial or fungal osteomyelitis and primary or secondary See Serum Total Calcium Concentration.
tumors of bone are rare causes of hypercalcemia. Neonatal
septicemia in puppies with septic emboli and lysis of bone is
PRIMARY HYPERPARATHYROIDISM IN DOGS
also rare. Hypercalcemia has been associated with blastomy-
cosis, histoplasmosis, schistosomiasis, aspergillosis, and coc-
cidioidomycosis in dogs without apparent bone involvement SIGNALMENT
(Legendre etal, 1981; Dow etal, 1986; Troy etal, 1987; Meu-
ten and Armstrong, 1989; Rohrer et al, 2000, Fradkin et al, Age, Gender, and Weight
2001; Parker, 2001). In one of these reports, increases in PHPTH is typically diagnosed in older dogs and appears to be much
PTHrP concentration were believed to cause hypercalcemia in less common, or at least less frequently diagnosed, in cats. The mean
two dogs with schistosomiasis (Fradkin etal, 2001). The patho- age of dogs with PHPTH is about 11 years with a range of about
genesis for sepsis-induced hypercalcemia is not certain, but 4 to 17 years (Fig. 15-14). More than 95% of dogs with this condition
inflammation associated with sepsis may cause sufcient bone are 7 years of age or older. There is no apparent gender predilection.
destruction and mobilization of calcium to cause hypercalce-
mia (Meuten, 1984). The production of bone-resorbing factors
such as prostaglandins and cytokines comprise the osteoclast-
activating factors produced by monocytes and lymphocytes 12
that may be involved in the pathogenesis (Mundy etal, 1984).
Viable macrophages have osteolytic capabilities that may be 10
enhanced by endotoxin (McArthur et al, 1980). Abnormal
Number of Dogs
metabolism of vitamin D may also be involved in the hyper- 8

calcemia associated with granulomatous disease (Lemann and
Gray, 1984). 6
4
Disuse Osteoporosis/Tumors Metastasizing to Bone
Disuse osteoporosis is a rare cause of hypercalcemia seen in animals 2
immobilized because of extensive musculoskeletal or neurologic
injury. This form of hypercalcemia is mild and is associated with 0
bone resorption and urinary hydroxyproline excretion, decreased 4 5 6 7 8 9 10 11 12 13 14 15 16
bone production, hypercalciuria, and osteopenia (Chew and Meu- Age (years)
ten, 1982). While metastasis of cancers to bone is relatively com- FIGURE 15-14 Age distribution of 78 dogs with primary hyperparathyroidism
mon in dogs and cats, hypercalcemia is not common. (PHPTH). Their mean age at the time of diagnosis was 10 years.
TABLE 15-3 B
REED DISTRIBUTION OF TABLE 15-4 APPROXIMATE DURATION
210 DOGS WITH PRIMARY OF CLINICAL SIGNS IN 210
HYPERPARATHYROIDISM DOGS WITH NATURALLY
OCCURRING PRIMARY
BREED PERCENTAGE HYPERPARATHYROIDISM
Keeshond 20
DURATION (MONTHS) PERCENTAGE OF DOGS
Mixed Breed 14
<1 20
Labrador Retriever 9
13 20
German Shepherd dog 6
36 20
Golden Retriever 6
612 25
Springer Spaniel 5
> 12 15
Poodle 4
Shih Tzu 4 Data from Feldman EC et al.: Pretreatment clinical and laboratory findings in dogs with
primary hyperparathyroidism: 210 cases (1987-2004), J Am Vet Med Assoc 227:756, 2005.
Australian Shepherd 3
Cocker Spaniel 3
TABLE 15-5 F
REQUENCY OF CLINICAL SIGNS
Doberman Pinscher 2 REPORTED PROSPECTIVELY
Rhodesian Ridgeback 2 OR RETROSPECTIVELY IN
210 DOGS WITH PRIMARY
Breeds represented once 22 HYPERPARATHYROIDISM*
Data from Feldman EC etal.: Pretreatment clinical and laboratory findings in dogs with
primary hyperparathyroidism: 210 cases (1987-2004), J Am Vet Med Assoc 227:756, 2005. SIGN PERCENTAGE OF DOGS
Urinary tract signs 50
Straining (stranguria)
The mean body weight (22 kg) in one study of dogs with PHPTH Frequency (pollakiuria)
included a range of 2.6 to 60 kg (Feldman etal, 2005). Blood (hematuria)
Polyuria/polydipsia 48
Breed Weakness 46
PHPTH has been diagnosed in dogs from almost every breed and Exercise intolerance 46
mixed breed. The etiology of the condition in most is unknown. Listlessness 43
PHPTH has been demonstrated to be an autosomal dominant, Incontinence (polyuria?) 39
genetically transmitted disease in Keeshonden with possible age-
dependent penetrance (Skelly and Franklin, 2006; Goldstein etal, Inappetence 37
2007). The breeds most commonly encountered, in addition to Weight loss 18
the Keeshond are dogs of mixed breeding, Labrador Retrievers, Muscle wasting 18
German Shepherd dogs, Golden Retrievers, Poodles, Shih Tzu,
Vomiting 13
or Springer Spaniels (Table 15-3). Hereditary neonatal PHPTH
(an extremely rare condition) with a possible autosomal recessive Shivering 10
mode of inheritance was reported in two German Shepherd dogs Constipation 6
(Thompson etal, 1984). Stiff gait 5
Data from Feldman EC etal.: Pretreatment clinical and laboratory findings in dogs with
ANAMNESIS: CLINICAL SIGNS
primary hyperparathyroidism: 210 cases (1987-2004), J Am Vet Med Assoc 227:756, 2005.
*Sixty-nine out of 210 owners reported no abnormalities.
Overview
Between 20% and 50% of owners do not observe clinical signs in promoted the suggestion that people with PHPTH be treated
their dog with PHPTH, even after being told of the signs to expect. regardless of perceived symptoms (Utiger, 1999).
Early, mild, or even more dramatic hypercalcemia due to PHPTH As many as half of dogs with PHPTH have had or have signs at
may not be associated with owner observed signs. In these dogs, the time of a diagnosis related to stones or a urinary tract infection
hypercalcemia was identied serendipitously only after a standard (pollakiuria, stranguria, and/or hematuria). Additional common
biochemical panel had been obtained for unrelated reasons. This owner observations include polyuria/polydipsia incontinence,
serendipitous finding of hypercalcemia is also true in a majority of decreased activity, lethargy, and muscle weakness; decreased appe-
people with PHPTH, in whom occult PHPTH is more preva- tite; weight loss; and muscle atrophy (Feldman etal, 2005; Gear
lent than the symptomatic form (Heath, 1989; Potts, 1990; Con- etal, 2005; Ham etal, 2009; Sawyer etal, 2011; Arbaugh etal,
sensus Development Conference Panel, 1991; Silverberg et al, 2012; Milovancev and Schmiedt, 2013). Less commonly, owners
1999; Wysolmerski and Insogna, 2012). When present, initial have noted shivering/trembling, vomiting, constipation, diarrhea,
clinical signs in dogs tend to be mild, insidious, and nonspecic. and stiff or painful gait. Although quite uncommon, some PHPTH
Many owners can only estimate duration of signs (Table 15-4). In dogs were extremely ill when first examined due to renal failure.
some cases, it is not until the pet has been treated for PHPTH that Central nervous system (CNS) signs include mental dullness and,
owners realize in retrospect that their dog had signs. This concept far less commonly, signs of obtundation, seizures, collapse, or coma
|
A B C D
FIGURE 15-15 Calcium-containing cystic calculi from two dogs with primary hyperparathyroidism (PHPTH) (A and C)
and individual cracked calculi from each dog (B and D).
(Table 15-5). In general, the more worrisome the clinical signs in and loss of function secondary to obstruction caused by nephroliths
a hypercalcemic dog, the greater the likelihood that the increase in or ureteroliths is logical, but some dogs with severe kidney failure and
calcium is not due to PHPTH. Extremely serious signs are usually PHPTH have not been described as having had obstructive disease.
the result of the underlying cause for the hypercalcemia (e.g., can- Dogs with PHPTH typically have decreases in serum phosphate
cer, renal failure, hypoadrenocorticism, and/or toxin). However, in concentrations and their calcium x phosphate products, usually simi-
one report, about one third of 29 dogs with PHPTH were described lar or less than values in healthy dogs, have been considered a predic-
as having renal failure (Gear etal, 2005). tor of stable kidney function. In more than 300 dogs with PHPTH,
renal failure was extremely uncommon (Feldman etal, 2005; Ham
Polydipsia and/or Polyuria etal, 2009; Sawyer etal, 2011; Arbaugh etal, 2012; Milovancev and
Schmiedt, 2013). However, in one report of 29 dogs with PHPTH,
The most common clinical signs in dogs with PHPTH are polyuria, 13 had mild to severe kidney failure (Gear etal, 2005).
polydipsia, and/or urinary incontinence. Polyuria develops as a result
of impaired renal tubular response to antidiuretic hormone (ADH).
Lethargy, Weakness, Shivering, and Muscle Atrophy
In the normal state, ADH binds to V2 receptors located in the baso-
lateral membrane of principal cells in the renal collecting tubules. Listlessness, decreases in activity and/or weakness are observed in
Binding causes increased expression of aquaporin-2 water channels one third to one half of dogs with PHPTH, whereas the signs
within apical cell membranes, increasing permeability to water and of shivering, trembling, or stiff gait are less common (Feldman
promoting water reabsorption (Shiel, 2012). Hypercalcemia inter- etal, 2005; Gear etal, 2005; Ham etal, 2009; Sawyer etal, 2011;
feres with ADH binding to V2 receptors. This acquired and reversible Arbaugh etal, 2012; Milovancev and Schmiedt, 2013). Increased
nephrogenic diabetes insipidus causes production of relatively dilute, serum calcium concentrations tend to hyperpolarize membranes.
solute-free urine (polyuria) and compensatory polydipsia. This may cause a range of muscular, neuromuscular, and/or neuro-
logic abnormalities in people with PHPTHsome of whom have
Urinary Tract Calculi and Infections been described as developing fatigue, weakness, and myopathies.
Some, but not all affected individuals, comment on their weak-
Nephrocalcinosis, the diffuse deposition of calcium phosphate ness, fatigue, listlessness, and difficulty concentrating. However,
complexes in the renal parenchyma, and ureteroliths have not been the specificity and origin of these symptoms are debated (Wysol-
commonly reported in dogs with PHPTH. Cystic calculi are com- merski and Insogna, 2012). Analogous abnormalities in dogs may
mon in dogs with PHPTH with the most common stone being explain the common observation of listlessness and/or depres-
calcium oxalate or mixed calcium oxalate and calcium phosphate sion associated with this disorder. Shivering and muscle twitch-
(Fig. 15-15). The risk factors for stone formation in patients with ing have uncommonly been observed in hypercalcemic dogs, as
PHPTH are hypercalciuria and a tendency to have renal losses of has the extremely unusual problems of circling or ataxia (Chew
bicarbonate and phosphate. The loss of bicarbonate leads to rela- and Capen, 1980). Seizure activity has been reported in several
tively alkaline urine, favoring the precipitation of calcium phos- dogs with PHPTH (Ihle etal, 1988; Gear etal, 2005; Arbaugh
phate. The incidence of urinary tract infection is increased with etal, 2012). The mechanism for these problems is not well under-
the presence of uroliths. Further, it is possible that the relatively stood but in rare cases may progress to stupor or coma. Collapse
dilute urine and, perhaps, some degree of decreased bladder tone was described in two of 29 dogs in one report (Gear etal, 2005).
following chronic excess urine production may also contribute to
their incidence of infection. Both of these latter factors can lead to
Inappetence, Weight Loss, and Abdominal
urine retention because of an inability to completely void.
or Nonspecific Pain
Chronic Kidney Disease or Acute Kidney Injury Hypercalcemia impairs gastrointestinal motility via decreases in
excitability of smooth muscle. This may contribute to the signs
It is unclear in people whether PHPTH impairs renal function. In of reduced appetite and subsequent weight loss observed in one-
the majority of untreated human PHPTH patients followed over third to one half of PHPTH people (Wysolmerski and Insogna,
time, some for longer than a decade, renal function remains both 2012) and dogs. Abdominal pain, vomiting, and diarrhea are rec-
normal and stable (Silverberg etal, 1999; Wysolmerski and Insogna, ognized but seem uncommon. Constipation, described in some
2012). Why PHPTH seems to adversely affect kidney function in a people with PHPTH, is quite uncommon in dogs. The develop-
few dogs and not the majority is not understood. Hydronephrosis ment of gastric or duodenal ulcers secondary to increases in gastrin
FIGURE 15-16 Lateral radiograph of the cervical spine from a dog

with multiple myeloma and hypercalcemia. Note the severe osteoly-
sis involving several vertebrae. These findings are consistent with
a diagnosis of the hypercalcemia of malignancy syndrome.
secretion has been documented in hypercalcemic people but has (Aurbach etal, 1985a). Band keratopathy results from the deposi-
not yet been reported in dogs (Aurbach et al, 1985a). Weight tion of calcium phosphate in the cornea. The condition is recog-
loss and decreases in appetite are far more common. Nonspecic nized as opaque material appearing as parallel lines in the limbus
arthralgias are complications recognized in humans with PHPTH of the eye, best visualized on slit lamp examination.
(Arnaud and Kolb, 1991) and may account for the pain or stiff
gait occasionally observed in dogs. Palpable Parathyroid Masses
It is extremely unusual to palpate an enlarged parathyroid gland in
Stiff Gait, Fractures, and Skeletal Pain
dogs. A palpable parathyroid mass has been reported in only one
Stiff gait and fractures are both uncommon but have been of more than 300 dogs with PHPTH (Feldman etal, 2005; Ham
associated with PHPTH (see Table 15-5). Excessive subperi- etal, 2009; Sawyer etal, 2011; Arbaugh etal, 2012; Milovancev
osteal bone resorption and osteoporosis induced by PHPTH and Schmiedt, 2013). Even with conrmed PHPTH, a nodule
can result in replacement of bone matrix with brous tissue felt in the neck is much more likely to involve the thyroid or
(Fig. 15-16). This thinning and weakening is more likely in some other structure than a parathyroid. About 10% to 20% of
cortical bone, leading to fracture predisposition (Wysolmerski dogs with PHPTH had an incidentally discovered thyroid mass
and Insogna, 2012). Lameness may be associated with pain as on cervical ultrasonography in one study (Pollard etal, in press).
skeletal changes progress. Parathyroid masses are not palpable because they are located dor-
solateral to the trachea, are usually 4 to 8 mm in diameter, and
PHYSICAL EXAMINATION they are covered by several muscle layers. Although an enlarged
parathyroid gland was not palpable in any of our dogs, palpable
General Observations tumors have been identied in cats with PHPTH.
The physical examination was unremarkable in about 66% to 75%

Importance of a Thorough Physical Examination
of dogs with PHPTH (Feldman etal, 2005). When abnormalities are
found, they typically are related to the presence of uroliths, some con- A thorough physical examination is imperative in any animal with
current and unrelated condition, or they are subtle and nonspecic. documented hypercalcemia. Physical examination results are usually
This concept is important, because the differential diagnoses for dogs normal in dogs with PHPTH. Because the more common causes of
with a serendipitous nding of hypercalcemia include lymphosar- hypercalcemia in dogs include malignant cancers, hypoadrenocor-
coma, CKD, apocrine gland carcinoma of the anal sac, hypoadreno- ticism, toxicosis, CKD, and other worrisome conditions, the diag-
corticism, multiple myeloma, vitamin D toxicosis, and granulomatous nostic approach to the dog with conrmed hypercalcemia is to rule
diseases. Dogs with any of these other conditions are usually ill or out these differential diagnoses as completely as possible. Careful
quite ill. In other words, a relatively stable or apparently healthy older palpation of peripheral lymph nodes, mammary glands, perineal
dog with hypercalcemia is more likely to have PHPTH than one of region, as well as digital rectal and vaginal examinations should be
the serious conditions that cause secondary hypercalcemia. included. Lymphosarcoma, for example, can be extremely easy or
extremely difcult to diagnose, and it is a condition not removed
Common Abnormalities from a list of differential diagnoses until an alternative diagnosis has
been conrmed. In addition to hypercalcemia of malignancy, other
Potential physical examination ndings in dogs with PHPTH, causes of hypercalcemia may be suspected after a thorough physical
other than those caused by uroliths, include thin body compo- examination. Dogs with CKD or AKI may have palpably abnormal
sition, generalized muscle atrophy, and/or weakness. Severity of kidneys. Dogs with hypoadrenocorticism may have bradycardia,
these abnormalities is variable, but they are usually mild. Bone weak femoral pulses, melena, or a bloody rectal discharge.
deformities involving the mandible or maxilla and fractures of
long bones have been reported (Capen and Martin, 1983; Gear
CLINICAL PATHOLOGY
etal, 2005) but are extremely rare.
Hemogram
Ophthalmologic Changes
The hemogram is usually unremarkable in dogs, whereas people
Infrequent ocular abnormalities in humans with PHPTH include with PHPTH may have a nonregenerative anemia and eleva-
band keratopathy and subconjunctival deposits of calcium tion in erythrocyte sedimentation rates. In dogs with PHPTH,
|
TABLE 15-6 S
ERUM BLOOD UREA NITROGEN, CREATININE AND INORGANIC PHOSPHORUS (PHOSPHATE)
CONCENTRATIONS, AND URINE SPECIFIC GRAVITIES AT TIME OF DIAGNOSIS OF PRIMARY
HYPERPARATHYROIDISM IN 210 DOGS
BLOOD UREA NITROGEN SERUM CREATININE SERUM PHOSPHATE URINE SPECIFIC GRAVITY
(mg/dL) (mg/dL) (mg/dL)
Reference range 18-28 0.5-1.6 3.0-6.2
Mean 16.9 0.8 2.8 1.012
Median 15 0.8 2.7 1.010
Ranges 5-92 0.4-4.1 1.3-6.1 1.008-1.037
Number / % reference range 9/4% 7/3% 0
Number / % reference range 132/63% 9/4% 136/65%
Data from Feldman EC etal.: Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004), J Am Vet Med Assoc 227:756, 2005.
TABLE 15-7 D
OGS WITH PRIMARY HYPERPARATHYROIDISM: SERUM TOTAL AND IONIZED CALCIUM
CONCENTRACTIONS (210 DOGS), SERUM PARATHYROID HORMONE CONCENTRATIONS
(185 DOGS), AND ULTRASONOGRAPHICALLY IDENTIFIED PARATHYROID MASSES (117 DOGS,
EACH WITH A SOLITARY NODULE, AND 13 DOGS, EACH WITH TWO NODULES)
TOTAL CALCIUM IONIZED CALCIUM PARATHYROID HORMONE ULTRASOUND MASS SIZE

(mg/dL) (mmol/L) (pmol/L) (mm)
Reference range 9.9-11.7 1.12-1.41 2-13 <4
Mean 14.5 1.71 11.3 6
Median 14.3 1.77 11.3 5
Range 12.1-23.4 1.22-2.41 2.3-121 3-23
Number / % reference range 0 0 0
Number / % reference range 210/100% 191/91% 50/27%
Data from Feldman EC etal.: Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004), J Am Vet Med Assoc 227:756, 2005.
no specic changes in bone marrow aspirates or peripheral blood concentration more than18 mg/dL in that study had a mildly
smears are seen. increased BUN concentration; the other seven had results within
or below the reference range.
It seems logical that untreated PHPTH would result in pro-
Biochemical Prole
gressively increasing serum calcium concentrations over time.
Serum Total Calcium Concentration This, however, has not been the experience in people. A group of
Various factors can alter the reported serum TCa concentration 60 people with untreated PHPTH were evaluated periodically for
and the differential diagnoses for hypercalcemia includes a num- 10 years. The mean total serum calcium concentration at the
ber of possibilities. This increases the importance of many serum time of diagnosis was 10.5 mg/dL (reference range, 8.4 to 10.2
biochemistry parameters. Specically, the serum calcium concen- mg/dL); after 5 years it was 10.6 mg/dL and after a total of 10
tration should be assessed relative to serum albumin, phosphorus, years, it was 10.3 mg/dL (Silverberg etal, 1999). However, eight
BUN, and creatinine concentrations (Table 15-6). individuals developed uroliths during the decade, leaving 52 who
Hypercalcemia is the hallmark abnormality of PHPTH (see remained asymptomatic. Two of 52 individuals (3.8%) devel-
Figs. 15-5 and 15-12). The mean serum calcium concentra- oped marked hypercalcemia (dened as a serum calcium con-
tions from four reports were 13.9, 14.3, 13.6, and 13.6 mg/ centration greater than 12 mg/dL) during the study period, eight
dL, respectively, with an approximate range of 12.1 to 23.4 mg/ had signicant hypercalciuria, and six had decreasing bone den-
dL (Feldman et al, 2005; Gear et al, 2005; Ham et al, 2009; sity. All 52, however, remained relatively asymptomatic. Dogs
Milovancev and Schmiedt, 2013; Table 15-7). These mean val- with PHPTH have persistent hypercalcemia and our subjective
ues could be slightly inflated because evaluation of hypercalce- experience suggests that their hypercalcemia slowly increases
mia is often limited to animals with a serum TCa concentration with time.
greater than 12.0 mg/dL (the upper reference range limit is often
about 11.5 to 11.8 mg/dL). After initial recognition of hyper- Factors Affecting the Serum Calcium Concentration
calcemia and referral, 52% of dogs with PHPTH had an initial Sample Error and Other Non-Pathologic Conditions.Marked
TCa concentration more than 12 but less than 14 mg/dL; about lipemia can falsely increase serum TCa concentrations deter-
30% had concentrations between 14 and 16 mg/dL, 12% had mined by some automated analyzers. Hemoconcentra-
results of 16 to 18 mg/dL, and 6% had values in excess of 18 mg/ tion (dehydration) and hyperproteinemia can produce mild
dL (Feldman etal, 2005). One of eight dogs with serum TCa increases in TCa. Hemolysis can also falsely increase the serum
USE OF ASSAYS
IN THE
EVALUATION OF HYPERCALCEMIA
SERUM TOTAL CALCIUM
NORMAL TO
SERUM [PTH]
SERUM [PTH]
IONIZED OR NORMAL OR NORMAL IONIZED

CALCIUM IONIZED CALCIUM IONIZED CALCIUM CALCIUM
Rerun total calcium Chronic kidney disease Primary hyper-

(see Fig. 15-18) (CKD)? parathyroidism
[25(OH)D] [PTHrP] (PTHrP low)?
INCREASED NORMAL INCREASED DECREASED
Vitamin D Hypercalcemia Run [vitamin D]

toxicosis? of malignancy?
FIGURE 15-17 Algorithm showing the potential value and use of various assays in the evaluation of hypercalcemic
dogs. 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; PTHrP, parathyroid hormonerelated protein.
TCa concentration measured with some automated analyz- component of determining the cause for a hypercalcemic condi-
ers. Young growing animals may have mild increases in serum tion (Figs. 15-17 and 15-18). The mean iCa concentration from
calcium concentration, and postprandial samples may, rarely, more than 135 dogs with PHPTH reported in five studies was
yield false increases. Excess use of oral phosphate binders may consistently above the reference range (Gear et al, 2005; Ham
cause the serum calcium concentration to increase. Collec- etal, 2009; Sawyer etal, 2011; Arbaugh etal, 2012; Milovancev
tion and storage of samples in glassware or plastic containers and Schmiedt, 2013). In one study, 19 (9%) of 210 dogs with
that have been washed with detergents may falsely increase or PHPTH had a serum iCa concentration within the reference
decrease calcium values. Simple prolonged storage may yield range. These reference range results may have been affected by
artifactual decreases in the calcium concentration, and contam- external factors (aerobic collection, pH) affecting the ionized
ination (chalk writing boards in the laboratory) may yield false result without altering serum TCa concentrations. In that latter
increases. Conrmation of hypercalcemia with a fresh blood study, about 25% had mildly increased serum iCa concentra-
sample would help rule out any of these concerns (Schenck and tions (1.42 to 1.65 mg/dL), about 50% had results of 1.66 to
Chew, 2012). 1.90 mg/dL, and less than 20% had iCa concentrations more
Acid-Base Status. Acidosis decreases plasma proteinbinding than1.9 mg/dL (Feldman etal, 2005).
afnity for calcium, increasing iCa concentrations and creating
mild physiologic hypercalcemia. Alkalosis has the opposite ef- Serum Phosphorus Concentration
fect, creating a physiologic hypocalcemia. The total serum cal- Low or low-normal serum phosphorus concentrations
cium concentration appears to change with the acid-base status (< 4.0 mg/dL) are typical of PHPTH (see Fig. 15-12).
in a manner roughly parallel to the change in iCa concentration Hypophosphatemia develops after PTH-induced inhibition
(Meuten, 1984). of renal tubular phosphorus resorption, resulting in exces-
Age. Age should be considered when serum concentrations sive urinary losses. In three reports on more than 300 dogs
of calcium, phosphorus, and alkaline phosphatase are evaluated. with PHPTH, the mean serum PO4 concentration was
Young dogs have higher concentrations than adults (Meuten, 2.9, 2.8, and 2.86 mg/dL (Feldman et al, 2005; Gear et al,
1984; Schenck and Chew, 2012). Reference values for TCa con- 2005; Milovancev and Schmiedt, 2013). Reference ranges
centrations in young dogs were approximately 11.1 0.4 mg/dL were similar in these reports (about 3.0 to 6.2 mg/dL).
(10.5 to 11.5 mg/dL), higher than those observed in adults (8.8 to In one report, dogs with PHPTH had results that ranged from
11.0 mg/dL) (Meuten etal, 1982). 1.3 to 6.1 mg/dL, with none above the reference range, and
in another report, only two of 29 dogs had values above their
Serum Ionized Calcium Concentration reference range despite 13 of 29 dogs having increases in BUN
The iCa fraction of total circulating calcium concentrations and evidence of CKD and/or AKI (Feldman etal, 2005; Gear
is biologically active. Valid assays for iCa can be an integral etal, 2005).
|
LOW IONIZED SERUM CALCIUM

CONCENTRATION
TOTAL SERUM CALCIUM TOTAL SERUM

CALCIUM
BUN NORMAL BUN NORMAL TO

[PTH]
CREATININE NORMAL CREATININE [PTH]
PHOSPHATE NORMAL PHOSPHATE
Rule out: Rule out:
Primary or iatrogenic Hypoalbuminemia

hypoparathyroidism Eclampsia
[PTH] NORMAL TO Hypercalcitoninism (rare) Pancreatitis
[PTH] LOW [PTH] NORMAL Hypomagnesemia (rare) Dietary imbalance
HIGH
Intestinal disease
IV phosphate
Primary renal failure Hypercalcemia of Recheck calcium
Renal secondary malignancy (factitious sample?)
hyperparathyroidism (PTHrP would be )
or (Ionized calcium should
Primary be increased; recheck)
hyperparathyroidism
(ionized calcium
should be increased;
recheck)
FIGURE 15-18 Algorithm for determining the cause of decreases in the ionized serum calcium concentration in
dogs. BUN, Blood urea nitrogen; IV, intravenous; PTH, parathyroid hormone; PTHrP, parathyroid hormonerelated
protein.
The serum phosphorus concentration should always be evalu-

ated relative to the serum calcium concentration and renal param-
eters. Hypophosphatemia, when dietary phosphate is adequate BOX 15-2 Potential Causes of Hypophosphatemia
and oral phosphate-binding agents are not being given, is con-
sistent with either PHPTH or hypercalcemia of malignancy (see Decreased Intestinal Absorption
Fig. 15-12). Other causes of hypophosphatemia are less com- Decreased dietary intake
mon (Box 15-2). Hyperphosphatemia in the absence of azotemia Malabsorption/steatorrhea
suggests a non-parathyroid cause of hypercalcemia. When both Vomiting/diarrhea
hyperphosphatemia and azotemia are present, the clinician must Phosphate-binding antacids
rely on the history, physical examination, and other parameters to Vitamin D deficiency
determine the primary disorder. Differentiation remains a diag- Increased Urinary Excretion
nostic dilemma. Dogs with CKD and an increased TCa concen- Primary hyperparathyroidism (PHPTH)
tration usually have iCa concentrations that are normal or mildly Diabetes mellitus ketoacidosis
low, in contrast to dogs with PHPTH, in which both total and the Hyperadrenocorticism (naturally occurring/iatrogenic)
ionized fractions are increased. Fanconi syndrome (renal tubular defects)
Age should also be considered when evaluating the serum Diuretic or bicarbonate administration
phosphorus concentration. Young dogs (< 1 year old) tend to Hypothermia recovery
have a higher serum phosphorus concentrations than adults. Hyperaldosteronism
Puppies may have similar serum phosphorus and calcium con- Aggressive parenteral fluid administration
centrations (i.e., both approximately 10 to 12 mg/dL). However, Hypercalcemia of malignancy (early stages)
the serum phosphorus concentration gradually declines during
puppyhood, reaching normal adult concentrations by 4 to 12 Transcellular Shifts
months of age. Insulin administration
Parenteral glucose administration
Blood Urea Nitrogen and Serum Creatinine Hyperalimentation
Blood Urea Nitrogen. Almost all dogs with PHPTH have normal Respiratory alkalosis
renal parameters (BUN, creatinine; see Table 15-6). Among about
320 dogs with PHPTH, the incidence of abnormally increased
renal parameters was 4% or less. In one study of 210 dogs with
PHPTH, their mean BUN of 16.9 mg/dL was below the reference
range of 18 to 30 mg/dL. Three percent had a BUN less than 10, in veterinary medicine; about 40% of dogs with PHPTH had
and 60% had concentrations of 10 to 17. Thus, almost two thirds an increased result. When present, increases were generally mild
of dogs with PHPTH had BUN concentrations less than the (twofold to sixfold) with a mean of 240 IU/L (range, 12 to more
lower limit of the reference range. About 25% had results in the than 4,000 IU/L; reference range, 5 to 92 IU/L). The increased
lower half of the reference range, and 10% had results in the upper activity of this enzyme, when present, is thought to result from a
half of the reference range. Nine of the 210 dogs had abnormally compensatory increase in osteoblastic activity in bone trabeculae
increased BUN concentrations, ranging from 31 to 92 mg/dL. The as a response to mechanical stress in bone weakened by excessive
serum TCa concentrations from these nine dogs were not signifi- resorption (Capen and Martin, 1983).
cantly different from the dogs whose BUN concentrations were
within or below the reference range (Feldman etal, 2005). One Serum Alanine Aminotransferase
report on 29 dogs with PHPTH, however, included 13 dogs with Serum alanine aminotransferase (ALT) concentrations are usu-
increases in BUN, 10 of which were marked (Gear etal, 2005). ally normal in dogs with PHPTH. Mild increases are nonspecific
By contrast, renal failure was not mentioned or rare in the reports and not usually worrisome. The suggestion that mild increases
on about 110 dogs with PHPTH (Ham etal, 2009; Sawyer etal, may reflect hepatic ischemia due to systemic dehydration seems
2011; Arbaugh etal, 2012; Milovancev and Schmiedt, 2013). unlikely. Moderate to marked increases in ALT should raise con-
Creatinine.Mean serum creatinine concentrations for 210 cern that a separate and concurrent liver condition exists.
dogs with PHPTH were 0.8 mg/dL. Sixty percent of the dogs
had results less than 1.0, and 37% had values of 1.0 to 1.5 mg/ Serum Chloride Concentration
dL. Thus, 97% had results within the reference range. Three per- In people, excess PTH secretion decreases the proximal renal tubu-
cent (seven dogs) had results above 1.5 mg/dL. The highest serum lar resorption of bicarbonate, leading to increased resorption of
creatinine concentration in any dog was 4.1 mg/dL, and six of the chloride and the production of mild hyperchloremic renal tubular
seven dogs had increases in both BUN and creatinine concentra- acidosis. Increased serum chloride concentrations in people with
tions. Four dogs with increases in both BUN and creatinine con- PHPTH often are associated with serum chloride-to-phosphate
centrations had been diagnosed with CKD 3 to 24 months before ratios greater than 33 (Arnaud and Kolb, 1991). With the avail-
becoming hypercalcemic. ability of reliable PTH and PTHrP assays, the increases in the
Renal Values in Dogs Who Do Not Have Primary Hyper- serum chloride concentration are less critical as a diagnostic tool
parathyroidism. In the study on 210 dogs with PHPTH, 200 but may aggravate existing hypercalcemia by impairing binding
control dogs that did not have PHPTH had significantly higher of calcium to albumin and by increasing the dissolution of bone
mean BUN and creatinine concentrations. It would appear that mineral.
dogs with PHPTH are less likely to have abnormal renal param-
eters than dogs that do not have PHPTH. Whether this is the Urinalysis
result of the low calcium x phosphate product or some other factor
is not known. In one study, the TCa x phosphate product was not Urine Specific Gravity
predictive of renal failure (Gear etal, 2005) and that study had far Many dogs with PHPTH have relatively dilute urine on randomly
more dogs with renal failure than was seen in five studies on 320 collected home-caught or in-hospital obtained samples. In 210
dogs with PHPTH (Feldman etal, 2005; Ham etal, 2009; Sawyer dogs with PHPTH, their mean urine specific gravity (USG) was
etal, 2011; Arbaugh etal, 2012; Milovancev and Schmiedt, 2013). 1.012. Fifty dogs (24%) had a USG less than 1.008 on randomly
The uncommonly encountered combination of azotemia, collected urine; 75 (36%) had a result of 1.008 to 1.012; 70 (33%)
hypercalcemia, hyperphosphatemia, and increases in serum PTH had a results ranging from 1.013 to 1.020; eight (4%) had a USG
concentrations represents a diagnostic challenge. Such changes of 1.021 to 1.030; and seven had a result greater than 1.030 (see
could lead to renal failure or develop as a consequence of renal fail- Table 15-6). These results reflect the effect of hypercalcemia inter-
ure. Increases in serum TCa concentration have been documented fering with the action of ADH action at the renal tubular level
in as many as 10% to 15% of dogs with CKD, with hypercalcemia causing a reversible form of nephrogenic diabetes insipidus. Ran-
worsening severity of azotemia. However, the deleterious effects of domly obtained USG from 140 age-matched control dogs that
hypercalcemia may only be associated with abnormally increased did not have PHPTH had a significantly higher mean of 1.025
serum iCa concentrations. Fewer than 10% of all dogs with CKD (Feldman etal, 2005).
have increases in iCa, most have normal or low concentrations. Isosthenuria (or hyposthenuria) is a common consequence
As discussed, the serum iCa is usually normal or low in CKD and of hypercalcemia, regardless of its etiology. The combination of
almost always increased with PHPTH. Rarely, tertiary hyperpara- hypercalcemia and dilute urine is considered a cause and effect
thyroidism occurs in dogs with CKD as an extremely unusual pro- phenomenon, but it is not specic for any condition. Confusion
gression of renal secondary hyperparathyroidism. It is most likely regarding cause may arise because CKD is a differential diagnosis
due to an alteration in the set point for circulating iCa (Schenck for isosthenuria. A thorough review of the serum chemistry prole
and Chew, 2012). Use of both serum iCa and PTH concentrations and other parameters may be necessary to determine cause of isos-
are useful in determining cause (see Figs. 15-17 and 15-18). It is thenuria or hyposthenuria.
possible for PHPTH to predispose a small percentage of dogs to
kidney injury, that some dogs with PHPTH may also have CKD, Urine Sediment
or that some dogs with CKD develop tertiary hyperparathyroid- Hematuria, pyuria, bacteriuria, and/or crystalluria are often
ism, accounting for what might be autonomous secretion of PTH. identied in the urine sediment of dogs with PHPTH. Hypercal-
ciuria, proximal renal tubular acidosis with impaired bicarbonate
Serum Alkaline Phosphatase resorption, and the production of alkaline urine may predispose
In humans, an increase in serum alkaline phosphatase (SAP) is dogs to the development of bacterial cystitis and urolith forma-
more common in hypercalcemia of malignancy than in PHPTH tion. Urinary tract infection, at the time of PHPTH diagnosis,
(Arnaud and Kolb, 1991). Increases in SAP activity are nonspecic was identified in almost 30% of 210 dogs. One third of those dogs
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had concurrent cystic calculi. Cystic calculi had been surgically Abdomen and Skeleton
removed from 42 of 210 dogs (20%) in the 6 month period pre- Other than urinary tract calculi, radiographic alterations associ-
ceding diagnosis of PHPTH. Fifty dogs (24%) had cystic calculi ated with PHPTH are rare. As previously discussed, cystic calculi
when seen at our hospital, but 27 of those 50 were among the 42 are common and urethral calculi are always a concern, especially
who had already had surgery, indicating recurrence. Thus, a total in male dogs. Uroliths have quite uncommonly been identified
of 65 dogs (31%) with PHPTH had cystic calculi. All analyzed in the kidneys and ureters. The sublumbar area and mesenteric
calculi were calcium oxalate, calcium phosphate, or both (Feld- lymph nodes can be evaluated for any mass effect that might be
man etal, 2005; see Fig. 15-15). indicative of metastatic apocrine gland carcinoma of the anal sac,
lymphoma, or other neoplastic process (Fig. 15-20). The liver and
Electrocardiography spleen should be similarly evaluated for enlargement or irregulari-
ties associated with neoplasia.
Experimentally induced hypercalcemia may increase myocardial Osteitis brosa cystica, the classic bony abnormality of primary
contractility, shorten mechanical ventricular systole, and decrease and secondary hyperparathyroidism in humans, is rarely seen in
myocardial automaticity. Potential electrocardiographic changes dogs. It is manifested radiographically as generalized osteopenia
caused by hypercalcemia include a prolongation of the P-R inter- due to increased bone resorption, especially at the subperiosteal
val and a shortening of the QT interval as a result of a shortened surfaces, and the formation of cysts or cystlike areas in bone. In
ST segment (Feldman, 1989). Theoretically, the decrease in myo- humans the phalanges and skull are usually involved. In severe
cardial conduction velocity and the shortened refractory period cases, the long bones, patella, and ribs may become involved.
could predispose to arrhythmias. Cardiac abnormalities are rare in The clinical manifestations of osteitis brosa cystica are bone
dogs with PHPTH. pain, pathologic fractures, bone cysts, and localized swelling of
bone (Hruska and Teitelbaum, 1995). Radiographic changes
IMAGING rarely associated with PHPTH in dogs include loss of the lamina
dura, fractures of the long bones and vertebrae, and soft tissue
Radiography calcication. Fractures have been described in only one of more
than 340 dogs with PHPTH (Feldman et al, 2005; Gear et al,
General 2005; Ham et al, 2009; Arbaugh et al, 2012; Milovancev and
Conventional radiography plays an integral role in the diagnostic Schmiedt, 2013).
evaluation of hypercalcemic dogs or cats. Thoracic radiographs
should be obtained in order to screen for neoplasia. Abdominal
Ultrasonography
ultrasonography may be preferred over radiographs, although
these imaging modalities are complementary. Lack of thoracic or Neck
abdominal radiographic or ultrasonographic abnormalities in a Background. Parathyroid ultrasonography has been used ex-
dog with hypercalcemia is consistent with PHPTH. tensively in people as part of the diagnostic evaluation for hyper-
calcemia. Applications have included differentiation of primary
Thoracic Radiographs and secondary hyperparathyroidism; conrmation of suspect le-
The anterior mediastinum, perihilar, and sternal lymph nodes sions by ultrasound-guided, ne-needle aspiration biopsy; and
should be evaluated for mass effect or lymphadenopathy. The presurgical localization of parathyroid adenomas (Attie et al,
classic nding in hypercalcemic dogs with lymphosarcoma is an 1988; Krubsack et al, 1989; Lloyd et al, 1990). Reported sen-
anterior mediastinal mass (Fig. 15-19). The ribs, vertebrae, and sitivity of ultrasonography in identifying one or more abnormal
any long bones included in the study should be evaluated for parathyroid glands in people is well over 90% (Wysolmerski and
osteolytic areas arising from myeloma or other metastatic tumors. Insogna, 2012). In dogs, parathyroid glands as small as 1 to 2 mm
The lung elds should be carefully assessed for nodules that might
represent primary or metastatic lesions.
FIGURE 15-20 Lateral radiograph of the caudal abdomen of a dog with apocrine
gland adenocarcinoma of the anal sac and hypercalcemia. Note the multiple
FIGURE 15-19 Lateral radiograph of the thorax of a dog with lymphosarcoma masses in the sublumbar region and pelvic canal (arrows), which are suggestive
and hypercalcemia. Note the sternal lymphadenopathy (arrow). of sublumbar lymph nodes that have been invaded by the neoplasia.
in diameter can be visualized. Accuracy of ultrasonographic evalu- etal, 2005; Ham etal, 2009; Sawyer etal, 2011; Arbaugh etal,
ation is determined by facilities as well as the skill and experience 2012; Milovancev and Schmiedt, 2013). Although a reference
of the ultrasonographer. range for parathyroid gland size on ultrasonographic examina-
An ectopic location for parathyroid tumors is possible. Although tion has not been established for dogs, it has been suggested that
reported in humans, ectopic parathyroid tumors have not been most healthy dogs have glands 1 to 3 mm in greatest diameter. For
reported in dogs or cats. Localization of ectopic abnormal parathy- the 142 masses correctly identified in one study, the mean abnor-
roid tissue can be difcult. In humans, noninvasive procedures that mal parathyroid gland was 6 mm (range, 3 to 23 mm) in greatest
can be used include esophagoscopy, computed tomography (CT), diameter. Sixty percent of the nodules were 3 to 6 mm in greatest
and radionuclide scans. Invasive procedures include thyroid arte- diameter, 24% were 7 to 10 mm, 10% were 11 to 15 mm, and
riography, selective venous catheterization of the neck and medi- 6% were greater than 15 mm in greatest diameter. In this study,
astinal veins, and surgical exploration of the anterior mediastinum 116 dogs had a solitary parathyroid mass and 13 dogs (10%) had
(Arnaud and Kolb, 1991). Although ectopic parathyroid tissue or 2 distinct masses. No dog had more than two masses identified
tumor is rare, this condition may be considered in any dog whose (Feldman et al, 2005; see Table 15-7). In another study, 76% of
testing is indicative of PHPTH but whose cervical ultrasonographic the ultrasonographic assessments were correct as determined by
examination is negative. Visualization of normal parathyroid the tissue identified and removed. However, in 19% of the dogs,
glands without seeing a nodule is not consistent with PHPTH. If ultrasonography results did not agree with surgical findings regard-
the parathyroid glands seem small or not visualized, one may suspect ing laterality of the parathyroid mass location (Milovancev and
an ectopic location. This would also be a concern should a surgeon Schmiedt, 2013). In another study, 12 ultrasonographic-identified
be unable to see any abnormal thyroid-parathyroid tissue. parathyroid masses were confirmed at surgery, but five enlarged
Dogs. The parathyroid glands in healthy dogs can be routinely masses seen at surgery had not been identified via ultrasonography
visualized (Wisner etal, 1991; Reusch etal, 2000; Pollard etal, and two masses identified with ultrasonography were not seen at
in press). Parathyroid masses are usually solitary, round or oval, surgery (Ham etal, 2009). By contrast, all 17 parathyroid carcino-
well marginated, and hypoechoic to anechoic compared with mas in another study were correctly identified via ultrasonography
surrounding thyroid gland parenchyma (Fig. 15-21). Occasion- (Sawyer etal, 2011).
ally two enlarged parathyroid glands may be identified in dogs Because results of cervical ultrasonography are often of use in
with PHPTH. Seeing three or four enlarged glands is not typical. establishing a diagnosis of PHPTH, we include and recommend
Not every nodule in the parathyroid anatomic region is obvious. cervical ultrasonography as a diagnostic aid for any hypercalcemic
Some masses have not been seen, whereas the cell type of others is dog. Failure to identify a parathyroid mass in a dog suspected as
sometimes questioned. The most common concern was whether having PHPTH is cause for reconsidering the differential diagno-
an identified mass was thyroid or parathyroid (see Incidentally sis for hypercalcemia. Experience of the operator and equipment
Discovered Thyroid Masses). quality (including use of the correct transducer) must be consid-
Parathyroid masses (usually adenomas) from dogs with PHPTH ered (Wisner etal, 1993; Wisner and Nyland, 1994).
have been as small as 2 mm to as large as 23 mm in diameter.
Most adenomas are 4 to 10 mm in diameter and easily visualized Abdomen
(Wisner et al, 1993; Wisner and Nyland, 1994). A statistically Ultrasonographic scanning of the abdomen, when possible,
signicant size difference was reported for solitary hyperplastic should be a component of the diagnostic evaluation of hypercal-
parathyroid glands (2 to 6 mm, mean 2.9 mm) as compared with cemic dogs and cats. If the liver, spleen, mesenteric lymph nodes,
solitary parathyroid adenomas or adenocarcinomas (4 to 20 mm, or other abdominal structures appear abnormal, percutaneous fine
mean 7.5 mm) (Wisner etal, 1997). needle aspiration or biopsy should be considered. Ultrasonogra-
Similar to reports in people, ultrasonography correctly identified phy has proven to be an excellent tool for identifying uroliths as
parathyroid mass size and location (as determined by surgery) in well. Most uroliths are found in the bladder, but renal, ureter, and
63% to 100% of dogs with PHPTH (Feldman etal, 2005; Gear urethral stones also have been identified.
A B
FIGURE 15-21 A, Cervical ultrasonogram of a dog with a functional parathyroid adenoma. Note the right thyroid
lobe, in which a well-marginated, hypoechoic mass (arrows) is visible at the cranial pole of the thyroid. B, Solitary
parathyroid adenoma removed from a dog with primary hyperparathyroidism (PHPTH; see Fig. 15-26, C ). (A, Courtesy
of Dr. Tom Nyland and Dr. Erik Wisner.)
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Incidentally Discovered Thyroid Masses concentrations would be expected to be normal to increased.

One study has assessed the prevalence of subclinical thyroid nod- Serum PTH concentration must always be evaluated relative
ules in dogs undergoing cervical ultrasonography as a compo- to the serum calcium concentration. In normal animals, as the
nent of evaluating hypercalcemia. No dog had a palpable mass, serum calcium concentration increases, the serum PTH concen-
and in no dog was the thyroid believed responsible for hypercal- tration decreases. Therefore, a serum PTH concentration in the
cemia. At least one incidentally discovered thyroid nodule was reference range from a hypercalcemic dog is not normal. Relative
identified in 14 of 91 PHPTH dogs. The thyroid gland masses to their hypercalcemia (using TCa or iCa) dogs with PHPTH
had a mean length, width, and height of 1.5, 1.0, and 0.75 cm, have excessive concentrations of serum PTH even though the
respectively. Histologic diagnoses included thyroid cysts, adeno- result may be within the reference range. These results are con-
mas, adenocarcinomas, and one dog with nodular hyperplasia. sistent with a condition associated with autonomous secretion of
These results suggest that subclinical thyroid nodules are pres- PTH (Fig. 15-23).
ent in some hypercalcemic dogs that do not have a palpable The challenge for laboratories that offer serum PTH assays is
neck mass (Pollard etal, in press). The clinical significance and that companies either go out of business or discontinue products.
management of incidentally identified thyroid nodules in dogs Therefore, assays utilized by laboratories invariably must change.
remains to be elucidated. Regarding PTH assays, quality of the results using newer products
has either been similar or more reliable as compared with older
USE OF PARATHYROID HORMONE AND products (see Fig. 15-5). Comparison of PTH assay results from
PARATHYROID HORMONERELATED different studies performed at various times and locations is dif-
PROTEIN ASSAYS ficult. Currently, the PTH assay that provides excellent correlation
in dogs and cats is an intact-molecule assay, which has numerically
In dogs with PHPTH, serum PTH concentrations are typically lower test values as compared with previously reported results. The
mid/normal to increased (Figs. 15-5 and 15-22), serum PTHrP N-terminal antibody in previously utilized intact sandwich assay
concentrations should be undetectable, and serum calcitriol systems cross reacted with a biologically inactive PTH 7-83 amino
acid fragment. The new intact-molecule PTH assay antibody
requires the first four amino acids of the N-terminal be present
50 for binding (Refsal, 2014). One study compared the intact sand-
45 wich PTH assay system that requires several days to complete
40
with a rapid, 20-minute chemiluminescent assay. Within-run
and day-to-day precisions were comparable, and there was a high
35
correlation in results. Numerical results from the rapid chemilu-
[PTH] (pmol/L)
30 minescent assay system were usually lower than the intact assay
25 (Ham etal, 2009).
20 In one study, serum PTH concentrations were determined
15 using an immunoradiometric intact sandwich assay for PTH
10 in randomly obtained serum samples from 185 dogs with
5
PHPTH. The mean serum PTH concentration of 11.3 pmol/L
was within the reference range (2 to 13 pmol/L). Almost 75%
0
Normal 1 PTH 1 PTH 1 PTH Hypercal- of these dogs had a serum PTH concentration within the refer-
(adenoma) (hyperplasia) cemia of ence range, about 45% in the lower half and almost 30% in the
malignancy upper half of the reference range. About 10% of the 185 dogs
FIGURE 15-22 Serum parathyroid hormone (PTH) concentrations for normal dogs had mildly increased serum PTH concentration, and about
and those with various disorders of calcium homeostasis. Note that some overlap 15% had moderate or extreme increases (see Table 15-7; Feldman
exists in test results and that the results shown in Fig. 15-23 are easier to interpret. etal, 2005). Other studies have reported similar results: a mean
1 PTH, primary hyperparathyroidism; 1 PTH, primary hypoparathyroidism. serum PTH concentration in dogs with PHPTH of 13.6 pmol/L
50
Normal
45 Primary hyperparathyroidism
40 Parathyroid hyperplasia
Primary hypoparathyroidism
35 Hypercalcemia of malignancy
[PTH] (pmol/L)
30
25
20
15
FIGURE 15-23 Serum parathyroid hormone (PTH) concentrations plot-
10 ted against simultaneous serum calcium concentrations from normal
5
dogs and those with abnormalities in calcium homeostasis. Note that
the various groups are more distinguishable than would be the case
0 if only the serum calcium or only the serum PTH concentrations were
0 2 4 6 8 10 12 14 16 18 20 22 24
evaluated. The shaded area represents the approximate reference
Serum Total Calcium (mg/dL) range.
Signalment
BOX 15-3 D
ifferential Diagnosis for Humoral Review of breed is emphasized because of the genetic predisposi-
Hypercalcemia of Malignancy tion for developing PHPTH in the Keeshond. PHPTH typically
occurs in dogs 7 years of age or older. CKD can occur at any
Hematologic Cancers age. Dogs of any age are at risk for malignancy (lymphosarcoma),
Lymphosarcoma toxin exposure, granulomatous disease, or hypoadrenocorticism,
Lymphocytic leukemia whereas apocrine gland carcinoma of the anal sac and some other
Myeloproliferative disease malignancies occur in older dogs.
Myeloma
Solid Tumors with Bone Metastasis History
Mammary adenocarcinoma The owner should be asked about their pets diet, travel history,
Nasal adenocarcinoma vitamin-mineral supplementation, and exposure to rat or mouse
Epithelial-derived tumors poisons or houseplants that contain vitamin D analogs. An
Pancreatic adenocarcinoma attempt can be made to determine whether the pet is in pain (lytic
Lung carcinoma bone lesions). Response to questions about the presence of poly-
dipsia, polyuria, appetite, activity, change in body weight, ability
Solid Tumors without Bone Metastasis
to exercise, vomiting, diarrhea, and any other pertinent informa-
Apocrine gland adenocarcinoma of the anal sac
tion, may be important. Generally, as the pet appears more ill,
Interstitial cell tumor
PHPTH becomes less likely.
Squamous cell carcinoma
Thyroid adenocarcinoma Physical Examination
Lung carcinoma
After assessment of the dogs hydration status and severity of ill-
Pancreatic adenocarcinoma
ness, the physical examination should include careful palpation
Fibrosarcoma
of peripheral lymph nodes and the mammary glands (lymphoma
and mammary cancer). A thorough rectal and perirectal examina-
tion is imperative to help rule in or out apocrine gland carcinoma
(reference range, 2 to 13 pmol/L) (Arbaugh etal, 2012); 8 out of of the anal sac. Anal sac tumors may be covered by haired skin
12 dogs (75%) with PHPTH had serum PTH concentrations and may not be identied unless rectal and perirectal examina-
within the reference range, and 4 out of 12 were increased (Ham tions are performed. A digital vaginal examination should also be
etal, 2009); and a mean of 17.7 pmol/L in 19 dogs with PHPTH performed (vaginal tumor). The veterinarian should gently pal-
with a range of 4.7 to 156 pmol/L (reference range, 3 to 17 pate as much of the skeleton as possible, searching for any area
pmol/L) (Sawyer etal, 2011). of focal bone pain, which then could be examined further with
radiographs (multiple myeloma). The kidneys should be palpated
DIAGNOSTIC APPROACH TO THE HYPERCALCEMIC in an attempt to assess size or irregularities.
PATIENT
Initial Database
General Comments Blood and Urine
The list of differential diagnoses for hypercalcemia is relatively The initial database should include a hemogram (complete blood
short (see Boxes 15-1 and 15-3), allowing a logical approach to count [CBC]), serum biochemical prole, serum iCa, urinalysis,
identication of its cause. At the same time, serum inorganic phos- and thoracic radiographs. The abdomen should be evaluated with
phorus should be assessed, and if low, that differential diagnosis ultrasonography, radiography, or both. If the serum phosphorus
can be considered as well (Box 15-2). The most common cause of concentration is normal or low, CKD and rodenticide toxicosis are
hypercalcemia and hypophosphatemia in the dog is malignancy- less likely (see Fig. 15-24). Dogs with hypoadrenocorticism usually
associated hypercalcemia. In an attempt to be practical, logical, have hyperphosphatemia in addition to their hyperkalemia and
and cost-effective, the veterinarian should design the diagnostic hyponatremia. Serum creatinine and BUN concentrations are also
approach to rst identify or rule out an underlying malignancy. critically important. Evaluation of the sodium-to-potassium ratio
Diagnostic testing can proceed to assess each patient for PHPTH should help identify hypoadrenocorticism. A sodium-to-potassium
simultaneously as the testing is interwoven. ratio less than 27:1 is consistent with but not necessarily diagnos-
tic of adrenal insufciency. An ACTH stimulation test should be
Review of the History and Physical Examination performed if Addisons disease is considered likely, whereas a basal
serum cortisol can be assessed if Addisons disease is considered
First Steps a possibility. If the serum phosphorus concentration is increased
The diagnostic approach to the hypercalcemic patient is usually and renal function is normal, bone osteolysis secondary to meta-
relatively straightforward (see Box 15-1; Fig. 15-24). One may static disease should be considered. Low, low-normal, or normal
wish to submit a second blood sample to recheck the calcium and serum phosphate concentrations are consistent with PHPTH and
phosphorus results, although the second sample is rarely different. malignancy-associated hypercalcemia (see Fig. 15-12). A striking
Next, submit appropriate samples for a serum iCa concentration increase in the total protein concentration, specically due to a
to confirm the presence of hypercalcemia. If the iCa concentration monoclonal spike, is classic for multiple myeloma.
is within or below the reference range in a dog with conrmed
increases in serum TCa concentration, CKD should be among the Primary Parathyroid Disease Versus Primary Renal Disease
conditions considered (see Fig. 15-18). Rechecking an illogical A diagnostic dilemma exists when hyperphosphatemia and hyper-
iCa result is always wise. calcemia coexist with azotemia. The clinician must determine
REPEATED (PERSISTENT) HYPERCALCEMIA
IN A CLINICALLY ILL DOG
Neither Lymph Node

Peripheral Lymph Node Palpable Perirectal or
Enlargement nor Tumor
Enlargement Mammary Tumor
Palpated
Biopsy node(s) CHECK: Serum ALT BUN Biopsy mass

Bone marrow aspirate BUN Cranial mediastinum
CHAPTER 15 Hypercalcemia and Primary Hyperparathyroidism

Alkaline phosphatase K, Na Check thoracic and/or
[PTH](decreased) Serum phosphate for mass Abnormal liver size Urine specific gravity bone radiographs and
[PTHrP](increased) Creatinine Bone marrow Liver biopsy < 1.025 abdominal ultrasonography
isosthenuria Lymph node biopsy Positive response to Abnormal ACTH stim- for metastasis
Skeletal demineral- Liver biopsy glucocorticoid therapy ulation test (low cortisols)
ization (rubber jaw)
Normal ionized calcium
|
VARIETY OF HYPOADRENO- APOCRINE GLAND
LYMPHOSARCOMA RENAL FAILURE LYMPHOSARCOMA ADENOCARCINOMA
MALIGNANCIES CORTICISM
(of the anal sac)
MAMMARY
ADENOCARCINOMA
[PTH] decreased
HYPER- PRIMARY KIDNEY PRIMARY HYPER- [PTHrP] increased
VITAMINOSIS D DISEASE PARATHYROIDISM
(rare) (common) (not likely)
A
FIGURE 15-24 Algorithm for the clinical and diagnostic evaluation of dogs that are persistently hypercalcemic, including those that are ill (A) and those with mild clinical signs (B).
Continued
605
606
SECTION 5 PARATHYROID GLAND
REPEATED (PERSISTENT) HYPERCALCEMIA IN A DOG
WITH MILD CLINICAL SIGNS
Liver enzymes or Ultrasonography or BUN or normal phosphate

Serum protein palpable mass: radiographs Creatinine Mild or no In SAP
Globulins Bone Isosthenuria May have dilute urine
Thyroid Phosphate Normal BUN
Soft tissue: +/Rubber jaw Bone marrow negative*
Lymph node Lymph node negative*
Liver *(these two are usually not performed)
Pelvic Lytic bone lesion Hepatomegaly
Serum protein Splenomegaly
Other
electrophoresis Lymphadenopathy:
Perihilar Primary renal Primary
Sublumbar disease hyperparathyroidism
Anterior mediastinal
Sternal Ionized calcium: [PTH]
normal or [PTHrP]
[PTH] Ionized calcium
Monoclonal No monoclonal
spike spike Biopsy lesion or Organ biopsy or Ultrasonography
bone marrow biopsy or bone marrow biopsy or of the neck
biopsy liver lymph node biopsy
[PTHrP]
[PTH] [PTHrP]
[PTH] Visible parathyroid
Reconsider mass?
Myeloma Serum calcium falls to
cause of Ca
normal with glucocorticoid
or L-asparaginase therapy?
No Yes
Variety of
No Lymphoma
malignancies
Yes 1) Surgical exploration

1) Repeat scan with more
of the neck
experienced radiologist
2) Ultrasoundguided
2) Reconsider diagnosis
heat ablation
B
FIGURE 15-24, contd ACTH, Adrenocorticotropic hormone; ALT, alanine aminotransferase; BUN, blood urea nitrogen; PTH, parathyroid hormone; PTHrP, parathyroid
hormonerelated protein, SAP, serum alkaline phosphatase.
|
whether the hypercalcemia is the cause or the consequence of Identication of a solitary mass in or near one thyroid lobe sup-
renal disease. Other abnormalities in the initial database supports the presence of an autonomously functioning parathyroid
portive of CKD as the primary problem include mild to marked mass if the dog does not have CKD (Reusch etal, 2000).
increase in the serum phosphorus concentration, a normal to low
serum iCa concentration, nonregenerative anemia, proteinuria,
Lymph Node and Bone Marrow Evaluations
and/or palpably or radiographically small and irregular kidneys.
The serum iCa fraction in dogs with PHPTH is increased. If If the initial database has not established a diagnosis, the clinician
hypercalcemia dissipates with aggressive fluid therapy and diure- may consider histologic evaluation of lymph nodes, bone mar-
sis, PHPTH is less likely. Furthermore, dogs with renal failure row, or both. Lymphosarcoma is the most common cancer associ-
usually have a TCa concentration less than 12.5 mg/dL. Dogs ated with hypercalcemia in the dog and cat. Involvement of the
with PHPTH and secondary renal disease typically have a total peripheral lymph nodes in lymphosarcoma can be present without
serum calcium concentration greater than 13 mg/dL (see Figs. enlargement of those nodes, although such a nding would be
15-5, 15-17, 15-18, and 15-24). unusual. Ideally, the largest lymph node (not the submandibular
node) should be assessed for histologic evaluation. Needle aspi-
Radiography and Ultrasonography rates for cytology are often diagnostic, but biopsy samples may
Radiographs of the thorax and ultrasonographic examination of be requested. These steps may be omitted in dogs that are rela-
the abdomen should be evaluated for soft tissue masses, soft tissue tively healthy according to their owners and veterinarians, who
calcication, evidence of fungal disease, organomegaly, osteolysis, have unremarkable CBCs, and no abnormalities seen on thoracic
and/or osteoporosis. The goal is to identify an abnormal area that radiographs.
could be biopsied in the hope of providing a denitive explanation A bone marrow aspirate may be considered in the hypercal-
for hypercalcemia. An anterior mediastinal mass is demonstrable cemic pet because the lymphosarcoma may invade the marrow
radiographically in as many as 40% of hypercalcemic dogs with (Meuten etal, 1983b). As with the peripheral lymph node evalu-
lymphosarcoma (see Fig. 15-19; Greenlee et al, 1990). If hepa- ation, the presence of a normal bone marrow aspirate does not
tomegaly or splenomegaly is identied, histologic evaluation of a denitively rule out lymphosarcoma. As with the lymph node
fine needle aspirate or of a biopsy could be considered. aspirate or biopsy, we usually omit this diagnostic tool when a dog
Adenocarcinomas derived from the apocrine glands of the is clinically well and when a CBC is unremarkable.
anal sac may appear radiographically as a mass in the pelvic
canal. Sublumbar lymphadenopathy caused by tumor metastasis Specic Assays: Parathyroid Hormone, Parathyroid
is also common (see Fig. 15-20; Meuten etal, 1983b; Meuten, HormoneRelated Protein, and Calcitriol
1984). Soft tissue calcication is most frequently observed with
hypervitaminosis D or CKD, although mineralization can be See previous discussions.
seen with any hypercalcemic disorder in association with hyper-
phosphatemia and a calcium x phosphorus product greater than Trial TherapyWhy This Approach Is Strongly
60 to 80. Discouraged
Discrete lytic lesions in the vertebrae or long bones are sug-
gestive of either myeloma or malignancy-associated hypercalce- If the diagnostic evaluation described fails to identify a cause for
mia with bone metastasis (see Fig. 15-16). Radionuclide bone hypercalcemia, the clinician is faced with a diagnostic decision:

scans (Fig. 15-25) may identify or exclude focal bone lesions not Wait and retest?
detected with plain radiography (Chew etal, 1991). One dog with Trial medical therapy?
PHPTH had the uncommon finding of fractures at the time of Exploratory surgery of the neck?

presentation (Gear etal, 2005). Concurrent hyperproteinemia is If a hypercalcemic dog is stable, eating, and not significantly ill,
supportive of myeloma. Solid tumors with metastasis to bone are we recommend rechecking any vague test result after a few days
more likely if lytic bone lesions and normoproteinemia (especially or weeks. The clinician should also consider referring the client
a normal serum globulin concentration) are present. A core biopsy and patient to a colleague more familiar with hypercalcemia and/
of a lytic lesion may be necessary to establish a denitive diagnosis or capable of performing high quality cervical ultrasonography,
of neoplasia. Mild generalized osteoporosis is difcult to diagnose fine needle aspiration under ultrasonographic guidance, or some
with plain survey radiographs. If present, however, it is suggestive other diagnostic aid. Ill hypercalcemic dogs may also benefit from
of PHPTH or hypercalcemia of malignancy. referral and a new opinion.
Ultrasonography of the cervical region has been reviewed. This Most of the disorders that cause hypercalcemia are not occult,
tool is noninvasive and can be quite valuable (see Fig. 15-21). but a diagnosis may occasionally be difcult. Diagnosis of PHPTH
or malignancy-associated hypercalcemia (usually lymphosarcoma)
can be straightforward (common) or problematic (uncommon).
The veterinarian is reminded to complete a thorough history,
bearing in mind the importance of diet, supplements, and poten-
tial exposure to toxins (Mellanby etal, 2005). The ability to uti-
lize the combination of cervical and abdominal ultrasonography
together with assessment of PTH and PTHrP assays usually leads
to a correct diagnosis. Occasionally, the results of these tests are
nebulous, and the clinician may consider one of two options:
(1) surgical exploration of the neck to look for a parathyroid
FIGURE 15-25 Bone scan from a dog with hypercalcemia caused by multiple tumor, or (2) trial therapy with a chemotherapeutic drug effec-
myeloma. Note that the focal black areas are those of increased bone activity, tive against lymphosarcoma to see if the hypercalcemia can be
as is typical for a metastatic lesion. (Courtesy of Dr. William Hornof, Davis, CA.) alleviated.
Nonspecific Medical Treatment for Hypercalcemia therapies is directed at ill or extremely ill dogs whose hypercalce-
mia is not caused by PHPTH. If a dog with PHPTH is ill, there
If hypercalcemia is caused by a lymphosarcoma (or other hemato- should be concern of a concurrent problem. Despite a dramatic
poietic tumor), a rapid decline in the serum calcium concentration increase in the serum calcium concentration (mean serum TCa
is common within 48 hours of glucocorticoid administration (Chew concentration > 14 mg/dL), dogs and cats with PHPTH are typi-
etal, 1991). The actions of glucocorticoids in inhibiting the growth cally stable and not in need of emergency therapy (Table 15-8).
of neoplastic lymphoid tissue and lymphocytolysis account for their
rapid benecial effect in most dogs with hematologic cancers, such Therapy for Renal Failure or Vitamin D Toxicosis
as lymphoma or multiple myeloma (Goodwin etal, 1986). Gluco- Severity of clinical signs and degree of kidney injury depends,
corticoids also counteract the effects of vitamin D, which accounts in part, on both serum calcium and phosphorus concentrations.
for their value, while limited, in animals with vitamin D toxicosis Renal damage induced by metastatic mineralization is thought
or granulomatous diseases (Sandler etal, 1984). In general, gluco- to correlate with the serum TCa x phosphate product. Products
corticoid therapy is ineffective in PHPTH or nonhematologic can- greater than 60 to 80 may be associated with nephrotoxicity.
cers (Bilezikian, 1992b). If the serum calcium concentration fails to Thus hypercalcemia associated with PHPTH (low-normal or low
decline after glucocorticoid administration, PHPTH may be con- serum phosphate concentrations) is less worrisome and dangerous
sidered as a possible explanation, but this represents a dangerous than the hypercalcemia associated conditions like renal failure or
and inappropriate protocol for diagnosis. Unfortunately, glucocor- hypervitaminosis D (high-normal to increased concentrations; see
ticoids have nonspecific effects on calcium homeostasis and may Table 15-8).
cause transient declines in TCa or iCa. If the serum calcium con-
centration decreases into the reference range after administration of
Indications and Alternatives for Acute Therapy in
a chemotherapeutic agent, lymphosarcoma and other malignancies
Hypercalcemia
should be suspected and further diagnostic tests implemented to
conrm this diagnosis. However, conrmation of lymphosarcoma Dogs with hypercalcemia of malignancy, vitamin D toxicosis,
in dogs who have received glucocorticoids may be challenging, and or other non-PHPTH causes of hypercalcemia often exhibit
their response to adjunct therapy may be adversely affected. extremely worrisome clinical signs that are caused by their under-
lying malignancy as well as their hypercalcemia. Treatment for
Exploratory SurgeryNo Longer Necessary? cancer may indirectly decrease serum calcium concentrations.
Dogs that have mild hypercalcemia and CKD also have worri-
Surgical exploration of the neck is an alternative approach for some clinical signs, moderate to severe hyperphosphatemia, and
attempting to manage a dog with hypercalcemia of undetermined are at risk for tissue mineralization. They may benet from treat-
origin. The use of PTH, PTHrP, and iCa assays together with cer- ment directed at maintaining fluid homeostasis while decreasing
vical and abdominal ultrasonography should negate the need for the calcium x phosphorus product.
a true exploratory procedure. In other words, PHPTH can be
confirmed in almost all dogs with PHPTH prior to surgery. Thus,
surgery becomes a therapeutic regimen rather than a diagnostic
tool. We again emphasize, condence in a diagnosis prior to surgery TABLE 15-8 CLASSIC SERUM TOTAL
or medical therapy is preferred over exploratory or trial therapies. CALCIUM AND INORGANIC
PHOSPHORUS (PHOSPHATE)
CONCENTRATIONS FOR VARIOUS
Spontaneous Resolution of Primary Hyperparathyroidism CONDITIONS TO DEMONSTRATE
Acute hypocalcemia has been described in two dogs with histories THEIR TYPICAL NUMERICAL
of chronic hypercalcemia. The acute hypocalcemia may have been PRODUCTS
the result of parathyroid gland tumor infarction and necrosis.
Hypocalcemia may have resulted because the remaining parathy- TYPICAL
roid glands were atrophied and transiently unable to compensate TYPICAL SERUM TYPICAL SERUM CALCIUM
for acute loss of PTH (Rosol etal, 1988). CALCIUM PHOSPHATE PHOSPHATE
(mg/dL) (mg/dL) PRODUCT
Normal dog 10 4.5 45
ACUTE MEDICAL THERAPY FOR HYPERCALCEMIA
(NOT PRIMARY HYPERPARATHYROIDISM) Primary hyper- 15 3.0 45
parathyroidism
Primary Hyperparathyroidism Versus Other Disorders (PHPTH)
Dogs with Primary Hyperparathyroidism Do Not Require Immediate Lymphosarcoma 15 3.0 45
Therapy for Hypercalcemia Apocrine cell 15 3.0 45
Treatment of dogs and cats with PHPTH involves ablation or sur- carcinoma of
gical excision of abnormal tissue. Their hypercalcemia would rarely the anal sac
be acute, and the calcium x phosphate product is usually normal Chronic kidney 11.5 10 115
or low. Although hypercalcemia can be theoretically cause miner- disease (CKD)
alization of nephrons, this not a concern among most dogs with Vitamin D 11.5 10 115
PHPTH. We have not employed any acute or other long-term toxicosis
medical therapy in dogs that we suspect as having PHPTH, other
than strongly advising owners to provide their dog with ready Note that therapy is likely indicated if the product of these two electrolytes exceeds 60
access to water at all times. The following discussion on medical to 80.
|
There is no single treatment protocol consistently effective SURGICAL THERAPY FOR PRIMARY
for all causes of hypercalcemia. Removal of the underlying HYPERPARATHYROIDISM
cause is definitive, but this is not always possible. The goals of
supportive treatment are to enhance renal excretion of calcium Introduction
and to prevent calcium reabsorption from bone. Hemoconcen-
tration contributes to increases in serum iCa concentration. Surgical techniques for the thyroid-parathyroid complex have
Parenteral fluid therapy (saline is often the fluid of choice) is been adequately described. Usually the surgery is not difficult; it
the single most important and potentially effective therapy. IV is often described to owners as easier than a spay and less time
fluids should correct dehydration and, once fluid volume and consuming than a dental prophylaxis. Recognition and surgi-
blood pressure have been restored, induce diuresis. Renal cal- cal excision of autonomously functioning abnormal parathyroid
cium excretion is enhanced by sodium, thus the recommenda- tissue is the most commonly employed treatment for dogs with
tion of saline. In the hydrated or rehydrated dog, furosemide PHPTH (see Fig. 15-21, B; Fig. 15-26). The cure rate has been
should be the next therapy considered to further enhance renal estimated at about 95% (Rasor etal, 2007; Ham etal, 2009). Fail-
calcium excretion. ure to cure can be due to the presence of multiglandular disease
Thiazide diuretics should be avoided as they may promote known to occur in about 10% of dogs with PHPTH, incorrect
renal reabsorption of calcium (Schenck and Chew, 2008; intraoperative decisions that result in incomplete excision of all
2012). Glucocorticoids are an effective therapy by inducing autonomously functioning tissue, ectopic autonomously func-
cytolysis (lymphosarcoma), as well as reducing bone resorp- tioning parathyroid tissue (extremely unlikely), or the presence of
tion, decreasing intestinal absorption, and increasing renal malignant disease with functioning distant metastases (extremely
excretion of calcium. Glucocorticoids have had demonstrable unlikely; Bilezikian etal, 2001; Ham etal, 2009). Correctly iden-
effect in dogs with hypercalcemia secondary to lymphosar- tifying all abnormal tissue can, uncommonly, be problematic
coma, multiple myeloma, hypoadrenocorticism, hypervitamin- because visible changes may be subtle or inapparent. Alternatively,
osis D, or granulomatous diseases, but have minimal effect on after removing an abnormal nodule, another nodule may be pres-
other causes. ent but not seen (Ham etal, 2009). An attempt must be made
Glucocorticoid therapy should be withheld if a definitive diagno- to ensure that at least one parathyroid gland remains intact to
sis has not been established. A bisphosphonate may be utilized for maintain calcium homeostasis and prevent permanent hypopara-
chronic control of hypercalcemia. Bisphosphonates lower calcium thyroidism. If none of the parathyroid glands appears abnormal,
by reducing the number and action of osteoclasts. Several bisphos- if all appear small, or if all are enlarged, the diagnosis of PHPTH
phonates have been employed in dogs (Box 15-4 and Table 15-9; must be questioned. The reader is reminded that 5% to 15% of
Schenck and Chew, 2012; Skelly, 2012). Oral administration is dogs with PHPTH due to an abnormal parathyroid gland(s) may
not typically effective because of poor intestinal absorption. IV also have an incidentally identified thyroid mass.
pamidronate, which is about 100 times more potent than etidro-
nate, has been more reliable, is relatively well tolerated, lasts as Surgical Observations
long as 3 weeks, and repeat dosing can be considered if necessary
(Hostutler etal, 2005). In three studies describing 53 dogs with PHPTH, each had a soli-
tary nodule successfully identified and removed (Gear etal, 2005;
Sawyer etal, 2011; Arbaugh etal, 2012). In another study, seven
of 12 dogs (58%) had a solitary nodule and five (42%) had two
(Ham etal, 2009). One study included the only four dogs with
BOX 15-4 General Treatment of Hypercalcemia three nodules excised (6% of 62 dogs). In that report, each of 16
dogs (26%) had two nodules and 42 dogs (68%) had a solitary
Definitive nodule (Milovancev and Schmiedt, 2013). In our series, about
Remove underlying cause 90% of dogs with PHPTH have had a solitary mass, and about
Supportive
10% have had two. It is rare to diagnose PHPTH associated with
Initial considerations
more than two abnormal and autonomously secreting glands.
Fluid (0.9% sodium chloride)
Furosemide Cervical Imaging
Sodium bicarbonate Ultrasonography
Glucocorticosteroids
Secondary considerations
The potential for excellence in sensitivity and specificity of cervical
Bisphosphonates
ultrasonography has been previously discussed. In three reports,
Calcitonin
ultrasonography results correctly identified the abnormal parathy-
Tertiary considerations
roid tissue in 58 of 61 dogs (95%) (Gear etal, 2005; Sawyer etal,
Mithramycin
2011; Arbaugh etal, 2012). However, in another study, ultraso-
Ethylenediaminetetraacetic acid (EDTA)
nography correctly identified all abnormal tissue in only 44 of 55
Peritoneal dialysis
dogs (80%) with PHPTH (Milovancev and Schmiedt, 2013). In
Hemodialysis
a study of 12 dogs with PHPTH, ultrasonography correctly iden-
Future considerations
tified 12 abnormal nodules but also identified two nodules that
Calcium channel blockers
were not seen at surgery and failed to identify five masses that were
Somatostatin congeners
seen at surgery (Ham etal, 2009).
Calcium receptor agonists
Cervical ultrasonography should be an integral component of
Non-hypercalcemic calcitriol analogues evaluating hypercalcemic dogs and cats. We are reluctant to rec-
ommend surgery in any dog suspected to have PHPTH but that
TABLE 15-9 TREATMENT OPTIONS FOR HYPERCALCEMIA NOT CAUSED BY PRIMARY HYPERPARATHYROIDISM
TREATMENT DOSE INDICATIONS COMMENTS

Volume Expansion
SC saline (0.9%) Small volumes Rarely indicated or beneficial
IV saline (0.9%)* 100 to 125 mL/kg/day or as needed Moderate to severe Careful in patients with congestive heart failure or
hypercalcemia hypertension (rarely indicated in dogs with PHPTH)
Diuretics
Furosemide 2 to 4 mg/kg every 8 to 12 hours, IV, SC, or Moderate to severe Volume expansion is necessary before use of this drug
by mouth hypercalcemia
Alkalinizing Agent
Sodium bicarbonate 1 mEq/kg IV slow bolus; may continue at Severe hypercalcemia Requires close monitoring
0.3 base deficit weight in kg/day
Glucocorticoids
Prednisone 1 to 2.2 mg/kg every 12 hours by mouth, Moderate to severe Use of these drugs before identification of etiology may
SC, or IV hypercalcemia make definitive diagnosis difficult
Dexamethasone 0.1 to 0.22 mg/kg every 12 hours, IV or SC Same Same
Bone Resorption Inhibitors
Calcitonin 4 to 6 IU/kg as IV infusion and then SC Hypervitaminosis D Response may be short-lived; vomiting and anorexia
every 8 or 12 hours may occur
Bisphosphonates
Etidronate 5 to 15 mg/kg every 12 to 24 hours Moderate to severe Expensive and use in dogs is limited
hypercalcemia
Clodronate 20 to 25 mg/kg in a 4-hour IV infusion Same Same
Pamidronate 1.3 mg/kg in 150 mL 0.9% saline in a Same Same
2-hour IV infusion; can repeat in 1 week
Alendronate 5 to 20 mg orally every 7 days Same Must ensure complete passage of medication into stomach
to avoid esophagitis
Miscellaneous
Sodium EDTA 25 to 75 mg/kg/h Severe hypercalcemia Nephrotoxicity
Peritoneal dialysis Low calcium dialysate Severe hypercalcemia Short duration of response; use in hypercalcemia not
reported
EDTA, Ethylenediaminetetraacetic acid; IHC, idiopathic hypercalcemia of cats; IV, intravenous; PHPTH, primary hyperparathyroidism; SC, subcutaneous.
*Potassium supplementation may be necessary.
fails to demonstrate at least one abnormal parathyroid nodule on radionuclide scans provide excellent results for localizing parathyroid
cervical ultrasonography. If a relatively inexperienced individual adenomas in people (ODougherty etal, 1992; Taillefer etal, 1992).
is performing the examination in which no abnormal nodules are Two reports suggested that this procedure might be help-
seen or if more than one is seen, we recommend that the examina- ful in localizing parathyroid adenomas in dogs with PHPTH
tion be repeated when one of our more experienced radiologists (Wright et al, 1995; Matwichuk et al, 1996). In a subsequent
is available. Disagreement between ultrasonography and surgi- study, double-phase parathyroid scintigraphy was evaluated in a
cal observations are not common. Incidentally identified thyroid group of PHPTH dogs with one of 10 having a scan that corre-
masses are encountered. lated with surgery. The poor sensitivity and specicity of parathy-
roid gland scintigraphy led the authors to conclude that use of this
Radionuclide Scans tool could not be recommended (Matwichuk etal, 2000).
Radionuclide procedures have been used for the detection and
localization of parathyroid adenomas in humans (Fine, 1987). The Selective Venous Sampling
most commonly used radionuclide imaging technique is a dual An attempt was made to determine the side on which an autono-
radioisotope procedure combining thallous chloride (201Tl) with mously functioning parathyroid nodule was located by taking
either pertechnetate (99mTc) or radioactive iodine (123I) (Picard blood from both jugular veins and measuring PTH concentrations
etal, 1987). Various problems with this methodology led to the use in each. The hypothesis was that the vein draining the side of the
of one radionuclide: technetium-99m-sestamibi (99mTc-sestamibi) autonomously functioning tissue would have greater amounts of
(ODougherty etal, 1992; Taillefer etal, 1992). The procedure and PTH than the opposite side. PTH concentrations were compared
hospitalization time for radionuclide scans using 99mTc-sestamibi in from the samples obtained from each jugular vein prior to surgery.
humans are similar to those for 99mTc scans in dogs. 99mTc-sestamibi Each dog had PHPTH caused by a solitary functioning adenoma.
|
C B
FIGURE 15-26 A, Surgical site during removal of a solitary parathyroid adenoma (tip of forceps). B, Surgical site
during removal of a solitary parathyroid adenoma (T, trachea). White arrows delineate the cranial and caudal
poles of the thyroid glands; black arrows point out the parathyroid adenoma. C, Surgical site during removal of an
internal parathyroid adenoma (t, trachea). Solid arrows delineate the cranial and caudal poles of the thyroid,
which is being retracted from the trachea to reveal the parathyroid adenoma (open arrows) on the dorsal surface
of the thyroid.
Unfortunately, a gradient between samples was identied in only a tumor was identied after the infusion. However, two of three
one of 11 dogs and this is not recommended (Feldman etal, 1997). dogs developed Heinz body anemia and red blood cell blistering
A rapid chemiluminescent PTH assay was employed on blood after the procedure (Fingeroth and Smeak, 1988).
samples obtained during surgery from local veins to help identify
laterality (left or right side) of autonomously functioning parathy-
Solitary Adenoma, Hyperplastic Nodule, or Carcinoma?
roid tumors. In addition, plasma PTH concentrations were obtained
from local veins to determine if all abnormal tissue had likely been In surgery, a large majority of dogs with PHPTH have had a soli-
removed. Systemic and local PTH concentrations decreased more tary nodule identified and removed. One cannot predict the histo-
than 50% from presurgical values in all dogs after complete excision logic classification from gross appearance. About 50% of nodules
of abnormal tissue. Mean preoperative systemic plasma PTH con- are identied on the ventral surface of the thyroid glands. If the
centrations were significantly higher than mean postoperative con- mass is not seen on the ventral surface, careful inspection of the
centrations. The mean local pre-excision PTH concentration from dorsal surface of each thyroid lobe should be conducted. Exter-
the affected side was significantly higher than mean pre-excision nal parathyroid nodules are usually removed easily and with-
concentration taken from the unaffected side. Unfortunately, local out damage to surrounding tissue (see Figs. 15-4 and 15-26). In
PTH concentrations from the affected side were greatly increased in some dogs with an internal parathyroid adenoma, surgeons may
comparison to the opposite side in a minority of the dogs. Thus, the choose to remove the entire thyroid-parathyroid complex from the
side on which an autonomously nodule was located and removed affected side. In a small number of dogs, tissue removed was based
was not consistently detected with intraoperative PTH sampling. on cervical ultrasonography identifying an intrathyroidal nodule.
Results of this elegant study did not support intraoperative blood
sampling for PTH to locate the side on which an autonomously Enlargement of Multiple Parathyroid Glands
functioning gland resided (Ham etal, 2009).
Approximately 10% of dogs with PHPTH have enlargement
of more than one gland in our experience. Others have identi-
New Methylene Blue Infusions
fied more than one gland enlarged in more than 20% of dogs
IV infusion of new methylene blue (3 mg/kg) has been described with PHPTH (Gear et al, 2005). Histologic classification of
as a means of improving the surgeons ability to recognize abnor- removed tissue may or may be similar. A dog may have more
mal glands. Three dogs with PHPTH were evaluated, and in each than one adenoma, carcinoma, or hyperplastic gland or have any
combination (DeVries etal, 1993). When more than one enlarged the estimated nodular volume, was inserted into the nodule (Fig.
gland is identied, the concern is primary versus secondary hyper- 15-27). That volume was slowly injected, with a goal of having
parathyroidism. The presurgical evaluation, as reviewed, should the entire parenchyma exposed to ethanol. Because parathyroid
discriminate dogs with PHPTH from non-surgical causes of nodules are small, considerable experience with ultrasonographic-
hypercalcemia. If the clinician is convinced that primary disease guided needle placement is necessary. Parathyroid nodules may
is present, the decision to remove two glands is straightforward. also be in close proximity to the carotid artery and vagosympa-
However, if three or four glands are involved, the decision regard- thetic trunk; therefore absolute certainty about needle placement
ing removal should be based on ones confidence in the presurgical is required prior to and during injection.
diagnosis and, potentially, the owners ability to treat permanent Because ethanol is hyperechoic, it is easily visualized with ultra-
hypoparathyroidism. sonography (see Fig. 15-27). The parathyroid nodules received dif-
ferent calculated volumes, as dictated by the monitored diffusion.
Recurrence of Primary Hyperparathyroidism The injected volumes ranged from 50% to 150% of the calculated
nodular volume. No dog was under anesthesia for more than an
About 8% to 10% of dogs with treated PHPTH have complete hour, and the mean duration of anesthesia was 38 minutes. A sin-
resolution of their condition for 6 months to longer than 5 years gle injection was administered to 11 of the 12 dogs. One dog was
and then have had a recurrence (Ham etal, 2009). In each, their injected a second time 48 hours after the rst dose failed to reduce
second diagnosis of PHPTH was caused by a solitary, autono- the serum calcium concentration into the reference range. In all
mously functioning parathyroid nodule, in a gland not previously 12 dogs, the serum TCa concentrations decreased into the refer-
affected. Nodules surgically removed after recurrence have had the ence range. In 11 dogs this decrease was documented within 48
same range of histologic diagnoses; adenoma is the most common, hours of injection (10 after the rst injection and one after the
whereas carcinoma or hyperplasia is each diagnosed in about second injection). One dog remained hypercalcemic for 4 days,
5% to 10% of the cases. Because recurrence of PHPTH has been but the serum calcium concentration decreased into the reference
documented, periodic rechecks are warranted. range 5 days after treatment (Fig. 15-28). One dog had a recurrence
of hypercalcemia 30 days after injection and was treated surgically.
Absence of a Parathyroid Mass at Surgery Each of the other 11 dogs remained normocalcemic for more than
12 months. The only adverse side effect was a transient change in
If an abnormal parathyroid nodule is not seen at surgery (or with the bark of two dogs, both of whom were believed, retrospectively,
ultrasonography), one must first consider the confidence with to have suffered transient, unilateral laryngeal paralysis.
which the diagnosis of PHPTH was established. If convinced of the Ethanol ablation was an efcacious mode of therapy for
condition, the most likely diagnoses include hypercalcemia due to PHPTH in dogs (Long etal, 1999). The cost of the procedure was
PTH production by a parathyroid tumor in an aberrant location considerably less than for surgery. Chemical ablation of parathy-
or the presence of a non-parathyroid tumor producing PTH (i.e., roid masses may be more effective in dogs than in humans because
ectopic hyperparathyroidism). Either would be extremely rare. The canine parathyroid nodules are considerably smaller, thus requir-
ventral neck should be carefully explored and any suspicious mass ing a smaller volume of ethanol for complete ablation. One group
excised. New methylene blue infusion, as previously described, can treated five dogs utilizing this approach without success (Gear
also be considered (Fingeroth and Smeak, 1988). etal, 2005). A subsequent study concluded that ethanol ablation
was an effective mode of therapy but not as effective as surgery or
PERCUTANEOUS THERAPIES FOR PRIMARY heat ablation. Control of hypercalcemia for a median of 540 days
HYPERPARATHYROIDISM IN DOGS was achieved in 13 of 18 dogs (72%) (Rasor etal, 2007).
Percutaneous Ultrasound-Guided Ethanol Ablation Percutaneous Ultrasound-Guided Radio Frequency

Heat Ablation
Based on experience using cervical ultrasonography as a diagnostic
aid for dogs and on the use of chemical ablation for small nodules Based on experience with cervical ultrasonography both as a diag-
in people (Bennedbaek etal, 1997), the efcacy of ethanol abla- nostic aid and for ethanol ablation, the efcacy of treatment with
tion as a treatment for dogs with PHPTH was evaluated (Long percutaneous ultrasonographic-guided radio frequency heat abla-
et al, 1999). Ethanol causes coagulation necrosis and vascular tion was evaluated. Radio frequency waves are converted to heat
thrombosis. PHPTH was diagnosed in twelve dogs whose clinical at the needle tip causing thermal necrosis at the needle tip (Pollard
and biochemical evaluation was typical for the condition. Each etal, 2001). This treatment modality has several advantages over
dog had a solitary, hypoechoic, round or oval mass near a thy- ethanol ablation. Radio frequency damages a discrete amount of
roid lobe on cervical ultrasonography. Parathyroid nodules were tissue surrounding the uninsulated portion of the needle. (There
identied on the right side in eight and left side in four dogs. The is no potential for leakage, as there is with ethanol.) Radio fre-
nodules ranged from 4 to 10 mm in greatest diameter; they were quency offers the additional advantage of not damaging regional
located at the cranial aspect of a thyroid lobe in six, within the vasculature. Vascular blood flow disperses heat. In humans, this
caudal pole of a thyroid lobe in three, and in the midbody of a treatment modality has a higher success rate than ethanol for mass
thyroid lobe in three dogs. The calculated volume of the nodules ablation and fewer retreatments required to achieve remission.
ranged from 0.06 to 0.16 cm3. Radio frequency heat ablation has been used in the treatment of
Each dog was placed under general anesthesia, and the ven- multifocal hepatic, breast and nasal masses, as well as for prostatic
tral cervical region was clipped and aseptically prepared. The hypertrophy (Jiao etal, 1999; Livraghi etal, 1999). One disad-
parathyroid nodule was identied and continuously monitored vantage of the radio frequency technique is equipment cost.
throughout the procedure via ultrasonography, using an appropri- In the first report using this treatment modality for dogs with
ate transducer. The tip of a 27-gauge needle, with arterial tubing PHPTH, 27 dogs were treated, 22 with a solitary parathyroid
attached to a syringe containing about 50% more ethanol than nodule and five dogs each had two nodules. In three of the five
|
Parathyroid mass Needle
A B
Injection
site
C D
FIGURE 15-27 Ultrasonographic appearance of chemical ablation of a parathyroid mass in a dog. A, Sagittal view of the
parathyroid mass prior to treatment. B, A 27-gauge needle is inserted into the mass. C, A test injection of 96% ethanol is
used to confirm placement of the needle inside the mass. Note that the ethanol is hyperechoic in relation to the parenchyma
of the mass. D, After injection of the target dose of ethanol, the entire mass has an echogenic appearance. (From Long CD,
etal.: Percutaneous ultrasoundguided chemical parathyroid ablation for treatment of primary hyperparathyroidism in
dogs, J Am Vet Med Assoc 215:217, 1999.)
dogs with two nodules, both were on the left side of the neck, and to expose all the parenchyma to heat. Mean anesthesia time was
two dogs had one nodule on each side. Ultrasonographic appear- 41 minutes, but with experience it now averages about 15 minutes.
ance of each nodule was similar: spherical to ovoid and hypoechoic The procedure was successful in 26 of the 27 dogs with a dramatic
to the surrounding thyroid parenchyma. Length of the masses reduction in the serum PTH concentration and normalization of
ranged from 3 to 15 mm. Each dog with a solitary parathyroid both the TCa and iCa concentrations within 24 hours (Fig. 15-30).
mass was treated once. When two parathyroid nodules were pres- Serum calcium concentrations remained within the reference range
ent and located on the same side, as in the three dogs, both were for more than a year in each dog. One dog improved for only 1
ablated during the first anesthesia. In the two dogs with one nod- month and was treated surgically after hypercalcemia recurred.
ule on either side of the neck, each nodule was treated separately, Immediately after heat ablation, one dog with a unilateral para-
30 days apart. Preparation was the same as utilized for ethanol thyroid nodule developed a transient voice change, which resolved
ablation. The parathyroid nodule was identied and continuously within 5 days. It is unclear whether this voice change occurred sec-
monitored with ultrasonography, including guiding the tip of a ondary to intubation or to the ablation procedure. Signs of pain,
20-gauge, over-the-needle (insulated) catheter into the mass. The swelling, or respiratory distress were not detected in any dog. Eleven
needle hub was removed, allowing for an insulated wire to connect of the 26 successfully treated dogs required vitamin D therapy for
the needle to the radio frequency unit (Radiotherapeutics Inc., postablation hypocalcemia (see next section). In a retrospective
Redwood City, CA). Initially, 10 watts of energy were applied to evaluation of ultrasonographic-guided heat ablation in dogs with
the tissue for 10 to 20 seconds. If echogenic bubbles were not seen PHPTH, success rates were comparable to those achieved with sur-
via ultrasonography at the needle tip, the wattage was increased by gery. Forty-four of 49 dogs with PHPTH (90%) experienced rapid
2 watts every 5 to 10 seconds until echogenic foci became appar- resolution (hours to days) of their condition following heat ablation,
ent (Fig. 15-29). Also, if a popping sound could be heard, the resulting in normal calcium concentrations for a median of 580 days
maximum heat application was assumed to have been reached and (Rasor etal, 2007). Inclusion criteria for heat ablation include hav-
no additional increases in wattage were made. The needle tip was ing a readily seen abnormal parathyroid nodule more than 2 mm but
arbitrarily redirected multiple times, as necessary, in an attempt less than 16 mm in greatest diameter, not too close to the carotid or
Total Calcium PTH

15 25
14
20
13
12 15
pmol/L
mg/dL
11
10 10
9
5
8
7 0
Pre Day 1 Day 2 Day 3 Day 4 Day 5 1 mo 3 mos 6 mos Pre Day 1 Day 2 Day 3 Day 4 Day 5 1 mo 3 mos 6 mos
A Time postinjection B Time postinjection
FIGURE 15-28 A, Serum total calcium (TCa) concentration in eight dogs before (Pre) and after chemical ablation of
a parathyroid mass. The horizontal black lines indicate the reference range. Dog 6 developed clinical signs of hypo-
calcemia 4 days after the ablation procedure. Dog 8 received two injections of ethanol (the data given represent val-
ues obtained after the second injection). Dog 7 underwent surgical removal of a parathyroid mass after the 1-month
reevaluation. Dog 5 died of unrelated causes after the 3-month reevaluation. B, Serum parathyroid hormone (PTH)
concentrations in eight dogs before (Pre) and after chemical ablation of a parathyroid mass. The horizontal black
lines indicate the reference range. (From Long CD, etal.: Percutaneous ultrasoundguided chemical parathyroid
ablation for treatment of primary hyperparathyroidism in dogs, J Am Vet Med Assoc 215:217, 1999.)
A B C
FIGURE 15-29 Left lateral sonographic images of an oval hypoechoic parathyroid nodule in a dog prior to heat
ablation (A), with the insulated needle passing through the superficial soft tissues into the cranial aspect of the
mass (B), and after heat ablation (C). Note the hyperechoic foci in the parenchyma of the gland in C. (From Pol-
lard RE, etal.: Percutaneous ultrasonographically guided radio frequency heat ablation for treatment of primary
hyperparathyroidism in dogs, J Am Vet Med Assoc 218:1106, 2001.)
any other vital structure, and no cystic calculi documented. It is rec- concentrations has been used in an attempt to predict dogs most
ommended that dogs with PHPTH and cystic calculi have parathy- likely to become seriously hypocalcemic after therapy. Surgical
roid and abdominal surgery performed during the same anesthesia. removal or percutaneous ablation of an autonomous source of
PTH results in rapid disappearance of circulating PTH (see Fig.
15-30; Fig. 15-31) and decreases in serum calcium concentrations.
POSTTREATMENT MANAGEMENT OF
Potential for serious decreases in serum calcium concentration (see
POTENTIAL HYPOCALCEMIA
Figs. 15-28 and 15-30; Fig. 15-32) exist for any dog treated suc-
A full discussion of vitamin D and calcium supplementation is cessfully for PHPTH. After resolution of PHPTH, decreases in
presented in Chapter 16. serum calcium concentrations usually continue for a period of 1 to
7 days but rarely longer. Our hypothesis and experience has been
that posttreatment hypocalcemia correlates with severity of hyper-
Background
calcemia prior to surgery. We compared 50 dogs with PHPTH
Physiologically, the long-term response to autonomous secretion who did not become seriously hypocalcemic (TCa < 7mg/dL; iCa
of PTH by an abnormal parathyroid nodule is atrophy of normal < 0.8mmol/L) with 50 who did following treatment. The mean
glands. Duration of hypercalcemia is apparent for some dogs but pretreatment serum TCa and iCa concentrations of those who did
is unknown for most. Thus, the use of pretreatment serum calcium not become seriously hypoglycemic (13.88 mg/dL, 1.61 mmol/L,
|
40
35
Serum [PTH] (pmol/L)
30 2.5
25 2
Ionized calcium
concentration
20
1.5
15
10 1
5 0.5
0
0
0 2 4 6 0 1 2 3 4 5
A Days B Days
FIGURE 15-30 A, Serum parathyroid hormone (PTH) concentration (pmol/L: individual data points) of eight dogs
that were successfully treated for primary hyperparathyroidism (PHPTH). The reference range is 2 to 13 pmol/L. B,
Serum ionized calcium (iCa) concentrations (mmol/L; individual data points) in five dogs that were successfully
treated for PHPTH on day 0 and eventually required vitamin D supplementation 1 to 4 days after treatment. The
reference range is 1.1 to 1.4 (From Pollard RE, etal.: Percutaneous ultrasonographically guided radio frequency
heat ablation for treatment of primary hyperparathyroidism in dogs, J Am Vet Med Assoc 218:1106, 2001.)
25 for discomfort as well as life-threatening hypocalcemia. The

next sections review dogs for which no therapy or immedi-
20 ate therapy (posttreatment) is suggested. Beginning therapy
Serum [PTH] (pmol/L)
before or soon after surgery or ablation but before docu-

15
mented decreases in the serum calcium concentration has not
prevented the serum calcium concentration to decline into or
below the reference range, but it has prevented serious hypo-
10 calcemia and tetany.
5 Protocol Based on the Pretreatment Total Calcium

Concentration
0 Pretreatment Total Calcium Less Than 14 mg/dL
Before One day Three days
surgery after surgery after surgery If the serum calcium concentration prior to surgery is less than 14
FIGURE 15-31Serum parathyroid hormone (PTH) concentrations before and mg/dL, the risk of postsurgical hypocalcemia is relatively small,
after surgery in eight dogs in which a solitary functional parathyroid adenoma but we now recommend that all dogs with PHPTH receive prophy-
was removed. lactic treatment to prevent posttreatment hypocalcemia. If prophy-
lactic treatment is withheld, the dog should be hospitalized for 3
to 5 days after treatment to monitor the TCa and/or iCa concen-
respectively) were significantly lower than results from those who trations once or twice daily. Hospitalization also reduces activity
did (16.12 mg/dL, 1.87 mmol/L). These unpublished data are levels of most dogs. Dogs sent home are likely to be more active
comparable to those reported by another group: Mean pretreat- and, if hypocalcemic, at much greater risk of clinical tetany than
ment TCa concentration of those who did not develop posttreat- one kept quiet. If the serum TCa concentration remains above
ment hypocalcemia (13.6 mg/dL) was significantly lower than the about 8.5 mg/dL (assuming a lower reference limit of about 9.5
TCa pretreatment of those who did become seriously hypocalce- mg/dL) and/or the serum iCa concentration remains above about
mic (16.8 mg/dL) (Gear etal, 2005). 0.95 mmol/L (assuming a lower reference limit of 1.10 mmol/L),
Although we and Gear and colleagues (2005) have noted vitamin D treatment can be withheld. It should be noted, how-
correlation between presurgical TCa or iCa concentrations ever, that these are general guidelines and prophylactic treatment
and development of posttreatment hypocalcemia, this has of all PHPTH dogs to prevent hypocalcemia may be warranted
not been appreciated in other studies (Arbaugh et al, 2012; (Box 15-5). Chapter 16 presents a complete discussion of the
Milovancev and Schmiedt, 2013). Size of unaffected parathy- acute and chronic management of hypocalcemia in dogs and cats.
roid tissue is another consideration with dogs that have unde-
tectable atrophied parathyroid glands being at greater risk for Chronicity of Primary Hyperparathyroidism
posttreatment hypocalcemia than dogs with small but visible Experience indicates an association between posttreatment hypo-
parathyroid glands. calcemia and chronicity of PHPTH in dogs. Often, duration of
Some veterinarians have suggested that it is imperative to hypercalcemia secondary to PHPTH is unknown. Occasionally,
document a decline in the serum calcium concentration after however, PHPTH has been documented for extended time peri-
surgery to subnormal levels before considering supportive ods. Dogs with protracted histories of confirmed disease often
therapy. Although such a protocol allows further conrmation have not been treated because owners have not observed worri-
that PHPTH existed and was corrected, it places a dog at risk some signs and they are monitoring the condition. Another cause
18
Dog #2 Dog #14
17 Dog #7 Dog #15
Dog #11 Dog #18
16 Dog #19
Dog #12
15
14 17
13 16 Dog #10

15 Dog #13
12 Dog #16
14
11 13
10 12
11
9
10
8 9
7 8
7
6
6
5 5
Before 1 2 3 4 5 6 7 8 14 21 1 mo 2 mo 3 mo Before 1 2 3 4 5 6 7 8 14 21 1 mo 2 mo 3 mo
surgery surgery
A Days B Days
17
16
20
19 Dog #1 15

18 Dog #3 14
17 Dog #4
Dog #5 13
16
Dog #6 12
15
Dog #8
14 11
13
12 10
11 9
10
8
9
8 7
7 6
6
5 5
Before 1 2 3 4 5 6 7 8 14 21 1 mo 2 mo 3 mo Before 1 2 3 4 5 6 7 14 21
surgery surgery
C Days D Days after surgery
FIGURE 15-32 Serial calcium concentrations before and after removal of a parathyroid tumor from dogs with
primary hyperparathyroidism (PHPTH). A, These eight dogs were placed on vitamin D2 and calcium supplementa-
tion after hypocalcemia was identified. B, These three dogs had mild hypercalcemia prior to surgery, and they were
not treated with vitamin D or calcium after surgery. C, These six dogs began receiving vitamin D2 and calcium
immediately after recovery from anesthesia. D, Serum calcium concentrations from 34 dogs that began receiving
dihydrotachysterol immediately after recovery from anesthesia.
Pretreatment Serum Calcium Concentration (More Than 15 mg/dL;

BOX 15-5 C
linical Signs Associated with the Acute Onset
Ionized Calcium More Than 1.75 mmol/L)
of Hypocalcemia
We assume that dogs with a serum TCa or iCa persistently greater
Panting than 15 mg/dL or 1.75 mmol/L, respectively, due to PHPTH have
Nervousness been hypercalcemic chronically or their level of negative feedback
Anxiety and resultant atrophy of normal glands greater. The recommendation
Muscle trembling, twitching is to prophylactically attempt to avoid hypocalcemia after PHPTH
Leg cramping, pain (may be seen as weakness) therapy by beginning vitamin D (calcitriol, 20 to 30 ng/kg/day,
Ataxia divided b.i.d. [twice a day]) that morning (see Chapter 16). In some
Atypical aggressive behavior cases we have begun calcitriol therapy 24 to 36 hours before sur-
Stiff gait gery, but this may not be necessary. Initiation of calcitriol has not
Facial rubbing prevented decreases in the serum calcium concentration to or below
Biting at feet reference ranges after surgery, but it has prevented or decreased the
Vocalizing severity of clinical and biochemical hypocalcemia. Each dog should
Hypersensitivity be kept quiet in a cage or run for at least 3 to 5 days after treatment.
Seizures: focal or generalized
Timing of Posttreatment Hypocalcemia and
Recommendations Regarding Vitamin D
for longer histories is the client/veterinarian team who choose a
more deliberate approach. We now recommend prophylactic Postsurgical hypocalcemia has been observed as early as 12 hours to as
treatment with vitamin D in an attempt to prevent hypocalcemia late as 20 days after curative therapy. Most dogs that become hypocal-
or, at least, to reduce its severity clinically and biochemically. cemic, usually do so between the second and sixth days posttreatment.
|
Tetany, when it has occurred, has usually been seen 4 to 7 days after Current Recommended Protocol
treatment. The serum calcium concentration should be monitored We have embarked on a new, more aggressive protocol to avoid
once or twice daily. The goal of vitamin D therapy is to maintain posttreatment hypocalcemia in dogs being treated for PHPTH.
serum calcium concentrations in the low to low-normal range (i.e., Results have been encouraging to date, and time will tell if this
TCa, 8 to 9.5 mg/dL; iCa, 0.9 to 1.2 mmol/L). Such serum calcium protocol is satisfactory. All dogs being treated for PHPTH should
concentrations are well above those associated with clinical signs, are be given calcitriol the morning of the planned treatment at a dose
not likely to be a cause of iatrogenic vitamin D toxicosis, and are of 20 to 30 ng/kg. That posttreatment night, the dog should be
low enough to stimulate functional recovery in atrophied parathyroid given 10 to 15 ng/kg, and that dose should be continued (20 to
glands. Mid- to high-normal or greater serum calcium concentrations 30 ng/kg/day divided b.i.d.) for the first 2 days following treat-
in dogs being given vitamin D should be avoided. Such concentra- ment. The third day after therapy, and every 4 days thereafter, the
tions may be associated with worrisome increases in serum phosphate dose of calcitriol should then be reduced by 10%, continuing for
concentration, and they predispose the dog to AKI. about 45 to 60 days. Twice daily monitoring of serum TCa and
iCa concentrations are strongly recommended while in the hos-
The Tapering Process pital. Both parameters should be checked prior to every planned
dose reduction. As described in the previous section, monitoring
In order to stimulate the remaining parathyroid glands to regain serum calcium concentrations are required in an attempt to avoid
control of calcium homeostasis, vitamin D supplements must be under or over dosage. If calcium concentrations are less than 8.5
gradually withdrawn. This process of returning parathyroid func- mg/dL (TCa) or 0.95 mmol/L (iCa) at any time, the dose of
tion in remaining glands is not completely predictable. Once vitamin D should be at least transiently increased to a previously
serum calcium concentrations have stabilized and the dog has used and safe dose. Monitoring of serum calcium concentrations
been returned to the owner, tapering vitamin D (calcitriol) begins. is also required in an attempt to avoid iatrogenic vitamin D toxi-
It is usually withdrawn by gradually extending the time between cosis. If calcium concentrations are within the upper portion of
administration (e.g., twice daily to once daily for 2 weeks; to once the reference range, the dose of calcitriol should be decreased by
every other day for 2 weeks; then once every third day for 2 weeks; 50%. If the serum calcium concentrations are above reference
then once every fourth day for 2 weeks; and nally, once weekly ranges, the calcitriol should be stopped for 48 hours and the val-
for 2 to 4 weeks). The serum calcium concentration should be ues again rechecked. If hypercalcemia and hyperphosphatemia
checked prior to each adjustment in the dosing interval to prevent are documented, IV saline therapy for 24 hours or longer should
the development of occult hypo- or hypercalcemia. If the serum be considered.
calcium concentration drops below 8 mg/dL, reduction of the vita-
min D supplementation should be delayed or the dose increased.
Vitamin D Resistance/Time Until an Effect Is Documented
The serum calcium concentration should remain above 8 mg/dL
to minimize the risk of tetany. However, if the serum calcium It is not common for calcitriol to begin to have an immediate
concentrations are high-normal or increased, vitamin D should effect. Rather, vitamin D gradually takes effect during the rst
be discontinued (permanently or transiently, as determined by the several days of therapy and almost always within 4 to 7 days. Indi-
patient). Once the vitamin D supplementation has been reduced vidual variation is typical.
to once weekly for 2 to 4 weeks, it may be discontinued. Also,
if serum calcium concentrations remain in reference ranges after
PATHOLOGY
the dose has been reduced to once weekly, any calcium supple-
ments should then be withdrawn. Specific calcium supplementa-
Subjectivity of Histologic Interpretation
tion should not be needed if the dog is being fed quality food. If
calcium content of the diet is questionable, supplemental calcium Abnormal, autonomously functioning parathyroid glands from
can be given (see Chapter 16). Using this protocol, the withdrawal people, dogs, and cats have been characterized histologically as
process for vitamin D and calcium usually takes 3 to 4 months. adenoma, carcinoma, and hyperplasia. Controlled studies review-
It is important to remember that there is considerable individual ing histologic interpretations by pathologists have shown that
variation in response to therapy, and it is difficult, therefore, to classifying a parathyroid nodule as adenoma, hyperplasia, or carci-
check the serum calcium concentration too frequently. noma is not straightforward (Aurbach etal, 1985a; DeVries etal,
1993; Ham etal, 2009). Histologic classication of parathyroid
Prophylactic Vitamin D (Calcitriol) Therapy in All Dogs tissue may be influenced to some degree by gross features observed
Treated for Primary Hyperparathyroidism during surgery. The surgeon determines the number, size, and
appearance of normal and abnormal glands. The pathologist then
Background determines whether removed tissue is parathyroid and further
Prediction of posttreatment hypocalcemia in dogs with PHPTH has classifies the tissue, when possible, as benign or malignant.
proven difficult and may depend on multiple factors, including but As previously discussed, single-gland involvement (ade-
not limited to signalment, history, physical examination findings, noma, carcinoma, or hyperplasia) occurs in about 80% to 90%
clinicopathologic results, and imaging results (Arbaugh etal, 2012; of people and dogs with PHPTH. Multiple-gland involve-
Milovancev and Schmiedt, 2013). Prophylactic vitamin D treatment has been documented in 10% to 20% (Arnaud and Kolb,
ment strategies have been employed based on pretreatment factors 1991; Gear etal, 2005; Ham etal, 2009; Sawyer etal, 2011;
used to identify dogs most likely to suffer serious hypocalcemia after Arbaugh et al, 2012; Milovancev and Schmiedt, 2013). The
being treated for PHPTH. Many dogs with PHPTH develop post- diagnosis of carcinoma is based on gross appearance, histologic
treatment subclinical hypocalcemia (Arbaugh etal, 2012). Further, features, and ultimately the biologic behavior of the lesion.
some dogs with PHPTH develop posttreatment clinical tetany, and Fewer than 2% of autonomously secreting parathyroid nodules
a few have had serious life-threatening hypocalcemia persist (Sawyer in people are malignant. Five percent to 10% of parathyroid
et al, 2011; Arbaugh et al, 2012; Milovancev and Schmiedt, 2013). tissue removed from dogs with PHPTH has been assigned the
diagnosis of carcinoma, but we are aware of only one dog being because microscopic alterations may be present in a normal-sized
described as having multicentric disease not amenable to sur- gland (Aurbach et al, 1985a). An accurate histologic diagnosis
gical extirpation (Ham etal, 2009). requires clear criteria for distinguishing adenoma from hyperplasia
and for distinguishing either of these from normal. A tentative dif-
ferentiation often is based on the number of glands involved (i.e.,
Solitary Parathyroid Mass
one gland supports a diagnosis of adenoma and multiple glands a
Background diagnosis of hyperplasia) (Verdonk and Edis, 1981).
In people, dogs, and cats, the most common cause of PHPTH is We reported a group of six dogs with PHPTH (8% of the 72
a solitary functioning chief cell adenoma, resulting in the secre- in our series at the time) that had hyperplasia as determined by
tion of excessive amounts of PTH. A denomas are usually solitary board certified pathologists (DeVries etal, 1993). That percent-
(developing in an existing parathyroid gland), light brown-red in age approximates the experience in the literature since. The terms
color, and located in close proximity to that thyroid lobe (see Figs. nodular hyperplasia and adenomatous hyperplasia may be applied
15-21 and 15-26). Because of the difculty involved in histologi- to parathyroids that contain multiple nodules less than 5 mm
cally classifying an enlarged parathyroid gland as an adenoma, in diameter as opposed to adenomas, which are often dened as
carcinoma, or adenomatous hyperplasia, a nodule is tentatively parathyroid tumors consisting of a solitary nodule greater than
diagnosed during surgery when a solitary abnormal parathyroid 5 mm in diameter.
gland is identied and the remaining glands are normal, atro- Differentiation of hyperplasia and adenoma has important
phied, or not seen. The term adenoma may also be arbitrary as implications regarding surgery, medical therapy, and long-term
applied to such tissue. prognosis. A dog or cat with PHPTH may be cured after com-
plete surgical removal of a solitary adenoma with three normal
Adenoma parathyroid glands (albeit atrophied in the immediate postsurgi-
Adenoma is diagnosed when a single nodule is easily seen, well cal period) remaining to prevent permanent hypoparathyroidism.
demarcated, and histologically compresses a rim of atrophied but In contrast, parathyroid hyperplasia implies that if all abnormal
otherwise normal parathyroid tissue (Capen and Martin, 1983; parathyroid tissue is not removed, the chance for persistent or
DeVries etal, 1993). Adenomas are generally composed of a dif- recurrent hyperparathyroidism is high. However, this has not
fuse pattern of parathyroid chief cells. About 75% to 85% of dogs consistently been observed in dogs with PHPTH. Most PHPTH
with PHPTH have a solitary parathyroid adenoma identified and dogs diagnosed as having a solitary hyperplastic parathyroid nod-
removed during surgical exploration of the neck. Multiple adeno- ule removed at surgery have complete resolution of the condition.
mas have been reported in people (Aurbach etal, 1985a) and are Their PHPTH seems no different than for dogs diagnosed as hav-
found in 3% to 5% of dogs with PHPTH (Pollard etal, 2001). ing a parathyroid adenoma or carcinoma (DeVries etal, 1993).
About 5% to 10% of dogs with PHPTH experience complete
resolution of their condition after removal or ablation of a soli- Summary
tary parathyroid nodule but have a recurrence of the condition In our series of dogs with PHPTH that have had surgery and that
6 months or more afterward. Each of those dogs then had this had a solitary mass, about 87% had a solitary parathyroid ade-
second nodule ablated or removed. In most cases the second mass noma, about 8% had a diagnosis of solitary primary parathyroid
was also an adenoma, but carcinoma and hyperplasia have been hyperplasia, and 5% had a diagnosis of carcinoma. In general,
diagnosed. In none of these dogs were two masses present ini- long-term response to therapy was similar regardless of histologic
tially, demonstrated in part by resolution of hypercalcemia for an classification. Recurrences occur regardless of the initial histo-
extended period. Thorough exploration of the neck, initially, also logic diagnosis. When recurrences occur (approximately 10% of
failed to demonstrate two masses. our dogs), the histologic diagnosis of tissue removed at second
surgery is just as likely to be different from the initial diagnosis
Carcinoma as it is to be similar. Distant metastasis from a parathyroid carci-
Chief cell carcinomas are identied in fewer than 3% to 4% of noma and/or local invasion has been described, but is extremely
people with PHPTH (Shane and Bilezikian, 1982). In as many as uncommon (Ham et al, 2009). It is also worth repeating that
50% of these people, the malignant lesion may be palpable in the about 10% of dogs with PHPTH have two parathyroid nodules
neck, and at surgery the mass is often rm and densely adherent to at the time of initial diagnosis. Again, the histologic classication
local structures (Aurbach etal, 1985a). Capsular and vascular inva- of these masses is as likely to be different (e.g., one adenoma and
sion are characteristic histologic ndings. Parathyroid carcinomas one carcinoma or one hyperplasia and one adenoma) as they are
in people tend to be locally invasive with the potential to spread to be the same. The recurrence rate in dogs with two masses at
to regional lymph nodes, lung, liver, and bone. Parathyroid gland the time of diagnosis is less than the recurrence rate of dogs with
carcinomas in dogs behave as an adenoma (Berger and Feldman, a single solitary mass.
1987; DeVries etal, 1993: Sawyer etal, 2011). In one study, each
of 19 dogs with PHPTH caused by a parathyroid carcinoma had a Mediastinal Parathyroid Tissue
solitary nodule identified at surgery. Each nodule was described as
having a benign gross appearance. Hypercalcemia resolved in 18 Parathyroid tissue, displaced into the anterior mediastinum dur-
of 19 after surgery, and no dog was confirmed to develop recurrent ing the embryologic expansion of the thymus and often referred
or metastatic PHPTH (Sawyer etal, 2011). to as ectopic because its location is not associated with the thy-
roid, may become autonomously functioning. In humans, this
Primary Hyperplasia is an uncommon but recognized location for a solitary adenoma
Hyperplasia implies an abnormality involving all parathyroid tis- (Heath, 1989). Mediastinal parathyroid tissue that results in
sue and is frequently diagnosed when more than one parathyroid PHPTH has been reported in a dog, and a mediastinal parathy-
gland is grossly and microscopically abnormal. Gross enlargement roid cyst was diagnosed in a normocalcemic cat (Swainson etal,
of all four glands is not a prerequisite for a diagnosis of hyperplasia 2000; Ham etal, 2009).
|
signs (70%). Vomiting, diarrhea, and/or constipation were observed

Multiple Endocrine Neoplasia and Adrenal Secondary
in 27%, polyuria and/or polydipsia were observed in 24%, urinary
Hyperparathyroidism
signs were seen in 23%, and neurologic signs were observed in 14%
Multiple Endocrine Neoplasia (Savary et al, 2000). Hypercalcemia secondary to malignancy was
Multiple endocrine neoplasia (MEN) refers to a group of syndromes diagnosed in 30% of these cats. The most common cancers diagnosed
in humans (often familial) consisting of hyperplasia or neoplasia in included lymphoma and squamous cell carcinoma. Less common
two or more endocrine glands. Two patterns of MEN involve the neoplasms included leukemia, osteosarcoma, brosarcoma, undif-
parathyroid gland: (1) MEN type I, parathyroid hyperplasia with ferentiated sarcoma, and bronchogenic carcinoma (Anderson etal,
pancreatic islet cell adenoma/carcinoma or adenoma/hyperplasia 2000; Bollinger etal, 2002; Geddes, 2013). CKD was diagnosed in
of the anterior pituitary; and (2) MEN type IIa, medullary carci- 25% of the cats, and half of those had urolithiasis. In a separate study,
noma of the thyroid with pheochromocytoma and/or parathyroid CKD in cats was usually associated with a serum TCa concentration
hyperplasia (see Chapter 5). In both conditions, hyperplasia, not in the reference range and a low-normal to low serum iCa concentra-
neoplasia, is the most common parathyroid abnormality. Although tion (Barber and Elliott, 1998). Of cats with hypercalcemia, several
the clinical expression of the MEN components is variable, hyper- had urolithiasis without renal injury. Four cats (6%) had PHPTH.
parathyroidism usually predominates in MEN type I, whereas med- One cat had hypoadrenocorticism. Several cats had hyperthyroidism
ullary thyroid carcinoma predominates in MEN type IIa (Leshin, or diabetes mellitus, but it would not seem likely that either of these
1985). Sporadic cases of dogs and cats with multiple endocrine endocrine conditions would contribute to hypercalcemia. However,
disorders are occasionally reported. Our experience of multiple four cats (6%) had infectious or granulomatous disease (e.g., feline
endocrine conditions involving PHPTH would include the com- infectious peritonitis [FIP], toxoplasmosis, actinomycosis, or cryp-
mon combination with Cushings syndrome. It remains elucidated tococcosis). Thus the differential diagnosis for hypercalcemia in cats
if dogs with these concurrent conditions have pituitary dependent is not dramatically different from that in dogs (Mealey etal, 1999;
Cushings and parathyroid hyperplasia. Further, as we recognize Savary etal, 2000; Pineda etal, 2012).
more thyroid tumors incidentally on cervical ultrasonography, this
may add to the combinations seen (Pollard etal, in press). IDIOPATHIC HYPERCALCEMIA OF CATS
Adrenal Secondary Hyperparathyroidism Idiopathic hypercalcemia of cats (IHC) may be their most com-
Hypercortisolism is associated with dysregulation of calcium homeo- mon cause of hypercalcemia. In contrast to hypercalcemic dogs,
stasis as illustrated by dogs with calcinosis cutis and/or bronchial tree in which a diagnosis can usually be made, this condition remains
calcification. A majority of dogs with hypercortisolism were demon- frustrating to understand and treat. IHC has been recognized in
strated to have increases in circulating PTH concentrations, although North America and in other areas (Schenck and Chew, 2012).
not associated with changes in TCa or iCa (Ramsey etal, 2005). With There is no age or gender predisposition. Long-haired cats may
successful treatment of hypercortisolism, serum PTH concentrations be over represented (Barsanti, 1997; Refsal etal, 1998; Midkiff
returned to reference range concentrations (Tebb etal, 2005). etal, 2000; Rosol etal, 2000; Schenck and Chew, 2005a). About
50% of cats with IHC have no apparent clinical signs. When
present, signs include any combination of weight loss, weakness,
Hereditary Neonatal Primary Hyperparathyroidism
diarrhea, constipation, vomiting, and decreases in appetite. Cal-
A rare form of hereditary neonatal PHPTH has been described cium containing uroliths have been documented in about 10%
in humans, which is associated with diffuse hyperplasia of the to 15% of cats with IHC. Increases in their serum iCa concentra-
parathyroid chief cells. Primary parathyroid hyperplasia has also tions are similar to or higher than expected from the increases
been reported in two German Shepherd pups from a litter of four noted in TCa. Serum PTH concentrations have been within or
females (Thompson etal, 1984). Clinical signs were apparent in below reference intervals, and PTHrP is not increased. Serum
these dogs by 2 weeks of age, including stunted growth, muscular magnesium and 25(OH)D concentrations have usually been
weakness, and polyuria/polydipsia. An autosomal recessive mode within reference intervals, and concentrations of 1,25(OH)2D3
of inheritance for the PHPTH was suggested, and an analogous are decreased (Schenck and Chew, 2012). Some cats with IHC
condition is recognized in children. have developed CKD.
The pathogenesis of IHC is not understood, making thera-
pies nonspecific. Increasing dietary fiber has been advocated to
PROGNOSIS: DOGS WITH PRIMARY
decrease intestinal absorption of calcium. Increasing dietary fiber
HYPERPARATHYROIDISM
has not been uniformly helpful, probably related to the many
The prognosis for most dogs with PHPTH is excellent. Hypocal- forms of fiber used. Use of diets formulated for cats with CKD
cemia may occur after therapy, but clinical hypocalcemia should have also been helpful in some but not all IHC cats. These diets
not be common with use of posttreatment calcitriol. Care must be are usually low in calcium and phosphorus and may have an alka-
taken not to overdose vitamin D. linizing effect. A positive dietary response with normalization of
serum calcium concentrations, however, does not usually persist.
Prednisolone has been beneficial in some cats with IHC. Doses
HYPERCALCEMIA IN CATS
of 5 to 20 mg/cat/day often reduce serum calcium concentrations
and in some cats contribute to long-term control. Prednisolone has
also improved appetite and body weight in some cats. When diet and
BACKGROUND
prednisolone fail to resolve IHC, the use of a bisphosphonate has been
In general, the same differential diagnoses for hypercalcemia in dogs recommended. IV administration is not recommended because of the
can be used in cats. In a study of 71 hypercalcemic cats, their mean chronic nature of IHC. Rather, oral alendronate is recommended, 10
age was about 9 years and their mean serum TCa concentration was mg weekly after a 12 hour fast, with special note made of the medica-
12.2 mg/dL. Anorexia and lethargy were their most common clinical tion causing esophagitis if not completely passed into the stomach. To
TABLE 15-10 C
LINICAL, LABORATORY, AND HISTOLOGIC FINDINGS IN 10 CATS WITH PRIMARY, NATURALLY
OCCURRING, HYPERPARATHYROIDISM IN THE UC DAVIS SERIES
BLOOD UREA
SERUM Ca SERUM PO4 NITROGEN SERUM CREATININE URINE SPECIFIC PARATHYROID
SIGNALMENT CLINICAL SIGNS (mg/dL) (mg/dL) (mg/dL) (mg/dL) GRAVITY HISTOLOGY
15 y.o. M/N, DLH Anorexia, vomiting 14.6 3.4 35 1.8 1.011 Solitary adenoma
14 y.o. F/S, Siamese Anorexia, vomiting, 22.8 6.6 70 3.2 1.013 Solitary adenoma
muscle fasciculation
15 y.o. M/N, Siamese None 13.5 3.3 21 2.2 1.031 Solitary adenoma
15 y.o. F/S, Siamese Polydipsia, polyuria 13.3 2.2 31 2.7 1.010 Solitary adenoma
8 y.o. F/S, DSH Anorexia, weight loss 13.8 1.8 15 1.0 1.015 Solitary adenoma
14 y.o. F/S, DSH Polydipsia, polyuria, 15.4 2.5 30 1.2 1.010 Solitary adenoma
lethargy
9 y.o. F/S, Siamese Anorexia 17.1 6.2 63 2.6 1.026 Bilateral
cystadenoma
9 y.o. M/N, DSH Anorexia, vomiting, 15.2 2.6 59 3.6 1.015 Solitary carcinoma
lethargy, dysuria
14 y.o. M/N, DSH Constipation 13.4 3.7 41 2.2 1.022 Solitary adenoma
12 y.o. M/N, DSH Weight loss, lethargy, 14.1 3.2 27 1.4 1.018 Bilateral
constipation carcinomas
Reference values 8.8-11.4 2.4-6.1 10-30 0.8-2.0
DLH, Domestic Long-Haired; DSH, Domestic Short-Haired; F, female; M, male; N, neutered; S, spay/ovariohysterectomy; serum Ca, serum total calcium; serum PO4, serum phosphate
concentration; y.o., years old.
avoid esophageal irritation and to enhance passage into the stomach, contrast to dogs. Cervical ultrasonography was described as nor-
water should be given (Schenck and Chew, 2012). mal in several cats, but others had visible masses that would be con-
sidered huge in a dog. On cervical ultrasonography, two cats each
PRIMARY HYPERPARATHYROIDISM IN CATS had a single parathyroid mass, one mass measuring 4.5 2 1 cm
and the other measuring 1.7 1.1 1 cm (Sueda and Stefanacci,
A relatively small number of cats with PHPTH have been reported 2000). Serum PTH concentrations, when measured, ranged from
(Kallet etal, 1991; Marquez etal, 1995; den Hertog etal, 1997; within the reference range (0 to 4 pmol/L) to increased. In one
Savary etal, 2000; Sueda and Stefanacci, 2000). Their mean age was cat, seven separate serum PTH samples were assayed; five results
approximately 13 years (range, 8 to 20 years) and various breeds were in the reference range and two were increased.
were represented. The most common clinical signs were anorexia, Most of the 19 cats had surgical nodule removal followed by reso-
lethargy, and vomiting. Owners also observed constipation, poly- lution of their PHPTH. Tetany has not been described in any
uria, polydipsia, and weight loss. Other signs were uncommon. A cat treated with surgery, although several cats became subclinically
parathyroid mass was palpable in 11 of the 19 cats. The presence hypocalcemic and were treated with vitamin D and calcium. Of
of a palpable mass and the owners observations contrast with our the nine cats we followed after surgery, all lived well beyond 1 year,
experience in dogs with PHPTH. A palpable parathyroid mass in although at 1 years, one had recurrence of hypercalcemia and at
dogs with PHPTH is quite uncommon (Sawyer etal, 2011). necropsy was demonstrated to have had both a parathyroid ade-
The only consistent abnormality on CBC and serum biochemi- noma and a parathyroid carcinoma. Histologic evaluation of tis-
cal proles is hypercalcemia (Table 15-10). Afflicted cats have per- sue removed showed that 13 cats had had a parathyroid adenoma,
sistent increases in both the serum TCa and iCa concentrations. three had had parathyroid carcinomas, two had had parathyroid
Several cats had cystic calculi and a large percentage had abnor- hyperplasia (involving all four glands), and one had had bilateral
malities in their BUN and serum creatinine concentrations, in cystadenomas.
REFERENCES
Anderson TE, etal.: Probable hypercalcemia Arnaud CD, Kolb FO: The calciotropic hor- Aurbach GD, etal.: Parathyroid hormone, cal-
of malignancy in a cat with bronchogenic mones and metabolic bone disease. In citonin, and the calciferols. In Wilson JD,
adenocarcinoma, J Am Anim Hosp Assoc Greenspan FS, editor: Basic and clinical Foster DW, editors: Williams textbook of
36:52, 2000. endocrinology, Los Altos, CA, 1991, Lange endocrinology, ed 7, Philadelphia, 1985a,
Arbaugh M, etal.: Evaluation of preoperative Medical Publications, p 247. WB Saunders, p 1137.
serum concentrations of ionized calcium Attie JN, etal.: Preoperative localization Bahri LE: Poisoning in dogs by vitamin D3
and parathyroid hormone as predictors of of parathyroid adenomas, Am J Surg containing rodenticides, Compend Continu
hypocalcemia following parathyroidectomy 156:323, 1988. Ed Pract Vet 12:1414, 1990.
in dogs with primary hyperparathyroidism: Attie MF: Treatment of hypercalcemia,
17 cases (2001-2009), J Am Vet Med Endocrinol Metab Clin North Am 18:807,
Assoc 241:233, 2012. 1989.
|
Barber PJ, Elliott J: Feline chronic renal Capen CC, Martin SL: Calcium-regulating Feldman EC, etal.: Comparison of results of
failure: calcium homeostasis in 80 cases hormones and diseases of the parathyroid hormonal analysis of samples obtained
diagnosed between 1992 and 1995, J glands. In Ettinger SJ, editor: Textbook of from selected venous sites versus cervical
Small Anim Pract 39:108, 1998. veterinary internal medicine, ed 2, ultrasonography for localizing parathyroid
Barber PJ, etal.: Measurement of feline intact Philadelphia, 1983, WB Saunders, p 1550. masses in dogs, J Am Vet Med Assoc
parathyroid hormone: assay validation and Carothers MA, etal.: 25-OH-cholecalciferol in- 211:54, 1997.
sample handling studies, J Small Anim toxication in dogs, Proc Am Coll Vet Intern Feldman EC, etal.: Pretreatment clinical and
Pract 34:614, 1993. Med Forum 12:822, 1994. laboratory findings in dogs with primary
Barsanti JA: Hypercalcemia and urolithiasis Chew DJ, Capen CC: Hypercalcemic nephropa- hyperparathyroidism: 210 cases (1987-
in cats, Proc Am Coll Vet Intern Med Ann thy and associated disorders. In Kirk RW, 2004), J Am Vet Med Assoc 227:756,
Forum 15:327, 1997. editor: Current veterinary therapy VII, Phila- 2005.
Bennedbaek FN, etal.: Percutaneous ethanol delphia, 1980, WB Saunders, p 1067. Fine EJ: Parathyroid imaging: its current status
injection therapy in the treatment of Chew DJ, Meuten DJ: Disorders of calcium and and future role, Semin Nucl Med 17:350,
thyroid and parathyroid diseases, Eur J phosphorus metabolism, Vet Clin North Am 1987.
Endocrinol 136:240, 1997. 12:411, 1982. Fingeroth JM, Smeak DD: Intravenous methylene
Bennett PF, etal.: Canine anal sac adeno- Chew DJ, etal.: Effect of sodium bicarbonate blue infusion for intraoperative identication
carcinomas: clinical presentation and infusions on ionized calcium and total of parathyroid gland tumors in dogs: III.
response to therapy, J Vet Intern Med calcium concentrations in serum of clini- clinical trials and results in three dogs, J Am
16:100, 2002. cally normal cats, Am J Vet Res 50:145, Anim Hosp Assoc 24:673, 1988.
Berger B, Feldman EC: Primary hyperpara- 1989. Flanders JA, Reimers TJ: Radioimmunoassay of
thyroidism in dogs, J Vet Med Assoc Chew DJ, etal.: Hypercalcemia in dogs and parathyroid hormone in cats, Am J Vet Res
191:350, 1987. cats: overview of etiology, diagnostic ap- 52:422, 1991.
Bilezikian JP: Hypercalcemic states. In Coe proach, and therapy, Proceedings of the Foley P, etal.: Serum parathyroid hormone
FL, etal.: editors: Disorders of bone and Waltham/OSU Symposium 1991, p 35. related protein concentration in a dog with
mineral metabolism, New York, 1992a, Consensus Development Conference Panel: a thymoma and persistent hypercalcemia,
Raven Press, p 493. NIH conference; diagnosis and manage- Can Vet J 41:867, 2000.
Bilezikian JP: Management of acute hyper- ment of asymptomatic primary hyper- Fooshee SK, Forrester SD: Hypercalcemia
calcemia, N Engl J Med 326:1196, parathyroidism: consensus development secondary to cholecalciferol rodenticide
1992b. conference statement, Ann Intern Med toxicosis in two dogs, J Am Vet Med Assoc
Bilezikian JP, etal.: The parathyroids: basic 114:593, 1991. 196:1265, 1990.
and clinical concepts, ed 2, San Diego, Cortadellas O, etal.: Calcium and phosphorus Fradkin JM, etal.: Elevated parathyroid hor-
CA, 2001, Academic Press. homeostasis in dogs with spontaneous monerelated protein and hypercalcemia in
Black KS, Mundy GR: Other causes of hy- chronic kidney disease at different stages two dogs with schistosomiasis, J Am Anim
percalcemia: local and ectopic secretion of severity, J Vet Intern Med 24:73, 2010. Hosp Assoc 37:349, 2001.
syndromes. In Bilezikian JP, etal.: editors: Crager CS, Nachreiner RF: Increased parathy- Gao P, etal.: Development of a novel immuno-
The parathyroids, New York, 1994, Raven roid hormone concentration in a Siamese radiometric assay exclusively for biological-
Press, p 341. kitten with nutritional secondary hyper- ly active whole parathyroid hormone 1-84:
Bollinger AP, etal.: Detection of parathyroid parathyroidism, J Am Anim Hosp Assoc implications for improvement of accurate
hormone-related protein in cats with 29:331, 1993. assessment of parathyroid function, J Bone
humoral hypercalcemia of malignancy, Vet den Hertog E, etal.: Primary hyperparathyroid- and Mineral Research 16:605, 2001.
Clin Pathol 31:3, 2002. ism in two cats, Vet Q 19:81, 1997. Garrett IR: Bone destruction in cancer, Semin
Boyce RA, Weisbrode SE: Effect of dietary DeVries SE, etal.: Primary parathyroid gland Oncol 20:4, 1993.
calcium on the response of bone to hyperplasia in dogs: six cases Gear RN, etal.: Primary hyperparathyroidism
1,25(OH)2D3, Lab Invest 48:683, (1982-1991), J Am Vet Med Assoc in 29 dogs: diagnosis, treatment, outcome
1983. 202:1132, 1993. and associated renal failure, J Small Ani-
Broadus AE, Stewart AF: Parathyroid hormone Dougherty SA, etal.: Salmon calcitonin as ad- mal Prac 46:10, 2005.
related protein: structure, processing, junct treatment for vitamin D toxicosis in a Geddes, etal.: Eight novel polymorphisms
and physiologic actions. In Bilezikian JP, dog, J Am Vet Med Assoc 196:1269, 1990. identified in the feline calcium sensing
editor: The parathyroids: basic and clinical Dow SW, etal.: Hypercalcemia associated with receptor in cats with varying plasma ion-
concepts, New York, 1994, Raven Press, blastomycosis in dogs, J Am Vet Med As- ized calcium concentrations, J Am Vet Med
pp 259294. soc 188:706, 1986. Assoc 687, 2013.
Brown EM, etal.: Calcium ionsensing cell Durie BG, etal.: Relation of osteoclast activat- Goldschmidt MH, Shofer FS: Skin tumors of
surface receptors, N Engl J Med 333:234, ing factor production to the extent of bone the dog and cat, Oxford, England, 1992,
1995. disease in multiple myeloma, Br J Haema- Pergamon Press, pp 103108.
Brown EM, etal.: G-proteincoupled, extracel- tol 47:21, 1981. Goldstein RE, etal.: Inheritance, mode of in-
lular Ca2+sensing receptor: a versatile Estepa JC, etal.: Dynamics of secretion and heritance and candidate genes for primary
regulator of diverse cellular functions, metabolism of PTH during hypo- and hyperparathyroidism in Keeshonden, J Vet
Vitam Horm 55:1, 1999. hypercalcemia in the dog as determined by Intern Med 21:199, 2007.
Brown RC, etal.: Circulating intact parathyroid the intact and whole PTH assays, Goodwin JS, etal.: Mechanism of action of
hormone measured by a two-site immuno- Nephrology Dialysis Transplantation glucocorticoids: inhibition of T cell pro-
chemiluminometric assay, J Clin Endocri- 18:1101, 2003. liferation and interleukin-2 production by
nol Metab 65:407, 1987. Eubig PA, etal.: Acute renal failure in dogs after hydrocortisone is reversed by leukotriene
Budayr AA, etal.: Increased serum levels the ingestion of grapes or raisins: a retro- B4, J Clin Invest 77:1244, 1986.
of parathyroid hormonelike protein in spective evaluation of 43 dogs (1992-2002), Grain E, Walder EJ: Hypercalcemia associated
malignancy-associated hypercalcemia, Ann J Vet Intern Med 19:663, 2005. with squamous cell carcinoma in a dog,
Intern Med 111:807, 1989. Feldman EC: Canine primary hyperparathyroid- J Am Vet Med Assoc 181:165, 1982.
Burtis WJ: Parathyroid hormone-related ism. In Kirk RW, Bonagura JD, editors: Greenlee PG, etal.: Lymphomas in dogs: a
protein: structure, function, and measure- Current veterinary therapy X, Philadelphia, morphologic, immunologic and clinical
ment, Clin Chem 38:2171, 1992. 1989, WB Saunders, p 985. study, Cancer 66:480, 1990.
Grone A, etal.: Dependence of humoral hy- Klausner JS, etal.: Calcium urolithiasis in two Messinger JS, etal.: Ionized hypercalcemia in
percalcemia of malignancy on parathyroid dogs with parathyroid adenomas, J Am Vet dogs: a retrospective study of 109 cases
hormonerelated protein expression in the Med Assoc 191:1423, 1987. (1998-2003), J Vet Intern med 23:514,
canine anal sac apocrine gland adenocar- Krubsack AJ, etal.: Prospective comparison 2009.
cinoma (CAC-8) nude mouse model, Vet of radionuclide, computed tomography, Meuten DJ: Hypercalcemia, Vet Clin North Am
Pathol 35:344, 1998. and sonographic and magnetic resonance (Small Anim Pract) 14:891, 1984.
Gross KL, etal.: Nutrients. In Hand MS, etal.: localization of parathyroid tumors, Surgery Meuten DJ, Armstrong PJ: Parathyroid disease
editors: Small animal clinical nutrition, ed 4, 106:639, 1989. and calcium metabolism. In Ettinger SJ,
Kansas, 2000, Mark Morris Institute, p 84. Legendre AM, etal.: Canine blastomycosis: a editor: Textbook of veterinary internal medi-
Gunther R, etal.: Toxicity of a vitamin D3 review of 47 clinical cases, J Am Vet Med cine: diseases of the dog and cat, ed 3,
rodenticide to dogs, J Am Vet Med Assoc Assoc 178:1163, 1981. Philadelphia, 1989, WB Saunders, p 1610.
193:211, 1988. Lemann J, Gray RW: Calcitriol, calcium, and Meuten DJ, etal.: Relationship of calcium to
Gwaltney-Brant S, etal.: Renal failure associ- granulomatous disease, N Engl J Med albumin and total proteins in dogs, J Am
ated with ingestion of grapes or raisins 311:1115, 1984. Vet Med Assoc 180:63, 1982.
in dogs, J Am Vet Med Assoc 218:1555, Leshin M: Multiple endocrine neoplasia. In Meuten DJ, etal.: Hypercalcemia in dogs with
2001. Wilson JC, Foster DW, editors: Williams lymphosarcoma: biochemical, ultrastruc-
Ham K, etal.: Validation of rapid parathyroid textbook of endocrinology, ed 7, Philadel- tural, and histomorphometric investigation,
hormone assay and intraoperative mea- phia, 1985, WB Saunders, p 1274. Lab Invest 49:553, 1983a.
surement of parathyroid hormone in dogs Livraghi T, etal.: Small hepatocellular car- Meuten DJ, etal.: Hypercalcemia in dogs with
with benign naturally occurring primary cinoma: treatment with radio frequency adenocarcinoma derived from apocrine
hyperparathyroidism, Vet Surg 38:122, ablation versus ethanol ablation, Radiology glands of the anal sacs: biochemical and
2009. 210:655, 1999. histomorphometric investigations, Lab
Harrington DD, Page EH: Acute vitamin D2 Llach F, etal.: The pathophysiology of altered Invest 48:428, 1983b.
(ergocalciferol) toxicosis in horses: case calcium metabolism in rhabdomyolysis- Michelangeli VP, etal.: Evaluation of a new,
report and experimental studies, J Am Vet induced acute renal failure, N Engl J Med rapid, and automated immunochemilu-
Med Assoc 182:1358, 1983. 305:117, 1981. minometric assay for the measurement of
Harris NL, etal.: Case records of the Massa- Lloyd MN, etal.: Preoperative localization in serum intact parathyroid hormone, Ann
chusetts General Hospital, N Engl J Med primary hyperparathyroidism, Clin Radiol Clin Biochem 34:97, 1997.
347:1952, 2002. 41:239, 1990. Midkiff AM, etal.: Idiopathic hypercalcemia in
Heath DA: Primary hyperparathyroidism: clini- Long CD, etal.: Percutaneous ultrasound cats, J Vet Intern Med 14:619, 2000.
cal presentation and factors influencing guided chemical parathyroid ablation for Milovancev M, Schmiedt CW: Preoperative
clinical management, Endocrinol Metab treatment of primary hyperparathyroidism factors associated with postoperative hypo-
Clin North Am 18:631, 1989. in dogs, J Am Vet Med Assoc 215:217, calcemia in dogs that underwent parathy-
Henderson JE, etal.: Circulating concentra- 1999. roidectomy: 62 cases (2004-2009), J Am
tions of parathyroid hormonelike peptide Marquez GA, etal.: Calcium oxalate urolithia- Vet Med Assoc 242:507, 2013.
in malignancy and in hyperparathyroidism, sis in a cat with a functional parathyroid Mischke R, etal.: The effect of the albumin
J Bone Miner Res 5:105, 1990. adenocarcinoma, J Am Vet Med Assoc concentration on the relation between the
Henry CJ: Paraneoplastic syndromes. In Et- 206:817, 1995. concentration of ionized calcium and total
tinger SJ, Feldman EC, editors: Textbook Marx SJ: Hyperparathyroid and hypoparathyroid calcium in the blood of dogs, Dtsch Tierar-
of veterinary internal medicine: diseases of disorders, N Engl J Med 343:1863, 2000. ztl Wochenschr 103:199, 1996.
the dog and cat, St Louis, 2010, Elsevier, Matus RE, Weir EC: Hypercalcemia of malig- Mol JA, etal.: Elucidation of the sequence
p 2213. nancy. In Kirk RW, Bonagura JD, editors: of canine (pro)-calcitonin: a molecular
Hirt RA, etal.: Severe hypercalcemia in a Current veterinary therapy X, Philadelphia, biological and protein chemical approach,
dog with a retained fetus and endome- 1989, WB Saunders, p 988. Regul Pept 35:189, 1991.
tritis, J Am Vet Med Assoc 216:1423, Matus RE, etal.: Prognostic factors for mul- Moore FM, etal.: Hypercalcemia associated
2000. tiple myeloma in the dog, J Am Vet Med with rodenticide poisoning in three cats,
Hollis BW, etal.: Quantication of circulating Assoc 188:1288, 1986. J Am Vet Med Assoc 193:1099, 1988.
1,25-dihydroxyvitamin D by radioimmu- Matwichuk C, etal.: Use of 99mTc-sestamibi for Morrow C: Cholecalciferol poisoning, Vet Med
noassay with an 125I-labeled tracer, Clin detection of a parathyroid adenoma in 2001, p 905.
Chem 42:586, 1996. a dog with primary hyperparathyroidism, Mundy GR: Hypercalcemia of malignancy revis-
Hostutler RA, etal.: Uses and effectiveness J Am Vet Med Assoc 209:1733, 1996. ited, J Clin Invest 82:1, 1988.
of pamidronate disodium for treatment of Matwichuk C, etal.: Double-phase para- Mundy GR, etal.: The hypercalcemia of can-
dogs and cats with hypercalcemia, J Vet thyroid scintigraphy in dogs using cer: clinical implications and pathogenic
Intern Med 19:29, 2005. 99mTc-sestamibi, Vet Radiol Ultrasound mechanisms,, N Engl J Med 310:1718,
Hruska KA, Teitelbaum SL: Renal osteodystro- 41:461, 2000. 1984.
phy, N Engl J Med 333:166, 1995. McArthur W, etal.: Bone solubilization by Murphy MJ: Rodenticides, Vet Clinics N Amer:
Ihle SL, etal.: Seizures as a manifestation of mononuclear cells, Lab Invest 42:452, Small Anim Pract 32:469, 2002.
primary hyperparathyroidism in a dog, 1980. Nicholson SS: Toxicology. In Ettinger SJ, Feld-
J Am Vet Med Assoc 192:71, 1988. McCauley LK, etal.: Invivo and invitro effects man EC, editors: Textbook of veterinary
Jiao LR, etal.: Clinical short-term results of interleukin-1a and cyclosporin A on internal medicine: diseases of the cat
of radio frequency ablation in primary bone and lymphoid tissues in mice, Toxicol and dog, ed 5, Philadelphia, 2000, WB
and secondary liver tumors, Am J Surg Pathol 19:1, 1991. Saunders, p 357.
177:303, 1999. Mealey KL, etal.: Hypercalcemia associated ODougherty MJ, etal.: Parathyroid imaging
Johnessee JS, etal.: Primary hypoadreno- with granulomatous disease in a cat, J Am with technetium-99m-sestamibi: preopera-
corticism in a cat, J Am Vet Med Assoc Vet Med Assoc 215:959, 1999. tive localization and tissue uptake studies,
183:881, 1982. Mellanby RJ, etal.: Hypercalcaemia in two J Nucl Med 33:313, 1992.
Kallet AJ, etal.: Primary hyperparathyroidism dogs caused by excessive dietary supple- Orloff JJ, Stewart AF: The carboxy-terminus of
in cats: seven cases (1984-1989), J Am mentation of vitamin D, J Small Animal parathyroid hormone: inert or invaluable,
Vet Med Assoc 199:1767, 1991. Prac 46:334, 2005. Endocrinology 136:4729, 1995.
|
Parker M: Personal communication, 2001. Reusch CE, etal.: Ultrasonography of the Scott-Moncrieff CR: Hypoadrenocorticism. In
Peterson ME: Hypercalcemia in dogs and cats: parathyroid glands as an aid in differen- Ettinger SJ, Feldman EC, editors: Textbook
differential diagnosis and treatment, Pro- tiation of acute and chronic renal failure of veterinary internal medicine: diseases
ceedings: 84th Annual Western Veterinary in dogs, J Am Vet Med Assoc 217:1849, of the dog and cat, ed 7, St Louis, 2010,
Conference, Las Vegas, NV, 2012. 2000. Elsevier, p 1847.
Peterson ME, Feinman JM: Hypercalcemia Rohrer CR, etal.: Hypercalcemia in a dog: a Seymour JF, Gagel RF: Calcitriol: the major
associated with hypoadrenocorticism challenging case, J Am Anim Hosp Assoc humoral mediator of hypercalcemia in
in sixteen dogs, J Am Vet Med Assoc 36:20, 2000. Hodgkins and non-Hodgkins lymphomas,
181:804, 1982. Rosol TJ, etal.: Acute hypocalcemia associated Blood 82:1383, 1993.
Peterson ME, etal.: Primary hypoadrenocorti- with infarction of parathyroid gland ad- Shane E, Bilezikian JP: Parathyroid carcinoma:
cism in ten cats, J Vet Intern Med 3:55, enomas in two dogs, J Am Vet Med Assoc a review of 62 patients, Endocrinol Rev
1989. 192:212, 1988. 3:218, 1982.
Peterson ME, etal.: Pretreatment clinical Rosol TJ, etal.: Parathyroid hormone Shiel RE: Disorders of vasopressin production.
and laboratory ndings in dogs with (PTH)related protein, PTH, and In Mooney CT, Peterson ME, editors: BSAVA
hypoadrenocorticism: 225 cases (1979- 1,25-dihydroxyvitamin D in dogs with manual of canine and feline endocrinology,
1993), J Am Vet Med Assoc 208:85, cancer-associated hypercalcemia, Endocri- ed 4, Gloucester, England, 2012, British
1996. nology 131:1157, 1992a. Small Animal Veterinary Association, p 15.
Philbrick WM, etal.: Dening the roles of Rosol TJ, etal.: Effects of mithramycin on Skelly BJ: Hyperparathyroidism. In Mooney
parathyroid hormonerelated protein in calcium metabolism and bone in dogs, Vet CT, Peterson ME, editors: BSAVA manual
normal physiology, Physiol Rev 76:127, Pathol 29:223, 1992b. of canine and feline endocrinology, ed 4,
1996. Rosol TJ, etal.: Disorders of calcium. In Gloucester, England, 2012, British Small
Picard D, etal.: Localization of abnormal para- DiBartola SP, editor: Fluid therapy in small Animal Veterinary Association, p 43.
thyroid glands using 201thallium/123iodine animal practice, ed 2, Philadelphia, 2000, Skelly BJ, Franklin RJM: Mutations in genes
subtraction scintigraphy in patients with WB Saunders, pp 108162. causing human familial isolated hyperpara-
primary hyperparathyroidism, Clin Nucl Ross JT, etal.: Adenocarcinoma of the apocrine thyroidism do not account for hyper-
Med 12:61, 1987. glands of the anal sac in dogs: a review of parathyroidism in Keeshond dogs, Vet J
Pineda C, etal.: Feline parathyroid hormone: 32 cases, J Am Anim Hosp Assoc 27:349, 174:652, 2006.
validation of hormonal assays and dynam- 1991. Silverberg SJ, etal.: A 10-year prospective
ics of secretion, Domest Anim Endocrinol Ross LA, Goldstein M: Biochemical abnormali- study of primary hyperparathyroidism with
42:256, 2012. ties associated with accidental hypother- or without parathyroid surgery, N Engl J
Pollard RE, etal.: Percutaneous ultrasono- mia in a dog and in a cat, Proceedings of Med 341:1249, 1999.
graphically guided radio frequency heat the Annual American College of Veterinary Stewart AF: Translational implications of the
ablation for treatment of primary hyper- Internal Medicine Meeting, St Louis, parathyroid calcium receptor, N Engl J
parathyroidism in dogs, J Am Vet Med 1981, p 66. Med 351:324, 2004.
Assoc 218:1106, 2001. Rumbeiha WK: Nephrotoxins. In Bonagura JD, Stewart AF: Hypercalcemia associated with
Pollard RE, etal.: Prevalence of subclinical editor: Kirks current veterinary therapy cancer, N Engl J Med 352:373, 2005.
thyroid nodules in dogs with hypercalcemia, XIII, Philadelphia, 2000, WB Saunders, Strewler GL: The physiology of parathyroid
J Vet Radiol Ultrasonography, (20082013) pp 212214. hormonerelated protein, N Engl J Med
in press Rumbeiha WK, etal.: Use of pamidronate to 342:177, 2000.
Potts JT Jr: Management of asymptomatic reverse vitamin D3induced toxicosis in Sueda MT, Stefanacci JD: Ultrasound
hyperparathyroidism, J Clin Endocrinol dogs, Am J Vet Res 60:1092, 1999. evaluation of the parathyroid glands in two
Metab 70:1489, 1990. Sandler LM, etal.: Studies of the hypercalce- hypercalcemic cats, Vet Radiol Ultrasound
Pressler BM, etal.: Hypercalcemia and high mia of sarcoidosis: effect of steroids and 41:448, 2000.
parathyroid hormonerelated protein exogenous vitamin D3 on the circulating Swainson SW, etal.: Radiographic diagnosis:
concentration associated with malignant concentration of 1,25-dihydroxy vitamin mediastinal parathyroid cyst in a cat, Vet
melanoma in a dog, J Am Vet Med Assoc D3, O J Med 53:165, 1984. Radiol Ultrasound 41:41, 2000.
221:263, 2002. Savary KC, etal.: Hypercalcemia in cats: Taillefer R, etal.: Detection and localization
Quigley PJ, Leedale AH: Tumors involving bone a retrospective study of 71 cases of parathyroid adenomas in patients with
in domestic cats: a review of fty-eight (1991-1997), J Vet Intern Med 14:184, hyperparathyroidism using a single radio-
cases, Vet Pathol 20:670, 1983. 2000. nuclide imaging procedure with techne-
Ramsey I, etal.: Hyperparathyroidism in dogs Sawyer ES, etal.: Outcome of 19 dogs with tium-99m-sestamibi (double-phase study),
with hyperadrenocorticism, J Small Animal parathyroid carcinoma after surgical exci- J Nucl Med 33:1801, 1992.
Prac 46:531, 2005. sion, Vet Comp Oncol 10:57, 2011. Tebb AJ, etal.: Canine HAC effects of trilo-
Rasmussen H: The cycling of calcium as an Schenck PA, Chew DJ: Idiopathic hypercal- stane on parathyroid hormone, calcium
intracellular messenger, Sci Am 261:66, cemia in cats, Waltham Focus 15:20, and phosphate concentrations, J Small
1989. 2005a. Animal Prac 46:537, 2005.
Rasor L, etal.: Retrospective evaluation of Schenck PA, Chew DJ: Prediction of serum Thompson KG, etal.: Primary hyperparathy-
three treatment methods for primary hyper- ionized calcium concentration by use of roidism in German Shepherd dogs: a disor-
parathyroidism in dogs, J Am Anim Hosp serum total calcium concentration in dogs, der of probable genetic origin, Vet Pathol
Assoc 43:70, 2007. Am J Vet Res 66:1330, 2005b. 21:370, 1984.
Refsal KR: Personal communication, 2014. Schenck PA, Chew DJ: Calcium: total or ion- Toribio RE, etal.: Cloning and sequence analy-
ized? Vet Clin North Amer: Small Anim
Refsal KR, Nachreiner RF: Hormone assays sis of the complementary DNA for feline
Pract 38:497, 2008.
and collection of samples. In Mooney CT, preproparathyroid hormone, Am J Vet Res
Schenck PA, Chew DJ: Investigation of hyper-
Peterson ME, editors: BSAVA manual of 63:194, 2002.
calcaemia and hypocalcaemia. In Mooney
canine and feline endocrinology, ed 4, Torrance AG, Nachreiner R: Human parathor-
CT, Peterson ME, editors: BSAVA manual
British Small Animal Assoc, 2012, p 1. mone assay for use in dogs: validation,
of canine and feline endocrinology, ed 4,
Refsal KR, etal.: Laboratory assessment of sample handling studies, and parathyroid
Gloucester, England, 2012, British Small
hypercalcemia, Proc Am Coll Vet Intern function testing, Am J Vet Res 50:1123,
Animal Veterinary Association, p 221.
Med Forum 16:646, 1998. 1989a.
Torrance AG, Nachreiner R: Intact parathyroid Weir EC, etal.: Humoral hypercalcemia of Wisner ER, Nyland TG: Clinical vignette, J Vet
hormone assay and total calcium concen- malignancy in canine lymphosarcoma, Intern Med 8:244, 1994.
tration in the diagnosis of disorders of Endocrinology 122:602, 1988a. Wisner ER, etal.: Normal ultrasonographic
calcium metabolism in dogs, J Vet Intern Weir EC, etal.: Adenyl cyclase stimulating, anatomy of the canine neck, Vet Radiol
Med 3:86, 1989b. bone resorbing and b-TGFlike activities 32:185, 1991.
Troy GC, etal.: Heterobilharzia americana infec- in canine apocrine cell adenocarcinoma Wisner ER, etal.: Ultrasonographic evaluation
tion and hypercalcemia in a dog: a case of the anal sac, Calcif Tissue Int 43:359, of the parathyroid glands in hypercalce-
report, J Am Anim Hosp Assoc 23:35, 1987. 1988b. mic dogs, Vet Radiol Ultrasound 34:108,
Uehlinger P, etal.: Differential diagnosis of Weir EC, etal.: Isolation of 16,000-dalton 1993.
hypercalcemia: a retrospective study of 46 parathyroid hormonelike proteins from Wisner ER, etal.: High-resolution parathy-
dogs, Schweiz Arch Tierheilkd 140:188, two animal tumors causing humoral hyroid sonography, Vet Radiol Ultrasound
1998. percalcemia of malignancy, Endocrinology 38:462, 1997.
Utiger RD: Treatment of primary hyperparathy- 123:2744, 1988c. Wright KN, etal.: Diagnostic and therapeutic
roidism, N Engl J Med 341:1301, 1999. Weller RE, etal.: Chemotherapeutic responses considerations in a hypercalcemic dog with
Verdonk CA, Edis AJ: Parathyroid double adin dogs with lymphosarcoma and hyper- multiple endocrine neoplasia, J Am Anim
enomas: fact or ction? Surgery 90:523, calcemia, J Am Vet Med Assoc 181:891, Hosp Assoc 31:156, 1995.
1981. 1982. Wysolmerski JJ, Insogna KL: The parathyroid
Weir EC, etal.: Primary hyperparathyroidism in Williams LE, etal.: Carcinoma of the apo- glands, hypercalcemia and hypocalcemia.
a dog: biochemical, bone histomorphomet- crine glands of the anal sac in dogs: 113 In Goldman L, Schafer AI, editors: Gold-
ric, and pathologic ndings, J Am Vet Med cases (1985-1995), J Am Vet Med Assoc mans Cecil medicine, ed 24, Philadelphia,
Assoc 189:1471, 1986. 223:825, 2003. 2012, Elsevier Saunders, p 1591.
CHAPTER 16 Hypocalcemia and Primary Hypoparathyroidism
Edward C. Feldman
CHAPTER CONTENTS In health, homeostatic control mechanisms maintain serum total

Physiology of Systemic Hypocalcemia, 625 calcium (TCa) and ionized calcium (iCa) concentrations within
Maintenance of a Normal Serum Calcium Concentration, 625 narrow ranges. In addition to providing skeletal support, calcium
Defense Against Hypocalcemia, 626 is a necessary component of numerous vital intra- and extracel-
Physiology of Hypocalcemia Caused by Hypoparathyroidism, 627 lular functions. Ionized calcium is required for bone formation
Clinical Features: Naturally Occurring Hypoparathyroidism in Dogs, 629 and resorption, cell growth and division, membrane transport and
Signalment, 629 stability, enzymatic reactions, nerve conduction, muscle contrac-
History, 630 tion, hormone secretion, hepatic glycogen metabolism, blood
Physical Examination, 630 coagulation, and numerous other activities. Ionized calcium in the
Clinical Features: Naturally Occurring Hypoparathyroidism in Cats, 632 extracellular fluid (ECF) contributes to regulation of cell function
Diagnostic Evaluation: Routine Studies, 632 by binding to cell membrane calcium-sensing receptors (Brown
Calcium, 632 etal, 1995). Intracellular calcium ions aid in cellular response to
Corrected Serum Calcium Values, 632 agonists by serving as messengers to transport signals received at
Serum Phosphorus, 633 cell surfaces to the interior (Rasmussen, 1989). Identification of
Remainder of the Serum Chemistry Profile, 633 abnormal serum calcium concentrations may help explain clini-
Laboratory Testing of Cats with Primary cal signs and may aid in determining cause of illness. Ability to
Hypoparathyroidism, 633 accurately assess concentrations of serum TCa, iCa, parathyroid
Electrocardiogram, 633 hormone (PTH), parathyroid hormonerelated protein (PTHrP),
Magnesium, 633 and vitamin D metabolites has enhanced our capacity to deter-
Diagnostic Evaluation: Parathyroid Hormone Concentrations, 635 mine the cause of hypocalcemia in most patients.
Clinical Usefulness in Humans, 635 Several historical landmarks in the understanding of parathy-
Clinical Usefulness in Dogs and Cats, 635 roid physiology and maintenance of calcium homeostasis are
Differential Diagnosis of Episodic Weakness, 635 signicant regarding current knowledge of hypocalcemia. Rickets
Differential Diagnosis for Hypocalcemia, 635 (hypovitaminosis D) was rst described in 1645. More than 200
Parathyroid-Related Hypocalcemia, 635 years later (1884), an association was made between thyroidec-
Pseudopseudohypoparathyroidism, 637 tomy in dogs and cats and the development of clinical hypocal-
Hypomagnesemia, 638 cemia (tetany). In 1891, Gley proved that the parathyroid glands
Chronic Kidney Disease (CKD), 638 must be removed with the thyroids to produce tetany and that
Hypoalbuminemia, 638 administration of calcium salts following parathyroidectomy
Acute Pancreatitis, 638 successfully prevented tetany. Almost a century later, the amino
Critically Ill Patients, 638 acid sequence of PTH was determined (Tepperman, 1980). Soon
Diabetes Mellitus, 638 thereafter, the amino acid sequence of a PTHrP, produced by
Puerperal Tetany (Eclampsia), 639 some cancers, was described in both humans and dogs (Broadus
Malabsorption Syndromes, 639 etal, 1988; Weir etal, 1988; Yates etal, 1988).
Nutritional Secondary Hyperparathyroidism, 639
Acute Kidney Injury (AKI) and Ethylene Glycol Toxicity, 639
PHYSIOLOGY OF SYSTEMIC HYPOCALCEMIA
Urinary Tract Obstruction, 639
Phosphate-Containing Enemas, 640
Maintenance of a Normal Serum Calcium Concentration
Miscellaneous Causes, 640
Therapy for Hypocalcemia and Hypoparathyroidism, 641 The parathyroid glands are exquisitely sensitive to small changes in
General Approach, 641 the serum iCa concentration. The integrated actions of PTH on cal-
Emergency Therapy for TetanyDiagnosis Not Apparent, 641 cium resorption from bone, distal renal tubular calcium reabsorption,
Subacute Management of Hypocalcemia: Post-Tetany Maintenance and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) (calcitriol)medi-
Therapy, 642 ated intestinal calcium absorption are responsible for the ne regula-
Maintenance (Chronic) Therapy for Hypoparathyroidism, 642 tion of serum iCa concentration. Precision in control is such that
Summary of Keys to Long-Term Success, 645 plasma iCa concentrations may fluctuate day-to-day by no more
Parathyroid Histology in Hypoparathyroidism, 646 than 0.1 mmol/L from their set normal value. The acute phases
Prognosis, 646 of bone resorption and distal renal tubular calcium reabsorption are
important components of minute-to-minute calcium homeostasis.
625
Parathyroid
gland
PTH PTH
PO4, Ca++
Ca++
1,25(OH)2D3
Ca++
Ca++ Ca++
ECF Ca++
Intake
100 mg/kg bw Soft tissue
calcium
Absorption
10-35 mg/kg bw Accretion
4-8 mg/kg bw
Extracellular fluid
FIGURE 16-1 A, Regulation of extracellular fluid (ECF) calcium calcium
concentration by the effects of parathyroid hormone (PTH) and Resorption
1,25-dihydroxyvitamin D3 (1,25[OH]2D3; calcitriol) on gut, kid- 4-8 mg/kg bw
Endogenous
ney, bone, and parathyroid gland. The principal effect of PTH is fecal excretion
to increase the ECF calcium concentration by mobilizing calcium 10-30 mg/kg bw
from bone, increasing tubular calcium reabsorption, and, indi-
rectly on the gut, by increasing calcitriol synthesis. The principal
effect of calcitriol is to increase intestinal absorption of calcium,
but it also exerts negative regulatory control of PTH synthesis and
further calcitriol synthesis. B, Normal calcium balance showing
the major organs that supply or remove calcium from ECF: bone,
gut, and kidney. Total calcium (TCa) input into ECF equals TCa
leaving the extracellular space. bw, Body weight, Ca++, ionized
calcium; PO4, phosphate. (From Rosol etal.: Disorders of calcium.
In DiBartola SP, editor: Fluid therapy in small animal practice, Urine
ed 2, Philadelphia, 2000, WB Saunders, p 108.) B 1-7 mg/kg bw
The effect of PTH on distal renal tubules is quantitatively most D. Acute effects occur in seconds to minutes, subacute or moder-
important. Adjustments in the rate of intestinal calcium absorption ate effects occur over several hours and may last a few days, and
via the calcium-PTH-vitamin D axis require about 24 to 48 hours to chronic effects occur over days to weeks and even months (Rosol
become maximal (see full discussion in Chapter 15). and Capen, 1997; Rosol etal, 2000).
Minor Transient Hypocalcemia Challenges

Defense Against Hypocalcemia
A 12- to 15-hour fast (or consumption of a diet completely decient
Physiologic responses to hypocalcemia have been characterized in calcium) in a normal mammal requires only subtle hormonal
(Fig. 16-1). The three classic challenges to maintaining serum adjustments. If there are slight decreases in serum calcium con-
calcium concentrations within the narrow reference range include centration, slight increases in secretion of preformed PTH quickly
(1) minor transient challenges, (2) moderate challenges, and (3) take place. With increases in PTH secretion, renal calcium reab-
severe, prolonged challenges. Hypocalcemia elicits corrective sorption and phosphorus excretion are enhanced within minutes,
homeostatic responses that are mediated by PTH and vitamin whereas bone mobilization of calcium and phosphate occurs over
|
CHAPTER 16 Hypocalcemia and Primary Hypoparathyroidism 627
a period of hours (Rosol etal, 2000). Hypocalcemia also decreases

the proportion of PTH that is degraded in the parathyroid BOX 16-1 S
igns Noted by Owners of Dogs and Cats
chief cells, making more hormone available for secretion. By with Primary Hypoparathyroidism*
12 hours, only minor increases in vitamin D synthesis have occurred.
Common
Moderate Hypocalcemia Challenges Muscle tremors, twitching, fasciculations
Moderate reductions in dietary calcium intake, or other causes of May be focal or diffuse; often worse with activity or excitement
hypocalcemia, initiate a series of adjustments in calcium metabo- Facial rubbing (possible paresthesia)
lism beyond those documented with minor decreases. The result is Intense biting or licking their paws (possible paresthesia)
a new steady state of PTH and vitamin D (calcitriol) synthesis and Oral chomping (possible paresthesia)
secretion. Moderate increases in the secretion rate of PTH result Generalized seizures (convulsions, fits)
in (1) increased calcium reabsorption from distal renal tubules, (2) Rear leg muscle cramping, pain, or stiff gait
increased mobilization of calcium and phosphorus from bone, and Can occur in forelegs, but rear leg signs are more common
(3) increased synthesis of 1,25(OH)2D3 (calcitriol). Calcitriol teams Behavior changes
with PTH in bone resorption and increases the efciency of cal- Restless, nervous, anxious
cium and phosphorus absorption from the intestine (see Fig. 16-1). Aggressive, biting
The increased concentrations of circulating PTH enhance renal Hypersensitive (reluctant to be petted, touched, or handled)
excretion of phosphorus, thereby compensating for the increased Poor appetite, weight loss
amounts of phosphorus mobilized from bone and absorbed from Less active, listless
the intestine. In this new steady state, the serum calcium concen- Uncommon
tration returns to normal, the serum phosphorus concentration is Weakness
unchanged or slightly reduced, and a state of mild secondary hyper- Anorexia, vomiting, diarrhea
parathyroidism with enhanced intestinal mineral absorption exists. Ataxia
Initial requirement of calcium mobilization from skeleton is largely Pyrexia
replaced by the enhanced absorption of calcium from intestine. Prolapsed third eyelid and/or ptyalism (cats)
Severe and Prolonged Hypocalcemia Challenges Rare

No signs observed
Lactation and chronic kidney disease (CKD) with decreasing abil-
Circling
ity to excrete phosphorus represent two common examples of
Respiratory arrest or death
severe challenges to calcium homeostasis. These issues cannot be
corrected by processes known to occur within minutes or hours. *Note: Most signs are seen episodically.
Assuming the four parathyroid glands are intact and functional, the
previously described sequence of events resulting from minor and
moderate challenges caused by hypocalcemia ensue. However, uncommon endocrine disorder, develops as a result of an absolute
continuing losses of calcium into milk associated with lactation (for or relative deciency in synthesis and secretion of PTH, the sole
example) prevents complete compensation by the usual calcium- product of the parathyroid glands. PTH deciency invariably leads
PTH-vitamin D absorption axis. Physiologic compensation in this to hypocalcemia, usually defined as a serum TCa concentration less
setting includes (1) a maximal PTH secretion rate of approximately than about 9 mg/dL and/or an iCa less than about 1.0 mmol/L
ve times normal, (2) a maximal rate of vitamin D synthesis, and in dogs. Values defining hypocalcemia in cats are slightly lower.
(3) initiation of maximal rapid and late phases of bone resorp- In dogs, the serum TCa concentration tends to underestimate the
tion in response to the combined effects of PTH and vitamin D. iCa. In cats, the serum TCa concentration tends to overestimate
Over days, weeks, or even longer periods of hypocalcemia, the iCa concentration (Schenck and Chew, 2005; Schenck et al,
increases in PTH secretion (beyond those already described) are 2012). Signs of hypocalcemia are similar, regardless of cause (Box
achieved largely via hyperplasia of parathyroid gland chief cells 16-1). Once hypocalcemia is identied, clinicians are encouraged
(Roth and Capen, 1974; Rosol etal, 2000). Hypocalcemia directly to determine cause in order to formulate appropriate short- and
stimulates the growth of parathyroid cells. This effect occurs long-term treatment strategies and a prognosis.
regardless of vitamin D metabolite concentrations (Li etal, 1998;
Malloy etal, 1999, Marx, 2000). With hyperplasia of parathyroid Initial Physiologic Alterations
chief cells, PTH secretion rates approach 10 to 50 times normal. The pathologic and biochemical consequences of parathyroid
These circulating concentrations of PTH result in recruitment of gland removal or loss of a critical number of parathyroid chief
an increasing osteoclast population and the incorporation of sub- cells secondary to immune-mediated destruction (a less com-
stantial bone surfaces into the resorption process. In the nal steady mon condition) can be appreciated by referring to the but-
state, serum calcium concentrations are maintained at the expense terfly diagram (Fig. 16-2). In this condition, the right limbs of
of the skeleton, and signicant bone losses ensue. Thus, the integ- the three feedback loops predominate with (1) decreased bone
rity of skeletal mineral homeostasis is sacriced in an attempt to resorption; (2) decreased renal phosphate excretion, increased
compensate for systemic mineral decits (Broadus, 1981). serum phosphate, decreased calcitriol and intestinal absorption
of calcium; and (3) excess renal excretion of calcium relative
Physiology of Hypocalcemia Caused by to the prevailing circulating concentration. Typically, there is
Hypoparathyroidism hypocalcemia and hyperphosphatemia if dietary phosphate
intake has been normal.
Definition All changes discussed can be explained by a PTH deficiency.
A pair of parathyroid glands is located in close proximity to each The processes that are not taking place include (1) mobiliza-
thyroid lobe in healthy individuals. Hypoparathyroidism, an tion of calcium and phosphate from the skeleton via increased
Bone resorption Ca++
1,25(OH)2D3
SP Intestinal absorption Ca++
Bone resorption Ca++
UP
CT
++
SCa
PTH
++
PTH SCa
Intestinal Renal excretion Ca++
absorption Ca++ CT
UP
SP
1,25(OH)2D3
Renal excretion Ca++
FIGURE 16-2 Regulation of calcium homeostasis. Three overlapping control loops interlock and relate to one an-
other through the level of blood concentrations of ionic calcium, parathyroid hormone (PTH), and calcitonin (CT).
Each loop involves a calciotropic hormone target organ (bone, intestine, or kidney). The limbs on the left depict
physiologic events that increase the blood serum concentration of calcium (SCa++), and the limbs on the right
depict physiologic events that decrease this concentration. 1,25(OH)2D3, 1,25-dihydroxyvitamin D3 (calcitriol); SP,
serum phosphorus; UP, urine phosphorus. (Modified and reproduced with permission from Arnaud and Kolb, 1991.)
osteoclast activity on bony surfaces, (2) retention of calcium and nerve impulses that pass to the peripheral skeletal muscles, where
enhanced excretion of phosphate by kidneys as a direct effect that they elicit tetanic contractions (cramps or tetany).
PTH has on the distal convoluted tubule and its indirect effects Tetany is defined as a random stiffening or tightening of various
on the thin ascending loop of Henle, (3) increased absorption of muscle groups. It is reasonable to assume that nerve bers are partic-
calcium and phosphate from the intestine, and (4) accelerating ularly sensitive to decreases in calcium in part because signs associ-
the formation of the active metabolite of vitamin D in the kid- ated with the nervous system precede others, and because those signs
ney by both inducing synthesis and by activating 1-hydroxylase are so acute, dramatic, and obvious. Dogs with tetany that had pre-
in mitochondria of renal epithelial cells of proximal convoluted viously undergone spinal cord transection had signs above but not
tubules (Skelly, 2012). Activation of vitamin D, under the control below the transection site, suggesting that tetany is primarily initi-
of PTH, increases intestinal absorption of calcium and phosphate, ated in the CNS (Arnaud and Kolb, 1991). Acute hypocalcemia can
a process diminished without PTH (Skelly, 2012). be fatal secondary to respiratory muscle paralysis, decreased myo-
PTH also stimulates release of magnesium from bone, enhances cardial contractility, hypotension, or from persistent seizure activity.
magnesium uptake through the intestinal wall, and supports renal Hypocalcemia, based on the serum TCa concentration, is a rela-
tubular magnesium resorption. An initial magnesium diuresis tively common laboratory abnormality, being observed on more
without signicant change in plasma magnesium concentration than 13% of serum biochemical proles in dogs in one report
has also been observed in hypoparathyroidism. In spite of dramatic (Chew and Meuten, 1982). If the diagnosis of hypocalcemia is
changes in the concentrations of serum calcium and phosphate based on the serum iCa concentration, the prevalence was 31%
secondary to PTH deficiency, bone mineralization is normal, (Schenck and Chew, 2005). Severe hypocalcemia and/or clinical
bone resorption rates decline, and bone formation declines only tetany are rarely observed unless the decreases in serum calcium
slightly. Ultimately, bones are slightly more dense than normal concentration are severe. For example, tetany is likely present
in humans with hypoparathyroidism and, in long-standing cases, when the serum TCa concentration declines to or below 6 to 7
osteosclerosis may be seen. mg/dL, or the serum iCa concentration declines to less than about
0.7 mmol/L. Concentrations slightly higher than these may be
Peripheral Neuromuscular Observations worrisome but are usually clinically silent. Serum TCa concentra-
Although all cells are affected by deciencies in iCa, clinical signs tions below 4 mg/dL for any length of time are frequently fatal.
are typically associated with the neuromuscular system, simply Although dogs with untreated hypoparathyroidism consistently
because alteration in the function of these cells results in obvious have obvious decreases in serum TCa concentrations, the onset
visible abnormalities. Ionized calcium is involved in the release of of clinical tetany is not entirely predictable. We tend to associate
acetylcholine during neuromuscular transmission and is essential clinical signs with serum TCa concentrations below 6 to 7 mg/dL
for muscle contraction. Ionized calcium stabilizes nerve cell mem- and serum iCa concentrations below about 0.7 mmol/L. It is
branes by decreasing their permeability to sodium. possible for a dog to have clinical signs with serum concentra-
When the ECF concentration of iCa progressively declines below tions slightly above these values, whereas others have no discern-
normal, the nervous system, in a parallel manner, becomes progres- ible signs despite extremely low calcium concentrations. Physical
sively more excitable, a result of increases in neuronal membrane activity and/or excitement have a role in development of clini-
permeability. This increased excitability occurs both in the central cal tetany. A quiet dog is less likely than an active dog to exhibit
nervous system (CNS) and in peripheral nerves. With severe hypo- signs. Individual variation, however, is the only consistent feature
calcemia, nerve bers begin to discharge spontaneously, initiating of this condition. Calcium concentrations within cerebrospinal
|
fluid (CSF) do not decrease as rapidly as serum concentrations in 7

parathyroidectomized dogs. Although the serum TCa concentra-
tion decreases as much as 27% (iCa, 28%) within 24 hours of 6
surgery, decreases in CSF TCa concentration are less than 5% and 5
in iCa less than 10% (Wysolmerski and Insogna, 2012). Rapid
Number of dogs
equilibrium does not occur between plasma and CSF iCa. Thus 4
the concentration of calcium ions in the CSF is relatively constant
despite large fluctuations in plasma. Conversely, relatively small 3
decreases in CSF calcium concentration may result in dramatic
clinical abnormalities. 2
When serum calcium concentrations decline to subnormal lev- 1
els but not low enough to cause obvious clinical tetany, a physical
state of latent tetany may exist. This condition is described as 0
one in which an individual can progress from appearing clinically <1 1 2 3 4 5 6 7 8 9 10 11 12 13
normal to becoming tetanic with minimal stimulation. Such a Age (years)
condition can be demonstrated to be present in people by weakly FIGURE 16-3 The ages of 38 dogs at the time of primary hypoparathyroidism
stimulating a nerve and observing an abnormal response (see Phys- diagnosis. These include 25 dogs in our series, as well as 4 dogs from Kornegay
ical Examination). Another example of tetany lurking under the and colleagues (1980), 1 dog from Crawford and Dunstan (1985), 6 dogs from
surface (being latent) can be demonstrated when a human with Sherding and colleagues (1980), 1 dog from Meyer and Tyrrell (1976), and 1 dog
latent tetany hyperventilates. The resulting subtle alkalinization of from Burk and Schaubhut (1975).
the body fluids can decrease the iCa concentration with increased
nerve irritability, causing overt signs of tetany. It is assumed that
similar situations develop in hypocalcemic dogs or cats. Some TABLE 16-1 BREEDS IDENTIFIED
owners have described that sudden excitement, activity, or petting AS HAVING NATURALLY
may unpredictably cause muscle cramping, lameness, facial rub- OCCURRING PRIMARY
bing, pain, irritability, or aggressive behavior. These signs usually HYPOPARATHYROIDISM
disappear quickly, only to recur sporadically. In addition, the non-
tetanic severely hypocalcemic pet is usually described by the owner BREED NUMBER OF DOGS (TOTAL = 87)*
as having a change in personality. Such dogs are often observed to Toy Poodle 13
have a poor appetite and to be irritable, non-playful, and slow- German Shepherd dog 9
moving. Frequently, owners report that their dog seems to be in
pain. Such signs are vague, but after hypocalcemia is diagnosed, Labrador Retriever 8
the clinical signs are most consistent with those of latent tetany. Miniature Schnauzer 8
Terrier breeds 8
The Heart
St. Bernard 4
Calcium has both positive inotropic and chronotropic cardiac
effects (Milnor, 1980). Hypocalcemia prolongs action potential Beagle 4
duration in cardiac cells. This may result in decreased force of Dachshund 4
myocardial contraction (negative inotropic effect) and, in severe Golden Retriever 3
cases, bradycardia (negative chronotropic effect).
Chihuahua 2
Miscellaneous Physiologic Effects of Hypocalcemia Boxer 2
Because calcium serves as a cofactor in both the intrinsic and Breeds represented once each 12
extrinsic blood clotting systems, coagulopathies are theoretically Mixed breed 10
possible in hypocalcemia. In hypocalcemic humans, disorders
less common and less dramatic than tetany may be encountered, *Includes 57 dogs from our UC Davis series, 17 dogs from Russell and colleagues
including (1) basal ganglia calcication and occasional extrapy- (2006), 6 dogs from Sherding and colleagues (1980), 4 dogs from Kornegay and col-
ramidal neurologic syndromes; (2) papilledema and increased leagues (1980), 1 dog each from Burk and Schaubhut (1975), Meyer and Tyrrell (1976),
intracranial pressure; (3) psychiatric disorders; (4) skin, hair, and and Crawford and Dunstan (1985).
ngernail abnormalities; (5) candidal infections; (6) inhibition of
normal dental development; (7) lenticular cataracts; (8) intestinal 30 dogs with hypoparathyroidism in the veterinary literature were
malabsorption; and (9) increased serum concentrations of cre- reviewed. Hypoparathyroidism can be recognized in dogs of any
atine phosphokinase and lactic dehydrogenase (Arnaud and Kolb, age; the youngest dog being 6 weeks and the oldest being 14 years
1991; Wysolmerski and Insogna, 2012). (Fig. 16-3). The average age was 5.4 years. Of 57 dogs in the ongo-
ing UC Davis series, about half were female; and in a published
CLINICAL FEATURES: NATURALLY OCCURRING series of 735 hypoparathyroid dogs, 62% were female (Refsal
HYPOPARATHYROIDISM IN DOGS etal, 2001; Skelly, 2012). The breeds most frequently identied as
having primary hypoparathyroidism were Toy Poodles, Labrador
Signalment Retrievers, Miniature Schnauzers, German Shepherd dogs, vari-
ous terrier breeds, and mixed breed dogs (Table 16-1). In a report
The records from 57 dogs seen at University of California, Davis on 17 dogs from Australia with naturally occurring hypopara-
(UC Davis) with naturally occurring primary hypoparathyroidism thyroidism, St. Bernards, Chihuahuas, Jack Russell Terriers, and
(includes Bruyette and Feldman, 1988) and from an additional West Highland White Terriers were each represented more than
once (Russell etal, 2006). As anticipated from the various breeds in a generalized seizure. In some dogs, seizure episodes were as brief
described, body weights vary greatly. as 30 to 90 seconds; in others, they lasted for more than 30 minutes.
Most, but not all, of the generalized seizures lasted less than 3 min-
utes and spontaneously abated.
History
Duration of Illness Miscellaneous Signs
As described by their owners, the 57 dogs in the UC Davis series As can be seen in Box 16-1, many owners observed overlapping
commonly developed an abrupt onset of intermittent neurologic or neurologic and neuromuscular signs. Retrospectively, each dog suf-
neuromuscular disturbances (see Box 16-1). About half of the owners fered bouts of signicant hypocalcemic tetany as a part of their initial
noted that signs were initiated or worsened by excitement, exercise, or signs. Some vague signs included panting, ataxia, circling, episodic
petting. The hypocalcemia-related signs had been observed for peri- weakness, complete anorexia, vomiting, diarrhea, and weight loss.
ods of only about 24 hours in some dogs to as long as 12 months in Veterinarians occasionally noted an increase in body temperature.
others. Only a minority of the 57 dogs had signs for longer than 14 All owners observed some clinical signs. Although hypocalcemia was
days before veterinary care was sought. Some dogs with prolonged almost always considered a serendipitous nding on laboratory test-
histories had been symptomatic for 1 to 12 months, but some of these ing, it remains an abnormality that made sense after being demon-
had been diagnosed and treated for nonspecic seizure disorders. The strated. Death remains a potential sequela of untreated hypocalcemia.
dogs with signs for more than several days invariably had neuromus-
cular disturbances that became progressively more frequent and vio- Facial Rubbing
lent despite administration of anticonvulsant medication. Thirty-five out of 57 dogs in our series were observed to paw
their muzzles, eyes, and ears and/or to rub their muzzles on the
Early Signs ground. Additionally, most owners noted their dogs intensely lick-
Clinical signs observed by owners that resulted in their seeking vet- ing or chewing at their paws. These signs of pain are thought to
erinary care varied (see Box 16-1). The most common reason for be associated with masseter and temporal muscle cramping caused
seeking veterinary care was apparent grand mal convulsions (dis- by hypocalcemia, or they could result from a tingling sensation
cussed in the next section). Owners also sought veterinary care after around the mouth or at the distal extremities. Classic signs of
seeing apparent muscle cramping, tonic spasm of leg muscles, or hypocalcemia in humans include paresthesias, which are dened
pain. Focal muscle twitching, tremors, fasciculations, or trembling as numbness and tingling that often occur around the mouth, fin-
were commonly seen as were stiff, hunched, or rigid gait. One of gers, and/or toes (Arnaud and Kolb, 1991).
the rst owner observations (retrospectively) was that their pet
appeared abnormally nervous or anxious. Owners also com- Hyperventilation
monly described their pets as having poor appetites or as being Because of the acute anxiety or pain associated with tetany, hypo-
slow, less playful, or not as friendly. A few were noted to have parathyroid humans (and presumably dogs) may episodically
had episodes of vomiting or diarrhea. Aggressive behavior was seen hyperventilate and secrete increased amounts of epinephrine.
in a majority of affected dogs and is assumed to be caused by pain Hyperventilation may lead to hypocapnia and alkalosis, either of
associated with muscle cramping. The muscle cramping could be which can worsen hypocalcemia by causing increased binding of
elicited by petting, possibly explaining why dogs that previously ionic calcium to plasma proteins. Hyperventilation in healthy peo-
suffered acute pain from such a mild stimulus are reluctant to be ple can decrease serum iCa concentration (Arnaud and Kolb, 1991).
handled. This likely also explains the observations of dogs appear-
ing to be less friendly or for their change in behavior or personality. Episodic Nature of the Illness
Also retrospectively, owners noted that their dogs would intensely All neurologic and neuromuscular signs in hypocalcemic dogs
use their paws or the ground to rub their muzzles (discussed later) tend to be episodic, often followed by asymptomatic periods. The
or they would intensely lick or chew their paws. Although common, periods of clinical well-being lasts minutes to days or even weeks.
such signs were usually not mentioned by owners until specically Tetany was rather unpredictable, although retrospectively, these
questioned or were noted as having disappeared after treatment had signs were more frequent or inducible with exercise (even slow or
been instituted. In one study, mandibular champing, possibly a short leash walks), excitement, petting (possible latent tetany),
reflection of masticatory muscle cramping or facial paresthesias, was or stress (being taken to the veterinarian).
observed by almost half the owners (Russell etal, 2006). All of the dogs were persistently hypocalcemic but displayed
tetany only episodically. This illustrates some adaptation in each
Seizures to hypocalcemia, suggesting that minor alterations in calcium con-
Grand mal convulsions were observed by owners of 49 out of 57 centration could result in profound clinical signs. One dog in our
dogs with naturally occurring primary hypoparathyroidism. As pre- series had been diagnosed as having primary hypoparathyroidism
viously reported, most of these dogs had typical-appearing grand but remained untreated for almost a year. This dog was persistently
mal convulsions. However, some dogs had atypical seizures in that hypocalcemic but had only one or two clinically obvious hypocalce-
the dogs either did not appear to lose consciousness or were neither mic episodes monthly. In spite of this tragic history, the dog was rela-
urinary nor fecal incontinent during the episode. Of interest was tively well, suffering primarily from a poor appetite and weight loss.
the incidence of seizure activity seen by veterinarians. Of the 57
dogs in our series, 45 were observed by a veterinarian to have sei- Physical Examination
zures. This frequency of observing seizure-like episodes represents
a much higher incidence of veterinarian-witnessed neuromuscular General Observations
disorders than expected with idiopathic epilepsy. Also, as noted by Other than signs related to hypocalcemia, dogs with primary
other investigators (Sherding etal, 1980; Russell etal, 2006; Skelly, hypoparathyroidism usually do not have additional physical
2012), muscle tremors during some episodes began in one limb and examination abnormalities. Physical examination findings on
gradually became generalized and more violent, nally culminating hypoparathyroid dogs varied (Table 16-2). Retrospectively, most
|
TABLE 16-2 INITIAL PHYSICAL EXAMINATION

FINDINGS IN 57 DOGS WITH
NATURALLY OCCURRING
PRIMARY
HYPOPARATHYROIDISM
SIGN NUMBER OF DOGS %

Seizure or in tetany
Initial examination 23 40
Total: First 4 days of 41 72
hospitalization
Intense rubbing or pawing at 35 61
face
Intense biting or licking at paws 34 60
Fever 31 54
Tense, splinted abdomen 30 53
Stiff gait 29 51
Thin 25 44 FIGURE 16-4 Lenticular cataract in the lens of a hypoparathyroid dog.
Generalized muscle fascicula- 24 42
tions
Twenty-three dogs were observed to have a convulsion during
Growling 23 40
their initial examination, and an additional 18 had at least one
Cardiac abnormalities convulsion observed within the first 96 hours of hospitalization.
Tachyarrhythmia 14 25 Complete neurologic examinations were attempted on 37 dogs
Muffled heart sounds/weak 4 7 revealing a variety of problemsthe most common of which was
pulse that the dog was too tense and nervous to complete a thorough
evaluation. Retrospectively, these dogs were recognized to have
Neurologic examination difficult 37 65 been in tetany. Other ndings included brisk reflexes, absent
to complete and/or interpret reflexes, clonus, and/or pain. Because these dogs were in latent
Cataracts 14 25 or active tetany, their neurologic examinations were difcult to
No abnormality 6 10 interpret until hypocalcemia was identied.
Induced Neurologic or Neuromuscular Signs
Two physical tests are used in humans as aids in diagnosing latent
dogs were in tetany on presentation, an observation made after tetany (hypocalcemia). Chvosteks sign is elicited by tapping the
review of serum biochemical results. Forty-eight of the 57 dogs facial nerve just anterior to the ear lobe. A positive sign is one of
were referred for evaluation of hypocalcemia. Thus, the veterinar- extensive facial muscle twitching or muscle contraction. Trous-
ian examining such a dog was primed to observe tetany. Obser- seaus sign is induced with a blood pressure cuff inflated above
vations (almost all of which are noted in Table 16-2), although systolic blood pressure for at least 2 minutes. A positive response
impressive to the uninitiated, may not have been made if the consists of carpal spasm, at least 5 to 10 seconds in duration,
history not alerted the clinician to the underlying condition. after release of the cuff or while the cuff is inflated (Arnaud and
A minority of dogs appeared healthy, despite their previous his- Kolb, 1991; Meininger and Kendler, 2000). Although such tests
tory of neurologic or neuromuscular disorders. A number of dogs are not described for dogs suspected of being hypocalcemic, epi-
were thin and/or growled when examined. It is accepted that the sodes of intense muscle spasm have been stimulated when testing
growling dogs were in pain or were anticipating that handling reflexes.
would cause them pain, because almost all of them became friendly
after resolution of their hypocalcemia. Cardiac abnormalities were Cataracts
suspected in 18 dogs on initial examination. These abnormalities Posterior lenticular cataract formation is the most common per-
consisted of paroxysmal tachyarrhythmias suspected in 14 dogs manent sequela of hypoparathyroidism in humans (Arnaud and
and muffled heart sounds with weak pulses suspected in four dogs. Kolb, 1991). Such cataracts are thought to require 5 to 10 years
before visual impairment occurs. Successful treatment of hypo-
Spontaneous Neurologic and Neuromuscular Signs calcemia generally halts their progression (Arnaud and Kolb,
On initial examination, 51 of the 57 dogs with primary hypopara- 1991). Cataracts were first described in two hypoparathyroid dogs
thyroidism had at least one abnormality that could be attributed (Kornegay etal, 1980) and have been seen in 14 of the 57 dogs
to hypocalcemia. Most of these dogs had a convulsion or were in our series. No dog was blind. Opacities are randomly distrib-
considered to be in tetany. Others growled, were extremely tense uted along the lens bers and are separated from the capsule by an
or rigid, or had splinted abdomens, stiff gaits, and/or muscle intervening zone of normal thin cortex (Fig. 16-4). Other ocular
fasciculations. Virtually every time that a dog growled, the owner signs not yet reported in dogs include papilledema, optic neuritis,
would comment that this new behavior had been noticed at conjunctivitis, keratitis, blepharospasm, loss of lashes, strabismus,
home as well. Fever was noted in 31 of the 57 dogs. nystagmus, and anisocoria.
uniform. No dog had a serum calcium concentration greater than

CLINICAL FEATURES: NATURALLY OCCURRING
6.1 mg/dL on any assessment until therapy began to have an effect.
HYPOPARATHYROIDISM IN CATS
After serum iCa concentrations became routinely available, each of
Hypocalcemia in cats, like dogs, is seen with hypoalbuminemia, these results was also profoundly low (see Table 16-3).
although iCa concentrations are typically within reference limits.
Hypocalcemia in cats has also been associated with renal failure, Corrected Serum Calcium Values
intestinal malabsorption, acute pancreatitis, lactation, and ethyl-
ene glycol toxicity. The most common iatrogenic cause of hypo- Calcium in plasma or serum exists in three fractions: ionized (free
calcemia is removal of all parathyroid glands as a complication of calcium), complexed or chelated (bound to phosphate, bicarbon-
cervical surgery, such as bilateral thyroidectomy for hyperthyroid- ate, sulfate, citrate, and lactate), and protein-bound (Fig. 16-5). In
ism. Surgical techniques have improved, and this complication is general, between 50% and 60% of TCa is in the ionized form in
now uncommon. However, parathyroid damage or removal is a normal animals. In clinically normal dogs, protein-bound, com-
risk with any cervical surgery involving both sides of the trachea. plexed, and iCa account for approximately 34%, 10%, and 56%
Less frequently, hypocalcemia may occur after administration of of the serum TCa, respectively (Schenck etal, 1996). Laboratories
phosphate containing enemas. generally measure these components together and report them as
Naturally occurring primary hypoparathyroidism in cats is
encountered less often than in dogs. Nine cats with naturally
occurring primary hypoparathyroidism have been reported in Extracellular Calcium
the veterinary literature, and an additional seven have been seen
at UC Davis. These 16 cats, 6 months to 11 years of age and
of various breeds, include 11 males. The clinical course of each
cat was characterized by an abrupt or gradual onset of intermit-
tent neurologic or neuromuscular disturbances, which included
focal or generalized muscle tremors, seizures, ataxia, stilted gait,
disorientation, and weakness. Other concerns included lethargy,
anorexia, panting, and raised nictitating membranes. Less com-
monly, dysphagia, pruritus, and ptyalism were observed. Physical
Ultrafilterable calcium
55% Ionized calcium
examination ndings included depression, weakness, fever, hypo- Ca++
thermia, bradycardia, and mild to severe dehydration. Lenticular
cataracts were detected in several of these cats (Forbes etal, 1990;
Parker, 1991; Peterson etal, 1991; Bassett, 1998; Ruopp, 2001;
Gunn-Moore, 2005; Skelly, 2012).
DIAGNOSTIC EVALUATION: ROUTINE STUDIES

Complexed calcium
Calcium Ca-citrate
10% Ca-lactate
Hypocalcemia was a serendipitous nding in each of our 57 dogs Ca-bicarbonate
with primary, naturally occurring, hypoparathyroidism. All had Ca-phosphate
a history consistent with a behavioral, neurologic, muscular, or
neuromuscular disorder. A complete blood count, urinalysis, and
serum chemistry prole were considered necessary aids in attempt-
ing to determine the cause of abnormalities noted by owners and
35% Protein-bound
the veterinarian. Severe hypocalcemia was suspected in few but calcium
noted in all (Table 16-3). Because severe hypocalcemia (serum cal-
cium concentration < 7.0 mg/dL) is an unusual nding in our clinic
population, this parameter was invariably rechecked with a separate
blood sample. Actually, each dog had its serum calcium concen-
tration monitored three to ve times during the rst 72 hours of FIGURE 16-5 Serum total calcium (TCa) concentration consists of ionized (free),
hospitalization as therapy was begun. Persistent hypocalcemia was complexed, and protein-bound fractions. Ca, Calcium; Ca++, ionized calcium.
TABLE 16-3 PERTINENT FINDINGS IN 57 DOGS (30 FEMALE, 27 MALE) WITH PRIMARY HYPOPARATHYROIDISM
TOTAL IONIZED SERUM PLASMA BLOOD UREA PARATHYROID

AGE DURATION OF CALCIUM CALCIUM PHOSPHATE MAGNESIUM NITROGEN HORMONE
(YEARS) SIGNS (DAYS) (mg/dL) (mm/L) (mg/dL) (mg/dL) (mg/dL) (pmol/L)
Result ranges 0.5-14 1-360 3.4-6.1 0.2-0.6 4.9-10.2 1.2-2.3 8-51 0.05-3.4
Mean values 5.4 26 4.6 0.3 7.7 1.9 15 0.5
Median values 4.0 3 4.3 0.3 7.9 1.8 17 0.6
Reference ranges 8.9-11.4 1.1-1.4 3.0-4.7 1.8-2.4 12-28 2-13
|
a TCa value. Ionized calcium is the biologically active component,

Remainder of the Serum Chemistry Profile
and protein-bound calcium serves as a reservoir or storage pool
for the ionized fraction. However, changes in serum concentration The diagnosis of primary hypoparathyroidism in the dog is usu-
of albumin and globulins may alter the measured serum TCa con- ally made by exclusion. In other words, clinicians develop
centration without altering iCa levels. Despite an alteration in the a complete differential diagnosis for hypocalcemia and then
total amount of serum calcium resulting from hyperproteinemia attempt to rule each condition in or out. In this context, a
or hypoproteinemia, the biologically active iCa concentration complete database is invaluable when assessing any nonlactat-
remains stable because of homeostatic mechanisms. Any dog or ing hypocalcemic animal. It has been suggested that hypopara-
cat with hypocalcemia should also have its serum albumin assessed thyroidism is the only possible diagnosis when one encounters
(Chew and Meuten, 1982). a combination of low serum calcium concentration, increased
Two formulas were developed for use in dogs to account for serum phosphorous concentration, normal renal function, and
changes in the reported serum calcium value attributed to changes a decreased (relative or absolute) serum PTH concentration
in serum protein values (Meuten etal, 1982). The formulas were (Rosol etal, 2000).
thought to be of signicant value prior to routine availability of There are three potential causes of hypoparathyroidism: sup-
iCa assays. These formulas are: pressed secretion of PTH without parathyroid gland destruction
(Dhupa and Proulx, 1998); sudden correction of chronic hyper-
corrected TCa (mg/dL) = measured TCa (mg/dL) albumin (g/dL) + 3.5
calcemia in which the remaining parathyroid glands are severely
or atrophied; and absence or destruction of the parathyroid glands.
In reviewing the additional routine laboratory tests performed
corrected TCa (mg/dL) = measured TCa (mg/dL) [0.4 total protein (g/dL)] on hypoparathyroid dogs, abnormalities were not seen. There-
+ 3.3 fore the only signicant alterations were hypocalcemia in all
Hypoalbuminemia is a common explanation for apparent hypo- patients and hyperphosphatemia in most.
calcemia. However, it is the least important, causes no hypocalce-
mia-related clinical signs, and is associated with only mild changes
Laboratory Testing of Cats with Primary
from reference ranges. Although correction to normal limits implies
Hypoparathyroidism
that the ionized fraction is normal, the ionized fraction may yet be
low. These formulas, developed more than three decades ago, were Laboratory testing in 16 cats (nine reported cases and seven in
derived from serum albumin concentrations obtained with analyti- our series) with naturally occurring primary hypoparathyroid-
cal methods no longer employed by modern automated analyzers. ism demonstrated severe hypocalcemia in each cat (range, 2.5 to
The reference range for serum albumin concentration reported then 4.4 mg/dL). Serum phosphate concentrations were inappro-
(Meuten etal, 1982) was considerably lower than those reported priately increased in each cat (range, 5.2 to 19 mg/dL). Serum
now. At the time, a positive correlation was noted, but only 33% protein, albumin, urea nitrogen, creatinine, and magnesium con-
of the variability in serum TCa concentration could be attributed centrations were within reference limits in each cat tested (Forbes
to serum albumin concentration, and only 17% of the variability et al, 1990; Parker, 1991; Peterson et al, 1991; Bassett, 1998;
could be attributed to serum total protein. There was no association Ruopp, 2001; Gunn-Moore, 2005).
in cats between serum total protein and serum calcium concentra-
tions, and only 18% of the variability in TCa concentration could
Electrocardiogram
be attributed to albumin concentration (Flanders etal, 1989). In
another study, only 17% and 29% of the variability in serum TCa A good correlation exists between severity of hypocalcemia
concentration in dogs and cats, respectively, could be attributed and duration of the electrocardiogram (ECG)-demonstrated
to serum albumin concentration (Bienzle et al, 1993). For these S-T segment. Most hypoparathyroid dogs in our series had no
reasons, plus the availability of serum iCa results via commercial clinical evidence of cardiovascular disease and were not assessed
laboratories, these correction formulas are no longer used (Rosol with an ECG. When an ECG was taken, changes observed that
etal, 2000). were consistent with hypocalcemia included (1) deep and wide
T waves, (2) prolonged Q-T or S-T intervals (also noted in four
Serum Phosphorus out of four dogs in a separate study [Russell etal, 2006]), and
(3) bradycardia (Kornegay et al, 1980; Sherding et al, 1980;
The most consistent laboratory findings among the dogs with pri- Russell, et al, 2006).When the ECGs obtained during hypo-
mary hypoparathyroidism in our series were the presence of both calcemia were compared with those taken following restora-
hypocalcemia and hyperphosphatemia. Most dogs with primary tion of normal calcium concentrations, the R waves appeared
hypoparathyroidism have a serum phosphorus concentration higher taller during hypocalcemia (Fig. 16-6). No obvious ECG expla-
than the TCa concentration on the same sample. All had had blood nation could be found for the arrhythmias, weak pulses, or
urea nitrogen (BUN), total protein, and serum albumin concentra- muffled heart sounds that were suspected on several physical
tions within the reference range. The absence of an absolute hyper- examinations.
phosphatemia in some of the dogs can be explained in part by the
wide variation in what is considered normal by veterinary labo-
Magnesium
ratories. Such reference ranges may include results of all ages, and
readers are reminded that immature pets typically have a relative Magnesium is an important cofactor for PTH secretion because
hyperphosphatemia. Their serum phosphorus concentrations gradu- it is required for release of stored hormone from secretory gran-
ally decline until puberty, at which time the levels remain relatively ules. In conditions of severe magnesium deficiency, suppressed
constant. Inappetent hypoparathyroid dogs were noted to have parathyroid secretion with concurrent hypocalcemia and hyper-
higher mean phosphate concentrations than those with adequate phosphatemia has been documented. Another contributor to the
food intake (Russell etal, 2006). hypocalcemia seen with hypomagnesemia is a reversible resistance
C
FIGURE 16-6 Electrocardiogram (ECG) illustrating various stages in the treatment of a dog with hypocalcemia
secondary to primary hypoparathyroidism. A, The serum calcium level was 4.0 mg/dL. On this ECG, prolonged S-T
and Q-T segments are obvious. The T wave itself is prolonged and deep. At this time the serum potassium (4.3
mEq/L), sodium (147 mEq/L), and chloride (103 mEq/L) levels were normal. The inorganic phosphorus level was
4.9 mg/dL. B, ECG taken when the serum calcium level was 6.2 mg/dL. The S-T, Q-T, and T wave durations are
diminished, as is the T wave amplitude. C, ECG taken of a dog with a normal serum calcium level of 9.7 mg/dL.
The S-T, Q-T, and T waves are normal. The three ECGs also suggest a diminishing R wave amplitude as the serum
calcium level rises to normal.
BOX 16-2 Causes of Hypomagnesemia and Magnesium Depletion in Humans
Decreased Intake and/or Absorption Endocrine

Protein-calorie malnutrition Diabetes mellitus, insulin therapy
Magnesium-free fluid therapy Hyperthyroidism
Magnesium-free total parenteral nutrition Primary hyperparathyroidism
Primary and secondary hyperaldosteronism
Gastrointestinal Disorders
Hyperadrenocorticism
Prolonged nasogastric suction
Syndrome of inappropriate secretion of antidiuretic hormone
Chronic diarrhea
Malabsorption syndromes Redistribution
Extensive bowel resection, intestinal fistulas Pancreatitis
Hyperadrenergic states
Renal Losses
Massive blood transfusion
Chronic parenteral fluid therapy without magnesium
Hypothermia
Nonazotemic renal tubular dysfunction (see text)
Acute respiratory alkalosis
Loop and osmotic diuretics
Sepsis
Hypercalcemia
Hypokalemia Other
Alcohol Burns
Excessive lactation
Metabolic
Excessive sweating
Hypercalcemia
Hypophosphatemia
to the actions of PTH at the level of both bone and kidney (Wysol- reabsorption and hypomagnesemia has been reported in people dur-
merski and Insogna, 2012). ing the diuretic phase of acute renal tubular necrosis, renal tubular
In humans, there are a variety causes for severe (serum concentra- acidosis, pyelonephritis, and hydronephrosis. Impaired magnesium
tion < 1.2 mg/dL) magnesium deficiency (Box 16-2; Yu, 2012). reabsorption and hypomagnesemia has been documented with
People with various intestinal disorders associated with small bowel gentamicin nephrotoxicity and is recognized as a potential adverse
malabsorption and/or steatorrhea are at risk for magnesium deple- reaction to cisplatin chemotherapy. Virtually all diuretics increase
tion. Responsible mechanisms include formation of magnesium magnesium excretion and symptomatic hypomagnesemia has been
soaps with unabsorbed fatty acids in addition to simple loss of mag- documented with primary and secondary states of hyperaldoste-
nesium into intestinal contents. Decreased renal tubular magnesium ronism (Yu, 2012). The osmotic diuresis associated with diabetic
|
ketoacidosis (DKA) can be associated with signicant urinary losses to conditions such as dietary calcium deciency or intestinal
of magnesium. The time course for the development of hypomag- malabsorption.
nesemia in response to treatment of ketoacidosis is similar to that
for decreasing serum potassium and phosphorus concentrations. Clinical Usefulness in Dogs and Cats
Normal pretreatment magnesium concentrations may decrease to
less than 1 mg/dL during the rst 24 hours of intensive therapy for Undetectable serum PTH concentration in a severely hypocalce-
DKA unless anticipated and treated. Hyperthyroidism is sometimes mic animal conrms the diagnosis of primary hypoparathyroid-
associated with negative magnesium balance and hypomagnesemia ism. Reliable and validated PTH assays are commercially available
due to bone resorption and altered distribution of magnesium into for cats and dogs. Serum PTH concentrations may be detectable
soft tissues (Yu, 2012). Primary infantile hypomagnesemia is a rare or low-normal in pets with hypoparathyroidism. A serum PTH
autosomal recessive disorder in people that appears to be caused by concentration within the reference range is not a healthy response
a specic abnormality in intestinal magnesium absorption (Wysol- to hypocalcemia (see Figs. 15-5, 15-22, and 15-23). Low-normal
merski and Insogna, 2012). to extremely low serum PTH concentrations were obtained from
Hypoparathyroidism secondary to hypomagnesemia in dogs each of 44 dogs with primary hypoparathyroidism we tested (see
with protein-losing enteropathies and in dogs with eclampsia have Table 16-3 and Figs. 15-22 and 15-23).
been reported (Aroch etal, 1999; Kimmel etal, 2000; Bush etal, Response to therapy, coupled with ruling out each differential
2001). Serum magnesium concentrations were determined in 38 diagnosis for hypocalcemia, has served as a relatively reliable and
of the 57 hypoparathyroid dogs included in Table 16-3. Eight of logical method for supporting a diagnosis of primary hypoparathy-
these dogs were hypomagnesemic. Hypocalcemia in people with roidism. This approach allows assessment of serum PTH concentra-
concurrent hypomagnesemia is often refractory to calcium ther- tion to serve in a confirmatory role. Because naturally occurring
apy unless magnesium is administered rst (Hansen, 2000). In primary hypoparathyroidism is a permanent condition requiring
humans, symptoms of hypomagnesemia do not usually occur at lifelong therapy, assaying serum PTH concentrations is warranted
serum levels of magnesium above 1.5 mg/dL, and obvious signs and serves to aid both veterinarian and client (Torrance, 1998).
are not always seen, even at serum magnesium levels below 1.0 Despite inevitable changes in methodologies over the years, PTH
mg/dL (Wysolmerski and Insogna, 2012). assays for both dogs and cats have provided excellent and reliable
Poor quantitative relationships between testing and clinical rel- information (Feldman and Krutzik, 1981; Torrance and Nach-
evance are limitations created by having only 0.3% of total body reiner, 1989; Flanders and Reimers, 1991; Flanders et al, 1991;
magnesium in plasma or serum (Elin, 1994). Serum magnesium Barber etal, 1993; Chew etal, 1995; see Chapter 15). The most
concentrations may be normal or high in the presence of intracellu- important differential diagnoses for hypocalcemia are laboratory
lar depletion. Although serum testing is the least expensive and most error, hypoalbuminemia, surgical removal of the parathyroids, use
convenient, most authorities recognize inaccuracies associated with of phosphate enemas, acute or chronic kidney failure, eclampsia,
such assessments. Furthermore, interest in measuring serum ionized malabsorption, and severe pancreatitis (Schenck and Chew, 2012).
magnesium concentration has involved expensive equipment or facil-
ities not widely available (Wysolmerski and Insogna, 2012). DIFFERENTIAL DIAGNOSIS OF EPISODIC
It is unclear whether mild/asymptomatic hypomagnesemia needs
WEAKNESS
to be treated. In humans, magnesium repletion is recommended if a
patient is symptomatic, has concurrent severe hypocalcemia, hypo- Because the clinical signs of hypocalcemia occur episodically, cli-
kalemia, or an underlying cardiac arrhythmia or seizure disorder. nicians may consider a variety of potential causes for episodic
Intravenous (IV) magnesium sulfate can be used for repletion, and its weakness or paroxysmal neurologic and/or neuromuscular dis-
redistribution from extracellular to intracellular space is relatively slow. orders. The differential diagnosis for episodic weakness presented
Normalization of serum concentrations usually precedes achieve- in Chapter 9 is worth reviewing because those clinical signs are
ment of total magnesium replacement needs. It is recommended, somewhat similar to those of hypocalcemia. Several of the dogs in
therefore, that humans receiving IV supplementation continue to be this series were initially believed to have idiopathic epilepsy. Tox-
treated for 24 to 48 hours beyond the time that serum concentrations ins were also commonly suspected (e.g., strychnine, metaldehyde,
normalize. In people with normal renal function, excess supplemen- and/or lead). Other tentative diagnoses after initial examination
tation should be excreted. Symptoms of hypermagnesemia in people of hypocalcemic dogs included tetanus, trauma, cardiac disease,
include hypotension and flaccid paralysis (Yu, 2012). myasthenia gravis, hepatic disease, and hypoglycemia.
DIAGNOSTIC EVALUATION: PARATHYROID DIFFERENTIAL DIAGNOSIS FOR HYPOCALCEMIA

HORMONE CONCENTRATIONS The differential diagnosis for hypocalcemia is listed in Box 16-3
and the diagnostic algorithm is in Fig. 16-7.
Clinical Usefulness in Humans
Measurement of serum PTH concentration is an important
Parathyroid-Related Hypocalcemia
aid to the diagnosis of parathyroid gland disorders in people
(Arnaud and Kolb, 1991; Wysolmerski and Insogna, 2012). Naturally Occurring Primary Hypoparathyroidism in Dogs and Cats
Decreases in serum PTH concentration are consistent with Naturally occurring hypoparathyroidism is an uncommon con-
primary parathyroid gland failure in hypocalcemic individuals. dition in dogs and cats. The onset of signs typically seem abrupt
Increases in serum PTH concentration (an appropriate physio- to owners and may be severe (e.g., tetany and/or seizures).
logic response to hypocalcemia) rules out hypoparathyroidism Although the onset of signs almost always seems sudden, the
in individuals whose hypocalcemia is unexplained, suggesting condition is likely insidious with mild subclinical hypocalce-
end-organ resistance to PTH (pseudohypoparathyroidism or mia present for some period. Surprisingly, some dogs and cats
vitamin D deciency) or secondary hyperparathyroidism due with naturally occurring disease have had signs for months at
BOX 16-3 Differential Diagnosis of Hypocalcemia
Parathyroid-related hypocalcemia Nutritional secondary hyperparathyroidism

Naturally occurring primary hypoparathyroidism Acute kidney injury (AKI) and ethylene glycol toxicity
Rare disorders in people Urinary tract obstruction
Iatrogenic (surgically removed or damaged glands) Phosphate-containing enemas
Acute resolution of chronic hypercalcemia Miscellaneous causes of hypocalcemia
Pseudohypoparathyroidism Laboratory error
Pseudopseudohypoparathyroidism Anticonvulsant therapy
Hypomagnesemia Hyperthyroidism
Chronic Kidney Disease (CKD) Vitamin D deficiency
Hypoalbuminemia Transfusion using citrated blood
Acute pancreatitis Use of EDTA-coagulated blood
Critically ill patients Trauma to the neck area
Diabetes mellitus Medullary carcinoma of the thyroid
Puerperal tetany (eclampsia) Primary and metastatic bone cancer
Malabsorption syndromes Side-effect to some cancer chemotherapies
CONFIRMED HYPOCALCEMIA
(TOTAL AND/OR IONIZED)
Decreased Increased BUN

albumin (should Increased PO4 Vomiting Pathologic
Lactating bitch Anorexia Weight loss
not cause a Increased fractures
or queen? Abdominal pain Diarrhea
decrease in creatinine Improper diet
ionized calcium) +/ Anorexia Increased lipase
Increased
pancreatic size on
abdominal
Likely to be Nutritional
ultrasound
transient secondary
Determine Acute or chronic Increased Consider
especially if hyperparathyroidism
ionized calcium kidney disease pancreatic
nursing is (usually have normal malabsorption
echogenicity
limited serum Ca++ and PO4)
Consider
pancreatitis
Increased PO4
Normal BUN
Normal creatinine
Normal albumin
Decreased PTH
(+) or () for CNS signs
Hypoparathyroidism
A) Naturally occurring
1. Primary
2. Secondary to nonparathyroid
disease in neck
B) Iatrogenic (post-surgery)
FIGURE 16-7 Algorithm for diagnosing the various causes of hypocalcemia. BUN, Blood urea nitrogen; Ca, cal-
cium; Ca++, ionized calcium; CNS, central nervous system; PO4, phosphorus; PTH, parathyroid hormone.
|
the time of diagnosis (one, in our series, for about a year) and aware of this complication and because techniques have improved
survive without appropriate treatment. Signs are not usually rec- (Henderson etal, 1991; Flanders, 1994; Graves, 1995; Klein etal,
ognized until there has been a decline in the TCa concentration 1995). Because this complication is recognized as possible, auto-
below some critical level (approximately 6 to 7 mg/dL). At such transplantation of removed parathyroid tissue has been success-
serum calcium concentrations, relatively small decreases in cal- fully employed in humans and has excellent veterinary potential
cium concentration may result in obvious clinical problems. For (Padgett etal, 1998).
example, a serum TCa decline of 0.3 mg/dL in a dog or cat with The transient nature of hypoparathyroidism following thyroid
a serum concentration of 10.5 mg/dL has no effect and remains surgery in many cats is not well understood. The physiology of this
normal, but the same decrease when the serum calcium con- complication may be related to the hyperphosphatemia and second-
centration is 5.7 mg/dL could result in convulsions. ary hyperparathyroidism documented in 18% and 77%, respectively,
Diffuse lymphocytic parathyroiditis was described in seven of untreated hyperthyroid cats (Barber and Elliott, 1996). It has been
dogs with hypoparathyroidism (Kornegay, 1982). Our series postulated that this may be the result of thyroxine (T4)-mediated
includes an additional 19 dogs with similar histologic ndings, alterations in bone metabolism and increased phosphate absorption
and a few others had their parathyroid tissue replaced by brous (Barber and Elliott, 1996). One group of cats had signicantly reduced
tissue. It is possible that brous tissue is an end result following serum PTH concentrations after thyroparathyroidectomy. During
lymphocytic/plasmacytic inflammation. Therefore the nding of the 12 weeks following surgery, serum PTH concentrations did not
either inflammatory inltrates or scar tissue is most likely depen- recover, but the serum calcium concentration did slowly increase.
dent on when tissue is obtained relative to the time course of the The increases in serum calcium concentration in these thyroparathy-
condition. Interestingly, two dogs with primary hypoparathyroid- roidectomized cats, it was theorized, were an accommodation of
ism from Australia had no histologic abnormalities (Russell etal, existing calcium-regulating systems that operate at suboptimal levels
2006). Detection of antibodies against parathyroid tissue in peo- in the absence of PTH. One example of such an accommodation
ple with idiopathic hypoparathyroidism has confirmed presence might involve changes in vitamin D metabolism, allowing continued
of an autoimmune disease. An immune-mediated mechanism calcium absorption from the intestine despite the PTH deciency
may explain the condition in some dogs and cats. (Flanders etal, 1991). The onset of biochemical or clinical signs sug-
gestive of parathyroid failure after neck surgery in dogs and cats can
Rare Disorders in Humans Causing Hypoparathyroidism begin within days or take as long as several weeks. Other potential
The DiGeorge syndrome in humans consists of parathyroid gland but rare destructive disorders of the parathyroids include neck injury,
absence and thymic aplasia (Rasmussen, 1981; Marx, 2000; Yu, neoplastic conditions within the neck, irradiation, and aminoglyco-
2012). This disorder presumably results from abnormal devel- side intoxication. We have not observed iodine131-induced parathy-
opment of the third pharyngeal pouch during embryogenesis. roid damage in any so-treated hyperthyroid cat.
Parathyroid agenesis has also been reported in dogs (Meuten and
Armstrong, 1989). Another form of idiopathic hypoparathyroid- Pseudohypoparathyroidism
ism in humans is a familial immune-mediated endocrine syn- Pseudohypoparathyroidism is a rare familial disorder in humans
drome that includes hypofunction of the adrenal cortex, ovarian characterized by target tissue resistance to PTH. These individuals
failure, pernicious anemia, thyroiditis, diabetes mellitus, candidia- have hypocalcemia, increased serum concentrations of PTH, and
sis, and occasionally malabsorption. Those patients who manifest a variety of congenital developmental growth and skeletal defects.
disease before 6 months of age conform to an X-linked recessive Increases in serum PTH concentration represent an appropriate
inheritance pattern, and older individuals likely have an autosomal physiologic response to hypocalcemia. If the serum calcium con-
recessive inherited condition (Arnaud and Kolb, 1991; Wysolmer- centration is transiently normalized by an infusion of calcium,
ski and Insogna, 2012). Calcium-sensing receptor mutations have the concentration of circulating PTH decreases. Therefore diag-
also been identied (Pearce etal, 1996). nosis of end-organ unresponsiveness involves (1) the inability of
PTH to increase cyclic adenosine 3,5-monophosphate (cAMP)
Surgically Induced Hypoparathyroidism excretion and (2) elevated circulating PTH concentrations. The
An uncommon cause for primary hypoparathyroidism in dogs hormone secreted by patients with pseudohypoparathyroidism is
and cats, but relatively common in people, is surgical removal, presumably normal in structure. Some of these patients have no
damage, or interruption of blood supply to the glands (Marx, developmental abnormalities (Wysolmerski and Insogna, 2012).
2000). Hypoparathyroidism is a risk of thyroid, parathyroid, A deciency in renal PTH-sensitive cAMP results in renal tubular
or other neck surgeries. Because the incidence of hyperthyroid- resistance to PTH and diminished phosphaturia. Decits in active
ism in cats is high and because canine thyroid tumors are often vitamin D and/or bone cAMP have also been claimed to be the
malignant, thyroid surgery is common in both species. One group inciting factor leading to pseudohypoparathyroidism. One dog
estimated that as many as 10% of hyperthyroid cats undergoing with apparent hypoparathyroidism had an increased serum PTH
surgery suffer from transient or permanent hypoparathyroidism concentration, urine cAMP, and plasma cAMP (Kornegay et al,
(Peterson, 1986). Of 41 hyperthyroid cats that had bilateral thy- 1980). Another dog with hypoparathyroidism had Fanconi syn-
roidectomy, postoperative hypocalcemia (not always associated drome, which was thought to occur secondary to a 1,25vitamin
with clinical signs) developed in 82% undergoing an extracapsu- D deciency (Freeman etal, 1994).
lar surgical technique, 36% with an intracapsular technique, and
11% with two separate thyroidectomies performed 3 to 4 weeks Pseudopseudohypoparathyroidism
apart (Flanders etal, 1987). Of 106 cats studied in a subsequent
report, postoperative hypocalcemia developed in 22% to 33% of Humans with this disorder have typical developmental defects
cats, depending on the surgical technique (Welches etal, 1989). (growth and skeletal abnormalities) associated with pseudo-
Clinical signs were observed only in severely hypocalcemic cats hypoparathyroidism, but they are not hypocalcemic or hyper-
(TCa < 7.0 mg/dL). The incidence of surgically-related hypophosphatemic, nor do they have abnormalities in serum PTH
parathyroidism is now much lower, because surgeons are more concentration (Marx, 2000).
PROGRESSIVE NEPHRON DESTRUCTION should augment phosphate excretion, but with time, secondary
hyperparathyroidism can no longer compensate for the alterations
of CKD; hyperphosphatemia develops and it becomes progres-
sively worse (Chew and Nagode, 1990). Because progressive renal
Decreased Increased disease leads to reduced capacity to form active vitamin D, intes-
formation of
1,25(OH)2D3
phosphate tinal absorption of calcium is limited, enhancing the potential for
retention hypocalcemia. Also, increased urinary calcium excretion may con-
tribute to the hypocalcemia sometimes seen in CKD.
Hypoalbuminemia
Decreased Increased
intestinal serum Reductions in total serum protein and/or albumin concentrations
absorption retention are encountered in a variety of disorders. Hypoalbuminemia is the
of Ca++
most common and clinically least important cause of hypocalce-
mia. As previously described, reductions in circulating albumin
concentration cause a decrease in the protein-bound fraction of
Decreased circulating calcium. However, since iCa concentrations remain
serum Ca++
normal, these animals rarely have clinical signs of hypocalcemia.
Acute Pancreatitis
Parathyroid
glands Hypocalcemia, when it occurs in dogs with acute pancreatitis, is
usually mild and subclinical. Coexisting acidosis, which is com-
monly present, increases the ionized fraction of TCa and further
Increased reduces the likelihood of clinical signs related to hypocalcemia (Hess
biosynthesis etal, 1998). The incidence of hypocalcemia may be higher in cats
and secretion with pancreatitis than in dogs. Results of one study suggest that low
of PTH TCa and iCa concentrations are common in cats with acute pancre-
FIGURE 16-8Pathogenesis of parathyroid hyperplasia during progressive atitis (41% and 61%, respectively). Furthermore, cats with ionized
destruction of nephrons. 1,25(OH)2D3, 1,25-dihydroxyvitamin D3 (calcitriol); Ca, hypocalcemia, even though none had clinical signs related to this
calcium; Ca++, ionized calcium; PTH, parathyroid hormone. complication, had a poorer prognosis than those with normal con-
centrations. A grave prognosis and aggressive medical therapy was
recommended for cats with both acute pancreatitis and a plasma
iCa concentration less than 1.00 mmol/L (Kimmel etal, 2001).
Hypomagnesemia
The traditional theory for development of hypocalcemia in
Magnesium deciency can result in hypocalcemia (see earlier pancreatitis is that calcium precipitates into insoluble soaps via
Magnesium section). saponication of peripancreatic fatty acids formed subsequent to
release of pancreatic lipase. Despite general agreement that this
occurs, it is not clear whether it is sufcient to account for hypocal-
Chronic Kidney Disease (CKD)
cemia in view of the large quantity of calcium that potentially can
Dogs and cats with CKD usually have (in addition to abnormal be mobilized from skeletal reserves. Other contributors to hypo-
BUN and serum creatinine concentrations) increased serum phos- calcemia may include hypomagnesemia, decreased secretion of or
phate and normal serum calcium concentrations. Despite hypocal- resistance to PTH secondary to magnesium deficiency, hypopro-
cemia being uncommon in dogs and cats with CKD, the prevalence teinemia, and glucagon-stimulated calcitonin secretion (Ryzen and
of CKD makes this condition one of the more frequent causes of low Rude, 1990; Dhupa and Proulx, 1998; Schenck and Chew, 2012).
calcium. Low serum TCa was detected in about 10% of dogs with
CKD, and the iCa concentration was low in about 30% (Schenck Critically Ill Patients
and Chew, 2012). In cats, as CKD progresses, the incidence of
hypocalcemia increases. About 15% of cats with moderate CKD Hypocalcemia due to decreases in TCa and/or iCa concentrations
had low iCa, and the percentage rises to 50% if the condition is is common among critically ill people, dogs, and cats, especially
advanced (Schenck and Chew, 2010). In CKD patients, hypo- those with sepsis. Magnitude of the decreases appears to correlate
calcemia is a biochemical problem and rarely clinically signicant. with severity of illness. In addition to sepsis, causes of hypocal-
When present in CKD, hypocalcemia is the result of decreased cemia include systemic inflammatory response syndrome, hypo-
vitamin D synthesis by diseased kidneys and mass law interactions magnesemia, blood transfusions, and acute kidney disease (Zivin
of calcium with the sometimes markedly increased phosphate. Early etal, 2001; Schenck and Chew, 2012).
stages of progressive CKD are associated with a decreased capac-
ity to excrete phosphate. Even mild hyperphosphatemia induces Diabetes Mellitus
subclinical ionized hypocalcemia which, in turn, stimulates PTH
synthesis and secretion. This ionized hypocalcemia is the classi- Almost 50% of diabetic dogs have ionized hypocalcemia. Because
cally described genesis of renal secondary hyperparathyroidism pancreatitis was diagnosed in less than 15% of these dogs, it is
(Fig. 16-8). In dogs with nonazotemic kidney disease (IRIS stage unlikely for pancreatitis to be the sole explanation for the hypo-
I; International Renal Interest Society; www.iris-kidney.com), 36% calcemia (Hess et al, 2000). In a study on more than 100 dogs
had secondary hyperparathyroidism. The hyperparathyroidism in DKA, slightly more than 50% had ionized hypocalcemia, the
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severity of which correlated with mortality (Schenck and Chew, such as lymphangiectasia. The degree of calcium malabsorption
2012). and the poor absorption of vitamin D appear to correlate with the
extent of small bowel disease (Mellanby etal, 2005). Hypomagne-
Puerperal Tetany (Eclampsia) semia may also play a role in the physiology resulting in hypocal-
cemia. In two studies, it was suggested that hypomagnesemia and
Eclampsia is an acute life-threatening condition that develops sec- hypocalcemia may have a related pathogenesis involving intestinal
ondary to extreme hypocalcemia in lactating bitches and queens loss, malabsorption, and abnormalities of vitamin D and PTH
(Fascetti and Hickman, 1999; Drobatz and Casey, 2000). Dogs metabolism. Magnesium supplementation was demonstrated to
and cats with clinical signs of eclampsia are usually severely hypo- normalize serum magnesium and PTH concentrations, improve
calcemic (< 6 to 7 mg/dL). Eclampsia is most common in small plasma iCa concentrations, and alleviate clinical signs of paresis
dogs and less common in cats and large dogs. Signs seen by veteri- (Kimmel etal, 2000; Bush etal, 2001).
narians usually depend on how quickly the owner recognizes the
problem and seeks professional care. Most bitches and queens are
Nutritional Secondary Hyperparathyroidism
affected during the rst 21 days of nursing, although eclampsia
has been diagnosed as early as during the last 2 weeks of gestation It would be rare for a pet being fed commercially available nutri-
and as late as 45 days after whelping. Diagnosis of eclampsia is tionally complete and balanced diet to ever develop this condi-
usually based on the presence of neuromuscular signs (tetany) in tion. However, dogs or cats exclusively fed diets containing a low
a lactating bitch or queen. In most situations, the diagnosis is so calcium-to-phosphorus ratio (the classical examples are beef heart
obvious that the serum calcium concentration is never assessed. and liver) can develop severe mineral deciencies. BARF (bio-
However, three cats with preparturient eclampsia had hypother- logically appropriate raw food or bones and raw food) diets
mia rather than the expected hyperthermia, and four cats had have also been implicated (DeLay and Laing, 2002). Severe gas-
clinical signs that included flaccid paralysis, rather than the more trointestinal disease may also result in this condition by directly
typical tonic-clonic muscle fasciculations noted in dogs (Fascetti impairing calcium absorption or, indirectly, by interfering with
and Hickman, 1999). vitamin D absorption (Mellanby et al, 2005; Skelly, 2012). If
Hypocalcemia typically arises as a consequence of lactation and either a dietary deficiency or an inability to absorb calcium from
its attendant calcium loss into milk. Other possible contributors intestinal content results in decreased circulating calcium concen-
include poor use of dietary calcium and loss of calcium to fetal skel- tration, a cascade of events begins. Those events include increased
etal development. Sometimes the stress of nursing reduces a bitchs PTH secretion, reduction in bone mass as calcium is removed
(or queens) appetite or interferes with her ability to eat. Another from bone to replace that not available in the diet, diffuse skel-
predisposing factor is the parathyroid gland atrophy that can be etal osteopenia, and, if persistent, nutritional secondary hyper-
caused by improper diet or dietary supplements. In one study, parathyroidism. Although renal secondary hyperparathyroidism
44% of bitches with eclampsia had hypomagnesemia. Decreased seems to target bones of the face (fibrous osteodystrophy), nutri-
magnesium-to-calcium ratios at the neuromuscular junctions can tional hyperparathyroidism appears to target long bones and ver-
promote tetany. Magnesium therapy may be benecial for treat- tebrae. This process can cause bone pain and pathologic fractures.
ment of eclampsia (Aroch etal, 1999). Because the skeletal disturbances are the result of physiologic
processes placing the serum calcium concentrations as highest
priority, affected dogs and cats usually have normal serum con-
Malabsorption Syndromes
centrations of TCa, iCa, and phosphorus. A minority of affected
Many patients with protein losing enteropathies have hypoal- dogs and cats have had mild to severe hypocalcemia (Tomsa etal,
buminemia and typical decreases in serum TCa concentrations 1999). Treatment involves providing balanced diets and restrict-
but serum iCa concentrations that are within reference intervals. ing activity until skeletal remodeling is complete. Diagnosis is
True enteropathy-associated vitamin D deficiency leading to based on recognizing skeletal disorders in a dog or cat receiving
hypocalcemia is uncommon but possible. Malabsorption con- an improper diet.
ditions, such as inflammatory bowel disease (IBD) or intestinal
lymphoma, in dogs, cats, and people are frequently associated Acute Kidney Injury (AKI) and Ethylene
with derangements in fat soluble vitamin metabolism (Gow etal, Glycol Toxicity
2011; Wysolmerski and Insogna, 2012; Lalor etal, 2014). Vari-
ous explanations have been proposed for enteropathy-associated Acute kidney injury (such as that which occurs with ethylene gly-
hypocalcemia, including decreased intestinal absorption or col poisoning) and postrenal failure (such as that which occurs
increased intestinal loss of both albumin and vitamin D bound to with urinary tract obstruction) may result in abrupt and severe
vitamin D-binding protein (Lalor etal, 2014). Decreased appetite increases in serum phosphate concentration. Mass law effects
in patients with significant enteropathies may contribute to vita- cause a secondary reduction in serum calcium concentrations.
min D deficiency. Serum vitamin D concentrations were signifi- Hypocalcemia may be exaggerated in acute failure because rapid
cantly lower in dogs with IBD and moderate to severe decreases onset of these disturbances blunts compensatory mechanisms.
in appetite as compared with dogs that had similar bowel disease Dogs with acute intrinsic renal failure had a mean serum TCa
but normal appetites (Gow etal, 2011). A majority of 10 IBD concentration of 9.8 mg/dL (Vaden etal, 1997). Ethylene glycol
cats and six with intestinal small cell lymphoma had low vitamin intoxication can cause severe renal failure, acidosis, hypocalcemia,
D concentrations, but only two were hypocalcemic (Lalor etal, tetany, and death.
2014). There is also evidence from experimental models suggest-
ing that IBD may be due to hypovitaminosis D rather than caused Urinary Tract Obstruction
by it (Mora etal, 2008).
Hypocalcemia may be caused by or worsened by excess fecal cal- Male cats with long-standing (more than 12 to 24 hours) urethral
cium excretion due to decreased resorption of calcium in disorders obstruction and severe hyperphosphatemia often have associated
hypocalcemia, hyperkalemia, azotemia, and sometimes experience Although this problem has not been recognized in the dog, it is
seizures (Chew and Meuten, 1982). Hypocalcemia was diagnosed described here to remind practitioners that a variety of drugs have
in 26% of male cats with urethral obstruction at initial presenta- the potential to cause unexpected endocrine problems. Further-
tion, based on serum TCa assessment. On the basis of iCa con- more, several of our hypoparathyroid dogs were referred because
centrations, however, 75% were hypocalcemic. The hypocalcemia of failure to respond to anticonvulsant therapy. The nding of
was dened as mild in 37.5%, moderate in 25%, and severe in hypocalcemia in dogs on relatively high doses of anticonvulsants
12.5% of affected cats. These abnormalities may contribute to car- may be mistakenly interpreted as iatrogenic.
diac dysfunction in severely affected cats. Although effects of IV
administration of calcium were not evaluated, results in this study Hyperthyroid Cats
support their use in cats with urethral obstruction (Drobatz and Cats with untreated hyperthyroidism have signicantly lower iCa
Hughes, 1997). concentrations than do control cats, although none had decreases
in TCa concentration, and only 4 of 15 had iCa concentrations
below the reference range. Hyperthyroid cats also had signicantly
Phosphate-Containing Enemas
increased serum PTH concentrations. These changes are likely
Phosphate-containing enemas may result in acute and severe associated with the hyperphosphatemia often noted in hyperthy-
hyperphosphatemia following colonic absorption, especially when roid cats. The importance of these ndings is not known (Barber
administered to dehydrated cats with colonic atony and mucosal and Elliott, 1996).
disruption. Colonic absorption of sodium and phosphate from
the enema solution as well as transfer of intravascular water to the Vitamin D Deficiency
colonic lumen (because of hypertonicity of the enema solution) Vitamin D deciency is an unlikely clinical cause of hypocalcemia
can cause hypernatremia and hyperphosphatemia. Acute increases (Henik etal, 1999). Dogs and cats with a significant and diffuse
in serum phosphate may cause reciprocal signicant declines in intestinal malabsorption syndrome may lose the ability to absorb
serum calcium concentration (Atkins etal, 1985; Jorgensen etal, vitamin D.
1985). Therefore use of phosphate-containing enemas is not rec-
ommended in animals predisposed to hyperphosphatemia, such Use of Citrated Blood
as with severe obstipation, marginal renal function, or abnormal Blood for transfusion that contains citrates as anticoagulant may
serum calcium-to-phosphorus ratios. Clinical signs of phosphate induce hypocalcemia, particularly if the volume of donor blood is
enema toxicosis (shock and neuromuscular irritability) result from small compared with the volume of anticoagulant.
hypocalcemia and hypernatremia. Treatment may require plasma
volume expansion and calcium. Diagnosis is based on the history Trauma
(Peterson, 1992). Trauma, especially soft tissue trauma, has been reported as a cause
of hypocalcemia (Chew and Meuten, 1982), but this is rare.
Miscellaneous Causes Medullary Carcinoma of the Thyroid
Laboratory Error Medullary carcinoma of the thyroid has been reported to cause
An uncommon cause of reported hypocalcemia is laboratory severe hypocalcemia and tetany in one dog and represents an
error. Incorrect reporting of the serum calcium concentration can unusual cause of hypocalcemia in humans.
reflect a simple mistake or artifact due to samples submitted in
tubes containing ethylenediaminetetraacetic acid (EDTA) as an Primary and Metastatic Bone Cancer
anticoagulant, because EDTA chelates calcium. Mixing of serum Primary and metastatic bone tumors are common in small animal
with air can signicantly decrease iCa concentrations. Freshly practice. Humans, dogs, and cats with tumors that have metasta-
obtained plasma for iCa determination should be transported to sized to bone usually have normal serum calcium concentrations.
reference laboratories with a cold pack. If a delay in processing Hypercalcemia is occasionally associated with primary bone neo-
lasting days seems likely, plasma should be sent frozen (Schenck plasia and with metastasis of certain cancers to bone. However,
etal, 1995). Caution should be exercised in the interpretation of hypocalcemia and hypophosphatemia rarely occur in humans.
iCa measured with portable analyzers, because results for dogs When osteoblastic metastases are present in humans, the incor-
and cats are lower than those obtained with standard methodol- poration of calcium into those lesions may be sufcient to result
ogy. The use of dry heparin syringes for sample collection may in measurable hypocalcemia and even clinical signs. This has not
negate this difference (Grosenbaugh etal, 1998). Whenever the been reported in dogs or cats.
reported serum calcium concentration is unexpectedly high or
low, it should be rechecked. Chemotherapy and the Tumor Lysis Syndrome
The tumor lysis syndrome can follow acute release of intracel-
Anticonvulsant Therapy lular potassium and phosphate during chemotherapy for highly
Surveys of humans receiving long-term anticonvulsant therapy sensitive neoplasms, such as lymphoid or bone marrow tumors
(principally phenobarbital and phenytoin) have shown a ten- (Persons etal, 1998). Among the multiple metabolic abnormali-
dency to develop hypocalcemia, hypophosphatemia, and abnor- ties that can occur in this setting is hypocalcemia due to mass
mal serum alkaline phosphatase activities. Studies of these subjects law interactions induced by acute and severe hyperphosphatemia
reveal a state similar to vitamin D deciency. Bone biopsies and (Calia etal, 1996; Piek and Teske, 1996). Further, calcium salts
radiographs suggest osteomalacia without evidence of malabsorp- can be deposited into soft tissues. Acute kidney injury may also
tion or renal disease. Serum PTH concentrations are increased but result (Schenck and Chew, 2012). In addition to hypocalcemia,
remain normally suppressible with calcium infusions. Severity of transient PTH deciency may occur (Horn and Irwin, 2000).
the altered calcium metabolism is directly related to dosage (Arn- One salicylate-intoxicated cat developed hypocalcemia associated
aud and Kolb, 1991). with sodium bicarbonate therapy (Abrams, 1987).
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THERAPY FOR HYPOCALCEMIA AND Emergency Therapy for TetanyDiagnosis Not Apparent
HYPOPARATHYROIDISM
In the event that a practitioner is treating a seizing animal with-
General Approach out a specic diagnosis, anti-convulsants are usually utilized. This
approach is usually benecial, even in hypocalcemic pets. How-
Primary hypoparathyroidism can be permanent, requiring acute ever, if treatment fails or if a diagnosis is still not obvious, blood
and then lifelong management to alleviate and prevent clinical should be drawn for glucose, calcium, and any other parameter
signs. Hypoparathyroidism following surgical removal or abla- that may lead to a diagnosis. In the meantime, IV glucose and/or
tion of a parathyroid adenoma that caused hyperparathyroidism calcium can be administered.
may require short-term therapy but, as remaining normal-but-
atrophied parathyroid cells return to function, one should be able Hypocalcemic Tetany: Intravenous Calcium
to taper and discontinue medications. Similarly, eclampsia (puer- When possible, hypocalcemic tetany should immediately be treated
peral tetany) is a classic condition due to hypocalcemia in which with calcium salts. Ten percent calcium gluconate, readily available
specic and acute correction of the calcium deciency is necessary and not as caustic as calcium chloride, is recommended and should
but chronic treatment is not. In contrast to these examples, no be slowly administered intravenously, usually over a 10 to 30 min-
treatment is indicated for animals with hypocalcemia attribut- ute period, or to effect. ECG monitoring is advisable and, if not
able entirely to hypoalbuminemia, assuming the iCa fraction is possible, one should listen to the heart and have a finger on the
normal. pulse during the calcium infusion. If bradycardia, pulse deficits,
Treatment of hypocalcemia virtually always requires that a pro- arrhythmias, S-T segment elevation, shortened Q-T intervals, and/
tocol be tailored to the individual needs of a dog or cat. Manage- or premature complexes are recognized, the IV infusion should be
ment will be effected by the magnitude of the hypocalcemia and slowed or temporarily discontinued (Peterson, 1992). This emer-
the rate of decline in calcium concentration. The trend in serum gency therapy is usually successful and cessation of seizures, for
concentrations (fluctuating, remaining stable, or quickly fall- example, is typically noted within a minute or minutes of initiating
ing) will influence decision processes. Aggressive approaches are the infusion. The total dose needed to control tetany is not predict-
needed for dogs and cats with obvious clinical signs, for those with able. Furthermore, some clinical signs may be slower to respond.
signicant decreases in TCa or iCa concentrations, or when severe Nervousness, panting, and behavioral changes may persist for as
hypocalcemia can be anticipated (e.g., with therapy for primary long as 30 to 60 minutes after return of eucalcemia, perhaps reflect-
hyperparathyroid dogs who have endured chronically increased ing a lag in equilibrium between CSF and circulating calcium.
serum TCa concentrations; see Chapter 15). Veterinarians should
not delay treatment for hypocalcemia until clinical signs are obvi- Calcium Dose and Salt Choices
ous. Such an approach, at best, exposes the pet to an extremely The calcium content of different salts varies considerably. For
painful condition. At worst, it places the pet at risk for developing example, both calcium gluconate and calcium chloride supple-
a life-threatening event. ments are available as 10% solutions in 10-mL ampules, and each
The goal of therapy, one that may be difcult to achieve, is to ampule provides 1 g of the parent compound. However, calcium
increase serum calcium concentrations smoothly above the thresh- chloride provides approximately 27 mg/mL of elemental calcium,
old responsible for clinical signs. That threshold is usually a TCa and calcium gluconate provides approximately 9 mg/mL. The
concentration of about 6.0 mg/dL, or above a plasma iCa concen- 200 mg/mL calcium borogluconate solution contains the equiva-
tration of about 0.6 to 0.7 mmol/L. Individual differences can be lent of about 15 mg/mL of elemental calcium. Calcium boro-
signicant, however. Clinical signs typically improve with slight gluconate is 1.6 times more concentrated and calcium chloride
increases in measurable calcium. Veterinarians should raise mea- is 3 times more concentrated than the 10% calcium gluconate
sured calcium concentrations conservatively, because values that solution. Thus, guideline doses for calcium gluconate (0.5 to 1.5
increase into reference ranges increase risk for hypercalcemia, asso- mL/kg), calcium borogluconate (0.3 to 0.9 mL/kg), and calcium
ciated hyperphosphatemia, tissue mineralization, and stone for- chloride (0.15 to 0.5 mL/kg) reflect these different concentrations
mation. For anticipated or known postsurgical hypocalcemia that (Table 16-4). It may be easiest to achieve a slow infusion by first
will be transient, as in pets being treated for primary hyperpara- calculating the estimated required dose and then diluting that
thyroidism, it is physiologically ideal to maintain calcium con- amount in a larger volume of 0.9% saline. Recommended doses
centrations above the threshold for tetany but below established should be used as guidelines, and patient response should be the
reference ranges, because below normal values should enhance denitive factor in determining the volume administered (Skelly,
functional recovery of atrophied parathyroid glands. 2012). Remember that extravasation of calcium chloride outside
TABLE 16-4 SOME AVAILABLE PARENTERAL CALCIUM PREPARATIONS
PREPARATIONS APPROXIMATE CALCIUM CONTENT DOSE COMMENT

10% Calcium gluconate (IV) 9.3 mg Ca/mL 0.5-1.5 mL/kg Administer slowly to effect
Stop if bradycardia or shortened Q-T interval
2.5-3.75 mg/kg/hr Infusion to maintain safe serum Ca level
10% Calcium gluconate (SC) 9.3 mg Ca/mL Dilute 2, 3, 4:1 SC to support serum calcium without IV (see text)
10% Calcium borogluconate (IV) 15.0 mg Ca/mL 0.3-0.9 mL/kg Same as for Ca gluconate
10% Calcium chloride (IV) 27.2 mg Ca/mL Do not use Do not use
Ca, Calcium; IV, intravenous; Q-T, interval on an electrocardiogram (ECG); SC, subcutaneous.
a vein is caustic, potentially causing large areas of tissue death and Subcutaneous Calcium. Once tetany has been controlled
sloughing. Extravasation may also cause calcinosis cutis (Schick with IV calcium gluconate, administration of subcutaneous (SC)
et al, 1987). In our opinion, calcium chloride should never be calcium has been effective, simple, and inexpensive. Continuous
stocked by small animal practitioners, thus eliminating any pos- IV administration of fluids is expensive and requires hospital-
sibility of its use. ization. However, one can utilize the dose of calcium gluconate
required to control tetany initially and administer that dose SC
Hyperphosphatemia every 6 to 8 hours. Alternatively, a calcium dose of 60 to 90
Infusion of calcium-rich fluids should be performed with caution in mg/kg/day, divided, can be given. The calcium gluconate should
any hyperphosphatemic dog or cat. Hyperphosphatemia, however, be diluted as one part of calcium to two, three, or four parts
is common among hypocalcemic animals due to mass law effects. of saline. This protocol has effectively supported serum calcium
Therefore, although a concern, as calcium increases with treat- concentrations and has not caused inflammation or sloughing of
ment, the phosphate concentrations should decrease. However, in skin. This is true even in dogs treated subcutaneously for months.
conditions like CKD, the combination of calcium administration The SC regimen is an efcacious method of supporting circulat-
and hyperphosphatemia could cause soft tissue mineralization and ing calcium while waiting for atrophied parathyroid glands to
further renal damage to the kidneys (Chew and Meuten, 1982). regain function, or while waiting for oral vitamin D and calcium
to have effect. The procedure is easily taught to owners, further
Fever decreasing expense.
Fever, sometimes greater than 105 F, commonly accompanies tet- Remember, calcium chloride should never be administered sub-
any. Veterinarians may be tempted to treat both hypocalcemia and cutaneously, but calcium gluconate is usually safe. Several cases
fever (using ice or alcohol baths and/or parenteral drugs). How- of calcinosis cutis following SC administration of calcium gluco-
ever, with administration of calcium, fever should be monitored nate have been reported (Ruopp, 2001; Schaer etal, 2001; Skelly,
but not treated. Fever usually dissipates rapidly with control of 2012). However, our experience with repeated SC injections of
tetany. Additional measures to lower body temperature may result diluted 10% calcium gluconate, without problems, suggests that
in hypothermia and the development of shock. Further, three of such terrible side effects are quite uncommon.
four cats reported to have had preparturient eclampsia were hypo- After normal or near-normal serum calcium concentrations
thermic (Fascetti and Hickman, 1999). have been maintained for 48 hours, the frequency of SC injec-
tions should be decreased from every 6 to every 8 hours. If serum
Subacute Management of Hypocalcemia: Post-Tetany calcium concentrations remain stable for the ensuing 48 to 72
Maintenance Therapy hours, the calcium can be tapered to twice daily. This protocol is
continued until parenteral calcium has been completely discontin-
The Issue. Once signs of hypocalcemic tetany are controlled ued. Obviously, the tapering process in each patient may not be
with an IV calcium infusion, its effects usually only last minutes to this smooth, because response to oral therapy is variable. Ideally,
an hour or so. On the other hand, long-term maintenance therapy the serum TCa concentration should be maintained above 8 mg/
with oral vitamin D and oral calcium supplementation usually dL. Concentrations below 8 mg/dL indicate a need to increase
requires 24 to 96 hours before effect is achieved. Therefore, par- the dose or frequency of parenteral calcium. Serum calcium con-
enteral calcium support during the initial post-tetany period is centrations of 8 to 9 mg/dL suggest maintaining the current par-
necessary. enteral dose. Concentrations greater than 9 mg/dL may indicate
The Alternatives. Repeated Intravenous Boluses. One method need for reducing the dose. The frequency and/or dosage of par-
for managing hypocalcemia in the immediate post-tetany period is enteral calcium are often increased before the therapy can be safely
repeated IV calcium boluses. This procedure is not recommended decreased and then discontinued. This is true regardless of the cal-
except in emergencies, because wide fluctuations in circulating calcium supplementation protocol used.
cium concentrations result.
Continuous Intravenous Infusion. Continuous IV infusion of
Maintenance (Chronic) Therapy for Hypoparathyroidism
calcium can be utilized at doses of 60 to 90 mg/kg/day elemen-
tal calcium (2.5 to 3.75 mg/kg/hr) until oral medications pro- General
vide control of serum calcium concentration. Initial doses in the The most appropriate therapy for hypoparathyroidism would be
high end of this protocol are recommended for dogs and cats with some form of PTH given to maintain normal physiologic con-
severe hypocalcemia. The dose should be decreased according to centrations, likely determined on an individual basis. However,
the serum calcium concentration achieved and as oral calcium and no long-acting commercially available PTH preparation is avail-
vitamin D become effective. able at the time of writing this comment, although such a prod-
Using 10% calcium gluconate solutions, 10 mL provides 93 uct is currently being evaluated. Parenteral PTH is available on
mg of elemental calcium. A convenient protocol for infusing a limited basis but lasts only hours. Thus, oral administration of
calcium assumes that the IV fluids are being administered at a both a vitamin D product and a calcium product, especially in
typical maintenance rate of about 60 mL/kg/day (2.5 mL/kg/ the early phases of therapy, remains the most successful means
hr). Approximately 1, 2, or 3 mg/kg/hr of elemental calcium is of treating hypoparathyroidism. It is emphasized that oral cal-
provided by adding 40, 80, or 120 mL of 10% calcium gluco- cium should be a component of any early treatment plan, espe-
nate, respectively, to each liter of fluid solution, equivalent to cially if the animal is not eating. Active intestinal calcium uptake
6.5 to 10 mL/kg/day. Calcium salts may precipitate if added to transport mechanisms are under control of vitamin D when cal-
solutions containing lactate, acetate, bicarbonate, or phosphates. cium intake is low, but vitamin D-independent passive intestinal
Additionally, IV solutions containing sodium bicarbonate should absorption of calcium occurs when intake is high. One can take
be avoided because systemic alkalinization can decrease circulat- advantage of this passive-but-enhanced calcium absorption pro-
ing iCa concentrations, precipitating clinical signs in dogs or cats cess while administered vitamin D has time to become effective
with borderline hypocalcemia (Rosol etal, 2000). (Chew etal, 2009).
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Because most commercially available pet food contains ade- Initially, large doses are required to induce normocalcemia. Dogs
quate calcium for daily needs, once a dog is home and stable, we and cats often require 4000 to 6000 U/kg daily doses to offset
typically slowly taper oral calcium therapy over a period of 12 the decreased biologic potency of this product in hypoparathy-
to 16 weeks. Recurrent hypocalcemia and worrisome hypercal- roid patients. Additionally, large doses are required to saturate fat
cemia represent potential complications of treatment if adequate depots, which is important because vitamin D is a fat-soluble vita-
calcium and phosphorus monitoring is neglected. On the other min. Effect of the medication is usually obvious 5 to 14 days after
hand, we have successfully helped monitor and manage a number beginning therapy. Parenteral calcium can usually be discontinued
of primary hypoparathyroid dogs for years and encourage clients 1 to 5 days after starting oral vitamin D treatment. The serum
to treat their pet. calcium concentrations should be below the level that might be
associated with hypercalciuria (risk for calculi formation) or severe
Vitamin D hypercalcemia and hyperphosphatemia (risk for nephrocalcinosis
General.Maintenance therapy for hypoparathyroidism con- and renal failure).
sists of oral vitamin D and calcium supplementation. The need Dogs and cats receiving vitamin D2 should remain hospitalized
for vitamin D therapy is usually permanent in dogs and cats with until the serum TCa concentration remains between 8 and 10 mg/
primary, naturally occurring, parathyroid gland failure. Calcium dL without parenteral support and the pet is eating and drinking
supplementation, however, can often be tapered and even stopped on its own. Once these goals are achieved, the pet can be returned
after several months of administration, because dietary calcium to the owner, and the vitamin D2 is usually given every other day.
is sufcient for maintaining the needs of the animal. Conserva- Serum calcium concentrations should be monitored weekly, with
tive doses of supplemental calcium given chronically, however, vitamin D2 doses adjusted to maintain a serum calcium concen-
ensure that vitamin D, which raises serum calcium by promoting tration of 8 to 9.5 mg/dL. The aim of therapy is to avoid hypo-
its intestinal absorption, has substrate upon which to function. calcemic tetany on one hand, while also limiting hypercalcemia.
Iatrogenic hypoparathyroidism in dogs and cats treated for pri- Even after a pet appears stable, monthly rechecks are strongly
mary hyperparathyroidism is often transient and lifelong therapy advised for 6 months and should be followed by rechecks every
is not always needed. 2 to 3 months indenitely. These animals cannot be rechecked
In contrast to tetany, for which the immediate goal of treatment too often. Underdose can place the pet at risk for tetany. Vitamin
is to avoid recurrence of neuromuscular signs, the aim of long- D-induced hypercalcemia can result in renal damage and failure, a
term therapy is to maintain serum TCa concentrations at mildly problem minimized through proper monitoring. Vitamin D2 has
low to low-normal concentrations (8.0 to 9.5 mg/dL). Such cal- been used in cats and dogs with success and is relatively inexpen-
cium concentrations are well above the risk threshold for clinical sive. Some of our dogs and cats receive medication as infrequently
hypocalcemia and well below concentrations (even with day-to- as twice monthly, whereas others require daily supplementation.
day fluctuations) that might be associated with hypercalcemia The drawbacks of vitamin D2 include the length of time to
and hyperphosphatemia, which would place the patient at risk achieve maximal effect and the length of time it takes to reduce
for renal damage due to nephrocalcinosis. Maintaining the serum effects if an overdose is documented. If hypocalcemia is docu-
calcium concentration at the low end or just below the reference mented, it may take days to weeks before an increase in dose is
range also reduces risk of hypercalciuria and associated calculi for- reflected in the serum calcium concentration. Hypercalcemia,
mation. Mild hypocalcemia should also serve to promote return to if it occurs, is not easily resolved because fat-soluble vitamin D
function of atrophied parathyroid glands may need to be discontinued for as long as 1 to 4 weeks before
Vitamin D2 (Ergocalciferol). Vitamin D2 is a widely available serum concentrations decline significantly. Hypercalcemia should
and relatively inexpensive drug (40,000 USP U/mg; Table 16-5). be aggressively treated with IV fluids, especially if the product of
TABLE 16-5 SOME VITAMIN D PREPARATIONS
DRUG DOSE* TIME TO MAXIMUM EFFECT TIME FOR TOXCITIY TO RESOLVE

1,25-dihydroxyvitamin D3 Initial: 1 to 4 days 2 to 14 days
(1,25[OH]2D3; calcitriol) 20 to 30 ng/kg/day, divided b.i.d.
Maintenance:
5 to 15 ng/kg/day
Vitamin D2 Initial: 5 to 21 days 7 to 28 days
(ergocalciferol) 4000 to 6000 U/kg/day
Maintenance:
1000 to 2000 U/kg/7 days
Alfacalcidol Initial: 1 to 4 days 2 to 14 days
0.01 to 0.03 g/kg/day
Maintenance:
May need to be increased or decreased
Dihydrotachysterol (DHT) Initial: 1 to 7 days 2 to 14 days
0.02 to 0.03 mg/kg/day
Maintenance:
0.01 to 0.02 mg/kg/24 to 48 hours
*Note: Doses are listed as mg, g, ng, and Units/kg of body weight.
the serum calcium multiplied by the serum phosphate is greater to effect and then progressively decreasing the dose. As with other
than 60 to 80. These factors make ergocalciferol the least attractive forms of vitamin D, in-hospital monitoring is recommended until
agent for long-term treatment of hypocalcemia. We restrict use of circulating calcium concentrations are stable. Owners can then
ergocalciferol to dogs whose owners have nancial limitations that administer the drug subcutaneously.
prevent use of calcitriol. Dihydrotachysterol. DHT, although not available at the time
Calcidiol and Alfacalcidol. Alfacalcidol has about twice the of writing, is described here, because it may be marketed in the
potency of ergocalciferol in binding capacity to natural calcitriol future. It is a synthetic vitamin D analogue. The advantages of
receptors. It is, however, 500 times less potent than calcitriol in DHT over vitamin D2 are that it raises the serum calcium con-
this regard. It is a reasonable alternative to calcitriol. This form of centration more rapidly (1 to 7 days) and its effect dissipates faster
vitamin D must undergo 25-hydroxylation by the liver before it when administration is discontinued. Veterinarians, therefore,
is metabolically active. The process occurs rapidly and is unregu- have more control over therapy. DHT is more potent than vitamin
lated; therefore the time required for effect is similar to that of D2; 1.0 mg of DHT is equivalent to 120,000 U of vitamin D2.
calcitriol (Skelly, 2012). The drug is available in some countries as The rapid onset of action and the increased effectiveness of DHT
0.25, 0.5, and 1 g capsules and in a liquid formulation of 2 g/ are a result of its stereochemistry; the A ring of the sterol structure
mL. As available, the drug can be used in cats and small dogs. The is rotated 180 degrees so that the hydroxyl group in the third posi-
recommended dose is 0.01 to 0.03 g/kg, once daily. The dose tion serves as a pseudo-1-hydroxyl group (Fig. 16-9). Therefore,
should be tailored to the needs of the individual (Skelly, 2012). after hepatic 25-hydroxylation, DHT has biologic activity that is
Oral 1,25-Dihydroxyvitamin D3; Calcitriol. Calcitriol is the greater than 25-hydroxyvitamin D (25[OH]D) and less than that
most potent form of vitamin D in stimulating intestinal calcium of 1,25 dihydroxyvitamin D3 (1,25[OH]2D3) (Peterson, 1982).
transport and osteoblastic activity in the skeleton. It also has the The polarity and lower dose requirements of DHT limit its storage
most rapid onset of maximal action and the shortest biologic half- in fat compared with ergocalciferol.
life (Chew and Nagode, 2000; Rosol etal, 2000). Oral calcitriol DHT was initially given at a dose of 0.03 mg/kg/day (divided
has a direct effect on intestinal receptors, stimulating intestinal and given twice a day) for 2 days or until effect is demonstrated,
calcium absorption to a greater degree than other forms of vitamin then 0.02 mg/kg/day for several days, and nally 0.01 mg/kg/
D, including parenteral administration (Coburn, 1990). Because day in divided dosages. As suggested with the less potent forms of
calcitriol only programs undifferentiated cells in intestinal crypts vitamin D, signicant individual variation in dose requirements
and turnover of these cells takes place every 24 hours, calcitriol is dictate that pets remain hospitalized until the serum TCa concen-
given twice daily to ensure continuous effect (Chew etal, 2009). tration remains stable between 8 and 9.5 mg/dL (or the iCa 1.0
The dose of calcitriol can be adjusted and changes take effect to 1.2 mmol/L) for several days. We have seen cats and dogs that
quickly because of its rapid onset of action and brief biologic effect. appeared to be resistant to the tablet and capsule forms of this
If hypercalcemia occurs, the effects of this drug abate quickly after drug (0.125, 0.25, 0.4 mg) but respond readily to the liquid (0.25
stopping therapy or with dose reduction. The peak serum concen- mg/mL). We have also seen dogs and cats fail to respond to any
tration of calcitriol is reached after 4 hours, the half-life is 4 to form of DHT but respond to calcitriol. Rechecks of the serum
6 hours, and the biologic half-life is 2 to 4 days. A loading dose calcium concentration on a weekly basis allow dosage adjustment
of 20 to 30 ng/kg/day can be administered for 2 to 4 days and while avoiding prolonged hypercalcemia or hypocalcemia. As with
then decreased to a maintenance dose of 5 to 15 ng/kg/day, divided vitamin D2, long-term rechecks at least every 2 to 3 months are
and given twice a day. (Note: This dose is in nanograms.) Calcitriol strongly encouraged. Serum calcium concentrations higher than
(250 and 500 ng capsules as well as 1000 ng/mL liquid formula- desired (> 10.5 to 11.0 mg/dL) should be treated by lowering or
tion; Rocaltrol, Hoffman-LaRoche) is formulated for humans and discontinuing vitamin D therapy and, depending on the severity
may require reformulation for dogs and cats. The concerns we have of the clinical signs and biochemistry abnormalities, possibly initi-
regarding calcitriol only relate to expense and the need for reformu- ating IV fluids (see Chapter 15). The lag period between stopping
lation. Although reformulation should be reliable, inconsistencies DHT and noting a fall in the serum calcium concentration has
occur among pharmacies. Reformulation by specialty pharmacies been 4 to 14 days, a longer period than is needed with calcitriol
of calcitriol into liquid or into capsule sizes tailored to the need of but a briefer period than with vitamin D2.
specic pets may not provide the same effectiveness to each patient.
We have had experience with one dog that did not respond C9H17
to oral calcitriol at any dose. This dog was known to have liver H3C
insufciency because a diagnosis of vascular anomaly had been
made 10 years earlier. Although calcitriol is active, it is interest-
ing to note lack of response in this setting. Although this dog was
not tested, it is now understood that if a patient is documented
to have concurrent hypomagnesemia, supplementation with the 8
sulfate form should be considered at a dose of 1 to 2 mEq/kg/day.
In some cases, normalization of serum magnesium concentrations 7
may lead to lower requirements of calcitriol and/or calcium. 6
Parenteral Calcitriol.In the event that oral medication can-
not be administered or if oral calcitriol is ineffective, parenteral 5
calcitriol can be given. Empirically, the same dose as that used for H3C
oral administration can be utilized (20 to 30 ng/kg/day). The drug 10
is usually given IV to human dialysis patients, three times weekly, A
immediately after dialysis (Rolla etal, 1993; Selgas etal, 1993). The
drug can also be given subcutaneously or intraperitoneally. We have OH
used parenteral calcitriol successfully by administering it IV, t.i.d. FIGURE 16-9 The chemical structure of dihydrotachysterol (DHT).
|
Calcium Supplementation Treatment Protocol. In cats, the dosage of calcium is approxi-

Initial Approach to Oral Calcium. Once tetany is controlled mately 0.5 to 1.0 g/day in divided doses. In dogs, the dosage is
with bolus IV calcium, serum calcium levels should be maintained usually 1.0 to 4.0 g/day in divided doses. Alternatively, the dose
with a slow IV infusion or SC injections. When the pet is able to of elemental calcium can be determined as about 25 to 50 mg/
eat without vomiting, oral calcium and vitamin D therapy should kg/day, divided into two or three daily doses. Recommendations
be initiated. Within 24 hours, parenteral calcium administration regarding calcium are always approximate, in part because the
can begin to be tapered, and within 72 hours it is usually discon- effectiveness of administered vitamin D, the oral preparation of
tinued. Meanwhile, oral therapy is maintained. In this manner, calcium used, and the intestinal milieu are major contributors to
smooth continuous control is achieved. Calcium available within the stability of serum calcium concentrations. As administered
intestinal content must be adequate when treating hypopara- vitamin D reaches a steady level, the dose of oral calcium can be
thyroidism, because long-term success depends on the action of gradually tapered over a period of 2 to 4 months. This method
administered vitamin D, which increases intestinal absorption of of treatment avoids unnecessary therapy, considering that dietary
calcium. Commercial pet food typically contains sufcient calcium calcium should be sufcient to supply the needs of the pet and
to supply the needs of hypoparathyroid dogs and cats. However, should decrease the demands of treatment placed on the owner.
because symptomatic hypocalcemia can be fatal, such catastrophic In spite of this logical approach, we tend to continue low dose
consequences of severe hypocalcemia must be avoided. For this calcium supplementation to our patients.
reason, especially early in the course of therapy, we continue oral
calcium at low doses indefinitely.
Summary of Keys to Long-Term Success
Calcium Supplements.Supplements can be provided by
administering calcium as the gluconate, lactate, chloride, or It is emphasized that the ideal serum calcium concentration
carbonate salt. Each has disadvantages. Calcium gluconate and in treated hypoparathyroid animals, long-term, is in the low-
lactate tablets contain relatively small quantities of elemental cal- normal-to-slightly-low range. We attempt to achieve serum TCa
cium, so relatively large numbers of tablets may need to be given. concentrations of 9.0 to 10.5 mg/dL. Alternatively, one could
Calcium chloride and carbonate tablets contain large quantities of utilize serum iCa concentrations with the goal of about 0.9 to
calcium but the chloride form tends to produce gastric irritation, 1.1 mmol/L. Serum TCa concentrations less than 8.0 mg/dL are
whereas the carbonate form could contribute to alkalosis, which a concern due to increased risk of symptomatic hypocalcemia,
has the potential to worsen hypocalcemia. Calcium carbonate is which can result in life-threatening convulsions or respiratory
40% calcium. One gram yields 20 mEq of calcium, and gastric arrest. Serum TCa concentrations above 10 are unnecessarily high
acid converts the calcium carbonate to calcium chloride. Calcium for avoiding tetany and increase risk of unwanted hypercalcemia,
lactate is 13% calcium, and 1 g yields 6.5 mEq. Calcium gluco- hyperphosphatemia, or a calcium-phosphorus product greater
nate contains 9% calcium, and 1 g yields 4.5 mEq. than 60 to 80. Each of these latter concerns could cause perma-
Although there are numerous calcium preparations available nent renal damage and failure. Avoiding excess serum calcium
(Table 16-6), calcium carbonate is the preparation of choice in concentrations also decreases calciuria (calcium in the urine) and
treating hypoparathyroid humans because of its high percentage risk of calculi within the urinary tract to which patients lacking
of calcium, low cost, lack of gastric irritation, and ready availabil- PTH are predisposed.
ity in stores in the form of antacids (Arnaud and Kolb, 1991). No It is quite valuable for the pet owner to understand as much as
specic research to support recommendations for use of this drug possible regarding hypoparathyroidism, hypocalcemia, and hyper-
is available for dogs and cats, although our success with calcium calcemia. As owner knowledge increases, they gain a better under-
carbonate has been excellent. standing of how difficult it can be to achieve goals of therapy and
TABLE 16-6 SOME AVAILABLE ORAL CALCIUM PREPARATIONS*
FORMULATIONS PREPARATIONS AVAILABLE APPROXIMATE CALCIUM CONTENT COMMENT

Calcium Carbonate Tablets: many 1 mg of Ca/2.5 mg tablet Commonly used
500 mg 200 mg of Ca/tablet
Calcium Gluconate Tablets: many 1 mg of Ca/11.2 mg tablet Less commonly used
Calcium Lactate Tablets: many 1 Ca/7.7 mg tablet Less commonly used
From Schenck PA, Chew DJ: Investigation of hypercalcaemia and hypocalcaemia. In Mooney CT, Peterson ME, editors: BSAVA manual of canine and feline endocrinology, ed 4, British Small
Animal Veterinary Association, 2012, p 221.
Ca, Calcium.
*All are dosed at 25 to 50 mg/kg/day.
Usually can be tapered to low doses or stopped once vitamin D reaches effective dose.
that one of the only means of improving of long-term success is being treated for primary hypoparathyroidism. As many as 80%
frequent monitoring of calcium, phosphorus, and renal parameters. of individuals treated for longer than 2 years have been reported to
The importance of blood monitoring is underscored by realizing have decreases in creatinine clearance. All of these problems can be
that one can never predict results. Remind clients that polydip- traced to occasional hypercalcemia due to excess vitamin D effect.
sia, polyuria, decrease in appetite, vomiting, or depression may be Because these patients lack PTH action at the level of renal tubules,
indicative of hypercalcemia, and veterinary attention should be hypercalciuria occurs more readily, even if the serum calcium con-
sought immediately should any of these signs be observed. Most centrations are within reference intervals. Therefore, as discussed, it
clients need little reminder regarding the clinical signs of hypocal- is extremely important to maintain calcium concentrations below
cemia because those were the signs in their pet that first necessitated reference limits as much as possible while understanding that this
veterinary care. Regardless, if an owner observes any signs of hypo- alone may not be sufficient to avoid hypercalciuria.
calcemia (from restlessness to convulsions), veterinary care should
be sought. PARATHYROID HISTOLOGY IN
Occasional calcium assessments will reveal results higher or lower HYPOPARATHYROIDISM
than desired, but catastrophic changes are quite uncommon when
frequent monitoring, changing dose as predicted from test results, Animals have been classied as having idiopathic hypoparathy-
and luck are linked. The need for modifying doses of vitamin D can roidism when there is no evidence of trauma, cervical malignancy,
usually be explained by changes in diet, activity, and alterations in surgical destruction, or other obvious damage to the neck or para-
individual health. How often should these patients be monitored? thyroid glands. The glands from these dogs have been difcult
Once returned to the owner, our uncomplicated patients have been to locate visually or via ultrasound and are microscopically atro-
checked twice the first week or two, weekly for 3 weeks, monthly phied. Approximately 60% to 80% of the glands are replaced by
for 3 months, and then every 2 to 3 months thereafter. mature lymphocytes, occasional plasma cells, extensive degenera-
If a dose of calcitriol needs to be increased or decreased, changes tion of chief cells, and/or brous connective tissue. Chief cells are
should be small (10% to 20%). Increasing or decreasing the vita- randomly isolated in multiple small areas or bands at the periph-
min D dose should be followed by adequate time to determine if ery. In the early stages of an immune-mediated attack, the gland
it had the anticipated result. The lag period varies because a dose is inltrated with lymphocytes and plasma cells with nodular
decrease in ergocalciferol, for example, might take several weeks regenerative hyperplasia of remaining chief cells. Later, the para-
before change is documented on serum testing. Use of calcitriol thyroid gland is completely replaced by lymphocytes, broblasts,
shortens this lag period from weeks to days (see Table 16-5). Ani- and neocapillaries with only an occasional viable chief cell. The
mals that develop worrisome iatrogenic hypercalcemia secondary nal interpretation is one of lymphocytic parathyroiditis (Sherd-
to excess vitamin D administration would most likely benefit from ing etal, 1980; Capen and Marten, 1983).
hospitalization, IV fluid therapy, and, perhaps, furosemide, ste-
roids, bisphosphonates, or calcitonin. Until the hypercalcemia is
PROGNOSIS
resolved, oral calcium and vitamin D should be discontinued.
Although studies evaluating long-term response to therapy have The prognosis in dogs and cats with primary hypoparathyroidism
not been published, it is fair to state that many of our patients have depends, for the most part, on the dedication of the owner, the
done well for long time periods. Success has been achieved using attention of the veterinarian, and luck. With proper therapy, the
all forms of vitamin D, because this is something determined in prognosis is excellent. A large majority of the dogs we have treated
part by owners. As previously discussed, it is the monitoring, owner have lived more than 5 years from the time of diagnosis and treat-
knowledge, and luck that have significant roles in long-term suc- ment. However, proper management requires close monitoring
cess. Whenever possible, we utilize calcitriol as the source of vitamin of the serum calcium concentration, ideally every 1 to 3 months
D because its relatively quick response to increasing or decreasing once the pet is stabilized. The more frequent the rechecks, the
doses is easier to manage than the more long acting products. It better chance the pet has of avoiding extremes in serum calcium
has been pointed out that hypercalciuria, nephrocalcinosis, uro- concentrations. The chance for a normal life expectancy is excel-
lithiasis, and reduced renal function have been noted in people lent with proper care.
REFERENCES
Abrams KL: Hypocalcemia associated with Barber PJ, Elliott J: Study of calcium homeo- Broadus AE, etal.: Humoral hypercalcemia of
administration of sodium bicarbonate for stasis in feline hyperthyroidism, J Sm cancer: identication of a novel parathy-
salicylate intoxication in a cat, J Am Vet Anim Pract 37:575, 1996. roid hormone-like peptide, N Engl J Med
Med Assoc 191:235, 1987. Barber PJ, etal.: Measurement of feline 319:556, 1988.
Arnaud CD, Kolb FO: The calciotropic parathyroid hormone: assay validation and Brown EM, etal.: Calcium-ion-sensing
hormones and metabolic bone disease. sample handling studies, J Small Anim cell-surface receptors, N Engl J Med
In Greenspan FS, Baxter JD, editors: Pract 34:614, 1993. 333:234, 1995.
Basic and clinical endocrinology, ed 5, Bassett JR: Hypocalcemia and hyperphospha- Bruyette DS, Feldman EC: Primary hypopara-
Los Altos, CA, 1991, Lange Medical temia due to primary hypoparathyroidism thyroidism in the dog: report of 15 cases
Publications, p 247. in a six-month-old kitten, J Am Anim and review of 13 previously reported
Aroch I, etal.: Serum electrolyte concentra- Hosp Assoc 34:503, 1998. cases, J Vet Intern Med 2:7, 1988.
tions in bitches with eclampsia, Vet Rec Bienzle D, etal.: Relationship of serum total Burk RL, Schaubhut CW: Spontaneous pri-
145:318, 1999. calcium to serum albumin in dogs, cats, mary hypoparathyroidism in a dog, J Am
Atkins CE, etal.: Clinical, biochemical, acid- horses, and cattle, Can Vet J 34:360, Anim Hosp Assoc 11:784, 1975.
base, and electrolyte abnormalities in 1993. Bush WW, etal.: Secondary hypoparathyroid-
cats after hypertonic sodium phosphate Broadus AE: Mineral metabolism. In Felig P, ism attributed to hypomagnesemia in a
enema administration, Am J Vet Res etal., editor: Endocrinology and metabolism, dog with protein-losing enteropathy, J Am
46:980, 1985. New York, 1981, McGraw-Hill, p 1056. Vet Med Assoc 219:1732, 2001.
|
Calia CM, etal.: Acute tumor lysis syndrome Flanders JA, etal.: Adjustment of total serum Klein MK, etal.: Treatment of thyroid carci-
in a cat with lymphoma, J Vet Intern Med calcium concentration for binding to noma in dogs by surgical resection alone:
10:409, 1996. albumin and protein in cats: 291 cases 20 cases (1981-1989), J Am Vet Med
Capen CC, Martin SL: Calcium-regulatory (1986-1987), J Am Vet Med Assoc Assoc 206:1007, 1995.
hormones and diseases of the parathyroid 194:1609, 1989. Kornegay JN: Hypocalcemia in dogs, Comp
glands. In Ettinger SJ, editor: Textbook Flanders JA, etal.: Functional analysis of Cont Ed Small Anim Pract 4:103, 1982.
of veterinary internal medicine, Philadel- ectopic parathyroid activity in cats, Am J Kornegay JN, etal.: Idiopathic hypocalcemia
phia, 1983, WB Saunders, p 1581. Vet Res 52:1336, 1991. in four dogs, J Am Anim Hosp Assoc
Chew DJ, Meuten DJ: Disorders of calcium and Forbes S, etal.: Primary hypoparathyroidism 16:723, 1980.
phosphorus metabolism, Vet Clin North in a cat, J Am Vet Med Assoc 196:1285, Lalor AM, etal.: Cats with inflammatory
Am Small Anim Pract 12:411, 1982. 1990. bowel disease and intestinal small cell
Chew DJ, Nagode LA: Renal secondary Freeman LM, etal.: Fanconis syndrome in a lymphoma have low serum concentrations
hyperparathyroidism, Proceedings of the dog with primary hypoparathyroidism, of 25-hydroxyvitamin D, J Vet Intern Med
4th Annual Meeting of The Society for J Vet Int Med 8:349, 1994. 28:351, 2014.
Comparative Endocrinology, 1990, p 17. Gow AG, etal.: Hypovitaminosis D in dogs Li YC, etal.: Normalization of mineral ion
Chew DJ, Nagode LA: Treatment of hypopara- with inflammatory bowel disease and homeostasis by dietary means prevents
thyroidism. In Bonagura JD, editor: Kirks hypoalbuminemia, J Small Anim Pract hyperparathyroidism, rickets, and
current veterinary therapy XIII, Philadel- 52:411, 2011. osteomalacia, but not alopecia in vitamin
phia, 2000, WB Saunders, p 340. Graves TK: Complications of treatment and D-receptor ablated mice, Endocrinol
Chew DJ, etal.: Utility of diagnostic assays concurrent illness associated with hyper- 139:4391, 1998.
in the evaluation of hypercalcemia and thyroidism in cats. In Bonagura JD, editor: Malloy PJ, etal.: The vitamin D receptor and
hypocalcemia: parathyroid hormone, vita- Kirks current veterinary therapy XII, Phila- the syndrome of hereditary 1,25-dihy-
min D metabolites, parathyroid hormone- delphia, 1995, WB Saunders, p 369. droxyvitamin D-resistant rickets, Endocr
related peptide, and ionized calcium. In Grosenbaugh DA, etal.: Evaluation of a Rev 20:156, 1999.
Bonagura JD, editor: Kirks current veteri- portable clinical analyzer in a veterinary Marx SJ: Hyperparathyroid and hypoparathyroid
nary therapy XII, Philadelphia, 1995, WB hospital setting, J Am Vet Med Assoc disorders, N Engl J Med 343:1863, 2000.
Saunders, p 378. 213:691, 1998. Meininger ME, Kendler JS: Trousseaus sign,
Chew DJ, etal.: Treatment of hypoparathyroid- Gunn-Moore D: Feline endocrinopathies, Vet N Engl J Med 343:1855, 2000.
ism. In Bonagura JD, Twedt DC, editors: Clinics North Amer Small Anim Prac Mellanby RJ, etal.: Hypocalcemia associated
Kirks current veterinary therapy XIV, St 35:171, 2005. with low serum vitamin D metabolite
Louis, 2009, Saunders/Elsevier, p 241. Hansen B: Disorders of magnesium. In concentrations in two dogs with protein-
Coburn JW: Use of oral and parenteral cal- DiBartola SP, editor: Fluid therapy in losing enteropathies, J Small Anim Pract
citriol in the treatment of renal osteodys- small animal practice, ed 2, Philadelphia, 46:345, 2005.
trophy, Kidney Int 38(Suppl):S54, 1990. 2000, WB Saunders, p 175. Meuten DJ, Armstrong PJ: Parathyroid disease
Crawford MA, Dunstan RW: Hypocalcemia Henderson RA, etal.: Development of hypo- and calcium metabolism. In Ettinger SJ,
secondary to primary hypoparathyroidism parathyroidism after excision of laryngeal editor: Textbook of veterinary internal
in a dog, Calif Vet May/June:21, 1985. rhabdomyosarcoma in a dog, J Am Vet medicine, ed 3, Philadelphia, 1989,
DeLay J: Laing: Nutritional osteodystrophy in Med Assoc 198:639, 1991. WB Saunders, p 1610.
puppies fed a BARF diet, AHL Newsletter Henik RA, etal.: Rickets caused by exces- Meuten DJ, etal.: Relationship of serum total
6:23, 2002. sive renal phosphate loss and apparent calcium to albumin and total protein in
Dhupa N, Proulx J: Hypocalcemia and hypo- abnormal vitamin D metabolism in a cat, dogs, J Am Vet Med Assoc 180:63, 1982.
magnesemia, Vet Clin North Am Small J Am Vet Med Assoc 215:1644, 1999. Meyer DJ, Tyrrell TG: Idiopathic hypopara-
Anim Pract 28:587, 1998. Hess RS, etal.: Clinical, clinicopathologic, thyroidism in a dog, J Am Vet Med Assoc
Drobatz KJ, Casey KK: Eclampsia in dogs: 31 radiologic, and ultrasonographic abnormali- 168:858, 1976.
cases (1995-1998), J Am Vet Med Assoc ties in dogs with fatal acute pancreatitis: Milnor WR: Properties of cardiac tissues.
217:216, 2000. 70 cases (1986-1995), J Am Vet Med In Mountcastle VB, editor: Medical
Drobatz KJ, Hughes D: Concentration of ion- Assoc 213:665, 1998. physiology, St Louis, 1980, CV Mosby Co,
ized calcium in plasma from cats with Hess RS, etal.: Concurrent disorders in dogs p 980.
urethral obstruction, J Am Vet Med Assoc with diabetes mellitus: 221 cases Mora JR, etal.: Vitamin effects on the im-
211:1392, 1997. (1993-1998), J Am Vet Med Assoc mune system: vitamins A and D take
Elin RJ: Magnesium: the fth but forgotten 217:1166, 2000. center stage, Nat Rev Immunol 8:685,
electrolyte, Clin Chem 102:616, 1994. Horn B, Irwin PJ: Transient hypoparathyroid- 2008.
Fascetti AJ, Hickman MA: Preparturient ism following successful treatment of Padgett SL, etal.: Efcacy of parathyroid
hypocalcemia in four cats, J Am Vet Med hypercalcemia of malignancy in a dog, gland autotransplantation in maintaining
Assoc 215:1127, 1999. Aust Vet J 78:690, 2000. serum calcium concentrations after bilat-
Feldman EC, Krutzik S: Case reports of Jorgensen LS, etal.: Electrolyte abnormali- eral thyroparathyroidectomy in cats,
parathyroid hormone concentrations in ties induced by hypertonic phosphate J Am Anim Hosp Assoc 34:219, 1998.
spontaneous canine parathyroid disorders, enemas in two cats, J Am Vet Med Assoc Parker JSL: A probable case of hypopara-
J Am Anim Hosp Assoc 17:393, 1981. 187:1367, 1985. thyroidism in a cat, J Small Anim Pract
Flanders JA: Surgical therapy of the thyroid, Kimmel SE, etal.: Hypomagnesemia and hy- 32:470, 1991.
Vet Clin N Am Small Anim Pract 24:607, pocalcemia associated with protein-losing Pearce SHS, etal.: A familial syndrome of
1994. enteropathy in Yorkshire Terriers: ve hypocalcemia with hypercalciuria due to
Flanders JA, Reimers TJ: Radioimmunoassay cases (1992-1998), J Am Vet Med Assoc mutations in the calcium-sensing recep-
of parathyroid hormone in cats, Am J Vet 217:703, 2000. tor, N Engl J Med 335:1115, 1996.
Res 52:422, 1991. Kimmel SE, etal.: Incidence and prognostic Persons DA, etal.: Tumor lysis syndrome and
Flanders JA, etal.: Feline thyroidectomy: a value of low plasma ionized calcium con- acute renal failure after treatment of non
comparison of postoperative hypocalce- centration in cats with acute pancreatitis: small-cell lung carcinoma with combina-
mia associated with three different surgi- 46 cases (1996-1998), J Am Vet Med tion irinotecan and cisplatin, Am J Clin
cal techniques, Vet Surg 16:362, 1987. Assoc 219:1105, 2001. Oncol 21:426, 1998.
Peterson ME: Treatment of canine and fKeline Russell NJ, etal.: Primary hypoparathyroidism Tepperman J: Metabolic and endocrine physiol-
hypoparathyroidism, J Am Vet Med Assoc in dogs: a retrospective study of 17 cases, ogy, Chicago, 1980, Year Book Medical
181:1434, 1982. Australian Vet J 84:285, 2006. Publishers, 297.
Peterson ME: Hypoparathyroidism. In Kirk RW, Ryzen E, Rude RK: Low intracellular magne- Tomsa K, etal.: Nutritional secondary hyper-
editor: Current veterinary therapy IX, sium in patients with acute pancreatitis and parathyroidism in six cats, J Sm Anim
Philadelphia, 1986, WB Saunders, hypocalcemia, West J Med 152:145, 1990. Pract 40:533, 1999.
p 1039. Schaer M, etal.: Severe calcinosis cutis associ- Torrance AG: Disorders of calcium metabo-
Peterson ME: Hypoparathyroidism and other ated with treatment of hypoparathyroidism lism. In Torrance AG, Mooney CT, editors:
causes of hypocalcemia in cats. In Kirk RW, in a dog, J Am Anim Hosp Assoc 37:364, Manual of small animal endocrinology, ed
Bonagura JA, editors: Current veterinary 2001. 2, British Small Animal Veterinary Associa-
therapy XI, Philadelphia, 1992, Schenck PA, Chew DJ: Prediction of serum ion- tion, 1998, p 129.
WB Saunders, p 376. ized calcium concentration by serum total Torrance AG, Nachreiner R: Intact parathyroid
Peterson ME, etal.: Idiopathic hypoparathy- calcium measurement in dogs, hormone assay and total calcium concen-
roidism in ve cats, J Vet Intern Med 5:47, Am J Vet Res 66:1330, 2005. tration in the diagnosis of disorders of
1991. Schenck PA, Chew DJ: Prediction of serum ion- calcium metabolism in dogs, J Vet Intern
Piek CJ, Teske E: Tumor lysis syndrome in a ized calcium concentration by serum total Med 3:86, 1989.
dog, Tijdschr Diergeneeskd 121:64, 1996. calcium measurement in cats, Vaden SL, etal.: A retrospective case-control
Rasmussen H: Theoretical considerations in the Can J Vet Res 74:209, 2010. study of acute renal failure in 99 dogs,
treatment of osteoporosis. In De Luca HF, Schenck PA, Chew DJ: Investigation of hypercal- J Vet Intern Med 11:58, 1997.
editor: Osteoporosis: recent advances in caemia and hypocalcaemia. In Mooney CT, Weir EC, etal.: Isolation of 16,000-dalton
pathogenesis and treatment, Baltimore, Peterson ME, editors: BSAVA manual of ca- parathyroid hormone like proteins from two
1981, University Park Press, p 383. nine and feline endocrinology, ed 4, British animal tumors causing humoral hyper-
Rasmussen H: The cycling of calcium as an Small Animal Veterinary Association, 2012, calcemia of malignancy, Endocrinology
intracellular messenger, Sci Am 261:66, p 221. 123:2744, 1988.
1989. Schenck PA, etal.: Effects of storage on nor- Welches CD, etal.: Occurrence of problems
Refsal KR, etal.: Update on the diagnosis and mal canine serum ionized calcium and pH, after three techniques of bilateral thyroid-
treatment of disorders of calcium regula- Am J Vet Res 56:304, 1995. ectomy in cats, Vet Surg 18:392, 1989.
tion, Vet Clinics N Amer Sm Anim Prac Schenck PA, etal.: Effects of storage on serum Wysolmerski JJ, Insogna KL: The parathyroid
31:1043, 2001. ionized calcium and pH from horses with glands, hypercalcemia, and hypocalcemia.
Rolla D, etal.: Effects of subcutaneous cal- normal and abnormal ionized calcium con- In Goldman L, Schafer AI, editors: Gold-
citriol administration on plasma calcium centrations, Vet Clin Pathol 25:118, 1996. mans Cecil medicine, ed 24, Philadelphia,
and parathyroid hormone concentrations in Schenck PA, etal.: Disorders of calcium: 2012, Elsevier/Saunders, p 1591.
continuous ambulatory peritoneal dialysis hypercalcemia and hypocalcemia. In Yates AJ, etal.: Effects of a synthetic peptide
uremic patients, Peritoneal Dialysis Int DiBartola SP, editor: Fluid, electrolyte, and of a parathyroid-related protein on calcium
13:118, 1993. acid-base disorders, ed 4, St Louis, 2012, homeostasis, renal tubular calcium reab-
Rosol TJ, Capen CC: Calcium-regulating Elsevier/Saunders, p 120. sorption and bone metabolism invivo and
hormones and diseases of abnormal min- Schick MP, etal.: Calcinosis cutis secondary invitro in rodents, J Clin Invest 81:932,
eral (calcium, phosphorus, magnesium) to percutaneous penetration of calcium 1988.
metabolism. In Kaneko JJ, Harvey JW, chloride in dogs, J Am Vet Med Assoc Yu ASL: Disorders of magnesium and phos-
Bruss ML, editors: Clinical biochemistry 191:207, 1987. phorus. In Goldman L, Schafer AI, editors:
of domestic animals, San Diego, 1997, Selgas R, etal.: The pharmacokinetics of Goldmans Cecil medicine, ed 24, Phila-
Academic Press, p 619. a single dose of calcitriol administered delphia, 2012, Elsevier/Saunders, p 753.
Rosol TJ, etal.: Disorders of calcium. In subcutaneously in continuous ambulatory Zivin JR, etal.: Hypocalcemia: a pervasive
DiBartola SP, editor: Fluid therapy in peritoneal dialysis patients, Peritoneal metabolic abnormality in the critically ill,
small animal practice, ed 2, Philadelphia, Dialysis Int 13:122, 1993. Am J Kidney Dis 37:689, 2001.
2000, WB Saunders, p 108. Sherding RG, etal.: Primary hypoparathy-
Roth SI, Capen CC: Ultrastructural and func- roidism in the dog, J Am Vet Med Assoc
tional correlations of the parathyroid gland, 176:439, 1980.
Int Rev Exp Pathol 13:161, 1974. Skelly BJ: Hypoparathyroidism. In Mooney
Ruopp JL: Primary hypoparathyroidism in a CT, Peterson ME, editors: BSAVA manual
cat complicated by suspect iatrogenic of canine and feline endocrinology, ed 4,
calcinosis cutis, J Am Anim Hosp Assoc British Small Animal Veterinary Associa-
37:370, 2001. tion, 2012, p 56.
Index
A Acromegaly (Continued) Adipokines, in feline diabetes, 264, 264f

Abdominal enlargement signalment of, 69 Adiponectin, 264
in adrenocortical diseases of dog, 388, 388f treatment of, 7172 Adipose tissue, actions of catecholamines on,
in feline Cushings syndrome, 457f, 458 in humans, 5556 526t
Abdominal pain treatment of, 6566 Adrenal adenomas, 385
in diabetic ketoacidosis, 320 polydipsia and polyuria in, 9 Adrenal carcinomas, 384
in primary hyperparathyroidism, 595596 ACTH. see Adrenocorticotropic hormone. Adrenal cortex, 486
Abdominal radiography Activator protein-1, 556558 layers of, 488f
in acromegalic cats, 59, 60f Acute hypoglycemic crisis, 368369, 368f369f Adrenal gland
in canine primary hyperparathyroidism, 601, Acute kidney disease, hypocalcemia and, 639 Addisons disease and, 485520
601f Acute kidney injury, 592 hypoglycemia in, 356
in diabetic ketoacidosis, 329 in primary hyperparathyroidism, 595 adrenocortical diseases of dog and, 377451
in feline hyperadrenocorticism, 471 Acute pancreatitis, 638 exogenous glucocorticoids and, in diabetic
of insulin-secreting tumor, 361 Addisons disease, 485520 ketoacidosis, 341
of pheochromocytoma, 531532, 532f abdominal ultrasound in, 500501, 500f glucocorticoid therapy and, 555578
Abdominal ultrasonography acid-base status in, 499 for primary hyperparathyroidism, 609, 609b
in adrenocortical diseases of dog, 405, aldosterone-to-renin ratio in, 507, 507f histopathology of, 491f
410413, 411f412f basal cortisol concentrations in, 501, 503f incidental discovered adrenal mass in,
in canine hypoadrenocorticism, 500501 blood pressure in, 494 547548
in diabetic ketoacidosis, 327328, 328f clinical pathology of, 494499, 494t nodular hyperplasia of, 385
feline cortisol-to-ACTH ratio in, 505506, 505f506f pheochromocytoma and, 521554
in acromegaly, 60, 60f cortisol-to-creatinine ratio in, 507 physiology of, 486489, 487f, 488t
in diabetes mellitus, 277, 278f diagnosis of, 501507 steroid biosynthesis in, 380381, 380f381f
of incidental discovered adrenal mass, 547 electrocardiography in, 501, 502f Adrenal hyperplasia, congenital, 516
in pheochromocytoma, 532534, 533f, 533b emergency management of, 508b Adrenal insufficiency, relative, 508
Absorption, of insulin, 304 endogenous adrenocorticotropic hormone in, Adrenal mass
Acarbose 504505, 505f non-traumatic rupture of, in adrenocortical
for cat, 285 feline, 514516 diseases of dog, 394
for dog, 231, 232f hepatic dysfunction in, 498 unexpected discovery of, 439441, 439f441f
Acetoacetate, 315 history in, 493494 Adrenal medulla, 486
Acetone, 315 hypercalcemia and, 592 Adrenal secondary hyperparathyroidism, 619
Acid-base status hypoalbuminemia in, 498 Adrenal sex hormone, as cause of bilaterally
in diabetic ketoacidosis, 323324, 324f, 324t hypocholesterolemia in, 498 symmetrical alopecia, 441442
in hypercalcemic dog, 598 hypoglycemia in, 356, 498 Adrenal steroids, 486, 488t
in hypoadrenocorticism, 499 hyponatremia in, 496497 biosynthesis of, 487f
Acidosis iatrogenic, 514 Adrenal tumor
in hypercalcemic dog, 598 physical examination in, 494 excessive sex hormone-secreting, in cats, 481
hyperkalemia and, 497 plasma aldosterone concentration in, 506507 functioning, 429431
mineralocorticoid deficiency and, 489 polydipsia and polyuria in, 89 hyperadrenocorticism due to, 383384
Acquired hyposomatotropism, 5455, 54b primary versus secondary, 489, 489f mitotane for, 430f
Acquired nephrogenic diabetes insipidus, 79 prognosis of, 513514 pheochromocytoma and, 521554
Acromegaly radiography in, 499500, 499f versus pituitary-dependent hyperadrenocor-
in cats, 5668 signalment of, 492493, 493t ticism, 405409
clinical manifestations of, 5759, 58f59f, 58t during stressful events, 513 Adrenalectomy
clinical pathology of, 59 treatment of, 508 in adrenocortical diseases of dogs, 417421,
diabetes mellitus and, 306 in the absence of electrolyte abnormalities, 418f420f, 427429
diagnosis of, 6465 513 in feline Cushings syndrome, 476477
diagnostic imaging in, 5960 diagnosis after, 513 in incidental discovered adrenal mass, 547
histopathology of, 6768 fluid therapy for, 509 in pheochromocytoma, 546
hormonal evaluation of, 6164, 63t glucocorticoid replacement for, 509 Adrenergic neurogenic response, to
pathophysiology of, 57 long-term, 510513, 510t hypoglycemia, 351
prevalence and etiology of, 5657 mineralocorticoid replacement for, 509 Adrenocortical diseases
prognosis of, 68 response to, 513 in cats, 452484
signalment of, 57 supportive care for, 509510 excessive sex hormone-secreting adrenal
treatment of, 6667 Adenohypophysis, 37 tumors in, 481
in dogs, 6872 Adenomas feline hypercortisolism in, 452453
clinical manifestations of, 6970, 70f adrenal, 385 primary hyperaldosteronism in, 478481
diagnosis of, 71 parathyroid of dog, 377451
diagnostic imaging in, 70 in cervical ultrasonogram, 602f abdominal enlargement in, 388, 388f
etiology of, 6869 post-treatment management of, 618 abdominal ultrasonography in, 405,
hormonal evaluation of, 7071, 70f71f thyroid, 137138 410413, 410f412f
pathology of, 70 Adenomatous hyperplasia, 137138, 618 acute weakness in, 394
prognosis of, 72 ADH. see Antidiuretic hormone (ADH). adrenal tumor and, 383384
Page numbers followed by f indicate figures; t, tables; b, boxes.
649
650 INDEX
Adrenocortical diseases (Continued) Adrenocortical diseases (Continued) Aldosterone, 478

adrenocortical nodular hyperplasia and regulation of glucocorticoid secretion and, see also Mineralocorticoids
food-dependent hyperadrenocorticism 378381 characteristics of, 559t
and, 385 reproductive abnormalities in, 392 in hypoadrenocorticism, 506507
adrenocorticotropic hormone in, 378 respiratory signs in, 392 hypoadrenocorticism and, 489490, 490f
adrenocorticotropic hormone stimulation resting (baseline) cortisol concentrations in primary hyperaldosteronism, 438
test in, 402404 in, 405 primary hyperaldosteronism and, 480
age and, 385 retinoic acid for, 436 regulation of secretion, 381
alanine aminotransferase in, 396 routine blood and urine evaluation in, Aldosterone-to-renin ratio, in hypoadrenocor-
alkaline phosphatase in, 396 395398, 396t ticism, 507, 507f
amylase and lipase in, 397 screening tests for, 400405 Alfacalcidol, for hypocalcemia, 643t, 644
bile acids in, 396397 serum corticosteroid-induced alkaline Alkaline phosphatase (ALP)
blindness in, 394 phosphatase activity in, 405 in adrenocortical diseases of dog, 396
blood glucose and serum insulin in, 396 signalment in, 385 in canine diabetes mellitus, 220
blood urea nitrogen in, 396 simultaneous pituitary-dependent and in feline Cushings syndrome, 460461, 462t
breed/body weight and, 385, 386t adrenal-dependent hyperadrenocorticism glucocorticoid-related increase of, 573
bromocriptine for, 435 and, 385 in pheochromocytoma, 530
bruisability, 394 specific evaluation of pituitary- in primary hyperparathyroidism, 600
calculi in, 398 adrenocortical axis in, 399400 Alkalosis, 598
cholesterol and triglycerides in, 396, 397f steroids in, 380381 Alloxan, 369
CNS signs in, 394395 sudden acquired retinal degeneration Alopecia
combined dexamethasone suppression/ syndrome in, 394 in adrenocortical diseases of dog, 389, 390f,
adrenocorticotropic hormone stimulation surgery for, 417422 432f
test in, 405 treatment of, 415417, 431435 in canine hypothyroidism, 87, 89f
complete blood count in, 395396 trilostane for, 431434, 433f and feline hyperadrenocorticism, 458
computed tomography and magnetic urinalysis in, 397398 in feline hyperthyroidism, 144
resonance imaging in, 413415, 413f414f, urinary crystals and calculi and, 398 in feline hypothyroidism, 125
416f urine cortisol-to-creatinine ratio in, 401402 growth hormone deficiency and, 55
corticotropin-releasing hormone and Adrenocortical failure hyperadrenocorticism versus hypothyroidism
vasopressin response testing in, 409 primary, 490492, 491b in, 115
corticotropin-releasing hormone in, 378 secondary, 492 Alopecia X, 55
cutaneous markers for, 389391 Adrenocortical hyperplasia, 150151 Alpha-glucosidase inhibitors, for feline diabetes
cyproheptadine for, 436 Adrenocortical insufficiency mellitus, 285
dexamethasone suppression with urine hypercalcemia in, 591592 Amino acid administration, in pituitary
cortisol-to-creatinine ratio in, 407 hypoglycemia in, 356 dwarfism, 52
diabetes mellitus and, 398 Adrenocortical nodular hyperplasia, 385 Aminoglutethimide (AGT), 481
dopamine in, 379380 Adrenocortical steroid biosynthesis, 487f for adrenocortical diseases of dog, 436
ectopic adrenocorticotropic hormone Adrenocortical tumor, 405409, 434 Amylase, 397
syndrome and, 384385 Adrenocorticotropic hormone, 486 in adrenocortical diseases of dog, 397
ectopic calcification in, 394 in adrenocortical diseases of dog, 383f Amylin, 265
electrolytes in, 397 in ectopic adrenocorticotropic hormone Amyloid, 265
endogenous adrenocorticotropic hormone syndrome, 384 Amyloidosis, pancreatic, 263f, 266267
measurement in, 407409, 408f, 408t in regulation of glucocorticoid secretion, 378 Anamnesis, in canine diabetes mellitus, 217218
facial paralysis in, 393 Adrenocorticotropic hormone stimulation test Androgen, excess, and feline sex hormone-
gallbladder mucocele and, 398399 (ACTHST), 464466, 465t secreting adrenal tumors, 468
gender and, 385 in adrenocortical diseases of dog, 402405, 403f Anemia
gonadal and sex hormone-related in beta-cell neoplasia, 356 in dogs with hypoadrenocorticism, 494
alterations in, 394 in feline hypoadrenocorticism, 515t, 516 in feline hyperthyroidism, 148
hepatomegaly in, 393394 in hypoadrenocorticism, 501504, 503f504f in pheochromocytoma, 530
high-dose dexamethasone suppression test inadequate response in, causes of, 504b Anesthesia
in, 406407, 407f Adult-onset growth hormone deficiency, 55 in feline thyroidectomy, 178
history in, 385393 Adult-onset hypothyroidism, 125 before pheochromocytoma excision,
hyperpigmentation in, 393 Age 544, 544f
hypertension and, 398 adrenocortical diseases of dog and, 385 Anestrus, canine, in adrenocortical diseases
hypothyroidism and, 398 canine primary hyperparathyroidism and, of dog, 394
ketoconazole for, 434435 593594, 593f Anion gap, in diabetic ketoacidosis, 326327,
L-deprenyl for, 435 effect on canine thyroid function tests, 109, 327t, 327b
low-dose dexamethasone suppression test 110f, 110t Anipryl, 435
in, 404406, 404f, 406f feline hyperthyroidism and, 142 Annexin I, 563
metyrapone and aminoglutethimide for, 436 pheochromocytoma and, 527 Anorexia
mitotane therapy for, 422431 serum phosphorus concentration and, 599 in hyperosmolar hyperglycemic state, 344
muscle weakness and lethargy in, 388389, total serum calcium and, 598 during mitotane therapy, 423424
389f Aggressive behavior ANP. see Atrial natriuretic peptide (ANP).
myotonia (pseudomyotonia) in, 392393, 393f in canine hypoparathyroidism, 630 Anti-inflammatory therapy, glucocorticoids for,
obesity in, 391 in feline hyperthyroidism, 144 568569
pathology and pathophysiology of, 381385 Alanine aminotransferase (ALT) Anti-thyroid drugs, 172177, 172f
phosphate in, 396 in adrenocortical diseases of dog, 396 Antibodies
physical examination in, 393395 in feline Cushings syndrome, 461, 462t anti-insulin, 304305
pituitary-dependent hyperadrenocorticism glucocorticoid-related increase of, 573 in lymphocytic thyroiditis, 8182
and, 381383, 387f388f, 427f428f in pheochromocytoma, 530 Anticonvulsant therapy, in hypocalcemia, 640
pituitary irradiation for, 436437 in primary hyperparathyroidism, 600 Anticonvulsants, effects on thyroid function
polyphagia in, 388 Alanine deficiency, 357358 tests, 116
polyuria and polydipsia in, 386388 Albumin, 565 Antidiuretic hormone (ADH)
primary hyperaldosteronism and, 438439 in feline Cushings syndrome, 462t, 463 biosynthesis, transport, and metabolism, 23
pulmonary thromboembolism and, 399, hypoalbuminemia and in feline hyperadrenocorticism, 454
399f, 399b in canine hypoparathyroidism, 633 Antineoplastic therapy, glucocorticoids for, 569
radiography in, 409410, 409f hypocalcemia and, 638 Apocrine gland adenocarcinoma of anal sac, 589
INDEX 651
Appetite Beta-cell neoplasia (Continued) Blood pressure (Continued)

adrenocortical diseases of dog, 388 etiology of, 348349 hypertension and, in pheochromocytoma, 528,
feline hyperthyroidism and, 145 euglycemia and, 349350, 349f 541542
mitotane therapy, 422423 history in, 353 hypoadrenocorticism in dogs and, 494
Arginine vasopressin, 1 hypoglycemia and counterregulatory hypotension and, during excision of
see also Vasopressin response in, 350351, 350b pheochromocytoma, 544
after dehydration, plasma osmolality and, 27f insulin-induced hypoglycemia in, 351 pheochromocytoma and, 531, 532t
deficiency of, 12 insulin secretion in, 351 primary hyperaldosteronism, 478479
levels, in syndrome of inappropriate medical therapy for acute hypoglycemic crisis Blood urea nitrogen (BUN)
antidiuretic hormone, 33f in, 368369, 368f369f in adrenocortical diseases of dog, 396
modified water deprivation test response to, medical therapy for chronic hyperglycemia in, in canine diabetes mellitus, 220
19 369371, 370f371f in canine hypoparathyroidism, 632t
Arrhythmias, feline hyperthyroidism and, 146 physical examination in, 353354, 354t in diabetes insipidus, 16
Arterial blood gases, in ketoacidotic dog, 333 prognosis in, 372 in diabetic ketoacidosis, 326, 326f
Arterial pH, in diabetic ketoacidosis, 324, 324t serum insulin determination in, 359361, 360f, in feline Cushings syndrome, 458t, 461t462t,
Artifactual hypoglycemia, 358 360b 462
Assay signalment in, 352353, 352f, 353t in feline hyperthyroidism, 149150
ionized calcium, 584 surgery for, perioperative management in primary hyperparathyroidism, 599600
parathyroid hormone, 584, 585f, 603604, 603f of dogs undergoing, 364368, 364b, Body temperature, effects on canine thyroid
parathyroid hormone-related protein, 586t, 365f366f, 367b function tests, 115
603604 surgical versus medical therapy for, 364 Bone
total calcium, 584 Betamethasone, 555556 actions of parathyroid hormone-related
vitamin D, 584, 603604 characteristics of, 559t protein on, 586t
Ataxia Bicarbonate, plasma, concentration, in diabetic effect of glucocorticoids on, 559561
in feline hyperthyroidism, 147 ketoacidosis, 336 feline hyperthyroidism and, 149
in hypoglycemia, 352 Bicarbonate therapy, in diabetic ketoacidosis, hypercalcemia and, 590
Atenolol, for feline hyperthyroidism, 189 336, 336f multiple myeloma and, 589
Atrial fibrillation, 91 Biguanides, 284285 primary hyperparathyroidism and, 583
Atrial natriuretic peptide (ANP), 9 Bile acids, in adrenocortical diseases of dog, Bone cancer, primary and metastatic,
Atrioventricular block, 91 396397 hypocalcemia and, 640
Atrophy, of thyroid gland, 8384, 84f Biochemical profile, in canine primary hyper- Bone isoenzymes, in feline hyperthyroidism, 149
Atypical hypoadrenocorticism, 496497 parathyroidism, 597601, 597t Bone marrow
Autoantibody, in lymphocytic thyroiditis, Biochemistry evaluation of, 607
8182, 83t in canine hypothyroidism, 9495 hematologic malignancies of, 589
Autoimmune hypothalamitis, central diabetes in feline Cushings syndrome, 458t, 461463, Bone tumor, hypercalcemia in, 590
insipidus from, 12 461t462t Brain
Autonomic nervous system response, to hyper- Biological half-life, 563 damage from hypoglycemia, 352
glycemia, 350b Biopsy, thyroid, in canine hypothyroidism, 117 edema, in treatment of diabetic ketoacidosis,
AVP. see Arginine vasopressin. Biopsy-responsive alopecia, 55 342
Azotemia Bitch, eclampsia in, 639 Breed, in adrenocortical diseases of dog, 385,
in diabetic ketoacidosis, 323 Black skin disease, 55 386t
in feline hyperthyroidism, 150 Blindness Bromide, 116
hypercalcemia and, 592 in adrenocortical diseases of dog, 394 Bromocriptine, for adrenocortical diseases of
hypoadrenocorticism and, 494t, 498 in pheochromocytoma, 528 dog, 435
in pheochromocytoma, 530 Blood Bronchiolar smooth muscle, actions of catechol-
citrated, hypocalcemia and, 640 amines on, 526t
B in primary hyperparathyroidism, 604 Bruising
Bacterial endotoxins, polydipsia with polyuria Blood cells, effect of glucocorticoids on, 561 in adrenocortical diseases of dog, 390,
and, 78 Blood glucose 391f392f, 394
Bacterial infections in adrenocortical diseases of dog, 396 in feline Cushings syndrome, 457f, 458
in canine hypothyroidism, 88 in diabetic ketoacidosis, 320, 323, 323f Budesonide, 555556
in diabetic ketoacidosis, 340 in feline Cushings syndrome, 459460 for inflammation, 568569
Baroreceptors, 2 in feline diabetes mellitus, 292, 292f BUN. see Blood urea nitrogen (BUN).
Basal cortisol concentrations, in hypoadrenocor- home monitoring of, 293298
ticism, 501, 503f sampling site, lancing device, and C
Basal free thyroxine, in feline hyperthyroidism, portable monitoring device, 294296, C-peptide, 269
157158, 157f, 158t 295f, 296t in canine diabetes mellitus, 215, 216f, 218f,
Basal growth hormone, in pituitary dwarfism, 49 in feline hyperthyroidism, 149150 224f
Basal total serum thyroxine, in feline hyperthy- in feline stress hyperglycemia, 300302 Cachexia, effects on canine thyroid function tests,
roidism, 154156, 154f155f, 156t in hyperosmolar hyperglycemic state, 344 115
Basal total serum triiodothyronine, in feline in insulin-secreting tumor, 353, 360 CAH. see Congenital adrenal hyperplasia.
hyperthyroidism, 157, 157f intraoperative, 365367 Calcidiol, for hypocalcemia, 644
Behavior, canine tissue utilization of, 351 Calcific band keratopathy, 394
in hypoglycemia, 352 Blood glucose curve (BGC), in feline diabetes Calcification, ectopic, in adrenocortical diseases
hypothyroidism and, 90 mellitus, 292, 293f of dog, 394
Benign thyroid tumors, feline, 137138, 138f generation in hospital of, 292293 Calcinosis cutis, 391, 393f
Beta-cell dysfunction, in feline diabetes, 265 interpretation of, 297298, 297f Calcitonin, primary hyperparathyroidism and,
Beta-cell neoplasia, 348376 variability of, 298, 299f 583
in cats, 372 Blood glycated hemoglobin, in canine diabetes Calcitriol
clinical pathologic abnormalities in, 354355, mellitus, 235236, 235f, 236t after feline thyroidectomy, 180
354b Blood pressure assay of, 584, 603604, 607
clinical signs in, 351352, 351t352t, 352f acromegaly in cats and, 5759 for hypocalcemia, 643t, 644
diagnostic approach to hypoglycemia in, 359 in feline Cushings syndrome, 463 normal serum concentrations of, 582t
diagnostic imaging in, 361364, 362f363f and hypertension, in feline hyperthyroidism, Calcium
differential diagnoses for fasting 151 in canine hypoparathyroidism, 632t
hypoglycemia and, 355359, 355b, 357b, hypertension and, in canine diabetes mellitus, continuous intravenous infusion of, 642
359f 253 in diabetic ketoacidosis, 328
652 INDEX
Calcium (Continued) Canine diabetes mellitus (Continued) Canine hypothyroidism (Continued)

effect of glucocorticoids on metabolism of, corneal ulceration, 252 dermatohistopathologic findings in, 95
559561 diabetic nephropathy in, 253 dermatologic signs in, 8788, 88f89f
in feline Cushings syndrome, 458t, 461t diabetic neuropathy in, 252253 establishing diagnosis in, 118
homeostasis of, 582f, 625629, 628f diabetic retinopathy in, 252 etiology of, 8186, 81f, 81b, 82t, 84f
hypercalcemia and, 580 dietary therapy, 229231, 229b230b, 230f gastrointestinal signs in, 9192
hypoadrenocorticism and, 497498 establishing diagnosis of, 218219, 218t levothyroxine sodium for, 120,
hypocalcemia and, 625648 etiology, 214216 121f122f, 121t
after thyroid surgery in cat, 179 exercise in, 231, 231f liothyronine sodium for, 123
normal levels of, 582t factors involved in, 214t metabolic signs in, 87
regulation of, 580, 581f history in, 234 myxedema coma in, 90
repeated intravenous boluses of, 642 hypertension in, 253 neurologic signs in, 8890
serum hypothyroidism and, 114 nuclear imaging in, 9596, 98f99f
after feline thyroidectomy, 179 insulin-dependent, 214, 227f, 232f ocular signs of, 91
in diabetic ketoacidosis, 328 insulin-induced hypoglycemia in, 242243 prognosis in, 124
maintenance of, 625626, 628f insulin resistance in, 217f, 248251, 248f, 249t, radiography in, 9596, 96f
normal levels of, 582t 250b251b reproductive signs in, 9091
skeletal, 580f insulin therapy in, 222228, 223t, 226t, 227f, secondary, 92
subcutaneous, 642 230f, 245f247f signalment in, 86, 86f, 86t
supplementation after feline thyroidectomy, allergic reactions to, 247248 therapeutic monitoring of, 119f, 120121
180 complications of, 242251 thyroid function tests in, 96107, 99f. see also
tetany and, 641642 inadequate insulin absorption in, 246 Thyroid function tests
Calcium carbonate, 645t initial adjustments in, 228 thyrotoxicosis and, 124
Calcium chloride, 641t mixtures, 227, 227f treatment of, 118124, 120b
Calcium glubionate, 645t preparations, 222, 223t, 226t ultrasonography in, 95, 97f
Calcium gluconate, for hypocalcemia, 641t, 642 prolonged duration of insulin effect in, 246, Canine insulin gene, and canine diabetes
Calcium ipodate, 190 246f247f mellitus, 214
Calculi, in adrenocortical diseases of dog, 398 recommendations, 228 Canine male reproduction, hypothyroidism
cAMP. see Cyclic adenosine monophosphate short duration of insulin effect, 230f, and, 90
(cAMP). 245246, 245f247f Canine pancreatic-specific lipase (cPL), 220221
Cancer Somogyi response and, 244245, 244f245f Canine thyroid tumor, 196212
canine thyroid tumor, 196212 during surgery, 242 benign, 198
benign, 198 underdosage in, 244 classification, 196, 197b
classification of, 196, 197b urinalysis, 220 clinical approach to, 198206
clinical signs of, 199, 199t urine glucose monitoring, 236 hyperthyroidism and, 196212, 200f
differential diagnosis in, 202b, 206 lens-induced uveitis in, 252 ionizing radiation and, 197
hyperthyroidism and, 196212, 200f negative psychological and social impacts of, lymphocytic thyroiditis/hypothyroidism,
ionizing radiation and, 197 222t 198
lymphocytic thyroiditis/hypothyroidism, nonketotic, treatment of, 221233 malignant, 198, 198t199t
198 oral hypoglycemic drugs for, 231232, 232f, basal serum thyroxine concentrations in,
malignant, 196, 198, 198t199t 233b 205206
medullary carcinoma in, 196197 overview of patient evaluation, 219 clinical signs of, 199, 199t
minimum data base, 199 pancreatic enzymes in, 220221 computed tomography and magnetic
normal anatomy, imaging planes, and pathophysiology of, 216217 resonance imaging, 202
indications, 201f, 202 persistence of clinical signs, 243244 differential diagnosis in, 202b, 206
oncogenes in, 197198, 197f physical examination in, 218, 234 equipment and positioning, 202
pathogenesis of, 197198 problems with owner administration and medullary carcinoma in, 196197
physical examination, 199, 200f activity of the insulin preparation, 243 prognosis of, 211
postsurgical monitoring for, 209 problems with the insulin treatment regimen, radiography in, 202
prognosis in, 211 244 scintigraphy in, 202205, 203f206f, 208f
radiography, 202 prognosis, 253 signalment, 198199
scintigraphy, 202205, 203f206f, 208f recurrence of clinical signs, 243244 staging, 197t, 197b
signalment, 198199 remission, 215216 treatment of, 206210
staging, 197t, 197b serial blood glucose curve, 226f, 236241, ultrasonography in, 201f, 202, 203f
surgical resection for, 208209, 208f 237f239f, 238t, 241f242f, 244f minimum data base, 199
treatment of, 206210 serum biochemical panel in, 220 oncogenes in, 197198, 197f
ultrasonography in, 202, 203f serum fructosamine in, 234235, 234t, 235f pathogenesis of, 197198
feline hyperthyroidism and, 154t, 190 serum insulin concentration, 221 physical examination, 199, 200f
Canine diabetes mellitus, 213257 serum thyroxine concentration, 221 surgical resection for, 208209, 208f
after surgical removal of insulin-secreting signalment in, 217 CAR. see Cortisol-to-adrenocorticotrophic
tumor, 367 single blood glucose determination, 234 hormone ratio.
anamnesis in, 217218 stress hyperglycemia, 241 Carbimazole, for feline hyperthyroidism, 176t,
blood glycated hemoglobin in, 235236, 235f, techniques for monitoring, 233242 177
236t type 1, 214, 216f Carbohydrate
breeds and risks for, 215t type 2, 214215, 216f canine diabetes mellitus and, 229
cataracts in, 217218, 217f, 251252 Canine hypothyroidism, 80 effect of glucocorticoids on metabolism of, 559
chromium for, 231 behavior changes in, 90 feline diabetes mellitus and, 287288, 288t
circulating anti-insulin antibodies in, 247f, 214, cardiovascular signs in, 91 growth hormone in metabolism of, 4243
246247, 248f classification of, 8081 Carcinoma
classification of, 214216, 219b clinical signs of, 8692, 87t, 87b adrenal, 384
clinical pathologic abnormalities in, 219221, clinicopathologic abnormalities in, 9295, 94b chief cell, 618
219b coagulopathy in, 92 hepatocellular, 357
complete blood count in, 220 combination thyroxine-triiodothyronine parathyroid, post-treatment management of,
complications of, 222t, 233b, 251253 products for, 123 618
concurrent problems in, 232233 cretinism in, 92, 92b, 93f94f squamous cell, metastasis to bone, 590
continuous glucose monitoring systems, 239, crude animal-origin hormonal preparations thyroid, 138
240f for, 123 medullary, 549, 640
INDEX 653
Cardiac disturbances, in feline hyperthyroidism, Central diabetes insipidus (CDI), 1214, 13f Coagulopathy signs, in canine
146147 in adrenocortical diseases of dog, 421422 hypothyroidism, 92
Cardiac muscle, actions of parathyroid causes of, in humans, dogs and cats, 13b Cold nodules, 202205
hormone-related protein on, 586t clinical features of, 1416 Colon, glucocorticoid-related perforation in,
Cardiac standstill, hyperkalemia and, 489 clinical signs of, 15 572573
Cardiomyopathy, in canine hypothyroidism, 91 complete blood count in, 16 Coma, in hyperosmolar hyperglycemic state, 343
Cardiovascular function, effect of glucocorti- desmopressin acetate, response to, 17 Combination chemotherapy, for canine thyroid
coids on, 561 etiology of, 1214 tumors, 210
Cartilage modified water deprivation test in, 2021, Combination thyroxine/triiodothyronine
actions of parathyroid hormone-related 20f21f products, 123
protein on, 586t MRI of pituitary region in dog with, 13f Combined dexamethasone suppression/adreno-
effect of glucocorticoids on, 559561 pathophysiology of, 12, 12f corticotropic hormone stimulation test,
Castration-responsive alopecia, 55 physical examination in, 16 405
Cat plasma osmolality in, 28, 28f Complete blood count (CBC)
acquired hyposomatotropism in, 5455, 54b polydipsia and polyuria in, 7 in adrenocortical diseases of dog, 395396
acromegaly in, 5668 duration of, 15f in canine diabetes mellitus, 220
adrenocortical diseases in, 452484 prognosis in, 31 in canine hypothyroidism, 9295
excessive sex hormone-secreting adrenal results of diagnostic studies in, 28t in diabetes insipidus, 16
tumors in, 481 serum chemistries in, 16 in diabetic ketoacidosis, 327
feline hyperadrenocorticism in, 452453 serum electrolytes in, 16 in feline Cushings syndrome, 459, 461t
primary hyperaldosteronism in, 478481 signalment of, 1415, 15f in feline diabetes mellitus, 275
beta-cell tumors in, 372 treatment of, 2931, 29b in hypoadrenocorticism, 494t
diabetes mellitus in, 258314 urinalysis in, 16 in insulin-secreting tumor, 354
eosinophilia in, causes of, 495b urine specific gravity in, 16f Compound E, 557
growth hormone secretion in, 39 Central nervous system (CNS) Computed tomography (CT), 472473, 473f, 473t
hypercalcemia in actions of parathyroid hormone-related in acromegalic cats, 60, 61f
differential diagnosis for, 619620 protein on, 586t in adrenocortical diseases of dog, 413415,
idiopathic, 620 damage from hypoglycemia, 351352 413f414f, 416f
hyperthyroidism in, 136195 effect of glucocorticoids on, 561 of insulin-secreting tumor, 362363, 363f
hypoadrenocorticism in, 514516 signs in adrenocortical diseases of dog, in pheochromocytoma, 534535
hypoparathyroidism in, 632, 635637 394395, 395f, 395b in pituitary dwarfism, 52
laboratory testing of, 633 Cerebral edema, 342 Concurrent diseases, in pheochromocytoma,
hypothyroidism in, 124 Cerebral hypoxia, 369 528, 529t530t
pheochromocytoma in, 521554 Cervical mass, in feline hyperthyroidism, Concurrent illness
abdominal and thoracic radiographs in, 145146, 146f147f in diabetic ketoacidosis, 340341
531532, 532f Cervical ultrasonography effects on canine thyroid function tests,
abdominal ultrasonography in, 532534, 533f, in canine thyroid tumor, 202, 203f 112115, 113f
533b in feline hyperthyroidism, 167169, 169f, 169t nonthyroidal, in feline hyperthyroidism, 145
biochemical testing in, 536541 in primary hyperparathyroidism, 601602, Concurrent problems, in feline diabetes mellitus,
blood pressure measurement in, 531, 532t 602f 289
clinical manifestations of, 527530, Chemotherapy Congenital adrenal hyperplasia, 516, 517f
528b529b, 529t530t in canine thyroid tumor, 210 Congenital adrenal hyperplasia-like syndrome,
clinical pathology of, 530548 hypocalcemia and, 640 55
computed tomography and magnetic in pheochromocytoma, 546 Congenital hepatic disease, hypoglycemia in,
resonance imaging in, 534535, 534f Chief cell carcinoma, 618 355, 356f
definition, embryology, anatomy, and Chloride Congenital hyposomatotropism. see Hyposo-
etiology of, 521523 hyperchloremia and, 343 matotropism, congenital.
diagnosis of, 541543 in primary hyperparathyroidism, 600 Congenital hypothyroidism, 8586
histopathology of, 545 Chlorpropamide, for central diabetes insipidus, canine, diagnosis of, 118
medical treatment of, 545546 30 feline, 125
in multiple endocrine neoplasia type 2, 549 Cholangiohepatitis, 327 Constipation, in canine hypothyroidism, 91
nuclear medicine scanning techniques in, Cholecalciferol, 591 Continuous glucose monitoring (CGM),
535 Cholesterol 299300, 300f301f
pathophysiology of, 523530, 525f, 526t, in adrenocortical diseases of dog, 396, 397f systems, in canine diabetes mellitus, 239, 240f
527b and canine diabetes mellitus, 220 Convulsion, in canine hypoparathyroidism, 630
physical examination in, 529530 in feline Cushings syndrome, 461462 Cori disease, 355
physiology of, 523530 feline hyperthyroidism and, 150 Corneal ulceration, in canine diabetes mellitus,
prognosis in, 546 hypercholesterolemia and, in pheochromo- 252
signalment in, 527 cytoma, 530 Corticosteroid binding protein (CBP), 565
surgical management of, 545 Chromium, for glycemic control, 231, 286 Corticosteroid-induced alkaline phosphatase,
treatment of, 543545 Chromogranin A (CGA), 523524 405, 406f
pituitary dwarfism in, 4454 Chronic hyperglycemia, 369371, 370f371f Corticosteroid insufficiency, critical illness
primary hyperparathyroidism in, 620, 620t Chronic kidney disease induced, 508
PTH concentration in, 635 and canine diabetes mellitus, 250251 Corticotropin-releasing hormone, 486
Cataract hypercalcemia and, 592, 592f in regulation of glucocorticoid secretion, 378,
in canine diabetes mellitus, 217218, 217f, hypocalcemia and, 638, 638f 379f
251252 in primary hyperparathyroidism, 595 Corticotropin-releasing hormone and
in canine hypoparathyroidism, 631, 631f Chronic pancreatitis vasopressin response testing, 409
Catechol-O-methyltransferase (COMT), 524 and canine diabetes mellitus, 250 Cortisol, 555
Catecholamine metabolites, 536 feline, diabetes mellitus and, 305 see also Glucocorticoids
Catecholamines Chronic renal failure, polydipsia and polyuria adrenocorticotropic hormone secretion and,
biosynthetic pathway of, 522f in, 6 378
diabetic ketoacidosis and, 316317, 318f Chvostek sign, 631 characteristics of, 559t
pheochromocytoma and, 523524, 536537 Ciclesonide, 555556 during critical illness, 508
in dogs and cats, 537541 Clonidine stimulation test, in pituitary diabetic ketoacidosis and, 316317, 318f
CDI. see Central diabetes insipidus (CDI). dwarfism, 51, 51f in feline hyperadrenocorticism, 454
Cell-mediated immune system, 82 Clouded consciousness, 326 hypoglycemia and, 350351, 350b
654 INDEX
Cortisol (Continued) Cushings syndrome (Continued) Diabetes insipidus (Continued)

lymphopenia from, 494495 pituitary macrotumor syndrome and, 477 confirming diagnosis of, 17
plasma, in feline hyperthyroidism, 150151 pituitary radiation in, 477478 etiology of, 1214
precursors as cause of occult polydipsia in, 456457 modified water deprivation test in, 1727
hyperadrenocorticism, 442443 polyphagia in, 457 physiology of water metabolism and, 26
regulation of secretion, 380 polyuria in, 456457 actions of vasopressin in, 35, 4f, 5t
resting (baseline), 405 prognosis of, 478 biosynthesis, transport and metabolism of
secretion, 381, 382f screening and discrimination tests in, vasopressin in, 23, 3f
structure of, 556f 467468 polydipsia and polyuria in, 7t
Cortisol-to-adrenocorticotrophic hormone screening tests in, 463468, 464t diagnostic approach for, 10, 11f
ratio, in hypoadrenocorticism, 505506, serum biochemistry in, 458t, 459463, differential diagnosis for, 7
505f506f 461t462t prognosis in, 31
Cortisol-to-creatinine ratio, in hypoadrenocor- serum calcium, albumin, globulins, and Diabetes mellitus
ticism, 507 total proteins in, 462t, 463 in adrenocortical diseases of dog, 398, 400401
Cortisone serum cholesterol and thyroxine in, 461462 canine, 213257
characteristics of, 559t serum sodium, serum magnesium, serum after surgical removal of insulin-secreting
structure of, 556f potassium, and muscle weakness in, tumor, 367
Cosyntropin, 465466 462463, 462t allergic reactions to insulin, 247248
Coughing, in canine thyroid tumor, 199, 199t signalment in, 454, 454t455t anamnesis in, 217218
Counterregulatory hormones skin fragility in, 456t457t, 458, 460f blood glycated hemoglobin in, 235f
diabetic ketoacidosis and, 316317, 318f surgery for, 477 cataracts in, 217218, 217f
glucose production and, 350 trilostane for, 473475 chromium for, 231
Creatinine ultrasound-guided biopsy in, 472 classification of, 214216, 219b
in diabetic ketoacidosis, 326, 326f urinary tract infection in, 462t, 463 clinical pathologic abnormalities in,
in feline Cushings syndrome, 458t, 461t462t, urine cortisol-to-creatinine ratio in, 463464, 219221, 219b
462 464t465t, 467468 complete blood count, 220
in feline hyperthyroidism, 150 weakness, lethargy, potbelly, and bruising complications of, 222t, 233b, 251253
in primary hyperparathyroidism, 600 in, 457f, 458 concurrent disorders in, 218, 248251, 248f
Cretinism, 92, 92b, 93f94f weight loss in, 457 continuous glucose monitoring systems,
CRH. see Corticotropin-releasing hormone. polydipsia and polyuria in, 8 239, 240f
Critically ill patients, hypocalcemia and, 638 Cutaneous metaplastic ossification, 391, 393f corneal ulceration, 252
Crude animal-origin hormonal preparations, 123 Cyclic adenosine monophosphate (cAMP), AVP diabetic nephropathy in, 253
Cushings syndrome and, 34, 4f diabetic neuropathy in, 252253
in dog, 378 Cyclopentanoperhydrophenanthrene nucleus, diabetic retinopathy in, 252
feline, 452453 555 dietary therapy, 229231, 229b230b, 230f
abdominal enlargement in, 456 Cyproheptadine, 436 establishing diagnosis of, 218219, 218t
abdominal radiology in, 471 Cyst, pituitary, 4445, 45f etiology, 214216
abdominal ultrasonography in, 471472, Cytokines, 586 exercise in, 231, 231f
471t472t factors involved in, 214t
adrenalectomy in, 476477 D history in, 234
adrenocorticotropic hormone stimulation Day-blooming jessamine, 591 hypertension in, 253
test in, 464466, 465t 1 deamino (8 d-arginine) vasopressin, 23, 29 inadequate insulin absorption in, 246
blood glucose concentrations in, 459460, 461t chemical structure of, 3f insulin-dependent, 214, 227f, 232f
blood urea nitrogen, serum creatinine, Dehydration insulin-induced hypoglycemia in, 242243
urinalysis in, 462, 462t after modified water deprivation test, 2426, insulin resistance in, 217f, 248251, 248f,
chief concern in, 454456, 455t 25f 249t, 250b251b
complete blood count in, 459, 461t in diabetic ketoacidosis, 320 insulin therapy during surgery in, 242
computed tomography and magnetic in hyperosmolar hyperglycemic state, 344 insulin therapy in, 222228, 223t, 226t, 227f,
resonance imaging scans in, 472473, Demodicosis, 389390, 391f 230f, 245f247f
473f, 473t L-deprenyl, 435 lens-induced uveitis in, 252
curled ear tips in, 458 Depression negative psychological and social impacts
dermatologic abnormalities in, 458, 459f in diabetic ketoacidosis, 320, 326 of, 222t
dexamethasone suppression test/adreno- in primary hyperparathyroidism, 595 nonketotic, treatment of, 221233
corticotropic hormone stimulation in, 467 Dermatohistopathology, in canine hypothy- oral hypoglycemic drugs for, 231232, 232f,
and diabetes mellitus, 455456 roidism, 95 233b
duration of clinical signs, 454, 455t Dermatologic abnormalities overview of patient evaluation, 219
endogenous adrenocorticotropic hormone in canine hypothyroidism, 8788, 88f89f pancreatic enzymes in, 220221
and adrenocorticotropic hormone in feline hyperadrenocorticism, 458, 459f pathophysiology of, 216217
precursor concentrations in, 470471 Desmopressin acetate, for central diabetes persistence of clinical signs, 243244
etiology of, 453454 insipidus, 17 physical examination in, 218, 234
etomidate for, 475 Desoxycorticosterone pivalate, for hypoadreno- problems with owner administration and
hair cortisol concentrations in, 467 corticism, 511512, 511f512f activity of the insulin preparation, 243
high dose dexamethasone suppression test Dexamethasone, 555556, 566, 571 problems with the insulin treatment
in, 467470, 469t470t for cerebral edema, 369 regimen, 244
hypophysectomy in, 476 characteristics of, 559t prognosis, 253
ketoconazole for, 475 for immunosuppression, 569 recurrence of clinical signs, 243244
laparoscopy in, 477 Dexamethasone sodium phosphate, suppression remission of, 215216
lethargy in, 456 of hypothalamic pituitary adrenal axis serial blood glucose curve, 226f, 236241,
liver enzyme activities in, 460461 by, 571 237f239f, 238t, 241f242f, 244f
low dose dexamethasone suppression test Dexamethasone suppression test, in feline serum biochemical panel in, 220
in, 465t, 466468 Cushings syndrome serum fructosamine in, 234235, 234t, 235f
medical treatment for, 473476 high-dose, 468470, 469t470t serum insulin concentration, 221
metyrapone for, 475476 low dose, 465t, 466467 serum thyroxine concentration, 221
mitotane for, 475 Dextrose, for acute hypoglycemic crisis, 368 short duration of insulin effect in, 230f,
observations, 456, 456t Diabetes insipidus, 136 245246, 245f247f
physical examination, abnormalities in, 456, clinical features of, 1416 signalment, 217
457t clinical pathology abnormalities in, 16 single blood glucose determination, 234
INDEX 655
Diabetes mellitus (Continued) Diabetic ketoacidosis (Continued) Diurnal rhythm, effects on canine thyroid
Somogyi response in, 244245, 244f245f hyperkalemia and, 497 function tests, 112
storage, mixing, and dilution, 227228 in-hospital diagnostic evaluation of, 322330, DOCP. see Desoxycorticosterone pivalate.
stress hyperglycemia, 241 322b Dog
techniques for monitoring, 233242 acid-base status in, 323324, 324f, 324t acquired hyposomatotropism in, 5455, 54b
type 1, 214, 216f anion gap in, 326327, 327t, 327b acromegaly in, 6872
type 2, 214215, 216f blood glucose in, 323, 323f adrenocortical diseases of, 377451
urinalysis in, 220 blood urea nitrogen and creatinine in, 326, beta-cell neoplasia in, 348376
urine glucose monitoring in, 236 326f diabetes mellitus in, 213257
differential diagnosis of, 460 calcium and phosphorus in, 328 after surgical removal of insulin-secreting
etiology of, 214216 complete blood count in, 327 tumor, 367
feline, 258314 diagnostic imaging in, 329 hypothyroidism and, 114
acarbose for, 285 electrocardiogram in, 329330, 329b, 330f eosinophilia in, causes of, 495b
anamnesis in, 272 liver enzymes in, 327 growth hormone secretion in, 39
biguanides for, 284285 magnesium in, 329 hypoadrenocorticism in, 485520
binding insulin antibodies in, 304305 pancreatic enzymes in, 327328, 328f hypoparathyroidism in, 629631, 635637
blood glucose curve in, 292, 293f serum osmolality in, 326 hypothyroidism in, 80
chromium for, 286 serum potassium concentration in, 324325, pheochromocytoma in, 521554
chronic complications in, 307308 325f abdominal and thoracic radiographs in,
clinical pathology of, 275277 serum sodium concentration in, 324, 325f 531532, 532f
concurrent disorders causing insulin total bilirubin in, 323324 abdominal ultrasonography in, 532534,
resistance in, 305306 urinalysis and urine culture in, 322323 533f, 533b
concurrent problems in, 289 pathogenesis and pathophysiology of, biochemical testing in, 536541
diagnosis of, 273275, 274f, 275t 315318, 316f319f blood pressure measurement in, 531, 532t
diagnostic imaging in, 277278 prognosis in, 343 clinical manifestations of, 527530,
dietary therapy in, 289, 289b signalment in, 318 528b529b, 529t530t
fluctuating insulin requirements in, 306307 treatment of, for sick dogs and cats, 331343, clinical pathology of, 530548
glinitides for, 284 331b computed tomography and magnetic
glycated hemoglobin concentration in, 291 bicarbonate therapy in, 336, 336f resonance imaging in, 534535, 534f
history in, 290 complications of, 341343, 342b definition, embryology, anatomy, and
hypoglycemia in, 302303 fluid therapy in, 331336, 332f, 333t etiology of, 521523
impaired absorption of insulin in, 304 insulin therapy in, 337340, 337f339f diagnosis of, 541543
initial insulin therapy in, 279281 magnesium supplementation and, 335336 histopathology of, 545
insulin underdose in, 303 phosphate supplementation and, 334335 medical treatment of, 545546
physical examination in, 272, 273f, 274b, 290 potassium supplementation and, 333334, in multiple endocrine neoplasia type 2, 549
prevalence and risk factors for, 259 334f, 335t nuclear medicine scanning techniques in,
prognosis in, 308 Diabetic nephropathy 535
prolonged duration of insulin effect in, 304 canine diabetes mellitus and, 253 pathophysiology of, 523530, 525f, 526t,
remission of, 266268, 266f feline diabetes mellitus and, 307308 527b
serum fructosamine concentration in, Diabetic neuropathy physical examination in, 529530
290291, 290f canine, 252253 physiology of, 523530
short duration of insulin effect in, 304 feline, 308 prognosis in, 546
signalment in, 271, 271t Diabetic retinopathy, 252 signalment in, 527
Somogyi effect in, 303, 304f Diagnostic imaging surgical management of, 545
stress hyperglycemia in, 300302 in adrenocortical diseases of dog, 409415 treatment of, 543545
sulfonylureas for, 283284, 283t in beta-cell neoplasia, 361364, 362f363f pituitary dwarfism in, 4454
technical problems in, 303 in diabetic ketoacidosis, 329 primary hyperparathyroidism in, 593, 608t
thiazolidinediones for, 285 in pheochromocytoma, 531535 adrenal secondary hyperparathyroidism
transient, 266267, 266f Diarrhea and, 619
type 1, 262, 263f in canine hypothyroidism, 91 assays in, 603604
type 2, 262265 in feline hyperthyroidism, 144 biochemical profile in, 597601, 597t
urine glucose in, 291292 Diazoxide therapy breed distribution of, 594, 594t
vanadium for, 286287 for beta-cell tumor, 364b chronicity of, 615616
and feline hyperadrenocorticism, 455456, 460 for chronic hypoglycemia, 369370 clinical pathology of, 596601, 617619
human Diestrus clinical signs of, 594596, 594t
classification of, 260f, 260b diabetic ketoacidosis during, 341 electrocardiography of, 601
prevalence and risk factors for, 259 effects on thyroid function tests, 111 enlargement of multiple parathyroid glands
type 1, 260261 Dietary fiber, feline diabetes mellitus and, 287 in, 611612
type 2, 261262, 261f Dietary therapy hemogram in, 596597
hypocalcemia and, 638639 in canine diabetes mellitus, 229231, hereditary neonatal, 619
polydipsia and polyuria in, 6 229b230b, 230f history in, 604
Diabetic cataracts, feline diabetes mellitus and, complications with, 229, 230b initial database in, 604607
307 feeding schedule in, 229230, 230f mediastinal parathyroid tissue and, 618
Diabetic control, in feline diabetes mellitus, modifications in, 230231 multiple endocrine neoplasia and, 619
289300 in feline diabetes mellitus, 289, 289b novel therapies for, 612614
blood glucose curve in, 292, 293f Diffuse lymphocytic parathyroiditis, 637 versus other disorders, 608
glycated hemoglobin concentration in, 291 DiGeorge syndrome, 637 percutaneous ultrasound-guided ethanol
history and physical examination in, 290 Dihydrotachysterol ablation in, 612, 613f614f
serum fructosamine concentration in, 290291, after feline thyroidectomy, 179 percutaneous ultrasound-guided radio
290f for hypocalcemia, 643t, 644, 644f frequency heat ablation in, 612614,
urine glucose in, 291292 1,25-Dihydroxyvitamin D3 614f615f
Diabetic ketoacidosis, 217, 315347 for hypocalcemia, 643t, 644 physical examination in, 596, 604
concurrent illness in, 340341 normal levels of, 582t prognosis of, 619
establishing diagnosis of, 320322, 320f321f Dilated cardiomyopathy, 91 radiography in, 601, 601f, 607, 607f
healthy dogs and cats with, treatment for, Disuse osteoporosis, 593 radionuclide scans in, 610
330331 Diuretics, for renal failure in ketoacidotic recurrence of, 612
history and physical examination in, 318320 dog, 333 selective venous sampling, 610611
656 INDEX
Dog (Continued) Energy requirement, for diabetic cat, 288289 Feline diabetes mellitus (Continued)
signalment in, 593594, 604 Environment diagnostic imaging in, 277278
solitary adenoma, hyperplastic nodule, or feline hyperthyroidism and, 141 goals of therapy for, 278279
carcinoma and, 611 temperature effects on canine thyroid function monitoring diabetic control in, 289300
solitary parathyroid mass and, 618 tests, 115 blood glucose curve in, 292, 293f
spontaneous resolution of, 608 Enzyme-linked immunosorbent assays glycated hemoglobin concentration in, 291
surgical therapy for, 609612, 611f (ELISAs), 99 history and physical examination in, 290
tapering process and, 617 Enzymes, steroidogenic, 380, 380t serum fructosamine concentration in,
ultrasonography in, 601603, 607 Eosinopenia, 561 290291, 290f
urinalysis in, 600601 glucocorticoid-related, 573 urine glucose in, 291292
urinary tract calculi and infections, 595, 595f Eosinophilia, in dogs and cats, causes of, 495b physical examination in, 272, 273f, 274b
PTH concentration in, 635 Epidermis, actions of parathyroid hormone- prevalence and risk factors for, 259
Dog leucocyte antigen (DLA), and canine related protein on, 586t prognosis in, 308
diabetes mellitus, 214 Epinephrine remission of, 266268, 266f, 268f269f
Domestic short-haired (DSH) cat, and feline for anaphylaxis, 569 signalment in, 271, 271t
Cushings syndrome, 454, 455t diabetic ketoacidosis and, 316317, 318f transient, 266267, 266f
Dopamine hypoglycemia and, 350351, 350b treatment of, 278289
pheochromocytoma and, 523524 metabolism of, 536f acarbose in, 285
in regulation of glucocorticoid secretion, pheochromocytoma and, 523524 biguanides in, 284285
379380 Epithelial tissues, 586t chromium in, 286
for renal failure in ketoacidotic dog, 333 Equilibrium dialysis, 157158 concurrent problems in, 289
Doxorubicin, for canine thyroid tumors, 210 Ergocalciferol, for hypocalcemia, 643644, 643t dietary therapy in, 289, 289b
Drugs, effects on canine thyroid function tests, Erythrocytes glinitides in, 284
115117, 115t116t, 117b effect of glucocorticoids on, 561 goals of, 278279
Dwarfism morphology in canine hypothyroidism, 9294 initial insulin therapy, 279281
in feline hypothyroidism, 125126 Escherichia coli, polydipsia and polyuria from, sulfonylureas in, 283284, 283t
pituitary, 4454 78 thiazolidinediones in, 285
clinical manifestations of, 4748, 48f, 48b Esophageal dilation, hypoadrenocorticism and, vanadium in, 286287
clinical pathology of, 48 499500 type 1, 262, 263f
dermatohistopathology of, 4849 Ethylene glycol toxicity, 639 type 2, 262265
differential diagnosis of, 44b, 49 Etomidate, for feline Cushings syndrome, 475 Feline hyperadrenocorticism, 452453
endocrinological evaluation and diagnosis Euglycemia, 349350, 349f see also Cushings syndrome, feline
in, 4952 Euthyroid sick syndrome, in cat, 128 Feline hyperthyroidism, 136195
etiopathogenesis of, 4447, 45f47f Exercise alopecia in, 144
prognosis of, 54 in canine diabetes mellitus, 231, 231f atenolol for, 189
signalment of, 47 in feline diabetes mellitus, 289 basal free thyroxine in, 157158, 157f, 158t
treatment of, 5254 External beam radiation therapy, for canine basal total serum thyroxine in, 154156,
thyroid tumor, 209 154f155f, 156t
E Extracapsular thyroidectomy, 178, 179f basal total serum triiodothyronine in, 157, 157f
Ear tip curling, in feline Cushings syndrome, Eye, actions of catecholamines on, 526t blood glucose in, 149150
458 blood pressure and hypertension in, 151
Echocardiography F blood urea nitrogen and creatinine in, 150
in feline acromegaly, 60 Facial paralysis, in adrenocortical diseases of dog, carbimazole for, 176t, 177
in feline hyperthyroidism, 152154 393 cervical ultrasound in, 167169, 169f, 169t
Eclampsia, 639 Facial rubbing, in canine hypoparathyroidism, cholesterol levels in, 150
Ectopic adrenocorticotropic hormone syndrome, 630 complete blood count in, 148, 148t
384385 Familial medullary thyroid carcinoma (FMTC), decreased appetite in, 145
Ectopic calcification, in adrenocortical diseases 549 diagnostic evaluation in, 148154, 151t
of dog, 394 Fast feedback, 378 diarrhea and vomiting in, 144
Edema, cerebral, 342 Fasting, effects on canine thyroid function tests, differential diagnosis for, 154, 154t, 162f
Electrocardiography 115 echocardiography in, 152154
in diabetic ketoacidosis, 329330, 329b, 330f Feedback effect, adrenocorticotropic hormone electrocardiography in, 151, 152f153f, 153t
in feline hyperthyroidism, 151, 152f153f, 153t and, 378 etiology of, 138141
in hypoadrenocorticism, 501, 502f Feeding heat and stress intolerance in, 145
Electrolytes frequent, in insulin-secreting tumors, 369 hypocalcemia in, 640
abnormalities in dogs with hypoadrenocor- schedule iodinated radiographic contrast agents for, 190
ticism, 495498, 496b in canine diabetes mellitus, 229230, 230f iodine for, 176t, 189190
in adrenocortical diseases of dog, 397 for diabetic cat, 288289 liver enzyme activities in, 148149
Endocrine evaluation, in feline Cushings Feline diabetes mellitus, 258314 methimazole for, 170f, 172177, 173f, 175f, 176t
syndrome anamnesis in, 272 nervousness, hyperactivity, aggressive
adrenocorticotropic hormone stimulation test, clinical pathology of, 275277 behavior in, 142t, 144
464466, 465t complications of insulin therapy in, 300307, panting and respiratory distress in, 145
low dose dexamethasone suppression test, 302b pathology of, 137138, 138f
465t, 466467 binding insulin antibodies in, 304305 percutaneous ethanol and heat ablation
urine cortisol-to creatinine ratio, 463464, chronic complications in, 307308 injection for, 188189
464t465t concurrent disorders causing insulin physical examination in, 144t, 145148,
Endocrine tissues, 586t resistance in, 305306 146f147f
Endogenous adrenocorticotropic hormone fluctuating insulin requirements in, 306307 plasma cortisol in, 150151
concentration hypoglycemia in, 302303 polydipsia and polyuria in, 144
in adrenocortical diseases of dog, 407409, impaired absorption of insulin in, 304 polyphagia in, 142144, 144b
408f, 408t insulin underdose in, 303 prognosis of, 190, 191f
in feline hyperadrenocorticism, 470471 prolonged duration of insulin effect in, 304 propranolol for, 189
in feline hypoadrenocorticism, 515t, 516 short duration of insulin effect in, 304 radioactive iodine for, 181185, 181f182f,
in hypoadrenocorticism, 504505, 505f Somogyi effect in, 303, 304f 182t, 184f
Endometritis, hypercalcemia and, 593 stress hyperglycemia in, 300302 radiography in, 151
-endorphin, 378 technical problems in, 303 renal function and, 170172
Endotoxic-induced hypoglycemia, 358 diagnosis of, 273275, 274f, 275t risk factors for, 139140, 139t
INDEX 657
Feline hyperthyroidism (Continued) Gastrointestinal disease Glucocorticoid therapy (Continued)

serum fructosamine in, 151 hyperkalemia and, 497 selected effects on immune system of, 562b
signalment in, 142, 143f hypoadrenocorticism versus, 497b therapeutic indications for, 567570
steatorrhea in, 144 Gastrointestinal hemorrhage, glucocorticoid- Glucocorticoid withdrawal syndrome, 572
surgery for, 177181, 178f179f related, 572573 Glucocorticoids
thyroid scintigraphy in, 161167, 163f168f, Gastrointestinal signs, in canine anti-inflammatory properties of, 562563, 564f
163t, 166b hypothyroidism, 9192 in AVP, 8
thyroid-stimulating hormone response test in, Gastrointestinal tract, effect of glucocorticoids biologic effects of, 559563
159160 on, 561 and canine diabetes mellitus, 250
thyrotropin-releasing hormone stimulation Gender characteristics of, 559t
test in, 160, 161f in adrenocortical diseases of dog, 385 chemistry of, 555556, 556f
triiodothyronine suppression test in, 158159, in canine hypothyroidism, 111 clinical pharmacology of, 563567
159f161f, 159t canine primary hyperparathyroidism and, combination products of, 567
urinalysis in, 148t, 150 593594 deficiency in, 486
weakness and lethargy in, 145 Genetic syndromes, associated with versus mineralocorticoid deficiency, 489490
weight loss in, 142, 143f, 144b pheochromocytoma, 523t distribution, metabolism and excretion of,
Feline hypoadrenocorticism, 514516 Genetic testing, for pituitary dwarfism, 49 565, 566f
differential diagnosis of, 515516 Gestational diabetes, in human, 262 dose equivalents of, 565566
electrocardiogram abnormalities in, 514515 Ghrelin, 42 drug interactions of, 570t
etiology of, 514 stimulation, in pituitary dwarfism, 51 duration of action, 563
laboratory abnormalities in, 514515, 515t GHRH. see Growth hormone-releasing hormone. effects of, 486
management of, 516 GHS-R. see Growth hormone secretagogue on carbohydrate, 559
prognosis of, 516 receptor. on lipid metabolism, 559
radiographic abnormalities in, 514515 Gigantism, 55 on protein, 559
signalment and clinical signs of, 514, 514t Glinitides, 284 on tissues, 559562
treatment of, 516 Glipizide, 283t, 284, 284b exogenous
Feline hypothyroidism, 124 Glitazones, 285 in diabetic ketoacidosis, 341
after thyroidectomy, 180181 Glomerular filtration rate feline, in development of diabetes mellitus,
clinical signs of, 125126, 125b, 126f in diabetic ketoacidosis, 327b, 323 305306
diagnosis of, 128 feline hyperthyroidism and, 171172 and feline hyperadrenocorticism, 458
etiology of, 124125 hypercalcemia and, 583 galenic formulations and steroid esters for,
thyroid function tests in, 126128, 127f Glucagon 566567, 567f, 567t
treatment and prognosis in, 128129 deficiency of, 356 genomic and nongenomic immunoregulation
Feline thyroid carcinoma, 187188, 188f189f diabetic ketoacidosis and, 316317, 318f by, 560f
Fetal retention, hypercalcemia and, 593 hypoglycemia and, 350, 350b genomic effects of, 556558
Fever, in tetany, 642 Glucocorticoid deficient hypoadrenocorticism, for hypoadrenocorticism, 509511
FFAs. see Free fatty acids (FFAs). 489490, 496497 immunosuppressive effects of, 562563, 564f
Fiber Glucocorticoid receptor, 556558 nongenomic effects of, 558559
in canine diabetes mellitus, 229 Glucocorticoid response elements, 556558 pharmacokinetics of, 563567
feline diabetes mellitus and, 287 Glucocorticoid therapy, 555578 reduction protocol for, 574
Fibrous osteodystrophy, 583 adverse effects of, 570574 regulation of secretion of, 378381, 486, 488f
Fludrocortisone, characteristics of, 559t anti-inflammatory properties of, 562563, adrenocorticotropic hormone in, 378
Fludrocortisone acetate, for 564f corticotropin-releasing hormone in, 378,
hypoadrenocorticism, 512513 for beta-cell tumor, 364b 379f
Fluid therapy biologic effects of, 559563 dopamine in, 379380
for diabetic ketoacidosis, 331336, 332f, 333t chemistry of, 555556 steroids in, 380381
for hypernatremia, 26 in chronic hypoglycemia, 369 route of administration of, 563565, 565t
for hyperosmolar hyperglycemic state, 344345 clinical pharmacology of, 563567 oral, 563
for hypoadrenocorticism, 509 combination products of, 567 parenteral, 563565
for surgery for insulin-secreting tumor, 365 distribution, metabolism and excretion of, topical, 565
Fluticasone, for inflammation, 568569 565, 566f selected effects on immune system of, 562b
Fluticasone propionate, 555556 dose equivalents of, 565566 serum thyroid hormone concentrations and,
Follicle-stimulating hormone (FSH) drug interactions of, 570t 115116, 116t
in dwarfism, 47f duration of action, 563 therapeutic indications for, 567570
in feline hyperadrenocorticism, 454 effects on carbohydrate, 559 Gluconeogenesis, 349
Follicular cell hyperplasia, 84 effects on lipid metabolism, 559 Glucose
Fractures, in primary hyperparathyroidism, 596, effects on protein, 559 blood
596f effects on tissues, 559562 in adrenocortical diseases of dog, 396
Free fatty acids (FFAs), ketone bodies and, 315 galenic formulations and steroid esters for, in canine diabetes mellitus, 234, 236241,
Free thyroxine, in feline hyperthyroidism, 566567, 567f, 567t 237f239f, 238t, 241f242f, 244f
157158, 157f, 158t free alcohol solutions, 566 in diabetic ketoacidosis, 320, 323, 323f
Fructosamine, serum insoluble steroid ester, 567 in feline Cushings syndrome, 459460
in feline diabetes mellitus, 290291, 290f water-soluble ester, 566 in feline diabetes mellitus, 292, 292f
in feline hyperthyroidism, 151 genomic and nongenomic immunoregulation in feline hyperthyroidism, 149150
FSH. see Follicle-stimulating hormone. by, 560f in feline stress hyperglycemia, 300302
Furosemide, for cerebral edema, 369 genomic effects of, 556558 in hyperosmolar hyperglycemic state, 344
immunosuppressive effects of, 562563, 564f in insulin-secreting tumor, 353, 360
G laboratory abnormalities related to, 573 intraoperative, 365367
G proteins, 138139 molecular mechanisms of, 556559 tissue utilization of, 351
Galactitol, and cataract formation, in canine nongenomic effects of, 558559 homeostasis, 269
diabetes mellitus, 251252 pharmacokinetics of, 563567 impaired glucose counterregulation and, 243
Gallop rhythm, 146147 for primary hyperparathyroidism, 585, 609b metabolism of, 356f
Gamma glutamyl transferase (GGT), glucocor- reduction protocol for, 574 urine, in adrenocortical diseases of dog, 397
ticoid-related increase of, 573 route of administration of, 563565, 565t Glucose-6-phosphatase deficiency, 355
Gastric inhibitory polypeptide (GIP), 269270, 384 oral, 563 Glucose counterregulation
Gastrinomas, in multiple endocrine neoplasia parenteral, 563565 in canine diabetes mellitus, 243
type 1, 549 topical, 565 in feline diabetes mellitus, 303, 304f
658 INDEX
Glucose-raising hormones, 350 Heart murmur, systolic, acromegaly in cats and, 17-Hydroxy-progesterone, 442443
Glucose transporters, 351, 351t, 352f 5759 -hydroxybutyrate, 315, 320
Glucotoxicity, in feline diabetes, 265 Heat intolerance, 145 17-Hydroxycorticoids, 555
Glyburide, 284 Hematocrit, in feline hyperthyroidism, 148 17-Hydroxycorticosteroids, 555
Glycated hemoglobin, in feline diabetes mellitus, Hematology, in dogs with hypoadrenocorticism, 11--hydroxysteroid dehydrogenase (11-HSD)
291 494495 type 1, 555556
Glycemic control, in canine diabetes mellitus, Hematopoietic neoplasia, and hypercalcemia, Hyperactivity, in feline hyperthyroidism, 144
231232, 232f, 233b 586 Hyperadrenocorticism, 387f388f, 396t, 562
Glycogen storage diseases (GSDs), 355 Hemoconcentration, hyperglycemia and, 593 canine, clinical manifestations of, 386t
Glycogenolysis, 349 Hemogram, in primary hyperparathyroidism, and canine diabetes mellitus, 250
Glycosuria 596597 complications associated with, 398399
in canine diabetes mellitus, 216219 Hemolytic anemia, 343 diabetes mellitus, 398
in diabetic ketoacidosis, 320, 323 Hemorrhage, in rodenticide toxicosis, 591 gallbladder mucocele, 398399
primary renal, polydipsia and polyuria in, 6 Hemorrhagic infarction, in adrenal gland, hypertension, 398
GNAS protein, 5556 490491 hypothyroidism, 398
Goiter Hepatic disease, hypoadrenocorticism versus, pulmonary thromboembolism, 399
congenital feline hypothyroidism and, 125 500b urinary crystals and calculi, 398
in feline hyperthyroidism, 145146, 146f147f Hepatic dysfunction, hypoadrenocorticism and, confirming diagnosis of, 400405
multinodular adenomatous, 137138, 138f 498 due to adrenal tumor, 383384
Goitrogens, 141, 141f Hepatic failure, in diabetic ketoacidosis, 344 feline, diabetes mellitus and, 306
Gonadal alterations, in adrenocortical diseases Hepatic insufficiency, polydipsia and polyuria food-dependent, 385
of dog, 394 from, 8 hypothyroidism and, 114115, 115b
Gonadotropins, effect of glucocorticoids on, 562 Hepatocellular carcinoma, 357 naturally-acquired, in diabetic ketoacidosis, 341
Growth and development, effect of glucocorti- Hepatomegaly, in adrenocortical diseases of occult, 441444
coids on, 559 dog, 393394 indications for diagnostic testing in, 443444
Growth failure, causes of Herbs, for glycemic control in dog, 232, 233b as sex hormone-mediated disease, 441443
in dogs and cats, 44, 44b Hereditary neonatal primary hyperparathy- treatment of, 444
in humans, 4344, 44b roidism, 619 pituitary-dependent, 381383, 382f
Growth hormone High-dose dexamethasone suppression test versus adrenocortical tumor, 405409
basal, 49 (HDDST) mitotane for, 422429
biosynthesis of, 3941 in adrenocortical diseases of dog, 406407, polydipsia and polyuria in, 8
deficiency of, 4344, 44b 407f simultaneous pituitary-dependent and
idiopathic adult, 54 in feline Cushings syndrome, 468470, adrenal-dependent, 385
effect of glucocorticoids on, 562 469t470t spontaneous remission of, 437438
hypoglycemia and, 350351, 350b, 356357 High-fiber diets, for glycemic control, 288 Hyperalbuminemia, in feline hyperadrenocor-
mammary, 4041 Histology ticism, 462t
metabolic actions of, 4243, 43f in canine thyroid tumors, 197b, 209 Hyperaldosteronism, primary, polydipsia and
regulation of secretion of, 4142, 41f, 42b in hypoparathyroidism, 646 polyuria in, 8
Growth hormone disorders, 3776 History Hypercalcemia, 579624
acquired hyposomatotropism, 5455, 54b in adrenocortical diseases of dog, 385393 in acute kidney injury, 592
acromegaly abdominal enlargement in, 388 acute medical therapy for, 608609
in cats, 5668 cutaneous markers, 389391 assays for, 584585
in dogs, 6872 facial paralysis, 393 in canine hypothyroidism, 95
congenital hyposomatotropism, 4454 muscle weakness and lethargy, 388389, in chronic kidney disease, 592, 592f
clinical manifestations of, 4748, 48f, 48b 389f diagnostic approach to, 604608
clinical pathology of, 48 myotonia, 392393, 393f differential diagnosis of, 585593, 587b
dermatohistopathology of, 4849 obesity, 391 in disuse osteoporosis/tumors metastasizing
differential diagnosis of, 44b, 49 polyphagia, 388 to bone, 593
endocrinological evaluation and diagnosis polyuria and polydipsia, 386388 exploratory surgery and, 608
in, 4952 respiratory signs, 392 feline
etiopathogenesis of, 4447, 45f47f in canine diabetes mellitus, 234 differential diagnosis for, 619620
prognosis of, 54 in canine primary hyperparathyroidism, 604 idiopathic, 620
signalment of, 47 in diabetic ketoacidosis, 318320 hemoconcentration, sodium bicarbonate
treatment of, 5254 in insulin-secreting tumor, 353 infusion, and plasma transfusion in, 593
Growth hormone-releasing hormone, 39, 41 in pulmonary thromboembolism, 399 history and physical examination for, 604,
Growth hormone-releasing hormone test, in Honeymoon period in diabetes mellitus, 215216 605f606f
pituitary dwarfism, 5051, 50f Hormonal disorders, causing insulin resistance, humoral, of malignancy, 590, 604b
Growth hormone-responsive alopecia, 55 in diabetic ketoacidosis, 341 hypervitaminosis D and, 590591, 590f591f
Growth hormone secretagogue receptor, 42 Hormonal evaluation hypoadrenocorticism and, 494t, 495496,
Growth hormone stimulation tests, in pituitary feline, in acromegaly, 6164, 63t 591592
dwarfism, 4950, 50t in feline Cushings syndrome induced by metastases of solid tumors to bone,
GSDs. see Glycogen storage diseases (GSDs). adrenocorticotropic hormone stimulation 590
test, 464466, 465t ionized serum calcium concentrations in, 584
H low dose dexamethasone suppression test, of malignancy, 585590
Hair 465t, 466467 nonspecific medical treatment for, 608
in canine hypothyroidism, 87, 88f urine cortisol-to creatinine ratio, 463464, normal serum calcium concentrations and, 582t
feline hypothyroidism and, 125 464t465t nutritional secondary hyperparathyroidism, 593
loss of, in pituitary dwarfism, 4748 HPA axis. see Hypothalamic pituitary adrenal osteolytic, 589
response to levothyroxine sodium therapy, axis. parathyroid hormone-related protein assays
120, 121f Humans in, 585
Hair follicle, actions of parathyroid hormone- disorders causing hypoparathyroidism, 637 pathogenesis of cancer-associated, 587f
related protein on, 586t PTH concentration in, 633 polydipsia and polyuria in, 8
Head trauma, central diabetes insipidus from, 13 Humoral hypercalcemia of malignancy, 586589, raisin/grape toxicity in, 592
Heart 588f, 604b in rodenticide toxicosis, 591
feline hyperthyroidism and, 146 Hydrochlorothiazide, 369370 in septic bone disease, sepsis, schistosomiasis,
hypocalcemia and, 629 Hydrocortisone acetate, for hypoadrenocor- and systemic mycoses, 593
Heart failure, in canine hypothyroidism, 91 ticism, 513 therapy alternatives for, 608609, 610t
INDEX 659
Hypercalcemia (Continued) Hypersomatotropism (Continued) Hypertriglyceridemia

trial therapy and, 607 in humans, 5556 and canine diabetes mellitus, 251, 251b
vitamin D assay in, 584 hormonal evaluation in, 6064 in canine hypothyroidism, 94
Hypercalciuria, 583 treatment of, 6566 in diabetic ketoacidosis, 324
Hyperchloremia, 343 Hypertension Hyperventilation, in canine hypoparathy-
Hypercholesterolemia, 220 in adrenocortical diseases of dog, 398 roidism, 630
in canine hypothyroidism, 8990, 94 in canine diabetes mellitus, 253 Hypervitaminosis D, 590591, 590f591f
in pheochromocytoma, 530 during excision of pheochromocytoma, 544 Hypoadrenal crisis, complications of, 510
Hyperadrenocorticism feline, 452453, 456 in feline Cushings syndrome, 463, 479 Hypoadrenocorticism, 485520, 591592
see also Cushings syndrome, feline in feline hyperthyroidism, 151 abdominal ultrasound in, 500501, 500f
Hyperglycemia, 218219, 219b in pheochromocytoma, 528, 531 acid-base status in, 499
in diabetic ketoacidosis, 320b, 324 Hyperthyroidism aldosterone-to-renin ratio in, 507, 507f
in feline Cushings syndrome, 459460 feline, 136195 basal cortisol concentrations in, 501, 503f
in feline transient diabetes, 268, 269f alopecia in, 144 blood pressure in, 494
in hyperosmolar hyperglycemic state, 344 atenolol for, 189 clinical pathology of, 494499, 494t
stress-induced, 300302 basal free thyroxine in, 157158, 157f, 158t cortisol-to-ACTH ratio in, 505506, 505f506f
Hyperkalemia basal total serum thyroxine in, 154156, cortisol-to-creatinine ratio in, 507
in diabetic ketoacidosis, 325 154f155f, 156t diagnosis of, 501507
differential diagnosis for, 496b, 497 basal total serum triiodothyronine in, electrocardiography in, 501, 502f
electrophysiologic alteration with, 329b 157, 157f emergency management of, 508b
in hypoadrenocorticism, 496497 blood glucose in, 149150 endogenous adrenocorticotropic hormone in,
management of, 508b, 509 blood pressure and hypertension in, 151 504505, 505f
mineralocorticoid deficiency and, 489 blood urea nitrogen and creatinine in, 150 feline, 514516
Hyperketonemia, 320b carbimazole for, 176t, 177 hepatic dysfunction in, 498
Hyperlipidemia, in canine hypothyroidism, 8990 cervical ultrasound in, 167169, 169f, 169t history in, 493494
Hypernatremia cholesterol levels in, 150 hypoalbuminemia in, 498
after modified water deprivation test, 2426 complete blood count in, 148, 148t hypocholesterolemia in, 498
causes of, 26b decreased appetite in, 145 hypoglycemia in, 356, 498
hypodipsic, 34 diagnostic evaluation in, 148154, 151t hyponatremia in, 496497
in treatment of diabetic ketoacidosis, 343 diarrhea and vomiting in, 144 hypothyroidism and, 8283
Hyperosmolality differential diagnosis for, 154, 154t, 162f iatrogenic, 514
in diabetic ketoacidosis, 326 echocardiography in, 152154 versus other diseases, 498b
in hyperosmolar hyperglycemic state, 344 electrocardiography in, 151, 152f153f, 153t physical examination in, 494
Hyperosmolar hyperglycemic state, 343345 etiology of, 138141 plasma aldosterone concentration in,
Hyperparathyroidism heat and stress intolerance in, 145 506507
feline, 149 hypocalcemia in, 640 polydipsia and polyuria in, 89
in multiple endocrine neoplasia type 1, 549 iodinated radiographic contrast agents primary versus secondary, 489, 489f
Hyperphosphatemia for, 190 prognosis of, 513514
acromegaly in cats and, 59 iodine for, 176t, 189190 radiography in, 499500, 499f
in canine hypoparathyroidism, 633 liver enzyme activities in, 148149 signalment of, 492493, 493t
in diabetic ketoacidosis, 328 methimazole for, 170f, 172177, 173f, 175f, 176t during stressful events, 513
in hypercalcemia, 599 nervousness, hyperactivity, aggressive treatment of, 508
and tetany, 642 behavior in, 142t, 144 in the absence of electrolyte abnormalities,
Hyperpigmentation panting and respiratory distress in, 145 513
in adrenocortical diseases of dog, 393 pathology of, 137138, 138f diagnosis after, 513
in canine hypothyroidism, 8788, 89f percutaneous ethanol and heat ablation fluid therapy for, 509
Hyperplasia injection for, 188189 glucocorticoid replacement for, 509
adenomatous, 137138, 618 physical examination, 144t, 145148, long-term, 510513, 510t
adrenocortical nodular, 150151, 385 146f147f mineralocorticoid replacement for, 509
follicular cell, 84 plasma cortisol in, 150151 response to, 513
pituitary, 378 polydipsia and polyuria in, 144 supportive care for, 509510
Hyperproteinemia, acromegaly in cats and, 59 polyphagia in, 142144, 144b Hypoalbuminemia
Hyperreninemic hypoaldosteronism, 490 prognosis in, 190, 191f in canine hypoparathyroidism, 633
Hypersomatotropism propranolol for, 189 in feline hyperadrenocorticism, 463
in cats, 5668 radioactive iodine for, 181185, 181f182f, hypoadrenocorticism and, 498
clinical manifestations of, 5759, 58f59f, 58t 182t, 184f in pheochromocytoma, 530
clinical pathology of, 59 radiography in, 151 Hypoaldosteronism, 490
diabetes mellitus and, 306 renal function and, 170172 Hypocalcemia, 625648
diagnosis of, 6465 risk factors for, 139140, 139t after thyroid surgery in cat, 179, 180b
diagnostic imaging in, 5960 serum fructosamine in, 151 calcium levels in, 632, 632f, 632t
histopathology of, 6768 signalment in, 142, 143f calcium supplementation for, 645
hormonal evaluation of, 6164, 63t steatorrhea in, 144 caused by hypoparathyroidism, 627629, 627b
pathophysiology of, 57 surgery for, 177181, 178f179f clinical signs associated with, 616b
prevalence and etiology of, 5657 thyroid scintigraphy in, 161167, 163f168f, defense against, 626627, 626f
prognosis of, 68 163t, 166b diagnostic evaluation in, 632635
signalment of, 57 thyroid-stimulating hormone response test differential diagnosis for, 635640, 636f, 636b
treatment of, 6667 in, 159160 effects of, 629
in dogs, 6872 thyrotropin-releasing hormone stimulation electrocardiography in, 633, 634f
clinical manifestations of, 6970, 70f test in, 160, 161f emergency therapy for tetany in, 641642, 641t
diagnosis of, 71 triiodothyronine suppression test in, in feline hyperadrenocorticism, 462t, 463
diagnostic imaging in, 70 158159, 159f161f, 159t heart in, 629
etiology of, 6869 urinalysis in, 148t, 150 history in, 630
hormonal evaluation of, 7071, 70f71f weakness and lethargy in, 145 hypoadrenocorticism and, 495496
pathology of, 70 weight loss in, 142, 143f, 144b magnesium and, 633635
prognosis of, 72 polydipsia and polyuria in, 9 minor transient challenges for, 626627
signalment of, 69 Hypertonic dehydration, 25, 25f moderate challenges for, 627
treatment of, 7172 Hypertrichosis, 87 parathyroid hormone concentrations and, 635
660 INDEX
Hypocalcemia (Continued) Hyponatremia Hypothyroidism (Continued)

pathophysiology of, 627628, 628f in adrenocortical insufficiency, 488 baseline serum thyrotropin, 104105,
physical examination in, 630631, 631t in central diabetes insipidus, 16 104f107f
posttreatment management of, 614617, in diabetic ketoacidosis, 324 baseline serum total thyroxine in, 98102,
615f616f differential diagnosis for, 496b, 497 100f102f, 102t103t
timing of, 616617 glucocorticoid deficiency and, 486 baseline serum total triiodothyronine in,
prognosis in, 646 in hypoadrenocorticism, 496497 102, 103f
serum chemistry profile in, 633 in syndrome of inappropriate antidiuretic behavior changes in, 90
serum phosphorus in, 633 hormone, 32 body size and, 110111, 110f, 111t
severe and prolonged challenges for, 627 Hypoparathyroidism breed and, 111
signalment in, 629630, 629f, 629t in dogs with hypoadrenocorticism, 492 cardiovascular signs in, 91
subacute management of, 642 feline, 632 classification of, 8081
systemic, physiology of, 625629 primary, 625648 clinical signs in, 8692, 87t, 87b
therapy for, 641646 calcium levels in, 632, 632f, 632t clinicopathologic abnormalities in, 9295,
vitamin D therapy for, 643644, 643t calcium supplementation for, 645 94b
weakness in, 635 definition of, 627, 627b coagulopathy in, 92
Hypocalcemic tetany, emergency therapy for, diagnostic evaluation in, 632635 combination thyroxine-triiodothyronine
641642 differential diagnosis for, 636f, 636b products for, 123
Hypochloremia, in adrenocortical insufficiency, electrocardiography in, 633, 634f concurrent illness and, 112115, 113f
488 emergency therapy for tetany in, 641642, cretinism in, 92, 92b, 93f94f
Hypocholesterolemia, hypoadrenocorticism 641t crude animal-origin hormonal preparations
and, 498 history in, 630 for, 123
Hypodipsic hypernatremia, 34 magnesium and, 633635 dermatohistopathologic findings in, 95
Hypoglycemia parathyroid hormone concentrations and, 635 dermatologic signs in, 8788, 88f89f
in Addisons disease, 356 pathophysiology of, 627628, 628f diurnal rhythm and, 112
artifactual, 358 physical examination in, 630631, 631t drugs and, 115117, 115t116t, 117b
in beta-cell neoplasia prognosis in, 646 environmental and body temperature and,
and counterregulatory response, 350351, serum chemistry profile in, 633 115
350b serum phosphorus in, 633 establishing diagnosis in, 118
diagnostic approach to, 359 signalment in, 629630, 629f, 629t etiology of, 8186, 81f, 81b, 82t, 84f
differential diagnoses for fasting therapy for, 641646 gastrointestinal signs in, 9192
hypoglycemia and, 355359, 355b, 357b, vitamin D therapy for, 643644, 643t gender and reproductive stage of female
359f weakness in, 635 and, 111
insulin-induced, 351 surgically induced, 637 levothyroxine sodium for, 120, 121f122f,
medical therapy for acute hypoglycemic Hypophosphatemia 121t
crisis in, 368369, 368f369f in adrenocortical diseases of dog, 396 liothyronine sodium for, 123
medical therapy for chronic hyperglycemia in diabetic ketoacidosis, 328 metabolic signs in, 87
in, 369371, 370f371f hemolytic anemia and, 343 myxedema coma in, 90
in canine diabetes mellitus in primary hyperparathyroidism, 599, 599b neurologic signs in, 8890
insulin-induced, 251 Hypophysectomy nuclear imaging in, 9596, 98f99f
oral hypoglycemic drugs for, 231232, 232f, in adrenocortical diseases of dog, 421422 obesity, fasting, and cachexia and, 115
233b and feline Cushings disease, 476 ocular signs of, 91
in congenital hepatic disease, 355, 356f for hypoadrenocorticism in dogs, 492 prognosis of, 124
in feline Cushings syndrome, 460 Hypopituitarism, 356357 radiography in, 9596, 96f
in feline diabetes mellitus, 302303 Hyporeninemic hypoaldosteronism, 490 random fluctuations in, 112, 112f
glipizide-related, 284, 284b Hyposomatotropism reproductive signs in, 9091
in glucagon deficiency, 356 acquired, 5455 secondary, 92
hypoadrenocorticism and, 498 etiology of, 54b signalment, 86, 86f, 86t
in hypopituitarism, 356357 congenital, 4454 therapeutic monitoring of, 119f, 120121
iatrogenic, 358359 clinical manifestations of, 4748, 48f, 48b thyroid function tests in, 96107, 99f
in kidney failure, 358 clinical pathology of, 48 thyroid-stimulating hormone stimulation
in non-beta-cell tumors, 357, 357b dermatohistopathology of, 4849 test in, 105
persistent, after beta-cell tumor surgery, 367 differential diagnosis of, 44b, 49 thyrotoxicosis and, 124
in polycythemia, 358 endocrinological evaluation and diagnosis thyrotropin-releasing hormone stimulation
in treatment of diabetic ketoacidosis, 342 in, 4952 test in, 105107, 107f
Hypoglycemic drugs, 279 etiopathogenesis of, 4447, 45f47f treatment of, 118124, 120b
acarbose, 231, 232f, 285 prognosis of, 54 ultrasonography in, 95, 97f
biguanides, 284285 signalment of, 47 diabetes mellitus and, 114
for canine diabetes mellitus, 231232, 232f, treatment of, 5254 in dogs with hypoadrenocorticism, 492
233b Hyposthenuria, hypercalcemia and, 600 feline, 124
chromium, 231, 286 Hypotension, during excision of after thyroidectomy, 180181
glinitides, 284 pheochromocytoma, 544 clinical signs of, 125126, 125b, 126f
sulfonylureas, 283284, 283t Hypothalamic pituitary adrenal axis, 379f, 488f diagnosis of, 128
thiazolidinediones, 285 alteration of, 571572 etiology of, 124125
vanadium, 286287 effect of glucocorticoids on, 561562 thyroid function tests in, 126128, 127f
Hypokalemia Hypothalamitis, autoimmune, central diabetes treatment and prognosis in, 128129
in diabetic ketoacidosis, 325 insipidus from, 12 in feline hyperadrenocorticism, 461462
electrophysiologic alteration with, 329b, 330, Hypothermia, hypercalcemia and, 593 physiology of thyroid gland and, 7780,
330f Hypothyroidism, 77135 78f79f
in feline hyperthyroidism, 147 acromegaly in dogs and, 69 Hypotonic dehydration, 25, 25f
and feline primary hypoaldosteronism, canine, 80 Hypoxia
479 age and, 109, 110f, 110t cerebral, 369
polydipsia and polyuria in, 8 baseline serum free thyroxine in, 103104, hyperkalemia and, 489
in treatment of diabetic ketoacidosis, 342 103f, 104t
Hypomagnesemia baseline serum free triiodothyronine in, 104 I
in diabetic ketoacidosis, 329 baseline serum reverse triiodothyronine Iatrogenic Cushings syndrome, 453
in hypocalcemia, 633634, 634b, 638 in, 104 Iatrogenic hyperadrenocorticism, 570571
INDEX 661
Iatrogenic hyperkalemia, 497 Insulin resistance, 424 Interestrus intervals, canine, hypothyroidism
Iatrogenic hypoglycemia, 358359 in canine diabetes mellitus, 217f, 248251, and, 90
Iatrogenic hypothyroidism, 124125 248f, 249t, 250b251b Interleukin-1 (IL-1), 586
Iatrogenic primary hypoadrenocorticism, in diabetic ketoacidosis, 341 Intestines
491492 in feline diabetes mellitus, 261262, 264, actions of catecholamines on, 526t
Iatrogenic secondary hypoadrenocorticism, 305306 actions of parathyroid hormone-related
492 in feline transient diabetes, 266267 protein on, 586t
Idiopathic adult growth hormone deficiency, 54 Insulin therapy Intracapsular thyroidectomy, 178, 179f
Idiopathic atrophy, of thyroid gland, 8384, 84f for acromegaly in dogs, 7172 Intravenous glucose tolerance test, 61
Idiopathic hypercalcemia, of cats, 620 after surgical removal of insulin-secreting Iodinated radiographic contrast agents, 190
IGF-1. see Insulin-like growth factor-1. tumor, 367 Iodine
IGFBP. see Insulin-like growth factor binding in canine diabetes mellitus, 214215, 219, canine hypothyroidism and, 84
proteins. 222228, 223t, 226t, 227f, 230f, 245f247f canine thyroid tumors, metastasis and, 198,
Immunosuppressive therapy, glucocorticoids allergic reactions to, 247248 206f207f
for, 569 complications of, 242251 deficiency, in canine thyroid tumor, 197
Inappetence inadequate insulin absorption in, 246 for feline hyperthyroidism, 176t, 189190
in canine diabetes mellitus, 243 initial adjustments in, 228 radioactive, for canine thyroid tumors,
in feline hypothyroidism, 125 mixtures, 227, 227f 209210
in primary hyperparathyroidism, 595596 preparations, 222, 223t, 226t Iodine-131 therapy, 181182, 182f
Incidentaloma, 547548 prolonged duration of insulin effect in, 246, 123Iodine-metaiodobenzylguanidine (123I-MIBG),
Incretin hormones, 269270 246f247f 535

Incretin-related therapeutics, for feline diabetes recommendations, 228 Ionized calcium
mellitus, 285286, 286f, 286t during surgery, 242 assays of, 584
Infection in diabetic ketoacidosis, 337340, 337f in hypercalcemic dog, 598
canine, in hypothyroidism, 88 constant low-dose intravenous infusion hypoadrenocorticism and, 497498
in diabetic ketoacidosis, 340 technique in, 339340 normal serum concentrations, 582t
Infertility, canine male, hypothyroidism hourly intramuscular technique in, 337339, Ionizing radiation, and canine thyroid tumor,
and, 90 338f339f 197
Insulin, 224f intermittent intramuscular/subcutaneous Islet amyloid polypeptide (IAPP), 215, 262
choice and initial dose of, 281282, 281b technique in, 340 Islet amyloidosis, 263f, 266267
concentrations, in insulin-secreting tumor, longer-acting, 340 Isosthenuria, hypercalcemia and, 600
360, 360f, 360b in feline diabetes mellitus, 279281, 300307 Isotonic dehydration, 2425, 25f
deficiency in diabetic ketoacidosis, 315316, binding insulin antibodies in, 304305 IVGTT. see Intravenous glucose tolerance test.
317f, 320b concurrent disorders causing insulin
dose of resistance in, 305306 J
adjustment of, 297298 fluctuating insulin requirements in, 306307 Juvenile hypoglycemia, 357358
reevaluations and adjustment of, 282283 hypoglycemia and, 302303 Juxtaglomerular cells, action of vasopressin on,
and glucocorticoids, 249 impaired absorption of insulin in, 304 5t
handling and owner instruction, 282 prolonged duration of insulin effect in, 304
metabolic effects of, 270271, 270f short duration of insulin effect in, 304 K
and pathophysiology of hyperglycemia, 271, Somogyi effect and, 303, 304f Ketoacidosis, and canine diabetes mellitus, 214
271f stress hyperglycemia and, 300302 Ketoacidosis profile, 323327
secretion in dogs with beta-cell neoplasia, 351 during surgery, 300 acid-base status in, 323324, 324f, 324t
serum technical problems in, 303 anion gap in, 326327, 327t, 327b
in adrenocortical diseases of dog, 396 underdose in, 303 blood glucose in, 323, 323f
in canine diabetes mellitus, 221 in hyperosmolar hyperglycemic state, 345 blood urea nitrogen and creatinine in, 326,
in feline diabetes mellitus, 277 Insulin:glucose ratios, 360361 326f
in hypoglycemia, 359361, 360f, 360b Insulinoma, 348376 calcium and phosphorus in, 328
storage, mixing, and dilution, 227228 acute hypoglycemic crisis in, 368369, complete blood count in, 327
synthesis, structure, and regulation, 269270, 368f369f diagnostic imaging in, 329
269t in cats, 372 electrocardiogram in, 329330, 329b, 330f
Insulin analogues, 223227 chronic hyperglycemia in, 369371, 370f371f liver enzymes in, 327
long-acting, for feline diabetes mellitus, clinical pathologic abnormalities in, 354355, magnesium in, 329
280281 354b pancreatic enzymes in, 327328, 328f
Insulin antibodies, 304305 clinical signs in, 351352, 351t352t, 352f serum osmolality in, 326
Insulin-dependent diabetes mellitus, canine, 114, diagnostic approach to hypoglycemia in, 359 serum potassium concentration in, 324325,
214, 227f, 232f diagnostic imaging in, 361364, 362f363f 325f
Insulin detemir, 207f, 227f, 280t differential diagnoses for fasting serum sodium concentration in, 324, 325f
Insulin glargine, 224225, 225f, 280, 280t hypoglycemia and, 355359, 355b, 357b, total bilirubin in, 327
Insulin-induced hypoglycemia, in pituitary 359f Ketoconazole
dwarfism, 52 etiology of, 348349 for adrenocortical diseases of dog, 434435
Insulin-like growth factor-1 euglycemia and, 349350, 349f for feline Cushings disease, 475
biosynthesis of, 3941 history in, 353 Ketone bodies, 315
deficiency of, 4344, 44b hypoglycemia and counterregulatory enhanced production of, physiologic
measurement of response in, 350351, 350b consequences of, 317318
in acromegalic cats, 62, 63f65f, 65b insulin-induced hypoglycemia in, 351 Ketonuria, in diabetic ketoacidosis, 320
in acromegalic dogs, 71 insulin secretion in, 351 Kidney
in pituitary dwarfism, 52 multiple endocrine neoplasia type 1 and, 549 actions of catecholamines on, 526t
metabolic actions of, 4243, 43f physical examination in, 353354, 354t aldosterone in, 486488
receptor, 40f prognosis in, 372 glucose production in, 349
Insulin-like growth factor-2, 40, 357 serum insulin determination in, 359361, 360f, primary hyperparathyroidism and, 583, 595
Insulin-like growth factor binding proteins, 360b Kidney disease, in diabetic ketoacidosis,
3940 signalment in, 352353, 352f, 353t 340341
Insulin lispro, 223227 surgery for, perioperative management Kidney failure
Insulin mixtures, 227, 227f of dogs undergoing, 364368, 364b, in diabetic ketoacidosis, 323
Insulin receptor, 3940 365f366f, 367b in hyperosmolar hyperglycemic state, 345
Insulin-receptor substrate (IRS) molecules, 270 surgical versus medical therapy for, 364 hypoglycemia in, 358
662 INDEX
L Lymphocytic infundibuloneurohypophysitis, 12 Methimazole (Continued)

Laboratory error, hypocalcemia and, 640 Lymphocytic thyroiditis disadvantages of, 174
Lanreotide, for acromegaly in humans, 6566 canine, 8182, 81f, 82t83t dosage protocol in, 172174
Laparoscopic adrenalectomy, 419420, 420f feline, 127 indications for, 170f, 172, 173f
Laparoscopy, for feline Cushings disease, 477 tests for, 107109 topical use of, 174
Laron syndrome, 4344 Lymphoma, hypercalcemia in, 588f Methylene blue, infusion of, 366
Leiomyoma, 357 Lymphopenia, 561 Methylprednisolone, 555556
Leiomyosarcoma, 357 in dogs with hypoadrenocorticism, 494495, characteristics of, 559t
Lente, 222 495f, 495t Methylprednisolone acetate, suppression of
Lente insulin, for feline diabetes mellitus, Lysodren. see Mitotane. hypothalamic pituitary adrenal axis by,
279280 571
Leptin, 264 M Methylprednisolone sodium succinate, for
Lethargy Macroadenoma, microadenoma versus, 381 anaphylactic shock, 569
in adrenocortical diseases of dog, 388389, Macrocytosis, 148 Metyrapone
389f Magnesium in adrenocortical diseases of dog, 436
in canine hypothyroidism, 87, 87b canine hypoparathyroidism and, 632t, 633635 for feline Cushings disease, 475476
in diabetic ketoacidosis, 320 in diabetic ketoacidosis, 329, 335336 Microadenoma, versus macroadenoma, 381
in feline hyperadrenocorticism, 456, 457f, 458 hypomagnesemia and Microcardia, in feline hypoadrenocorticism, 515
in feline hyperthyroidism, 145 in diabetic ketoacidosis, 329 Mineralization, in adrenocortical diseases of dog,
in feline hypothyroidism, 125 in hypocalcemia, 633634, 634b 410
in hyperosmolar hyperglycemic state, 344 Magnesium chloride, 335336 Mineralocorticoids, 555
in hypoglycemia, 352 Magnesium sulfate, 335336 deficiency in, 488489
in mitotane therapy, 434 Magnetic resonance imaging (MRI), 472473, versus glucocorticoid deficiency, 489490
in primary hyperparathyroidism, 595 473f, 473t effects of, 486488
Leukemia inhibitor factor, 4547 in acromegalic cats, 60, 62f excess of, 438439
Leukocytes, effect of glucocorticoids on, 561 in adrenocortical diseases of dog, 413415, for hypoadrenocorticism, 509, 511513
Leukogram, in dogs with hypoadrenocorticism, 413f414f regulation of secretion of, 486489, 488f
494495 in canine thyroid tumor, 202 Mitogen-activated protein kinase (MAPK)
Levothyroxine sodium, for canine hypothy- in pheochromocytoma, 534535 phosphatase, 563
roidism in pituitary dwarfism, 52 Mitotane
improved cardiac performance and, 120 of pituitary gland, 28, 29f for feline Cushings disease, 475
initiation of, 120, 121f122f, 121t Magnocellular neurons, 2 hypoadrenocorticism from, 491492
monitoring of, 119f, 120121 destruction of, in central diabetes insipidus, 13 Mitotane therapy, for adrenocortical diseases of
thyrotoxicosis and, 124 Malabsorption, in feline hyperthyroidism, 144 dog, 422431
treatment with, 122b Malabsorption syndromes, hypocalcemia and, adrenalectomy and, 427429
Libido, decreased, canine hypothyroidism and, 639 adrenocortical tumors and, 429431
90 Malignant thyroid tumors, feline, 138 failure to respond, 435
LIF. see Leukemia inhibitor factor. Mammary growth hormone, 4041 glucocorticoid therapy during, 427
Liothyronine sodium, 123 Mammary tissue, actions of parathyroid goals of, 417418
Lipase hormone-related protein on, 586t loading phase, 422424
in adrenocortical diseases of dog, 397 Mannitol maintenance, 424427, 429
in diabetic ketoacidosis, 327328 for cerebral edema, 342, 369 planned medical adrenalectomy, 427429
Lipemia for renal failure in ketoacidotic dog, 333 prognosis, 431
in diabetic ketoacidosis, 322b, 324 Mass time sequence for improvement, 426427
hyponatremia and, 497 adrenal, 547548 Modified water deprivation test, 1727
Lipid metabolism, effect of glucocorticoids on, parathyroid approach for dehydrated dog/cat, 2324
559 post-treatment management of, 618 in central diabetes insipidus, 2021, 20f21f
Lipocortin-1, 563 in primary hyperparathyroidism, 596, 612 complications of, 2426
Lipotoxicity, 265 Mediastinal parathyroid tissue, 618 guidelines for interpretation of, 22t
-lipotropin (-LPH), 378 Mediastinal thyroid tissue, 163164, 167f168f misdiagnosis in, 2223, 23f
Liver Medroxyprogesterone acetate, for pituitary in nephrogenic diabetes insipidus, 2122, 22f
actions of catecholamines on, 526t dwarfism, 53 plasma vasopressin determinations and,
destruction of, hypoglycemia and, 355356 Medullary thyroid carcinoma 2627, 27f
glucose production in, 349 canine, 196197 preparation for, 18
Liver disease, in diabetic ketoacidosis, 344 hypocalcemia in, 640 principle of, 1718
Liver enzymes Megaesophagus protocol in, 24b
activities in feline hyperthyroidism, 148149 canine hypothyroidism and, 9192 in psychogenic polydipsia, 22, 23f
in diabetic ketoacidosis, 327 hypoadrenocorticism and, 499500 responses to, 1922, 19f
Liver function, in feline Cushings syndrome, -melanocyte-stimulating hormone, 378, 379f results of, 18f
460461, 462t -melanocyte-stimulating hormone, 378, 379f Mometasone, for inflammation, 568569
Liver function test, in beta-cell neoplasia, 359 Mesenchymal tissues, 586t Monitoring
Loteprednol etabonate, 555556 Metabolic acidosis after surgery for canine thyroid tumor, 209
Low-dose dexamethasone suppression test in diabetic ketoacidosis, 323324, 324f, 324t in feline diabetes mellitus, 289300
(LDDST) hyperkalemia and, 489 blood glucose curve in, 292, 293f
in adrenocortical diseases of dog, 404405, 404f, management of, 508b, 509, 510f glycated hemoglobin concentration in, 291
406f Metanephrines, 536537 history and physical examination in, 290
in feline Cushings syndrome, 465t, 466467 in dogs and cats, 537541 serum fructosamine concentration in,
Luteinizing hormone (LH), in feline hyperadre- Metastasis 290291, 290f
nocorticism, 454 in beta-cell neoplasia, 366 urine glucose in, 291292
Lymph node, evaluation of, 607 insulinoma and, 349 of fluid therapy in ketoacidotic dog, 333
Lymphocytes pheochromocytoma and, 522 of thyroid hormone supplementation, 119f,
in dogs with hypoadrenocorticism, 494495, Metastatic tumors, in adrenal gland, 490491 120121
495f, 495t Metformin, 284285 Monoamine oxidase (MAO), 524
effect of glucocorticoids on, 561 Methimazole, 172177 Multinodular adenomatous goiter, 137138, 138f
hypoadrenocorticism and, 494495, 495t abnormal renal parameters and, 174176 Multiple endocrine neoplasia (MEN), 548549, 548t
Lymphocytic adenohypophysitis, in dogs with advantages of, 172174 malignant canine thyroid tumor and, 202b, 210
hypoadrenocorticism, 492 adverse effects of, 176177, 176t in primary hyperparathyroidism, 619
INDEX 663
Multiple myeloma, 589 Nervousness Oral hypoglycemic agents (Continued)

Murmurs, in feline hyperthyroidism, 146147 in canine hypoparathyroidism, 630 chromium, 231, 286
Muscle in feline hyperthyroidism, 144 glinitides, 284
actions of catecholamines on, 526t Neurohypophysis, 2, 2f, 37 sulfonylureas, 283284, 283t
cramping, in canine hypoparathyroidism, 630 Neurologic signs thiazolidinediones, 285
Muscle atrophy, in primary hyperparathyroidism, in canine hypoparathyroidism, 630 vanadium, 286287
595 induced, 631 Osmolytes, 25
Muscle wasting, in feline hyperthyroidism, spontaneous, 631 Osmotic diuresis, 67
142144 in canine hypothyroidism, 8890 Osteitis fibrosa cystica, 601
Muscle weakness Neurological diseases, glucocorticoids for, 570 Osteocalcin, 149
in adrenocortical diseases of dog, 388389, 389f Neuromuscular signs, in canine Osteomyelitis, 593
and feline hyperadrenocorticism, 457f, 458 hypoparathyroidism, 630 Osteopenia, 409410
in hypocalcemia, 635 induced, 631 Overdose of insulin, in feline diabetes mellitus,
and primary hyperaldosteronism, 479 spontaneous, 631 303, 304f
Myasthenia gravis, 90 Neuropathy Oxytocin, 23
Myocardial excitability, hyperkalemia and, 489 diabetic, feline, 308 chemical structure of, 3f
Myometrium, actions of parathyroid hormone- peripheral, in insulin-secreting tumor, 353354
related protein on, 586t Neurophysins, 3 P
Myotonia, in adrenocortical diseases of dog, Neurosecretory material, 3 Pain, in diabetic ketoacidosis, 320
392393, 393f Neutral protamine Hagedorn (NPH) insulin, for Palpation, in feline hyperthyroidism, 146
Myxedema, 8788 feline diabetes mellitus, 279 Pancreas
Myxedema coma, 90 Neutrophilia, mature, 561 beta-cell neoplasia and, 348376
New methylene blue infusions, 611 canine diabetes mellitus and, 213257
N Nodular hyperplasia, 618 after surgical removal of insulin-secreting
N-terminal fragment, 378 Non-beta-cell tumors, 357, 357b tumor, 367
Naturally occurring hyperadrenocorticism Non-insulin-dependent diabetes mellitus diabetic ketoacidosis and, 315347
(NOH), 452454 (NIDD), 214215 feline diabetes mellitus and, 258314
NDI. see Nephrogenic diabetes insipidus (NDI). Non-insulin injectables, for feline diabetes Pancreatic enzymes
Neck mellitus, 283287, 283t in diabetic ketoacidosis, 327328, 328f
parathyroid ultrasonography and, 601602, Nonsteroidal anti-inflammatory drugs in feline diabetes mellitus, 276
602f, 609611 (NSAIDs), 116t, 117 Pancreatic islet cells, actions of catecholamines
thyroid tissue in, 163164 Norepinephrine on, 526t
Negative feedback effects, adrenocorticotropic metabolism of, 536f Pancreatic islets, actions of parathyroid
hormone, 378 pheochromocytoma and, 523524 hormone-related protein on, 586t
Neonatal hypoglycemia, 357358 Normal electrolytes, in dogs with Pancreatic lipase immunoreactivity (cPLI),
Neonatal septicemia, 593 hypoadrenocorticism, 496497 measurement of, 219
Neoplasia Normetanephrine, 536 Pancreatitis
beta-cell. see Beta-cell neoplasia. NPH (neutral protamine Hagedorn) insulin, 222, acute, hypocalcemia and, 638
canine thyroid tumor, 196212 225f in adrenocortical diseases of dog, 397
basal serum thyroxine concentrations in Nuclear factor of activated T-cells, 556558 after beta-cell tumor surgery, 367
malignant, 205206 Nuclear imaging, in canine hypothyroidism, in diabetes mellitus
benign, 198 9596, 98f99f canine, 214
classification, 196, 197b Nuclear medicine scanning techniques, in feline, 265266
clinical signs, 199, 199t pheochromocytoma, 535 in diabetic ketoacidosis, 327328, 340
differential diagnosis in, 202b, 206 Nutritional management, of feline glucocorticoid-related, 573
hyperthyroidism and, 196212, 200f hyperthyroidism, 185187, 186f, 186t hyperkalemia and, 497
medullary carcinoma in, 196197 Nutritional secondary hyperparathyroidism, Paraganglioma, 546547
minimum data base in, 199 593, 639 Parathyroid adenoma, post-treatment
oncogenes in, 197198, 197f management of, 618
pathogenesis of, 197198 O Parathyroid axis, 581f
physical examination in, 199, 200f Obesity Parathyroid gland, 579624
postsurgical monitoring for, 209 in adrenocortical diseases of dog, 391 actions of parathyroid hormone-related
prognosis in, 211 in diabetic cat, 287 protein on, 586t
radiography, 202 effects on canine thyroid function tests, 115 anatomical position of, 582f
scintigraphy, 202205, 203f206f, 208f in feline hypothyroidism, 125 canine primary hyperparathyroidism and, 593
signalment, 198199 insulin resistance and, 261262, 264 hypercalcemia and, 579624
staging, 197t, 197b Obstruction, urethral, in hypocalcemia, 639640 hypocalcemia and primary hypoparathy-
surgical resection for, 208209, 208f Occult hyperadrenocorticism, 441444 roidism, 625648
treatment of, 206210 indications for diagnostic testing in, 443444 mass in
ultrasonography in, 202, 203f as sex hormone-mediated disease, 441443 post-treatment management of, 618
feline hyperthyroidism and, 138, 168f treatment of, 444 in primary hyperparathyroidism, 596
Nephrocalcinosis, 583 Octreotide Parathyroid hormone, 580582, 582t
Nephrogenic diabetes insipidus (NDI), 595 for acromegaly in humans, 6566 assays of, 603604, 603f, 607
primary for chronic hypoglycemia, 370371, 370f calcium homeostasis and, 625626
clinical features of, 15 Ocular lesions, in feline hyperthyroidism, 147 effect of glucocorticoids on, 560561
complete blood count in, 16 Oliguria, in diabetic ketoacidosis, 342b Parathyroid hormone-related protein (PTHrP),
definition of, 14 Oncogenes, in canine thyroid tumor, 197198, 197f 582
etiology of, 14 o,p-DDD. see Mitotane. actions of, 587f
modified water deprivation test in, 2122, Ophthalmologic changes, in primary assay of, 585, 586t, 603604, 607
22f hyperparathyroidism, 596 humoral hypercalcemia of malignancy, 586
plasma osmolality in, 28, 28f Oral anti-thyroid drugs, 170f, 171t, 172177, serum concentrations of, 582t, 588f
polydipsia and polyuria in, 7 172f173f, 175f, 176t structural and functional domains of, 586f
prognosis in, 31 Oral hypoglycemic agents, 283287, 283t Parathyroid ultrasonography, 601602
results of diagnostic studies in, 28t acarbose, 231, 232f, 285 Pars distalis tumor, 378
serum chemistries in, 16 biguanides, 284285 Pars intermedia tumors, 382
therapies for, 29b for canine diabetes mellitus, 231232, 232f, Pasireotide, for acromegaly in humans, 6566
urinalysis in, 16 233b Pegvisomant, for acromegaly in humans, 66
664 INDEX
Percutaneous ultrasound-guided ethanol Physiologic replacement therapy, glucocorticoids Polycythemia

ablation, 188189 for, 568 hypoglycemia in, 358
Percutaneous ultrasound-guided radiofrequency Pituitary-adrenocortical axis, specific evaluation polydipsia and polyuria in, 9
heat ablation, 188189 of, 399400 Polydipsia
Peripheral neuromuscular observations, in Pituitary anterior lobe function test, for dwarfism, in adrenocortical diseases of dog, 386388
hypocalcemia, 628629 46f and canine diabetes mellitus, 217
Peripheral neuropathy, in insulin-secreting Pituitary-dependent hyperadrenocorticism diagnostic approach to, 912
tumor, 353354 (PDH), 17, 381383, 382f, 387f388f, diagnostic plan in dog/cat with, 11f
Phenobarbital 405409, 422429, 427f428f, 452453 differential diagnosis for, 69, 7t
administration in hyperadrenocorticism, 400 versus adrenocortical tumor, 405409 drug-induced, 9, 9b
effects on thyroid function tests, 116, 116t control, feedback and cortisol secretion in, 381 in feline Cushings syndrome, 456457
Phenoxybenzamine etiology of, 382383 in feline hyperthyroidism, 144
before adrenalectomy, 543 maintenance therapy for, 424427, 426f in feline primary hyperaldosteronism, 479
for pheochromocytoma, 546 microadenoma versus macroadenoma in, 381 mineralocorticoid deficiency and, 489
Phentolamine, 544 mitotane for, 422429, 423f, 425f in pheochromocytoma, 528
Phenytoin, for hypoglycemia, 371 pathology of, 381382 primary, 9, 1214
Pheochromocytoma, 521554 Pituitary dwarfism. see Dwarfism, pituitary. in primary hyperparathyroidism, 595
abdominal and thoracic radiographs in, Pituitary function test, in pituitary dwarfism, psychogenic, 9, 14
531532, 532f 5152 urinalysis results in dogs with, 10t
abdominal ultrasonography in, 532534, 533f, Pituitary gland urine specific gravity in, 1011
533b acquired hyposomatotropism and, 5455 Polyendocrine syndromes, 492
adrenocortical tumors, 384 acromegaly and Polyglandular autoimmune syndrome, 8283
biochemical testing in, 536541 in cats, 5668 Polyphagia
blood pressure measurement in, 531, 532t in dogs, 6872 acromegaly in cats and, 5759
clinical manifestations of, 527530, 528b529b, computed tomography, 413415, 413f414f, 416f in adrenocortical diseases of dog, 388
529t530t development of, 3739, 38f and canine diabetes mellitus, 217
clinical pathology of, 530548 diabetes insipidus and, 136 in feline Cushings syndrome, 456457
computed tomography and magnetic growth hormone secretion from, regulation of, in feline hyperthyroidism, 142144, 144b
resonance imaging in, 534535, 534f 4142, 41f, 42b Polyuria
definition, embryology, anatomy, and etiology hyperplasia of, 378 in adrenocortical diseases of dog, 386388
of, 521523 magnetic resonance imaging, 413415, and canine diabetes mellitus, 217
diagnosis of, 541543 413f414f diagnostic approach to, 912
histopathology of, 545 malformation in canine hypothyroidism, 85 diagnostic plan in a dog/cat with, 11f
history of, 521 water metabolism and, 136 differential diagnosis for, 69, 7t
medical treatment of, 545546 Pituitary hormone deficiency, combined, 5152 drug-induced, 9, 9b
nuclear medicine scanning techniques in, 535 Pituitary hyperplasia, acidophilic, acromegaly in feline Cushings syndrome, 456457
pathophysiology of, 523530, 525f, 526t, 527b and, 57 in feline hyperthyroidism, 144
physical examination in, 529530 Pituitary irradiation, in adrenocortical diseases in feline primary hyperaldosteronism,
physiology of, 523530 of dog, 436437 479
prognosis of, 546 Pituitary macrotumor syndrome, 477 mineralocorticoid deficiency and, 489
signalment in, 527 Pituitary neoplasia, acromegaly in dogs and, 68 in pheochromocytoma, 528
surgical management of, 545 Pituitary tumors in primary hyperparathyroidism, 595
treatment of, 543545 ACTH-secreting, in feline hyperadrenocor- urinalysis results in dogs with, 10t
Phosphate ticism, 454 urine specific gravity in, 1011
in adrenocortical diseases of dog, 396 adrenocortical diseases of dog and Pompe disease, 355
supplementation in diabetic ketoacidosis, computed tomography in, 413415 Porcine growth hormone, for pituitary
334335 hypophysectomy for, 421422 dwarfism, 5253, 53f
Phosphate-containing enemas, 640 incidence of, 381 Portable blood glucose monitoring (PBGM)
Phosphorus magnetic resonance imaging in, 413415 devices, and canine diabetes mellitus, 237,
hyperphosphatemia and radiation therapy for, 437f 238f239f, 238t
in canine hypoparathyroidism, 633 in humans, etiology of, 56b Portosystemic shunts, polydipsia and polyuria
in diabetic ketoacidosis, 328 secondary hypothyroidism and, 85 from, 8
in hypercalcemia, 599 Placenta, actions of parathyroid hormone- Portovascular anomalies, 355
hypophosphatemia and related protein on, 586t Postobstructive diuresis, 7
in diabetic ketoacidosis, 328 Plasma aldosterone, 438 Postoperative complications, in surgery for
hemolytic anemia and, 343 in hypoadrenocorticism, 506507 insulin-secreting tumor, 367
in primary hyperparathyroidism, 599 in primary feline hyperaldosteronism, 480 Postoperative management
serum and renin concentrations, in feline primary in feline thyroidectomy, 179180, 180b
in canine hypoparathyroidism, 633 hyperaldosteronism, 480 in surgery for pheochromocytoma, 545
canine hypoparathyroidism and, 632t Plasma bicarbonate, 336 Potassium
in diabetic ketoacidosis, 328 Plasma cortisol diabetic ketoacidosis and, 324325,
in primary hyperparathyroidism, 598599 in adrenocortical diseases of dog, 382f, 415f 325f, 327t
supplementation, in hyperosmolar hypergly- in feline hyperthyroidism, 150151 feline Cushings syndrome and, 462463,
cemic state, 345 Plasma endogenous adrenocorticotropic 462t
Physical examination hormone, 470471 feline hyperthyroidism and, 147
in adrenocortical diseases of dog, 393395 Plasma-free normetanephrine, 541f542f hyperkalemia and, 501, 502f
canine Plasma half-life, 563 hypokalemia and
diagnostic evaluation in, 632635 Plasma osmolality in diabetic ketoacidosis, 325
in hypoparathyroidism, 630631, 631t in hyperosmolar hyperglycemic state, 344 electrophysiologic alteration with, 329b,
in primary hyperparathyroidism, 596 vasopressin level and, 6f 330, 330f
in diabetic ketoacidosis, 318320 water balance and, 2 in primary hypoaldosteronism, 479
feline Plasma sodium concentration, 2 in treatment of diabetic ketoacidosis, 342
in diabetes mellitus, 272, 273f, 274b Plasma thyroid hormone, 79 supplementation of
in hyperadrenocorticism, 456458 Plasma transfusion, hyperglycemia and, 593 in diabetic ketoacidosis, 333334, 334f, 335t
in hyperthyroidism, 144t, 145148, 146f147f Platelet count, in feline hyperthyroidism, 148 in hyperosmolar hyperglycemic state, 345
in insulin-secreting tumor, 353354, 354t Pleural effusions, hyperkalemia and Potassium iodide, 185
in pheochromocytoma, 529530 hyponatremia in, 497 Prediabetes, 274275
INDEX 665
Prednisolone, 555556 Pruritus, in adrenocortical diseases of dog, 389, Renal failure

characteristics of, 559t 390f acromegaly in cats and, 59
combination chemotherapy, 569 Pseudohyperkalemia, 497 chronic, polydipsia and polyuria in, 6
for immunosuppression, 569 Pseudohypoparathyroidism, 637 feline hyperthyroidism versus, 142
suppression of hypothalamic pituitary adrenal Pseudomyotonia, in a

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CONVERSION TO SYSTEME INTERNATIONAL (SI) UNITS

FOR HORMONE ASSAYS

Measurement SI Unit Common Unit Common SI* SI Common*

Corticotropin (ACTH) pmol/L pg/mL 0.220 4.51

Cortisol nmol/L g/dL 27.59 0.036

C-peptide nmol/L ng/mL 0.331 3.02

-Endorphin pmol/L pg/mL 0.292 3.43

Epinephrine pmol/L pg/mL 5.46 0.183

Estrogen (estradiol) pmol/L pg/mL 3.67 0.273

Gastrin ng/L pg/mL 1.00 1.00

Gastrointestinal polypeptide pmol/L pg/mL 0.201 4.98

Glucagon ng/L pg/mL 1.00 1.00

Growth hormone g/L ng/mL 1.00 1.00

Insulin pmol/L U/mL 7.18 0.139

Metanephrine pmol/L pg/mL 5.07 0.197

MSH pmol/L pg/mL 0.601 1.66

Norepinephrine pmol/L pg/mL 5.91 0.169

Normetanephrine pmol/L pg/mL 5.46 0.183

Pancreatic polypeptide mmol/L mg/dL 0.239 4.18

Parathyroid hormone (PTH) pmol/L pg/mL 0.11 9.1

Progesterone nmol/L ng/mL 3.18 0.315

Prolactin g/L ng/mL 1.00 1.00

Renin ng/L/s ng/mL/hr 0.278 3.60

Somatostatin pmol/L pg/mL 0.611 1.64

Testosterone nmol/L ng/mL 3.47 0.288

Thyroxine (T4) nmol/L g/dL 12.87 0.078

Free Thyroxine (fT4) pmol/L ng/dL 12.87 0.078

Triiodothyronine (T3) nmol/L g/dL 0.0154 64.9

Vasoactive intestinal polypeptide pmol/L pg/mL 0.301 3.33

*Factor to multiply to convert from one unit to other.

Measurement SI Unit Common Unit Common SI* SI Common*

Bile acids mol/L mg/L 2.55 0.392

Bilirubin mol/L mg/dL 17.10 0.058

Calcium mmol/L mg/dL 0.250 4.00

Carbon dioxide content mmol/L mEq/L 1.00 1.00

Cholesterol mmol/L mg/dL 0.026 38.7

Chloride mmol/L mEq/L 1.00 1.00

Creatinine mol/L mg/dL 88.40 0.011

Creatinine clearance mL/s mL/min 0.017 60.0

Glucose mmol/L mg/dL 0.056 18.0

Inorganic phosphorus nmol/L mg/dL 0.323 3.10

Magnesium mmol/L mg/dL 0.41 2.44

Osmolality nmol/kg mOsm/kg 1.00 1.00

Potassium mmol/L mEq/L 1.00 1.00

Protein, total g/L g/dL 10.0 0.100

Sodium mmol/L mEq/L 1.00 1.00

Triglycerides mmol/L mg/dL 0.01 10.0

Urea nitrogen mmol/L mg/dL 0.357 2.8

Richard W. Nelson, DVM, DACVIM (Internal Medicine)

Claudia E. Reusch, DVM, DECVIM-CA

Ellen N. Behrend, VMD, PhD, DACVIM (Small Animal Internal Medicine)

CANINE AND FELINE ENDOCRINOLOGY, EDITION 4 ISBN: 978-1-4557-4456-5

Library of Congress Cataloging-in-Publication Data

Vice President and Publisher: Loren Wilson

Printed in the United States of America

Last digit is the print number: 987654321

Edward C. Feldman, DVM, DACVIM (Internal Medicine), is a Professor of

CANINE AND FELINE ENDOCRINOLOGY, EDITION 4 ISBN: 978-1-4557-4456-5

2 Disorders of Growth Hormone, 37 11 Hyperadrenocorticism in Cats, 452

SECTION 2 12 Hypoadrenocorticism, 485

3 Hypothyroidism, 77 13 Pheochromocytoma and Multiple Endocrine

8 Diabetic Ketoacidosis, 315

9 Beta-Cell Neoplasia: Insulinoma, 348

TABLE 1-4 GUIDELINES FOR INTERPRETATION OF THE WATER DEPRIVATION TEST*

BOX 1-3 Protocol for the Modified Water Deprivation Test

Preparation for the Test C . End of phase I