Disorders of The Thyroid Gland

SECTION 7 Thyroid/Parathyroid
121 Disorders of the Thyroid Gland

Phillip K. Pellitteri, David Goldenberg, Brian Jameson
KEY POINTS Thyroid diseases are common; they occur in the form of abnormali-
ties in the size and shape of the thyroid gland (goiter) and as
abnormalities of thyroid secretion. Nonthyroid illness can be
• Thyroxine (T4) and triiodothyronine (T3), produced by accompanied by any alteration in thyroid physiology that can
the thyroid gland, are iodinated derivatives of tyrosine. complicate the evaluation of thyroid status.
• Most circulating thyroid hormones are bound to one of The scope of problems relating to thyroid disease can be so
several plasma proteins, the most important of which is complex and encompassing as to create a major challenge to the
thyroxine-binding globulin, which accounts for nearly clinician’s diagnostic abilities. The patient may have such a variety of
75% of circulating hormone. seemingly unrelated signs and symptoms as to lull the practitioner
• Circulating T3 accounts for most of the physiologic into a suspicion of hypochondriasis. This is especially true in
activity of thyroid hormone. our current “cost-effective” frame of mind, in which screening
batteries of diagnostic tests are no longer in vogue and time is of
• The primary internal regulation of thyroid activity
the essence. The patient’s symptoms can be confusing and bizarre,
is through the production of thyroid-stimulating
which leads the physician sometimes to nonspecific diagnoses,
hormone by the anterior pituitary gland by way of
such as psychologic problems with depression or anxiety, chronic
thyrotropin-releasing hormone released by the
fatigue syndrome, cardiac failure, fibromyalgia, and a host of other
hypothalamus.
nonspecific entities. The dilemma is more than simply one of
• The most effective biochemical study for assessing hyperfunction versus hypofunction, nodular versus diffuse, or benign
thyrometabolic status is through measurement of versus malignant. The examination should not comprise merely
thyrotropin. placing the thumb on the lower neck while the patient swallows
• The greatest clinical value of thyroglobulin a few sips of water and answers a couple of quick questions about
measurement is in the management of patients with heat intolerance, weight changes, and gastrointestinal function.
differentiated thyroid cancer. The thyroid gland controls body metabolism and has a profound
• Circulating thyroid antibodies, both antimicrosomal and effect on all bodily functions. In addition, the peculiarities of
antithyroglobulin antibodies, are usually present in development and the strategic location of the thyroid gland may
patients with autoimmune thyroid disease. produce symptom complexes that divert the physician’s attention
away from the thyroid gland and toward the symptoms themselves.
• The principal usefulness of the radioactive iodine uptake To be proficient in the management of thyroid disease, the physician
study is to differentiate hyperthyroidism into high- and must be knowledgeable about all phases of thyroid embryology
low-uptake states. in addition to anatomy, endocrine function, genetic implications,
• A palpable, hypofunctional nodule in the presence of and environmental issues that may affect the thyroid. He or she
Graves disease should be regarded as highly suspicious must also maintain a keen suspicion of all the patient’s signs
for harboring malignancy. and symptoms.
• A patient with Graves disease who manifests thyroid The patient’s history and review of symptoms should be
ophthalmopathy should be treated with surgery, not comprehensive. Generalized symptoms that relate to hypothyroid-
radioactive iodine ablation, to avoid complicating the ism include weakness and fatigue with cold intolerance; weight
ocular problems attributable to the disease. gain; hair loss; edema of the hands and face; thick, dry skin and
dry hair; and a decreased tendency to sweat. Otolaryngologic
• Acute or subacute thyroiditis may be treated with symptoms include hearing loss, dizziness, tinnitus, voice aberrations,
salicylates or nonsteroidal anti-inflammatory drugs. If middle ear effusion, and slurred speech with an enlarged tongue.
the thyroiditis is resistant to these medications, a trial of Gastrointestinal symptoms include constipation, anorexia, intermit-
prednisone may be considered. tent nausea and vomiting, dysphagia, and bloating. Dysphagia is
• Acute suppurative thyroiditis is most commonly caused especially common if there is external compression on the esophagus
by staphylococcal and streptococcal species of bacteria. by a circumferential or enlarged thyroid gland. Genitourinary
• Toxic thyroid adenoma may be effectively treated by symptoms include menstrual disorders and a tendency toward
surgical resection, leaving a normally functioning polyuria. Cardiovascular symptoms include bradycardia, some
thyroid remnant. elevation of the blood pressure, intermittent angina, pericardial
effusion (sometimes), and peripheral edema. Central nervous system
• Medical treatment for acute life-threatening
(CNS) symptoms include daytime somnolence but insomnia at
thyrotoxicosis (thyroid storm) is antithyroid medication,
night, headaches and dizziness, mental and physical slowness,
propranolol to reduce peripheral effects of T3, and
delayed reflexes, and psychologic symptoms suggestive of depression
glucocorticoid administration to combat cortisol
or anxiety. Pulmonary symptoms include shortness of breath if
degradation.
there is tracheal compression or pleural effusion. Musculoskeletal
• Myxedema coma, a late manifestation of symptoms include arthritis and stiffness of the joints with muscle
hypothyroidism, is managed with administration of large cramps and weakness.
doses of intravenous T4 and hydrocortisone. The general symptoms of hyperthyroidism commonly include
a rapid heartbeat or perceptible palpitations, irritability, anxiety,
1852
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CHAPTER 121 Disorders of the Thyroid Gland1852.e1
Abstract Keywords
121
Thyroid disorders comprise a broad and complex spectrum of Thyroid
disease states. These include both benign and malignant entities metabolism
which may be managed medically, surgically, with nuclear medicine, thyroxine
or with a combination of all modalities. This chapter is primarily Graves disease
directed toward the description and characterization of benign hypothyroidism
thyroid disorders and their management. hyperthyroidism
surgery
CHAPTER 121 Disorders of the Thyroid Gland 1853
easy fatigue, increased number of bowel movements with weight substernal goiter or kyphosis—may be examined more easily and
loss, and heat intolerance. Physical findings include tachycardia accurately. In patients with limitation of cervical extension or in 121
with or without arrhythmia; moist, warm skin; a fine tremor of the elderly, the caudal portion of the thyroid gland may lie below
the fingers; and often an enlarged thyroid. Eye signs may be the sternum and be difficult to palpate.1
present, including lid lag, eyelid retraction, and exophthalmos. Moderate pressure in the tracheal groove on one side facilitates
The thyroid gland is strategically located in the lower anterior more accurate palpation of the contralateral lobe. The examiner
neck in close relationship to the larynx, trachea, esophagus, carotid notes the size relative to a normal thyroid gland. Similarly, the
sheath structures, sympathetic chain, recurrent laryngeal nerve, and size and locations of nodules should be accurately recorded. A
mediastinal structures. Diffuse or nodular enlargement, whether pyramidal lobe of the thyroid can sometimes be palpated, especially
benign or malignant, may cause compression or invasion of these those with Graves or Hashimoto disease. A thyroid nodule with
adjacent structures. Resulting symptoms include dysphagia, dyspnea, recent hemorrhage may be moderately tender, whereas an acute,
voice aberration, vocal cord paralysis, Horner syndrome, superior suppurative, or subacute viral thyroiditis is usually exquisitely tender
vena cava syndrome, and sometimes pericardial or pleural effusions. to palpation. Commonly, the pain from the thyroid radiates to
The medical history may disclose thyroid agenesis; prior the ipsilateral ear.
thyroidectomy; therapeutic irradiation with iodine-131 (131I), The texture of the thyroid may suggest the etiology of the
external radiation therapy, Hashimoto thyroiditis, history of disease. Autoimmune thyroid disease is often seen as a firm, bos-
laryngeal cancer or laryngectomy, history of cancer elsewhere selated (cobblestone-like) gland. This in conjunction with a low
with possible metastasis to the thyroid, and a history of other or elevated level of serum thyroid-stimulating hormone (TSH)
recent head and neck infections that may have resulted in an should strongly suggest Graves disease (low TSH) or Hashimoto
inflammatory process within the thyroid gland. thyroiditis (elevated TSH). Smooth-contoured nodularity of the
thyroid usually represents colloid goiter. Although firm nodules
may represent thyroid cancer, this clinical characteristic is
PHYSICAL EXAMINATION not diagnostic.
Facility with the examination of the thyroid and surrounding Attention is next turned to the areas of lymphatic drainage of
structures is essential for the accurate diagnosis and appropriate the thyroid. The superior pole and the lateral lobes drain superiorly
management of malignant and benign thyroid disease. The patient and laterally toward the jugular lymph nodes, whereas the isthmus
is initially observed anteriorly. Some findings may be obvious and lower poles of the thyroid drain inferiorly along the tracheo-
whereas others may be subtle. A clinical patient with hypothyroidism esophageal groove and into the mediastinum. Each side of the
usually seems more lethargic, may be overweight, and will be neck should be examined methodically from the mandible to the
slower in response. His or her skin and hair may appear dry supraclavicular notch.
and coarse. Conversely, a hyperthyroid patient may seem more After observation of the external surfaces and examination of
anxious and will be thinner and more apprehensive with moist, the external neck, attention is turned to the internal examination
warm skin and perhaps a visible tremor in the fingers. Eye signs of the aerodigestive system. Intraorally, the tongue in a myxede-
including exophthalmos, lid lag, or lid retraction may or may not matous patient may be enlarged and thickened. The base of the
be present. tongue should be examined carefully to rule out a lingual thyroid
In either a hypothyroid or hyperthyroid patient, a diffuse or gland. If present, this would indicate a developmental anomaly.
nodular goiter is commonly visible in the neck on simple inspection, The lingual thyroid can enlarge during periods of increased
and there may be some aberration of the patient’s voice. The hormonal demand, such as puberty and pregnancy. When this
patient with hypothyroidism with myxedematous infiltration of enlargement occurs, the guttural qualities of the voice may be
the vocal cords has a husky, raspy tone of voice. A patient whose even more profound. In addition, bleeding may occur from the
recurrent laryngeal nerve is compromised by pressure or tumor lingual thyroid; finally, enlargement of the lingual thyroid may
infiltration has the voice of a paralyzed vocal cord, which is breathy, continue to the point of dysphagia and airway obstruction that
barely audible, and inefficient as far as air use is concerned. In may precipitate a semiemergent condition. Most commonly,
other circumstances, the voice may have a guttural quality that hormonal treatment reduces the size of the mass on the back of
signifies obstruction of the aerodigestive passage, usually at the the tongue. Occasionally surgical intervention is required to ensure
level of the tongue base. This would suggest a lingual thyroid that a safe airway. This area of the oropharynx and tongue base is
has failed to descend along normal developmental pathways. usually readily examined with the aid of a tongue blade and a
Horner syndrome may be present with either benign or laryngeal mirror. In patients with an extremely active gag reflex,
malignant thyroid disease. The patient may seem to have a however, a better examination is usually obtained with a fiberoptic
hearing deficit in normal conversational situations. This may be the nasopharyngolaryngoscope.
result of middle ear effusions, which can be drained and reversed. The etiology of the patient’s hoarseness is determined with a
Inner ear myxedematous changes that involve the cochlear or dynamic examination of the hypopharynx and larynx using the
vestibular structures may contribute to a sensorineural type of fiberoptic nasopharyngolaryngoscope. In the hypothyroid patient,
hearing loss accompanied by tinnitus and vertigo. Facial swell- the vocal cords are mobile; however, they may exhibit myxede-
ing or plethora and distension of the jugular veins may signify matous changes that cause them to be thickened and sometimes
obstruction of the superior vena cava from benign or malignant even polypoid along the edges of the vocal folds. The voice in
substernal thyroid disease. The Pemberton sign should be elicited these instances is quite harsh and raspy. The airway may become
in patients with large goiters by having the patient extend both partially compromised by the thickened myxedematous polypoid
arms above the head and observing for facial erythema, swelling, tissue, and sometimes it is necessary to trim this back surgically
or distention of the jugular veins, indicating cervicothoracic to ensure an adequate airway.
inlet obstruction. When one vocal cord is paralyzed, the airway initially becomes
After careful observation of the patient’s general appearance, incompetent. The patient may cough or choke on liquids or
the neck is examined. The thyroid should be examined from behind secretions unless careful swallowing is followed. The larynx is
the patient, and it is palpated initially for gross pathology. The inefficient and produces only two or three words with each breath
patient is then asked to swallow several sips of water; this moves of air. The voice is of an exaggerated, forced, whispered quality.
the thyroid cephalad and makes the lower portion of the gland As time passes, the larynx compensates by having the mobile vocal
easier to approach. If the patient extends the neck less fully, the cord cross the midline to close the deficit in the airway partially.
more inferior aspects of the thyroid—especially in patients with This compensation improves speech and swallowing almost to
1854 PART VI Head and Neck Surgery and Oncology
normal levels. It is important that preoperative laryngeal examina- Lumen Storage Apical cell
MIT
tion be done before thyroid surgery to establish the mobility of area surface
the vocal cords. Because it is possible to have a nearly normal- DIT
Tg
sounding voice with one cord paralyzed, it is important for the
T4
operating surgeon to know that a cord is paralyzed because injury 4
to the opposite cord would precipitate the more emergent situation T3
of bilateral vocal cord paralysis and the probable need for subse- I– + Tg
quent tracheostomy thyroplasty, or both. Paralysis of the vocal 6
cords usually implies compromise of the recurrent laryngeal nerve
on the ipsilateral side. This compromise may be secondary to
5
pressure on the nerve, but more likely it is caused by infiltration
of the nerve by malignancy. AV CD
External compression on the trachea, esophagus, or both by Endosomes
3
thyroid masses can lead to severe dyspnea, dysphagia, or both. It
is important to know whether the airway and esophageal involve-
ment is secondary to external compression alone or whether an CD
element of tumor infiltration is present within these organs. Internal Golgi Lysosomes
examination with a bronchoscope and an esophagoscope is necessary
to determine the status of these organs. Radiographic studies are
sometimes necessary to complement the examinations and aid in
surgical planning. Under such circumstances, barium swallow of Endoplasmic
the esophagus may outline the areas of obstruction. Elucidation reticulum 7
of the various etiologies of thyroid disease is often accomplished 2
by considering the aggregate data obtained from the patient’s I–
history, clinical examination, chemical and imaging studies, and
specific diagnostic examinations. 8 DIT
MIT T4
PHYSIOLOGY OF THE THYROID GLAND
T3
The thyroid gland produces two major hormones, 3,5,3′-triiodo- Nucleus
thyronine (T3) and 3,5,3′,5′-tetraiodothyronine, or thyroxine (T4).
Both are iodinated derivatives of tyrosine. Hormone production
depends on an external iodine supply and on intrathyroidal 1 T3
mechanisms for concentrating ingested iodide and then incorporat- T4
I–
ing it into the tissue-specific protein, thyroglobulin. The thyroid
gland is unique within the endocrine system in that it has a large
extracellular space, the follicular lumen, that is used for storage of Fig. 121.1 Synthesis and release of thyroid hormone. 1, Iodide
the hormones and their precursors. As hormone is needed by the transported into the thyrocyte at the basal cell membrane by the
organism, thyroglobulin is retrieved by the cell, where the biologi- sodium iodide/symporter travels down its electrochemical gradient to
cally active hormones are released from it before being passed the apical surface. 2, Polypeptide chain of thyroglobulin (Tg) is
into circulation (Fig. 121.1). synthesized on the surface of the endoplasmic reticulum and is then
translocated into its lumen. Synthesis of carbohydrate units begins
and conformational changes transform the polypeptide chains into
Iodide Transport stable dimers. Tg enters the Golgi, where carbohydrate units are
A dietary intake of at least 100 µg of iodine per day is required completed. 3, Uniodinated Tg travels to the apical surface in small
in humans to ensure adequate production of thyroid hormone. vesicles (AV). 4, Tg is iodinated, and iodotyrosyls are coupled to form
In North America, the average daily intake is higher than this, T4 and T3 by thyroperoxidase in the presence of H2O2. 5, Tg retrieved
largely because of the use of iodine as a food additive.2 In many by micropinocytosis enters the endosome-lysosomal pathway, where
parts of the world, however, consumption is significantly below proteolysis and hormone release occurs. 6, Alternatively, Tg retrieved
the minimum level, and iodine deficiency is the leading cause of by macropinocytosis travels to lysosomes in colloid droplets (CD). 7,
thyroid-related disorders. Thyroid hormones and precursors leave the lysosomes, and T4 and T3
The thyroid normally concentrates iodide 20- to 40-fold over enter the bloodstream. 8, Monoiodotyrosine (MIT) and diiodotyrosine
the extracellular space and against an electrical gradient of (DIT) are deiodinated, and released iodide is recirculated. (From Dunn
approximately 40 mV. Key to this trapping action is a protein AD: Thyroid physiology. In Pellitteri PK, editor: Endocrine surgery of
located in the basal membrane of the thyroid cell known as the the head and neck, New York, Delmar, 2003, p 50.)
sodium/iodide symporter (NIS).3 NIS couples with the influx of Na+
down its electrochemical gradient with the simultaneous influx
of I− up its electrochemical gradient. An Na+-K+-ATPase acts to
maintain the Na+ gradient. Iodide travels down its electrochemical
Thyroglobulin
gradient to the apical surface of the thyrocyte, where it is incor- Thyroglobulin is essential to thyroid physiology. It is a tissue-
porated into thyroglobulin. More recent evidence suggests that specific protein that serves as a matrix for the synthesis of hormone
pendrin, an apical membrane protein, aids in releasing iodide into and a vehicle for its storage.5 The human thyroglobulin gene has
the follicular lumen.4 Mutations in the gene and coding for this been cloned and is located on the long arm of chromosome 8q24.
protein are responsible for the common hereditary disorder known Thyroglobulin is a large dimeric glycoprotein of approximately
as Pendred syndrome, which is associated with mild hypothyroidism, 660 kDa that in humans consists of two identical polypeptide
goiter, and hearing loss.4 Mutations in the gene that codes for chains each of 2750 amino acids. About 10% of its weight is
NIS have been identified in patients with iodide trapping defects, carbohydrate, and about 0.1% to 1% is iodine. Synthesis and
a rare cause of congenital hypothyroidism.3 maturation of thyroglobulin follow a pathway typical of proteins
destined for secretion: The polypeptide chain is synthesized on large colloid droplets. However, under physiologic conditions in
the surface of the rough endoplasmic reticulum. As that passes most species, including humans, thyroglobulin is retrieved by 121
through a series of intracellular compartments, it undergoes micropinocytosis into small vesicles. It is then passed through the
important posttranslational modifications before reaching the endosome-lysosomal system, where the combined actions of several
follicular lumen.6 Carbohydrate units are added to the polypeptide acid proteases—including cathepsins B, D, and L and lysosomal
chain as it is translocated into the lumen of the rough endoplasmic dipeptidase 1—release the hormones and their iodotyrosine precur-
reticulum. Folding and dimerization of the polypeptide chain sors from the polypeptide backbone.5 Evidence suggests the
occurs within this compartment, aided by folding enzymes and a iodoamino acids may be preferentially cleaved first; but ultimately,
group of proteins known as molecular chaperones. Perturbations of thyroglobulin is broken down into amino acids or small peptides
this process result in block of protein transport beyond this point within the lysosomes.
and cause congenital hypothyroidism.6 Under normal circumstances, When released from thyroglobulin, the thyroid hormones and
the properly folded thyroglobulin dimers migrate to the Golgi their precursors enter the cytosol; there MIT and DIT are deiodin-
complex, where processing of the carbohydrate units is completed. ated by an iodotyrosine-specific deiodinase, and the released iodide
Mature but as of yet uniodinated thyroglobulin is transferred from reenters the iodine pool. Some T4 is deiodinated to T3 before it
the Golgi complex to the apical cell surface in small vesicles. is released into the circulation by 5′−iodothyronine deiodinase,
similar to that found in peripheral tissue.9 The mechanism by
which T4 and T3 is released from the thyrocyte is unknown, but
Iodination and Thyroperoxidase more recent evidence suggests a carrier protein may be involved.10
Newly formed thyroglobulin and iodide meet at the apical cell
surface, where hormone synthesis occurs. This process includes
(1) the oxidation of iodide; (2) its subsequent transfer to thyrosyl
Circulating Thyroid Hormones
residues on thyroglobulin, which produces monoiodotyrosine Less than 1% of circulating thyroid hormones exist as free
(MIT) and diiodotyrosine (DIT); and (3) coupling of two iodo- iodoamino acids; the remainder are bound in reversible, noncovalent
tyrosine molecules, either one each of MIT and DIT to form T3 linkage to one of several plasma proteins.11 In humans, the most
or two of DIT to form T4. Thyroperoxidase (TPO), an enzyme important of these is thyroxine-binding globulin (TBG), which
present in the apical cell membrane, is responsible for each of accounts for nearly 75% of circulating hormone. The TBG
these steps.7 Hydrogen peroxide (H2O2), required in the iodinating molecule has one hormone-binding site with a very high affinity
and coupling reactions, is generated at the apical membrane by for T4 and a lower affinity for T3. A second plasma protein,
a reduced nicotinamide adenine dinucleotide phosphate oxidase.8 transthyretin, accounts for approximately 10% of circulating T4
Mutations in the TPO gene have been found in patients with and T3. Each transthyretin molecule has two hormone-binding
congenital hypothyroidism caused by defective organification. sites, but the affinity of the first is lower than that of TBG and
Abnormalities in H2O2 generation seem to be more rare. that of the second site is very low for both hormones. Albumin
Under normal circumstances, iodide, when trapped, is rapidly also serves as a thyroid hormone transport protein. Although it
incorporated into thyroglobulin, so that little free iodide exists has low affinity, its abundance allows it to account for 10% to
within the thyroid gland at any given time. The extent to which 20% of bound circulating hormone.
thyroglobulin is iodinated depends on the thyroid’s iodide supply. The bound hormones are in equilibrium with the minute
At a level of 0.5% iodine, the thyroglobulin dimer in humans fraction of free circulating hormone available for use in peripheral
contains on average 5 residues of MIT, 5 of DIT, 2.5 of T4, and tissue. Under euthyroid conditions, approximately 0.2% of T4
0.7 of T3 of a total of 132 residues of tyrosine.5 and about 0.3% of T3 in circulation is unbound. The larger free/
Hormone formation involves the coupling of two residues bound ratio of T3 to T4 is caused by the lower affinity of TBG
of iodotyrosine within the thyroglobulin polypeptide chain. At for T3.12 To date, no change in thyroid state has been attributed
the hormonogenic site, the “acceptor” DIT receives the iodin- to abnormalities in these hormone-binding proteins, despite their
ated phenol ring of the “donor” iodothyrosyl (either MIT or apparent role in thyroid function homeostasis.
DIT) located at some distal site on the polypeptide chain. In the
process, the alanine side chain of the donor remains behind, now
presumably in the form of hydroalanine. Iodination in vitro of
Metabolism of Thyroid Hormones
low iodine human thyroglobulin indicates that certain thyrocele T4 must first be deiodinated to T3 to exert most of its biologic
sites are favored for early iodination, and that three or four actions. Because little T3 is directly synthesized on thyroglobulin,
major sites exist for hormone formation. The most important this transformation becomes an important step in hormonogenesis.
hormonogenic site is located five residues from the amino terminal Three iodothyronine deiodinases are present in mammals.9 These
thyroglobulin, whereas a second major site is located three residues membrane-bound enzymes are closely related structurally and are
from the carboxy terminal. The locations of donor thyrosyls are distinguished by the presence of selenocysteine at their active
incomplete. To date, only one has been identified in human sites. Each has distinctive substrate preferences, activity charac-
thyroglobulin, and this resides in the amino terminal region of teristics, inhibitor sensitivities, and relative tissue specificity.
the molecule.5 Through their combined action, the first two types are responsible
for generating approximately 80% of the total T3 production.
Type I deiodinase is the primary source of circulating T3 and is
Storage and Release of Hormone found in tissues of the liver, kidney, and thyroid—where it is
Most mature iodinated thyroglobulin is stored in the colloid as activated by TSH—and to a lesser extent in other tissues. It
soluble dimers, although some highly iodinated molecules (∼10%) is positively regulated by thyroid hormones and is greatly reduced
associate as tetramers. The colloidal nature of the follicular lumen during pathophysiologic states such as starvation and nonthyroid
is caused by its high concentration of protein. This intracellular illnesses. Type I deiodinase is inhibited by the antithyroid drug
space contains a large supply of iodine and hormone available to propylthiouracil (PTU). Type II deiodinase is present primarily in
the organism, which protects it against times of iodine deprivation. the CNS, pituitary, placenta, and skin and has more recently been
Hormone release is initiated by the retrieval of thyroglobulin found in the thyroid.13 Its major role is thought to be in the local
from the follicular lumen. Under stimulatory conditions in some production of T3, but it may also contribute to circulating T3. In
species, this process may occur by macropinocytosis. Pseudopods contrast to type I deiodinase, the type II enzyme is negatively
form at the thyrocytes’ apical surface and engulf thyroglobulin as regulated by thyroid hormone and is unaffected by PTU. Type III
deiodinase inactivates T4 and T3 by inner-ring deiodination in the TABLE 121.1 Drugs Used in Hyperthyroidism
five position, forming reversed T3. The enzyme is present in the
Drug Usual Starting Dose
adult brain, skin, and placenta, and it is present in high levels in
fetal tissues, where it is thought to be important in protecting Methimazole 10 mg PO bid
developing tissue from excess levels of thyroid hormone.14 Propylthiouracil 100 mg PO tid
Atenolol 25 mg PO qd
Propranolol 10–40 mg PO qid
Control of Thyroid Function Diltiazem 60 mg PO qid
Esmolol 150 µg/kg/min IV infusion
The anterior pituitary is the primary internal regulator of thyroid Prednisone 40–60 mg PO qd
function, and it influences virtually all phases of thyroid metabo- Dexamethasone 2 mg PO qid
lism.15 It secretes TSH, also known as thyrotropin, which is a 28- to Colestipol 5 g PO qid
30-kDa lipoprotein that consists of α and β subunits. The α subunit Saturated solution of potassium iodide 1–2 drops PO qd/tid
is common to the pituitary hormones, follicle-stimulating hormone, Compound solution of iodine (Lugol 2–5 drops PO qd/tid
and luteinizing hormone and to chorionic gonadotropin. The β solution)
subunit is responsible for the binding of the hormone to its receptor Lithium 300–450 mg PO tid
Perchlorate* 1 g PO qd
in the basal membrane of the thyroid cell. On interaction with
Ipodate 1 g PO qd
TSH, the receptor, a member of a family of G protein–coupled
receptors, undergoes conformational changes that activate one or *Not available in the United States.
two regulatory pathways. Most TSH effects are mediated by the
activation of the cyclic adenosine monophosphate (cAMP) pathway;
others involve the Ca2+/phosphatidylinositol cascade. The pathway
used to elicit a given effect may vary among species. TSH stimulates treatment of bipolar illness, is a potent inhibitor of thyroid hormone
the efflux of iodide into the follicle and stimulates the resorption release and acts by blocking thyroglobulin endocytosis.19
of colloid into the cell within minutes. Later effects include
increased expression of the NIS, Tg, and TPO genes; stimulation
of H2O2 production; promotion of glycosylation; and increased
Thyroid Hormone Mechanism of Action
production of T3 relative to T4. The thyroid has multiple effects on development, growth, and
Circulating levels of TSH are controlled by the opposing metabolism. The effects on development are widespread phylo-
influences of thyroid hormone and of thyrotropin-releasing genetically and can be dramatically observed during the course
hormone (TRH) from the hypothalamus.16 The latter is a modified of amphibian metamorphosis. The appropriate levels of thyroid
tripeptide secreted to the anterior pituitary by way of the hypo- hormone during fetal and neonatal stages in humans are crucial
thalamohypophyseal portal system. TRH binds to the plasma for the normal maturation of the CNS, muscle, bone, and lung.
membrane of the thyrotrope and stimulates the release of TSH In severe cases of thyroid hormone deficiency during this period,
and the expression of its gene. Levels of circulating TSH are the syndrome of cretinism results with its associated mental
under strict control by the thyroid in a classic negative feedback retardation, deafness, mutism, and stunted growth.20 Similarly, an
system. As levels of thyroid hormone increase in response to TSH excess of thyroid hormone during these critical developmental
stimulation, T4 and T3 block the TRH-stimulated release of TSH periods can result in neurologic abnormalities. The metabolic
in the thyrotrope. The thyroid hormones also act indirectly by effects of thyroid hormone seem to be confined to birds and
inhibiting TRH gene expression in the hypothalamus. mammals and presumably evolved in response to the increased
Iodine supply is the major external factor that influences the metabolic pressures of thermogenesis. Oxygen consumption and
thyroid state. Autoregulatory mechanisms present in the thyroid the metabolism of proteins, carbohydrates, and fats are all under
help to compensate for variations in iodide intake. In response to thyroid hormone control.
increasing doses of iodine, the thyroid initially increases hormone Most effects of thyroid hormone are now believed to be exerted
synthesis but then reverses this process as intrathyroidal levels of by interactions with specific nuclear thyroid hormone receptors,
iodide reach a critical level and further organification is inhibited. resulting in the altered expression of specific genes.21 T4 has little
Withdrawal of iodide from the diet leads to a rapid decrease affinity for the nuclear receptors and must first be converted to
in serum T4 and an increase in serum TSH. Serum T3 levels T3 to be effective. The receptors themselves belong to a large
initially are unaffected, but they eventually decline with prolonged superfamily of nuclear receptors, which includes the steroid
withdrawal. In response to TSH stimulation, the thyroid (1) hormones, retinoic acid, and vitamin D. The thyroid hormone
increases iodide uptake and organification, (2) alters the distribution receptors are closely related isoforms, despite being encoded by
of iodoamino acids within thyroglobulin by increasing the ratios two different genes (α and β).
of MIT to DIT and T3 to T4, and (3) increases the intrathyroidal The thyroid hormones may have some nongenomic actions,
conversion of T4 to T3 by type I and II deiodinases.9 With prolonged including plasma and mitochondrial membrane transport, famil-
iodine deficiency, TSH-stimulated cell proliferation eventually iarization of actin in astrocytes, and modulation of the activities
leads to goiter. of several enzymes, including type II deiodinase. Such nongenomic
effects tend to occur rapidly and, in contrast to nuclear events,
T4 may be as effective as T3 or more so.
Antithyroid Agents
Antithyroid drugs can inhibit thyroid hormone synthesis secretion
or metabolism.17 Common agents and their major actions are
THYROID FUNCTION STUDIES
summarized in Table 121.1. Numerous agents used in the treatment Thyroid function may be assessed by measuring circulating thyroid
of nonthyroid illnesses may have profound effects on the production hormone levels, serum TSH concentrations, and thyroidal uptake
of thyroid hormone. Notable among these are the iodinated of iodine-123.
radiocontrast agents that are potent inhibitors of thyroid hormone
deiodination, and they can interfere with hepatic uptake of T4
and binding of T3 to nuclear receptors.18 The antiarrhythmic agent
Circulating Thyroid Hormone Measurement
amiodarone, which is also heavily iodinated, elicits similar alterations Radioimmunoassay remains the standard method for measuring
in thyroid hormone metabolism and action. Lithium, used in the serum total T4, although isotopic methods may also be used.
Previous methods, none of which are used today, include the improvement in sensitivity over radioimmunoassay methods. More
protein-bound iodine test, the butanol extraction iodine test, and recently, nonisotopic immunometric TSH assays have been 121
T4 measurement by column or by competitive protein binding. developed with a chemiluminescent label. These newer assays
Although the serum total T4 measurement generally reflects the have a 10-fold greater sensitivity than the early immunometric
functional status of the thyroid gland, many factors can alter total TSH assays and are 100 times more sensitive than radioimmunoas-
T4 levels without changing the individual’s thyrometabolic status. say methods. These latest TSH assays, with a sensitivity of
In an ambulatory individual, the most common of these is a change 0.01 mU/L, are currently termed third-generation TSH assays and
in concentration of TBG. High or low TBG states, with their represent the most sensitive method for detecting the TSH level.29
respective increases and decreases in total T4 concentrations, do The clinical application of TSH detection may be summarized
not affect metabolic status. as follows:
Elevated total T4 levels may also occur when there is pro-
1. The diagnosis of primary hypothyroidism. The presence of an
duction of endogenous antibodies to T4, especially in patients
elevated TSH is confirmation of primary hypothyroidism. The
with Hashimoto thyroiditis or other autoimmune disorders and
degree of hypothyroidism may be determined by obtaining a
occasionally in patients with Waldenström macroglobulinemia
serum T4 level. TSH levels are also elevated in patients with
associated with a benign monoclonal gammopathy.22 Another
subclinical hypothyroidism, in which total serum T4 is normal
condition of elevated total T4 levels is peripheral resistance to
or borderline low.
thyroid hormone. Individuals with this condition may have goiter,
2. Guidance of thyroid hormone replacement therapy. The goal of
and they may be hyperactive.23 Patients with this disorder are
treatment of primary hypothyroidism with levothyroxine is
euthyroid, and although rarely found, this has led to inappropriate
normalization of serum T4 and TSH levels. Current TSH assays
treatment for hyperthyroidism.
may detect overreplacement with levothyroxine because TSH
The gold standard measurement of thyrometabolic status is
concentrations would be low. Chronic overreplacement with
measurement of serum free T4 by equilibrium dialysis.24 When
levothyroxine may be associated with cardiac abnormalities,
measured by the dialysis method, free T4 is not affected by changes
including ventricular arrhythmias and ventricular septal
in binding-protein concentrations or by nonthyroid illness. This
hypertrophy as well as bone demineralization, especially in
method is cumbersome and expensive, and thus it is not routinely
postmenopausal women.30–32
performed. Free T4 levels are most commonly measured com-
3. Determination of TSH suppression in treating thyroid cancer.
mercially by immunoassay techniques, but their reliability is
Thyroid-suppressive therapy is part of the routine management
suboptimal because they may be affected by illness or by significant
of some patients with well-differentiated thyroid carcinoma
changes in binding proteins.25 The clinical usefulness of free T4
because growth of these tumors may be responsive to TSH.
measurements by any method may be limited.26
Treatment with levothyroxine is titrated to suppress TSH while
Although the thyrometabolic status is best reflected by the
attempting to avoid clinical hyperthyroidism. With few excep-
free T4 level, from a clinical standpoint, an index or estimate of
tions, suppressed TSH levels measured in third-generation
free T4 is generally adequate. The free T4 index is obtained by
assays correlate with absent TSH response.33
multiplying the serum total T4 and an indirect assessment of
4. Determination of suppressive therapy for nodular goiter. TSH
thyroglobulin. Serum thyroglobulin is generally estimated by one
measurements are useful for following patients with either
of two methods: the thyroid uptake test and the T3 uptake test.26
solitary or multinodular goiter, in whom suppressive thyroid
The thyroid uptake test is directly proportional to thyroglobulin
hormone therapy may be used. Although the efficacy of
levels in serum, whereas the T3 uptake test is inversely proportional
levothyroxine suppression for benign goiter is not uniformly
to thyroglobulin levels.27 The result, by use of either method, is
agreed on, it is generally not used in the United States.
that variances in serum thyroglobulin levels are largely eliminated,
5. Diagnosis of subclinical hyperthyroidism. Patients with few or
and the calculated free T4 index accurately reflects actual free T4
equivocal symptoms and signs of hyperthyroidism, with normal
status. Extreme changes in thyroglobulin levels, or the presence
or borderline elevated total T4 and T3 levels, and with suppressed
of severe nonthyroid illness, may result in poor correlation between
serum TSH levels have subclinical hyperthyroidism.34 Before
calculated and measured free T4 levels.
the development of more sensitive TSH assays, these individuals
T3 is measured in serum by radioimmunoassay. Similar to T4,
usually went undiagnosed.
T3 is bound to thyroglobulin, although less avidly. Alterations in
thyroglobulin levels result in changes in total T3 (but not free T3) The fact that serum TSH is abnormal in hypothyroidism and
concentrations. As with serum T4, an estimate or index of free T3 hyperthyroidism would seem to make it ideally suited as a screen
may be obtained by using the same formula used in calculating of thyroid status because, with rare exceptions, a normal TSH level
the free T4 index. Because most T3 is derived from peripheral would suggest normal thyroid hormone homeostasis. Experience
metabolism of T4, clinical states or pharmacologic agents that in ambulatory individuals suggests that a normal TSH virtually
impair normal T4 metabolism result in lower T3 levels. excludes the possibility of thyroid dysfunction.35 In addition, the
The principles used for obtaining the serum T3 are to determine serum TSH level is more sensitive than the serum T4 level as a
the severity of hyperthyroidism and to confirm the diagnosis of test for thyroid dysfunction because TSH can detect subclinical
suspected thyrotoxicosis in cases in which serum T4 levels are thyroid disorders in which serum total T4 (and T3) is usually
normal or equivocal. In addition, the serum T3 may be indicated normal. As a result of advances in TSH methodology, measure-
in evaluating patients with autonomously functioning thyroid ment of circulating thyroid hormones may become assigned to a
adenomas, in whom so-called T3 toxicosis may be present. Such second line of assessment of suspected thyroid dysfunction. Many
patients may have normal or borderline elevated serum T4 levels investigators believe that the serum TSH is preferable as a screening
along with suppressed serum TSH levels.28 method for thyrometabolic status in the absence of known or
suspected pituitary or hypothalamic abnormality.12,30 Fig. 121.2
is an algorithm for the use of TSH levels in the evaluation of
Serum Thyrotropin Measurement thyroid function.
Until approximately 10 years ago, virtually all clinical TSH assays
were performed by radioimmunoassay. By the mid-1980s, many
commercial laboratories began using more sensitive immunometric
Serum Thyroglobulin Measurement
TSH methods with either monoclonal or polyclonal antibodies. Thyroglobulin is elevated in the serum of patients with nearly all
Functional sensitivity of these assays represented a tenfold types of thyroid disorders, which limits its usefulness as a diagnostic
Serum TSH
High Low
? Hypothyroidism ? Hyperthyroidism
T4 (FT4I) T3 (FT3I), T4 (FT4I)
Normal Low Normal High
Subclinical Subclinical Fig. 121.2 Algorithm for using the

Hypothyroidism Hyperthyroidism thyroid-stimulating hormone (TSH) level in
hypothyroidism hyperthyroidism
the evaluation of thyroid function.
test. Its greatest clinical value is in managing patients with well-

differentiated thyroid carcinoma. An elevated or increasing thy-
Measurement of Thyroid-Stimulating Antibodies
roglobulin level after initial surgical and ablation therapy suggests The immunopathogenesis of Graves disease was first suspected
persistence or recurrence of tumor.36 Thyroglobulin is measured in the mid-1950s, when it was observed that injecting the sera of
by either radioimmunoassay or immunometric technique. Although patients with Graves disease into rats produced a prolonged uptake
antithyroid antibodies may cause interference with accurate of radioactive iodine in the rat thyroid glands; the term long-acting
thyroglobulin measurement in up to 25% of individuals, in these thyroid stimulator (LATS) was thus coined.42 Later, LATS was
patients measurements of thyroglobulin and antithyroglobulin characterized as a 7S immunoglobulin, and in recent years, several
antibodies (ATAs) may be used concurrently to provide information assays have been developed for the detection of LATS or thyroid-
regarding the tumor status.36 stimulating antibodies. Two methods are commonly used: one
depends on generation of cAMP and the other is a radioreceptor
method that relies on the TSH-binding inhibitory properties of
Thyroid Antibody Status the immunoglobulin. The cAMP-generating assay is termed
Circulating antithyroid antibodies, specifically antimicrosomal thyroid-stimulating immunoglobulin, and it is detectable in 90% to
antibodies (AMAs) and ATAs, are usually present in patients with 95% of hyperthyroid patients with Graves disease. The other
autoimmune thyroid disease.37 Since the introduction of immunoas- assay detects stimulating and blocking antibodies, termed TBII
say techniques, the term antithyroperoxidase (anti-TPO) has become antibodies, which are detected in 85% of patients with hyperthyroid
interchangeable with AMA. AMAs are detectable in more than Graves disease.43 Thyroid-stimulating antibody measurements are
90% of patients with chronic autoimmune thyroid disease; nearly not indicated for the routine diagnostic evaluation of suspected
100% of patients with Hashimoto thyroiditis and more than 80% Graves disease, but they may be useful when the diagnosis of
of patients with Graves disease have positive titers.38 Although Graves disease is not evident.
ATAs are more specific than AMAs, they are less sensitive and are
not as useful in the detection of autoimmune thyroid disease.39
Elevated levels of AMA are also frequently positive in various
Radioactive Iodine Uptake Test
other organ-specific autoimmune diseases, such as lupus, rheumatoid The thyroid radioactive iodine uptake test is performed by oral
arthritis, autoimmune anemia, Sjögren syndrome, type 1 diabetes, administration of an isotope of iodine (usually 123I) and measurement
and Addison disease.40 of the percentage of the 123I trapped by the thyroid gland. The test
Approximately 15% of adults in the United States, and especially is usually performed 24 hours after administration of the isotope,
women, have elevated AMA titers.32 Prevalence of positive AMA although this may be done earlier. Before the development of
titers increases with age, as does the incidence of primary hypo- sensitive and specific assays for thyroid hormones, the radioac-
thyroidism. The presence of a positive AMA titer should alert the tive iodine uptake test was used as an adjunct to differentiate
clinician to the possibility of hypothyroidism. Individuals with hyperthyroid from hypothyroid states, with elevated and low
positive AMA and elevated TSH levels, even with normal serum radioactive iodine uptake values implying hyperthyroidism and
total T4 levels (subclinical hypothyroidism), had a 3% to 5% per hypothyroidism, respectively. Today, the principal usefulness of this
year likelihood of clinical hypothyroidism developing.41 In this test is in differentiating hyperthyroidism into high- or low-uptake
manner, determination of AMA levels may be useful in the diagnosis states. Radioactive iodine uptake generally provides an accurate
of individuals with suspected autoimmune thyroid disease and in estimate of the thyroid gland’s functional activity, provided that
providing prognostic information when used in conjunction with the iodide pool has not been expanded by iodine-containing drugs
TSH levels. or radiocontrast materials.
THYROTOXICOSIS BOX 121.1 Etiology of Thyrotoxicosis 121

Thyrotoxicosis is a clinicopathologic and biochemical syndrome
Graves disease
that results from exposure to excessive concentrations of thyroid
Thyroiditis
hormones. The syndrome is usually categorized as overt or
Subacute thyroiditis
subclinical. Overt thyrotoxicosis is defined as high serum T4 and
Painless (silent) thyroiditis
T3 concentrations and low serum TSH concentrations, whereby
Postpartum thyroiditis
most patients have symptoms and signs of this entity. Subclinical
Radiation-induced thyroiditis
thyrotoxicosis is defined as normal serum T4 and T3 concentrations
Exogenous thyrotoxicosis
and low serum TSH concentrations; most patients in this category
Thyroid hormone–induced thyrotoxicosis
have no symptoms or signs of this disorder. Thyrotoxicosis may
Iodine-induced thyrotoxicosis
develop suddenly or gradually, it may be transient or persistent;
Drug- and cytokine-induced thyrotoxicosis
it may be of little importance, or it may be life threatening. The
Toxic uninodular goiter (toxic thyroid adenoma)
diagnosis may be obvious, and it can be confirmed easily by a few
Toxic multinodular goiter
simple laboratory studies; or, conversely, it may be exceedingly
Autosomal-dominant and sporadic thyrotoxicosis
difficult and may require repeated serial investigations or prolonged
McCune-Albright syndrome
clinical observation.
Ectopic thyrotoxicosis (struma ovarii)
Thyrotoxicosis is a common disorder. The overall prevalence
Thyroid carcinoma
rates of overt and subclinical thyrotoxicosis gleaned from clinical
Thyrotropin-dependent thyrotoxicosis
surveys in the United States and Europe show an incidence of
Pregnancy-related thyrotoxicosis
approximately 0.5 to 1 (United States) and 10 to 40 (Europe) per
Gestational thyrotoxicosis
1000 people.44–47 Within these ranges, the rates are generally higher
Trophoblastic tumors
in older individuals, especially women, and seem to be lower in
community-based screening programs.
Thyrotoxicosis is about 10 times more common in women
than in men, especially with regard to overt thyrotoxicosis. The
etiology is Graves disease in 60% to 85% of patients, toxic
nodular goiter in 10% to 30% and toxic thyroid adenoma in
Graves Disease
2% to 20%, with the remainder being represented by some Graves disease is the most common cause of thyrotoxicosis. It
type of thyroiditis.48,49 The frequency of toxic multinodular most commonly occurs in women 30 to 60 years of age, but it
goiter and toxic adenoma varies the most and is higher in areas can occur in children and in men and women of any age. It is
of lower iodine intake.49 Most individuals with Graves disease fundamentally an autoimmune disorder that consists of one or
are 30 to 60 years old, whereas individuals with toxic multi- more of the following: hyperthyroidism (with thyrotoxicosis),
nodular goiter or toxic thyroid adenoma are generally 40 to 70 diffuse thyroid enlargement, infiltrative ophthalmopathy (exoph-
years old.50 thalmos), localized myxedema (dermopathy), and thyroid acropachy.
Toxic goiter may appear alone or may be seen before, during, or
after ophthalmopathy develops. Ocular signs range from mild
Pathophysiology periorbital puffiness to severe extraocular muscle dysfunction with
Thyrotoxicosis results from the unregulated release of T4 and T3 proptosis, corneal ulceration, and optic neuritis and blindness.
from the thyroid gland or the ingestion of excessive amounts of The extrathyroidal manifestations of Graves disease can occur in
T4 or T3, or both. It may be due to increased T4 and T3 synthesis the absence of thyroid disease.
and release because of intrinsic thyroid disease, excessive TSH, The major gross anatomic abnormality in patients with
or, theoretically, excessive TRH secretion or the production of Graves thyrotoxicosis is diffuse thyroid enlargement. Microscopic
other TSHs, such as TSH receptor–stimulating autoantibody and examination reveals hypertrophy and hyperplasia of the thyroid
chorionic gonadotropin. It also may be caused by the destruc- follicular cells.
tion of thyroid tissue with the subsequent release of stored The natural history of Graves thyrotoxicosis varies considerably
T3 and T4. among patients. Some have a single episode of thyrotoxicosis (and
Most patients with thyrotoxicosis have increased production Graves disease) that subsides spontaneously in a few months or
of T4 and T3 and increased serum T4 and T3 concentrations. The years. Others have lifelong thyrotoxicosis, and still others have
increases in the production rate of T3 and serum T3 concentrations repeated remissions and relapses. In patients who are treated with
are characteristically greater than the increases found in T4. Some an antithyroid drug, the occurrence of a remission of Graves disease
patients with thyrotoxicosis have high serum T3 concentrations means that prolonged therapy is not required. Although the disease
but normal serum T4 concentrations. This is called T3 thyrotoxicosis; potentially undergoes spontaneous remission, prolonged antithyroid
in these patients, T3 production is increased relative to that of T4, medication, 131I ablation, or surgery is usually necessary to control
even more than is the case in the usual patient with thyrotoxicosis. the thyrotoxicosis.
There are, however, no characteristic clinical manifestations of Well-differentiated thyroid cancer is approximately twice as
T3. It is most common in patients whose thyrotoxicosis is due to prevalent in patients with Graves disease as in the general popula-
a toxic thyroid adenoma or recurrent Graves disease, but it may tion.51 Well-differentiated thyroid cancers may contain TSH
be due to hyperthyroidism of any cause. It is more common in receptors that can be stimulated by the thyroid-stimulating
regions where iodine intake is limited, and it is rare in the United immunoglobulins. These tumors associated with Graves disease
States. The abnormality responsible is probably relative intrathy- tend to be larger and more aggressive and have more local invasion
roidal iodide deficiency. with more regional lymph node metastases than cancers that occur
Box 121.1 lists the causes of thyrotoxicosis, which can usually without Graves disease.52 When a palpable, hypofunctional thyroid
be identified with reasonable certainty by history and physical nodule is found in a patient with Graves disease, it has about a
examination. The most important findings to elicit concern are 45% probability of being a thyroid malignancy.52 A palpable
the duration of symptoms, the degree and pattern of thyroid hypofunctional nodule in a diffuse toxic goiter of Graves disease
enlargement, and the presence or absence of thyroid pain and should be regarded with great suspicion and, if proven to be
tenderness. malignant, should be managed aggressively.51
An antithyroid drug and 131I are the two best treatments for supraventricular arrhythmias and hypertension in preparation
patients with Graves thyrotoxicosis. Both methods are effective, for surgery.
safe, and relatively inexpensive. They represent treatments for In the United States, radioactive iodine is the preferred manage-
hyperthyroidism rather than for the autoimmune process itself, ment for most adults, for children when thionamides fail, or where
although some antithyroid drugs may also have an immunosup- the patient does not respond well to these medications. The goal
pressive effect. The antithyroid drugs used in the United States of 131I therapy is to reduce the amount of functioning thyroid
are methimazole and PTU. These drugs inhibit thyroid hormone tissue, and its efficacy is independent of whether a remission of
biosynthesis by inhibiting the oxidation and organification of iodine Graves disease occurs. Major advantages of 131I therapy for patients
and the coupling of iodotyrosines, reactions catalyzed by thyroid with Graves thyrotoxicosis are that usually only a single dose is
peroxidase.53 PTU also inhibits the thyroidal and extrathyroidal necessary, it reduces thyroid size to normal in most patients, and
conversion of T4 to T3.54 Both medications are concentrated it is safe.61 Thionamides should be stopped for about 3 days before
in the thyroid, and intrathyroidal concentrations, especially and after radioactive iodine therapy, which is usually effective in
of methimazole, remain high for considerably longer than do 2 to 4 months.
serum concentrations.55 Radioactive iodine usually causes a transient exacerbation of
Methimazole and PTU have immunosuppressive actions that thyrotoxicosis and rarely precipitates thyroid storm. This occurs
may contribute to remissions of Graves disease. Both drugs reduce within 1 to 2 weeks and is caused by radiation-induced thyroiditis;
the number of intrathyroidal T cells and inhibit lymphocyte it is a major problem in seriously thyrotoxic or elderly patients.
function, which includes thyroid autoantibody production in vitro, Thyrotoxicosis may also be exacerbated by stopping thionamides
although the latter actions require very high concentrations.56 before radioactive iodine therapy. Hypothyroidism is not so much
The initial goal of antithyroid drug therapy is to inhibit thyroidal a complication of 131I treatment as it is an almost inevitable
T4 and T3 synthesis almost completely. Neither drug has an effect consequence of it. Early hypothyroidism, defined as occurring within
on the release of thyroid hormones stored in the thyroid gland, 1 year after treatment, is caused by the acute destructive effects
and their onset of action is relatively slow, depending on the of 131I. Its frequency ranges from 40% to 80% in patients treated
severity of disease, size of the goiter, drug dosage, and timing. with higher doses of radioactive iodine.62 Lower doses result in
Release of intrathyroidal hormone stores, which may be substantial, early hypothyroidism less often and in persistent thyrotoxicosis
continues until they are depleted. more often.
Although adverse reactions to antithyroid drugs are uncommon Some physicians have been reluctant to treat young adults and
and probably occur with equal frequency with either methimazole especially adolescents and children with 131I. This is because it
or PTU, those associated with PTU are potentially severe and might cause thyroid or other tumors or gonadal damage, or the
can lead to fatality. Pruritus, urticaria, or other rashes; arthralgia patient may be pregnant, which is an absolute contraindication
or myalgia; and fever occur in approximately 5% of patients to the treatment. 131I crosses the placenta and can destroy the fetal
taking either drug.17 Both drugs may result in dysgeusia. The thyroid, and therefore care must be taken to ensure that any
most dangerous adverse effect is agranulocytosis, which occurs in woman about to be treated with 131I is not pregnant.
0.2% or less of patients taking these medications.47 Rare adverse Surgical therapy for thyrotoxic Graves disease is effective
effects include aplastic anemia, thrombocytopenia, hepatocellular and expeditious. The classic operation for surgical treatment
hepatitis (with PTU), cholestatic hepatitis (with methimazole), of Graves disease is subtotal thyroidectomy. Performing this
and a lupus-like vasculitis (with PTU).57,58 With reference to operation either unilaterally or bilaterally, a narrow margin of
those side effects related to PTU, this medication is no longer thyroid tissue in the superolateral aspect of the thyroid, where
recommended for primary medical treatment of Graves disease by the recurrent laryngeal nerve enters the larynx, is preserved by
the American Thyroid Association with the exception of clinical dividing across thyroid tissue at that location.63 This operation
settings that include the first trimester of pregnancy, thyroid provides the additional benefit of preserving the blood supply
storm, and patients who show sensitivity and intolerance to to the superior parathyroid gland on one or both sides. The
methimazole. intended goal of subtotal thyroidectomy is to leave 3 to 6 g of
Inorganic iodine inhibits thyroid hormone secretion, primarily thyroid tissue, providing the benefit that patients become euthyroid
by inhibiting thyroglobulin proteolysis, and it inhibits thyroidal without hormone replacement therapy.33 The amount of thyroid
iodine transport, oxidation, and organification.53 These actions tissue remnant preserved directly affects the recurrence rate of
require only a few milligrams of iodine daily, which may be hyperthyroidism and the development of long-term hypothy-
administered in dosages of 5 to 10 drops of a saturated solution roidism.64 For patients who have larger remnants preserved, an
of potassium iodide (Lugol solution) several times daily. This increased incidence of recurrent hyperthyroidism is noted, which
compound is often given in preparation for thyroidectomy, for can often be treated efficiently with radioactive iodine ablation
its antithyroid action and because it reduces thyroid blood flow, because of the preserved small amount of residual thyroid tissue.65
which theoretically reduces hemorrhage at the time of surgery. Patients in whom more complete thyroid removal is performed are
Lithium carbonate shows antithyroid action similar to that of generally guaranteed to have resolution of their hyperthyroidism;
inorganic iodine and has proved effective in doses of 300 mg three however, long-term hypothyroidism would be the outcome of
or four times daily.59 Cholestyramine, when added to thionamides therapy.66
and β blockers, leads to a more rapid decrease in thyroid hormone Authors who favor more complete surgical resection of thyroid
levels, especially in the first few weeks.54 tissue in the form of near-total thyroidectomy for Graves disease
Beta blockers are valuable in the management of hyperthyroid- point out that long-term hypothyroidism may be easily remedied
ism. Independent of alteration of thyroid function, these drugs by appropriate hormone replacement therapy, whereas recurrent
minimize many of the sympathetic overdrive symptoms found hyperthyroidism, as a result of leaving behind a larger than intended
in hyperthyroidism, such as tachycardia, excessive sweating, ner- thyroid remnant, carries with it the need for further treatment.67
vousness, tremors, and hyperdynamic cardiac activity. They are Arguments have been raised in favor of subtotal thyroidectomy
contraindicated in patients with severe thyrotoxic cardiomyopathy as a means by which complications such as permanent hypopara-
and heart failure, but they can benefit patients with atrial fibrillation thyroidism and recurrent laryngeal nerve injury may be avoided.67
and heart failure.60 β-Blockers are useful for reducing symptoms The rate of permanent recurrent laryngeal nerve injury approaches
of thyrotoxicosis before and for several weeks after 131I therapy, zero, however, as does the rate of long-term hypocalcemia, in
before subtotal thyroidectomy, in thyroiditis, and in thyroid patients operated by experienced surgeons.68 The introduction of
storm. Esmolol may be used in clinical situations that manifest electrophysiologic monitoring of the recurrent laryngeal nerve
during thyroidectomy, in an effort to reduce risk of nerve injury, stores of thyroglobulin are limited and the new T4 and T3 synthesis
has been advocated by many investigators, especially in the setting ceases, thyrotoxicosis is generally transient. Approximately half 121
of total thyroidectomy, where the risk of bilateral nerve injury is of patients with subacute or granulomatous thyroiditis have clinical
potentially increased.69 manifestations of thyrotoxicosis, and a significant proportion of
Using this technology, the finding of loss of electrical signal the remainder have high serum T4 and T3 concentrations.80 This
(LOS) on the thyroid side operated first (indicating potential injury illness is dominated by nonspecific systemic manifestations of
to the recurrent laryngeal nerve), will provide the surgeon with inflammation that include fever, malaise, and myalgias. In addition,
the latitude to stage the operation and avoid the potentially cata- local symptoms of thyroid pain and tenderness are also noted and
strophic complication of bilateral vocal cord paralysis.70 may be severe. Approximately 50% of patients have a history of
The general recommendation for the surgical approach in a recent upper respiratory tract infection preceding the illness.
patients with indications for thyroidectomy is a near-total thy- Any manifestations of thyrotoxicosis together with thyroid pain
roidectomy, which completely eliminates the potential for recurrent and tenderness are usually short lived and last approximately 4 to
or persistent hyperthyroidism.71,72 6 weeks or less. This inflammatory and thyrotoxic phase may be
The absolute indications for surgical treatment for Graves followed by transient hypothyroidism, but permanent hypothyroid-
disease are in patients who have significant adverse reactions to ism is rare. The thyroid gland is usually firm in consistency and
thionamide drugs who cannot be appropriately blocked before may be quite hard. Cervical lymphadenopathy is uncommon. If
radioactive iodine administration.73 Included in this category are pursued, thyroid radionuclide uptake scanning is generally low,
patients with very severe skin reactions, hepatic damage, or and ultrasonography reveals thyroid hypoechogenicity.81
agranulocytosis. Other indications for surgery in patients with Indirect evidence suggests that subacute thyroiditis may be
Graves disease include very large thyroid glands in excess of 75 g a viral illness, but conclusive proof is lacking. The disorder has
and neoplasia, either suspected or proven, within the setting of been associated with mumps, influenza, adenovirus, and other
diffuse toxic nodular goiter. viral infections, and small epidemics of subacute thyroiditis have
Surgical therapy is relatively indicated in young women of been reported.82
childbearing age, who wish to attempt achieving pregnancy or The inflammatory and thyrotoxic components of subacute
who are in the process of lactating and want to continue to do thyroiditis may be so mild and transient that no therapy is required.
so. An additional relative indication for surgery, as opposed to More often, thyroid pain and tenderness result in sufficient discom-
radioactive iodine, is moderate or severe ocular symptoms related fort to warrant anti-inflammatory therapy. Salicylates in divided
to Graves ophthalmopathy, which may be worsened with radioactive dosages of 2.4 to 3.6 g daily or high doses of other nonsteroidal
iodine administration secondary to the development of tissue edema anti-inflammatory drugs usually provide effective relief. Patients
and worsening of the ocular symptoms.74 with severe thyroid pain and tenderness and those who do not
Patients who undergo surgery for Graves thyrotoxicosis require improve readily and quickly with one of these medications should
preoperative preparation so as not to induce thyrotoxicosis on be treated with prednisone in a dosage of approximately 40 mg/
induction of general anesthesia and subsequent manipulation of day for 3 to 4 weeks, after which the dose should be gradually
the thyroid intraoperatively. This is accomplished by administering reduced and then discontinued to minimize the likelihood of
antithyroid drug treatment for 4 to 6 weeks and inorganic iodine recurrence. Anti-inflammatory therapy promptly relieves not only
treatment for 7 to 10 days preoperatively. It is critical to avoid the symptoms of subacute thyroiditis but also probably reduces
the administration of iodinated compounds until several hours thyroid hormone release, which accelerates recovery from thyro-
after starting antithyroid therapy so as to avoid worsening the toxicosis. Thyrotoxicosis itself usually requires no therapy, but in
thyrotoxic condition. Treatment with a β-adrenergic antagonist patients in whom thyrotoxic symptoms may become a problem,
drug for several weeks with or without concomitant inorganic a β-adrenergic drug may be administered for approximately
iodide for 10 to 14 days has also proved to be a safe and effective 1 to 2 weeks.
preoperative therapy.75 Thyrotoxicosis, which is caused by thyroid inflammation in
Postoperative problems after thyroidectomy include wound the absence of thyroid pain and tenderness, is known as painless
hematoma, transient or permanent hypocalcemia, vocal cord paresis or silent thyroiditis and has also been termed subacute lymphocytic
or paralysis, recurrent thyrotoxicosis, and transient or permanent thyroiditis. It is an uncommon cause of thyrotoxicosis. In contrast
hypothyroidism.76 The frequency of nonthyroid complications is to Graves disease, it occurs in almost equal proportions of men
low, especially in experienced surgical hands. Transient hypocalcemia and women. The thyroid gland is not painful or tender and does
may occur secondary to temporary hypoparathyroidism or the not appear enlarged, or it may be only slightly enlarged. In contrast
healing of thyrotoxic osteopenia. The incidence of wound hematoma to subacute thyroiditis, there is generally no history of antecedent
is less than 1%, as is the incidence of permanent hypoparathyroid- upper respiratory tract infection. Generally no extrathyroidal
ism. In addition, the risk of permanent injury to the recurrent manifestations of Graves disease are present. When present, the
laryngeal nerves in the setting of initial surgery is a fraction of thyrotoxicosis associated with painless thyroiditis lasts 2 to 6 weeks
1%.77 Recent investigations have identified nonlabeled techniques and is followed by either recovery or transient hypothyroidism
for the intraoperative identification of parathyroid glands, seeking that lasts an additional 2 to 8 weeks. Approximately half of patients
to preserve these glands in the event that severe fibrovascular later have goitrous autoimmune thyroiditis, hypothyroidism, or
adherence to central neck structures is encountered during surgery, both. Painless thyroiditis with thyrotoxicosis likely may represent
especially in large hypervascular thyroid glands.78 a variant form of chronic autoimmune thyroiditis.
These techniques exploit the inherent properties of parathyroid Radiation-induced thyroid follicular necrosis and inflammation
glands to autofluoresce in the presence of specific wavelengths occur regularly after 131I therapy and are occasionally sufficiently
of infrared spectrometry, which may be applied intraopera- intense to cause exacerbations of thyrotoxicosis with or without
tively in order to identify parathyroid glands that are difficult thyroid pain and tenderness. These complications of 131I therapy
to visualize.79 are most likely to occur 1 to 2 weeks after treatment, to last 1 to
2 weeks, and then to subside spontaneously.
Acute suppurative thyroiditis is most commonly caused by
Thyroiditis Staphylococcus aureus, hemolytic Streptococcus, or Streptococcus
The thyrotoxicosis that occurs in all forms of thyroiditis is caused pneumoniae, but occasionally it is caused by other organisms, such
by T4 and T3 release from thyroglobulin as a result of thyroid as Fusobacterium and Haemophilus.83 This bacterial infection of the
inflammation and the disruption of thyroid follicles. Because the thyroid gland may be the result of trauma, hematologic seeding
from a distant infected site, or direct extension from a deep cervical these adenomas, about 20% have overt thyrotoxicosis and 20%
infection. The infection is usually localized to a single lobe and have subclinical thyrotoxicosis at the time of diagnosis.88 Although
most commonly develops an abscess cavity that may rupture through these neoplasms occur in adults of all ages and occasionally in
the glans capsule and extend into the mediastinum or the deep children, most patients who have thyrotoxicosis are in older age
neck spaces along fascial planes. This disorder is especially common groups. Hemorrhagic infarction of a nontoxic thyroid adenoma
in children, in whom a prodrome of malaise is followed by the may result in a transient thyrotoxicosis.89
acute onset of fever, neck pain and tenderness, severe systemic The characteristic finding in patients with toxic thyroid adenoma
symptoms, and marked leukocytosis. Referred pain to the homo- is a solitary thyroid nodule, which is usually 3 cm or more in
lateral mandible and ear may be present, and typically the child diameter. Radionuclide uptake imaging of the thyroid shows
fixes the head and neck in a single position similar to torticollis. intense nuclear uptake in the location of the palpable nodule
Localized tenderness over the gland and pain on head movement and nearly complete absence of uptake in the remainder of the
are commonly noted. This disorder may be difficult to distinguish thyroid gland.
from subacute nonsuppurative thyroiditis, but the pain is generally Management of the toxic adenoma is required, unless spon-
more severe, the thyroid hormone levels are generally normal, taneous infarction occurs because the resultant thyrotoxicosis is
the erythrocyte sedimentation rate is normal, and the leukocyte usually permanent. Definitive treatment may be obtained by either
count is high. Although the diagnosis is generally made on clinical surgical resection of the adenoma through thyroid lobectomy or
grounds, needle aspiration of the abscess cavity establishes the by 131I ablative therapy. Definitive 131I therapy carries a slight to
bacterial organism causing the infection. moderate risk of either transient or permanent hypothyroidism
The initial therapy is the administration of high-dose antibiotics, after completion of therapy, although with appropriate dosing of
131
usually penicillinase-resistant penicillin, together with a cephalo- I, this risk can be minimized. Surgical resection can be carried
sporin, although antibiotics that cover anaerobic organisms should out after 4 to 6 weeks of antithyroid drug administration and
be considered. Antibiotic therapy that is started before the cavitary a 7- to 10-day course of inorganic iodine therapy in the form
phase of the infection may be successful in limiting its progression. of Lugol solution. Complications after lobectomy are generally
When an abscess has been shown on needle aspiration, however, exceedingly rare, and the surgical resection is usually definitive,
surgical drainage is usually required. Drainage may involve a partial resulting in no evidence of recrudescent thyrotoxicosis or evidence
thyroidectomy to remove all evidence of abscess and necrotic of hypothyroidism.90
tissue and to prevent recrudescence. The neck should be drained An alternative approach that is performed more commonly in
externally until purulence ceases, and antibiotics should be con- Europe than in the United States is the percutaneous administration
tinued for at least 2 weeks after the surgical procedure. Thyro- of ethanol directly into the adenoma by use of ultrasound needle
toxicosis during the course of infection and posttreatment guidance. Although there may be some discomfort associated with
hypothyroidism rarely develop in this entity, in contrast to other the injections, long-term complications are rare, and it seems to
types of inflammatory thyroiditis. be a safe procedure done in appropriately experienced hands. The
shortcoming of this technique is that it may require multiple
treatment sessions. This approach may be desirable in patients
Exogenous Thyrotoxicosis who are poor candidates for surgical resection and who wish to
Thyrotoxicosis may occur as a result of either intentional or avoid exposure to radioactive iodine.
accidental administration of inappropriately high doses of thyroid
hormone initiated by caregivers or patients. An important clue to
the presence of exogenous thyrotoxicosis is the absence of thyroid
Toxic Multinodular Goiter
enlargement. This occurs together with normal or low serum T4 Thyrotoxicosis may occur late in the natural course of multinodular
concentrations if the patient is taking T3 or preparations that goiter, usually in women 50 years of age or older. The charac-
contain T3. These patients also show low thyroid radioactive iodine teristic patient with this disorder has a long history of thyroid
uptake values and low serum thyroglobulin concentrations. Despite enlargement with insidious development of subclinical and then
the ability of iodine supplementation to decrease the size of goiter subsequently overt thyrotoxicosis. These patients generally do not
and to improve thyroid function in patients who live in regions have ophthalmopathy or localized myxedema and do not undergo
of endemic goiter, it has the potential to induce thyrotoxicosis in spontaneous remissions; thyrotoxicosis generally persists until the
these same patients. This usually occurs as a result of a preexisting autonomous thyroid tissue is destroyed.
131
thyroid abnormality that results in autonomous thyroid secretion— I is generally the treatment of choice for patients with
Graves disease or, more commonly, a nodular goiter—but insuf- thyrotoxicosis caused by a multinodular goiter, primarily because
ficient iodine intake to permit excessive production of T4 and T3. spontaneous remission does not occur and because surgical resection
Iodine-induced thyrotoxicosis may also occur in regions where generally requires removal of most of the thyroid gland. Patients
goiter is not endemic.84 Most of these patients have autonomously who are not candidates for radioactive iodine therapy or who
functioning thyroid tissue, such as a multinodular goiter or a refuse this modality may undergo surgery after preparation with
thyroid adenoma, that transports iodide poorly. an antithyroid medication and inorganic iodine therapy, similar
Because it contains iodine, amiodarone can cause iodine-induced to patients being treated for Graves disease surgically. The usual
thyrotoxicosis in patients with nodular goiter.85 It may also cause operation is either bilateral subtotal thyroidectomy or near-total
painless thyroiditis that is sufficiently severe to cause thyrotoxicosis, thyroidectomy with preservation of a 3- to 6-g remnant of thyroid
apparently because of a direct toxic effect of the drug or one of tissue. Surgery is more effective in rapidly reducing the effects of
its metabolites. thyrotoxicosis than is 131I and is attractive in terms of volume
Approximately 2% of patients who are treated with interferon-α reduction of goiter size, but surgery may be more likely to result
develop thyrotoxicosis, caused mostly by painless thyroiditis but in long-term or permanent hypothyroidism.91
sometimes by overt Graves disease.86 This thyrotoxicosis is generally
more subclinical than overt.
Ectopic Thyrotoxicosis
The only recognized etiologies of thyrotoxicosis secondary to
Toxic Thyroid Adenoma excessive ectopic thyroid hormone secretion are dermoid tumors
Toxic uninodular goiters and toxic thyroid adenomas are autono- and teratomas of the ovary. Most of the uncommon patients with
mously functioning thyroid neoplasms.87 Among patients with substantial amounts of thyroid tissue in their tumors (struma
ovarii) who have thyrotoxicosis also have Graves disease or a administration of the antithyroid medication. Additional supportive
multinodular goiter.92 They have one of the common causes systemic therapy should include treatment to reduce hyperpyrexia 121
of thyrotoxicosis that affects the thyroid gland and the ectopic and also appropriate parenteral fluid and electrolyte support. Plas-
thyroid tissue within the ovarian tumor. In the absence of a mapheresis can offer assistance in preparing patients for surgery in
functional thyroid gland because of surgical removal or radioac- difficult situations.101
tive iodine ablation, the ovarian tumor containing a toxic thyroid
adenoma may be the only source of excessive thyroid hormone in
these patients.93
HYPOTHYROIDISM
Prevalence
Special Situations in Thyrotoxicosis Hypothyroidism affects women fourfold to sixfold more often
than men, and the prevalence increases with advancing age. The
Subclinical Thyrotoxicosis National Health and Nutrition Examination Survey (NHANES
Subclinical thyrotoxicosis is characterized chemically by a normal III)—a sample of 17,353 individuals 12 years of age and older,
serum T4 and T3 with low TSH concentrations. Most patients representative of the geographic and ethnic distribution of the
with subclinical thyrotoxicosis are asymptomatic, but a few may US population from 1988 to 1994—reported a prevalence of
have nonspecific symptoms or physical signs compatible with overt clinical hypothyroidism at 0.3% and subclinical hypothyroid-
thyrotoxicosis. The course of this disorder generally varies: some ism at 4.3%.102 Thyroid peroxidase antibodies were elevated in
patients show resolution within weeks to years, whereas others 11.3%, and thyroglobulin antibodies were elevated in 10.4%.
maintain a state of subclinical thyrotoxicosis, and a smaller percent- Thyroid peroxidase antibody positivity was associated with
age (∼10%) show the development of overt thyrotoxicosis.94 There hypothyroidism and hyperthyroidism but thyroglobulin antibodies
seems to be some increased risk of progression to overt thyro- were not.
toxicosis in patients who also have thyroid adenomas, multinodular
goiters, or a history of Graves disease.95,96
If the disorder is due to overt administration of exogenous
Etiology
thyroid hormone, the treatment of choice is to reduce the dosage Hypothyroidism can be classified in order of decreasing frequency
of thyroid hormone supplementation. If the disorder is secondary as thyroid (primary), pituitary (secondary), or hypothalamic (ter-
to native thyroid disease, treatment is rarely required, primarily tiary) failure and thyroid hormone receptor resistance. Causes of
because the disorder generally remains asymptomatic. If the disorder primary hypothyroidism are listed in Box 121.2. Worldwide, the
is associated with a solitary thyroid adenoma, surgical resection most common cause of hypothyroidism is iodine deficiency.103,104
of the adenoma or therapy with 131I may be a treatment option. In iodine-sufficient areas such as the United States, the most
In the setting of multinodular goiter or Graves disease, patients
may be treated with 131I, antithyroid medication, or both.
Thyroid Storm BOX 121.2 Causes of Primary (Thyroid) Hypothyroidism

Severe, life-threatening thyrotoxicosis is referred to as thyroid storm.
This disorder usually occurs abruptly in a thyrotoxic patient who Thyroid agenesis
has had an acute infection or other medical illness, an injury, or Destruction of thyroid tissue
a major operation.97 It may also occur after 131I therapy, after Surgical removal
discontinuation of an antithyroid medication, or spontaneously. Therapeutic irradiation (131I or external radiation)
The index clinical findings in patients with thyroid storm are Autoimmune (Hashimoto) thyroiditis
fever greater than 38.5°C, tachycardia, and generally some type Replacement by cancer and infiltrative diseases (amyloidosis,
of CNS dysfunction. CNS abnormalities include anxiety; agitation scleroderma)
and delirium; possibly acute psychosis or seizures; and, as a terminal Postthyroiditis (acute or subacute)
event, coma. Severe cardiovascular effects, such as congestive heart Postlaryngectomy alone or with external irradiation
failure or atrial fibrillation, may also be present.98 Inhibition of thyroid hormone synthesis, release, or both
Determinative laboratory abnormalities in patients with thyroid Iodine deficiency
storm are generally not found. Serum T4 and T3 concentrations Iodine administration in individuals with underlying autoimmune
may be high, but no more so than in ordinary thyrotoxicosis. thyroiditis (amiodarone, iodine-containing expectorants, kelp,
Serum free T4 and T3 concentrations may be more elevated than saturated solution of potassium iodide, Lugol solution,
in less ill patients with thyrotoxicosis.99 povidone-iodine, iodine-containing radiocontrast agents)
The treatment of thyroid storm should be directed toward Other medications with antithyroid action (methimazole,
decreasing the production of T4 and T3, peripheral production of propylthiouracil, lithium, interferon-α, interferon-β,
T3, and peripheral actions of thyroid hormone and by administering interleukin-2, bile acid sequestrants, proton pump inhibitors,
supportive treatment to maintain adequate cardiovascular and CNS raloxifene, ciprofloxacin, soy products)
function.100 Antithyroid medications should be given in large doses, Inherited enzyme defects
if necessary by nasogastric tube or rectally. Propranolol given orally Transient hypothyroidism
or intravenously is the most immediately effective treatment for After surgery or after 131I therapy
tachycardia and the neuromuscular dysfunction of thyroid storm. Postpartum
Glucocorticoids are usually given in large doses, such as 50 mg of Recovery from thyroiditis
hydrocortisone or 2 mg of dexamethasone intravenously every 8 Autoimmune (Hashimoto) thyroiditis
hours. The rationale for glucocorticoid therapy is that adrenocorti- After withdrawal of thyroid hormone in euthyroid patients
cotropic hormone and cortisol secretion may not increase sufficiently Modified from Braverman LE, Utiger RD: Introduction to hypothyroidism. In
to meet cortisol requirements in patients who are quite ill and in Braverman LE, Utiger RD, editors: Werner and Ingbar’s the thyroid: a
whom cortisol degradation is increased. Inorganic iodine should fundamental and clinical text, ed 7, Philadelphia, Lippincott-Raven,
be given orally or by nasogastric tube in a dose of 50 to 100 mg 2012, p 736.
four times daily to inhibit the thyroidal release of T4 and T3 after
BOX 121.3 Risk Factors for Hypothyroidism BOX 121.4 Symptoms and Signs of Hypothyroidism
Older age General
Female gender Fatigue, weakness, lethargy
Graves disease Weight gain
Hashimoto disease Cold intolerance
Other autoimmune disease (e.g., type 1 diabetes, adrenal Eye, ear, nose, throat
insufficiency, vitiligo) Macroglossia
Postthyroidectomy Hearing loss, vertigo, tinnitus
Goiter Hoarseness of voice
Prior neck irradiation Middle ear effusion
Laryngectomy alone or with external irradiation Blurred vision
Drugs (lithium, amiodarone, iodine-containing compounds) Central nervous system
Slowed speech, movement, and mentation
Delayed relaxation phase of deep tendon reflexes
Gastrointestinal
common cause is chronic autoimmune (Hashimoto) thyroiditis.
Constipation
With current administered doses of 131I for patients with Graves
Anorexia, nausea, vomiting
disease, approximately 90% become hypothyroid by the first
Dysphagia
year.105 External neck irradiation in a cohort of 1677 patients
Ascites
with Hodgkin disease followed for a mean of 9.9 years was
Cardiovascular
associated with a cumulative incidence of hypothyroidism of
Bradycardia
30.6%, which highlights the importance of continued clinical and
Diastolic hypertension
biochemical evaluation.106
Pericardial effusion
Integumentary
Clinical Features Dry, rough, thick skin
Coarse hair
The severity of clinical features depends on the severity of thyroid
Nonpitting edema (myxedema)
hormone deficiency rather than on etiology. Individuals with mild
Periorbital edema
hypothyroidism with elevated TSH but normal free T4 (subclinical
Loss of lateral eyebrows
hypothyroidism) may have few or no symptoms. At the opposite
Decreased perspiration
extreme, individuals with severe hypothyroidism may experience
Carotenemia
myxedema coma. Even in individuals with overt biochemical
Musculoskeletal
hypothyroidism, the severity of symptoms varies. Generally patients
Arthralgia
are more symptomatic if hypothyroidism develops rapidly, and
Carpal tunnel syndrome
elderly patients have fewer symptoms than younger patients.5
Pulmonary
Common symptoms of hypothyroidism—such as fatigue, constipa-
Pleural effusion
tion, dry skin, and cold intolerance—may be mistakenly misin-
Dyspnea on exertion
terpreted as part of the normal aging process.
Genitourinary
Hypothyroidism should be suspected in individuals with goiter
Menstrual irregularity (oligomenorrhea, menorrhagia)
and risk factors (Box 121.3). With the widespread use of the serum
TSH assay, hypothyroidism is frequently detected at an earlier Modified from Watanakunakorn C, Hodges RE, Evans TC: Myxedema: a
stage. The classic symptoms and signs of hypothyroidism are now study of 400 cases, Arch Intern Med 116:183–190, 1965.
less frequently found (Box 121.4).
Otolaryngologic Manifestations
Hearing Loss Some adults with severe myxedema have bilaterally symmetric
Hearing loss may be conductive, mixed, or sensorineural in origin. and progressive sensorineural hearing loss that worsens as the
It occurs more frequently and with greater severity in congenital severity of hypothyroidism increases. Conductive losses may also
than in adult hypothyroidism.107 Progressive mixed hearing loss occur as a result of edema of the eustachian tube mucosa.
is reported in half to nearly all children with endemic cretinism,108
but only about 30% to 40% of adults with myxedema have bilateral
sensorineural hearing loss. Substantial deafness persists after T4
Vertigo
therapy in 10% of children with congenital hypothyroidism.109 Vertigo is experienced in two-thirds of patients with hypothyroid-
Although it mainly occurs in primary hypothyroidism, deafness ism. Attacks are usually mild and brief and are not associated with
has been reported with panhypopituitarism.110 electronystagmography changes or concurrent hearing loss.113
Children with cretinism may have anomalous ossicles that
involve any bone in the middle ear, and they may have atrophy
of the organ of Corti.111 The tectorial membrane is the first
Hoarseness
structure to change, followed by degeneration of hair cells at the Gradual and progressive hoarseness occurs in hypothyroidism as
basal turn of the cochlea, with prolongation of wave I; outer hair a result of mucopolysaccharide infiltration of the vocal cords and
cells remain intact.112 Patients with acquired hypothyroidism who possibly tissue edema in the ambiguous nucleus or the cricothyroid
have hearing loss may display similar abnormalities. Only a few muscles.114 The finding of bilaterally edematous, mobile vocal
adults and almost no children with a well-established hearing loss cords should raise suspicion for hypothyroidism. Hoarseness almost
improve with thyroid hormone therapy. invariably dissipates with thyroid hormone replacement alone.
causes include lymphocytic hypophysitis, tumors, infarctions,

Goitrous Hypothyroidism trauma, and infiltrative diseases. 121
The most common cause of goitrous hypothyroidism in US adults
is autoimmune thyroiditis (Hashimoto disease).115 Other less
common causes are drugs (lithium, amiodarone, sulfisoxazole, large
Subclinical Hypothyroidism
doses of iodides, aminosalicylic acid, interferon, and antithyroid
drugs), infiltration of the gland with tumor or inflammatory
Diagnosis
processes, and familial defects in thyroid hormonogenesis. The diagnosis of subclinical hypothyroidism is made by an elevated
TSH with normal free T4 or a free T4 index. Clinically, there are
few if any mild symptoms of hypothyroidism. Some patients may
Transient Hypothyroidism have goiter, especially when antithyroid antibodies are positive.
Hypothyroidism resulting from Hashimoto thyroiditis is transient
in approximately 10% of cases. Spontaneous remission is associated
with the presence of a larger goiter, a high initial TSH level, and
Prevalence
a family history of thyroid disease.116 Autoimmune thyroid dysfunc- In population-based studies, the prevalence of subclinical hypo-
tion may become apparent after surgery for Cushing disease.117 thyroidism is approximately 8% in women and 3% in men, and
Smoking increases the metabolic effects of overt and subclinical it is higher in whites than in blacks and in individuals older than
hypothyroidism in a dose-dependent manner.118 75 years versus those age 55 to 64 years.125,126 NHANES III reported
that of the 16,533 participants who reported no known thyroid
disease, goiter, or thyroid hormone use, 4.3% had subclinical
Excessive Iodine Intake hypothyroidism.102
In iodine-sufficient areas of the world such as the United States,
excess iodine intake can cause hypothyroidism in individuals with
autoimmune thyroiditis, 131I-treated or surgically treated Graves
Natural History
disease patients, and patients treated with hemithyroidectomy for Progression from subclinical to overt hypothyroidism is not
thyroid nodules.47 Hypothyroidism may develop in individuals inevitable in all individuals. In a large population study in Great
taking amiodarone, especially those with an underlying thyroid Britain followed for more than 20 years, women with an elevated
abnormality. Thyroid autoantibodies are risk factors for the TSH and elevated antithyroid antibody titers progressed to overt
development of hypothyroidism.119 hypothyroidism at a rate of 4.3% per year, a rate greater than
that for women with elevated TSH alone (2.6% per year) or
antithyroid antibodies alone (2.1% per year).47 In this study, no
Endemic Goiter increase was reported in all-cause or cardiac mortality in participants
Endemic goiter is uncommon in the United States, but TSH with subclinical hypothyroidism at baseline. In a natural history
levels are elevated in more than 50% of patients with this disorder, study of 26 elderly subjects with subclinical hypothyroidism,
many of whom have no clinical features of thyroid failure.120 one-third developed overt biochemical hypothyroidism within 4
years of follow-up. Progression to overt hypothyroidism occurred
in subjects with an initial TSH greater than 20 µIU/mL and in
Familial Hypothyroidism 80% with high-titer AMAs greater than 1 : 1600.83 In a more recent
Kindreds with hypothyroidism usually have inherited defects in prospective study of 82 women with subclinical hypothyroidism,
hormonogenesis, but they may rarely have generalized thyroid the cumulative incidence of overt hypothyroidism was 43% in
hormone resistance.121 women with TSH of 6 to 12 µIU/mL, 77% in those with TSH
greater than 12 µIU/mL, and in no women with TSH less than
6 µIU/mL followed for 10 years. TPO antibody positivity was
Nongoitrous Hypothyroidism associated with the development to overt hypothyroidism.127
Nongoitrous hypothyroidism is most often caused by thyroid
disease, most commonly autoimmune diffuse thyroid atrophy,
and by management of Graves disease with 131I, thionamides,
Effects on Lipids, Hypothyroid Symptoms, and Mood
or thyroidectomy; however, it may be caused by pituitary and Treatment of subclinical hypothyroidism prevents progression to
hypothalamic disorders.122,123 overt hypothyroidism. Other potential benefits of therapy include
improvement in hypothyroid symptoms and mood, improvement
Hypothyroidism After Laryngectomy in lipid profile, and decrease in thyroid volume by 20%.
The relationship between subclinical hypothyroidism and
and Radiotherapy the effects of lipids is inconsistent. Some studies show that
Hypothyroidism may start within 4 months of surgery, but it may individuals with subclinical hypothyroidism have an atherogenic
not become clinically apparent for 1 year.124 In a multivariate lipid profile—higher total cholesterol, low-density lipoprotein
analysis of 221 patients, risk factors for hypothyroidism were high (LDL) cholesterol, lipoprotein(a), and apolipoprotein B and
radiation dose, combination of radiotherapy and cervical surgery, lower high-density lipoprotein cholesterol—than euthyroid
time from therapy, and no shielding of the midline neck. Patients individuals,128–130 but other studies show no difference.131–133 In
who receive irradiation to the neck, particularly those who undergo the largest cross-sectional study of 25,862 subjects in the United
neck dissections or total laryngectomy, should have routine thyroid States, subjects with subclinical hypothyroidism had a higher total
function studies performed every 3 to 6 months the first year after cholesterol than the euthyroid group (223 mg/dL vs 216 mg/dL;
management and annually thereafter. P < .003) and had higher LDL cholesterol than the euthyroid
group (144 mg/dL vs 140 mg/dL; P < .003).44 In small studies,
T4 therapy of patients with subclinical hypothyroidism leads to an
Pituitary and Hypothalamic Hypothyroidism increase in high-density lipoprotein cholesterol134 and a decrease
Pituitary and hypothalamic hypothyroidism is uncommon and in total and LDL cholesterol.129,131,135 Meta-analysis of T4 therapy
includes large pituitary tumors and pituitary apoplexy. Hypothalamic in subclinical hypothyroidism shows a decrease of 10 mg/dL in
LDL cholesterol and decrease of 7.9 mg/dL in total cholesterol TABLE 121.2 Thyroid Function Tests in Hypothyroidism and Other
concentration.136 Greater improvement was seen in subjects with Low-Thyroxine Syndromes
baseline total cholesterol levels of 240 mg/dL or greater versus
Free T4/T3 TSH
subjects with total cholesterol less than 240 mg/dL.
T4 therapy leads to significantly increased cardiac output, HYPOTHYROID HYPOTHYROIDISM
increased mean arterial pressure, and decreased systemic vascular Primary hypothyroidism
resistance.137 In a survey of postmenopausal women, subclinical Overt Low NL, low High
hypothyroidism was associated with an increased risk of myocar- Subclinical NL NL High
Pituitary (secondary) Low Low, NL NL, low,
dial infarction (odds ratio 2.3) and aortic atherosclerosis (odds
hypothyroidism slightly high
ratio 1.7), but no subsequent risk of myocardial infarction was Hypothalamic (tertiary) Low Low, NL NL, low,
found at 4.6 years of follow-up.138 It is unclear whether thyroid hypothyroidism slightly high
hormone therapy in subclinical hypothyroidism improves cardiac
EUTHYROID HYPOTHYROXINEMIA
mortality.
Low TBG NL Low NL
Subclinical hypothyroidism is associated with depression in
Nonthyroid illness
some,139 but not in all, studies.140 Similarly, some randomized Mild NL Low NL
placebo-controlled trials in subjects with subclinical hypothyroid- Severe Low Low NL
ism show improvement in symptoms of hypothyroidism,141,142
but one reported no difference.143 Depressed patients with NL, normal; T4/T3, thyroxine/triiodothyronine; TBG, thyroxine-binding
globulin; TSH, thyroid-stimulating hormone
subclinical hypothyroidism have a poorer response to antide-
pressant therapy than depressed patients who are euthyroid.144
Individuals with subclinical hypothyroidism show impairment in
neurobehavioral scores, such as memory, that improve with T4
therapy. Treatment of subclinical hypothyroidism is reasonable
in pregnant women to avoid impairment of the fetus’s intellec- of hypothyroidism because low, normal, or high values can occur,
tual potential145 and in women who have ovulatory dysfunction depending on the cause.
with infertility.141 Central hypothyroidism caused by pituitary or hypothalamic
disorder shows a low free T4 and TSH that is low, inappropriately
normal, or mildly elevated. TRH stimulation testing of TSH has
Treatment traditionally been used to distinguish between these two entities,
Patients with subclinical hypothyroidism and positive TPO antibod- but this is unreliable.148,149 Prior to the advent of routine validated
ies, with TSH greater than 10 µIU/mL, are prone to have overt chemical measurements of serum thyroid hormones and TSH, tests
hypothyroidism develop and should receive thyroid hormone that correlated with thyroid status, but not sufficiently specific to
replacement. Risk of overt disease may depend on the etiology diagnose hypothyroidism, were used to diagnose hypothyroidism
of the subclinical hypothyroidism. Individuals who receive radioac- and to gauge the response to thyroid hormone therapy. The fol-
tive iodine therapy or high-dose external radiation are likely to lowing are notable and more current examples:
progress to overt hypothyroidism and should probably be treated
• Basal metabolic rate was the gold standard for diagnosis.
with thyroid hormone. Others who may benefit include patients
Extremely high and low values correlate well with marked
with goiter, individuals with elevated total or LDL cholesterol,
hyperthyroidism and hypothyroidism, respectively, but are
pregnant women, and women with ovulatory dysfunction with
affected by unrelated, diverse conditions such as fever, pregnancy,
infertility.141 Small doses are usually needed (e.g., 50–75 µg daily),
cancer, acromegaly, hypogonadism, and starvation.
with monitoring of TSH and dose titration in 4 to 6 weeks until
• Decrease in sleeping heart rate.
TSH is normalized. Patients with coronary artery disease should
• Elevated total cholesterol, as well as LDL, and the highly
begin at a lower dose of 25 µg daily.
atherogenic subfraction lipoprotein.
• Delayed Achilles reflex time.
Nonthyroid Illness • Increased creatine kinase because of an increase in MM fraction,
which can be marked and can lead to an increase in MB fraction.
TSH elevation may occur in conditions other than hypothyroidism,
The increase in myoglobin is less marked, and no change in
including recovery from nonthyroid illness, also known as sick
troponin levels is seen even in the presence of an increased
euthyroid syndrome. Hospitalized and critically ill patients may have
MB fraction.
a decreased free T4 index or free T4 concentration by radioim-
munoassay. When measured by equilibrium dialysis, however, free
T4 is normal or elevated. In one report, serum total T4 levels less
than 3 µg/dL were associated with mortality in 84% of critically
Management
ill patients.146 In a randomized prospective study, T4 treatment in Oral synthetic levothyroxine (T4) is the therapy of choice to correct
an intensive care unit did not alter mortality rates.147 hypothyroidism. Gastrointestinal absorption is 81%.150 Because
the plasma half-life of T4 is long (6.7 days),151 once-daily administra-
tion leads to stable T4 and T3 concentrations. Numerous brand-
Laboratory Diagnosis name (Euthyrox, Levothroid, Levoxyl, Synthroid, Unithroid) and
There is a set point for optimal serum free T4 concentration in generic preparations of T4 are available, each in varying doses
a given individual. Because of the log-linear relationship between with different color-coded tablets to allow dose titration at precise
serum TSH and T4 concentrations, small changes in free T4 from increments. In one study, comparison of two brand-name and two
this set point led to relatively large changes in TSH by negative generic preparations in the United States showed bioequivalency.152
feedback. The most sensitive test for hypothyroidism is an elevated Equivalent doses of different formulations of T4 are generally
serum TSH. In subclinical hypothyroidism, TSH is elevated, interchangeable; however, the clinician should repeat the TSH
whereas free T4 remains normal. If the disorder progresses to level 4 to 6 weeks after switching.150,153
overt hypothyroidism, free T4 is decreased (see Table 121.2 for In young, otherwise healthy adults, a full replacement dose
thyroid function tests in hypothyroidism and other low T4 syn- can be prescribed at 1.6 µg/kg/day for nonmalignant conditions.
dromes). Radioactive iodine uptake is not indicated for the diagnosis In patients with known coronary disease, those with multiple
coronary risk factors, and elderly patients who may have previously
silent coronary disease, conservative therapy with an initial dose
Myxedema Coma 121
of 25 µg/day is advisable. The clinician should repeat TSH measure- Myxedema coma, a thyroid emergency, is a late manifestation of
ments with dose adjustment every 4 to 6 weeks (four to six half-lives hypothyroidism characterized by coma or precoma with severe
of T4), until the serum TSH normalizes or until cardiac symptoms clinical manifestations of myxedema. An underlying infection or
arise that may limit therapy to less than a full replacement dose. other precipitating cause of the myxedema coma is usually present.
In individuals without residual thyroid tissue, such as a patient Patients characteristically have extreme hypothermia, bradycardia,
with thyroid cancer who has undergone thyroidectomy, the mean pleural and pericardial effusions, hyponatremia, hypoventilation,
T4 dose required to achieve euthyroidism is generally higher respiratory acidosis, and hypoxia. Focal or generalized seizures
(2.1 µg/kg/day).154 typically precede the coma.
In patients with primary hypothyroidism, the goal of therapy Management is with large doses of intravenous T4 and
is to normalize the serum TSH level. After initiation or change hydrocortisone. Although management is usually instituted
in dose of T4, TSH should be repeated in 4 to 6 weeks. Ultimately, without laboratory confirmation, the clinical diagnoses should
TSH measurements are needed annually or sooner, depending be certain before large doses of intravenous T4 are given. Sup-
on clinical status. In individuals with central hypothyroidism, free portive care includes intubation and assisted ventilation, cau-
T4 alone should be normalized, also with repeat measurements tious warming, support of blood pressure, and management of
in 4 to 6 weeks. The use of the patient’s symptoms to judge the infection. Mortality rates are approximately 50% and depend on
adequacy of T4 dosing is often inaccurate. When subjective the severity of superimposed illnesses and underlying coronary
symptoms were used to determine T4 dosing, patients chose a heart disease.
dose that produced mild hyperthyroidism.155
Potential adverse effects of overtreatment with an excessive
dose of T4 include bone loss in postmenopausal but not premeno-
Surgery
pausal women156,157 and in elderly patients; cardiac complications With mild to moderate hypothyroidism, postoperative complications
including cardiac arrhythmias, heart failure, angina, and myocardial are frequent but are rarely serious or lasting, and necessary surgery
infarction can also occur.93 Occasionally patients develop manic should not be postponed simply to replete thyroid hormone.170
behavior with T4 replacement. Severe behavioral manifestations This is not true for patients with severe myxedema, who should
of T4 therapy for juvenile hypothyroidism are uncommon, but be given preoperative thyroid hormone except in the most urgent
mild behavioral symptoms and poorer school achievement may surgical emergencies or with uncontrolled ischemic heart disease.
occur in approximately 25% of patients, who represent the most In the event that surgery is the preferred treatment option, all
severe cases at the time of diagnosis.158 of the precautionary measures applicable to total thyroidectomy—
Poor patient compliance with taking thyroid hormone leads that is, with reference to identification/protection of the recur-
to therapeutic failure. Alternatives to a daily regimen include rent nerve and preservation of the parathyroid gland—should
twice-weekly159 or once-weekly regimens.160 These probably should be employed.
not be used in patients with coronary artery disease. Numerous In euthyroid patients, total T4 tends to decrease in the first
medications may bind to and interfere with intestinal absorption postoperative day and then spontaneously normalizes in 7 days;
of T4, including aluminum hydroxide,161 ferrous sulfate,162 sucral- the same occurs in hypothyroid patients, but T4 levels do not
fate,163 cholestyramine,102 and calcium carbonate.149 Thyroid normalize until thyroid supplementation is given.171 It is usually
hormone administration should be separated in time from these unnecessary to increase the postoperative dose of T4, however,
medications by a few hours. and it is almost never necessary to use parenteral T4, unless the
Thyroid hormone preparations that contain T3 alone (e.g., patient cannot take medication by mouth for several weeks. If
Cytomel), combinations of T4 and T3 (e.g., Thyrolar), and desiccated parenteral T4 therapy is necessary, half of the patient’s usual daily
thyroid extract (Armour Thyroid) should not be used for the T4 dose is ordinarily given, and attention is given to the patient’s
treatment of hypothyroidism. Serum T3 levels fluctuate widely cardiac status because this therapy may precipitate cardiac arrhyth-
because of the short half-life of T3. Temporary T3 therapy is mias, angina, and heart failure.
indicated in patients with thyroid cancer who have undergone Cardiac and pulmonary problems are prevalent in elderly
thyroidectomy and await thyroid remnant ablation to shorten the patients with hypothyroidism. The prevalence of coronary artery
period of hypothyroidism. T3 can be discontinued 2 weeks before disease is high, but the diagnosis is easily overlooked because
131
I treatment.164 In addition, temporary switching from T4 to T3 patients often have few symptoms because of their low metabolic
therapy in individuals undergoing thyroid hormone withdrawal activity or because they fail to communicate their symptoms
whole-body scanning also reduces the period of hypothyroidism. clearly.113 Pericardial effusions are often apparent and rarely cause
Thyroid hormone requirements are increased during preg- tamponade. Patients with severe hypothyroidism also respond
nancy by an average of 45%161 because of an estrogen-mediated poorly to stress by developing hypothermia and hypotension, and
increase in TBG, fetal T4 transfer, and increased T4 clearance. they do not develop tachycardia in response to infection or
Serum TSH should be obtained at each trimester of pregnancy. hypotension. Shock responds poorly to vasoconstrictors.
If the T4 dose requires adjustment, TSH should be remeasured Patients with severe hypothyroidism often display upper airway
in 4 weeks with further dose adjustment as necessary. After obstruction caused by oropharyngeal muscle dysfunction and tissue
delivery, the prepregnancy T4 dose should be resumed.165 A infiltration with mucopolysaccharide.172 They may have central
hypothyroid woman starting oral estrogen therapy, such as with sleep apnea, insensitivity to hypoxia and hypercarbia,173 and
hormone replacement therapy, may also require a higher thyroid respiratory muscle weakness,174 changes that often lead to severe
hormone dose,166 and a TSH level should be obtained 3 months postoperative hypoxia and difficulty in weaning from a ventilator.
after initiation of estrogen to determine whether a dose increase These defects are reversible with T4 replacement therapy, but
is needed. Increases in dose may be necessary in patients who obstructive sleep apnea may be more closely related to obesity
start medications that increase T4 catabolism (e.g., phenytoin, and male gender than hypothyroidism.175
carbamazepine, phenobarbital, rifampin) and in those who have A von Willebrand disease–like defect is common in hypothyroid-
gastrointestinal malabsorption or who develop nephrotic syn- ism, which may lead to bleeding.176,177 It resolves promptly with
drome.167 A decreased thyroid hormone dosage requirement may be infusion of desmopressin, which suggests that it acts through the
seen in elderly patients168 and in women with breast cancer treated β-adrenergic receptor.94 This can be helpful in the acute manage-
with androgens.169 ment of bleeding, and it resolves permanently with T4 therapy.178,179
5. In cardiac disease
When to Consult an Endocrinologist 6. In the presence of goiter, nodule, or other structural changes
Although most physicians can diagnose and treat hypothyroidism, in the thyroid
consultation with an endocrinologist is recommended in the 7. In the presence of other endocrine diseases, such as adrenal
following situations: and pituitary disorders
8. With an unusual constellation of thyroid function test results
1. In children and infants
9. With unusual causes of hypothyroidism, such as those induced
2. In patients in whom it is difficult to render and maintain a
by various chemical agents
euthyroid state
3. During pregnancy
4. In women planning to conceive For a complete list of references, visit ExpertConsult.com.
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Disorders of The Thyroid Gland

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Disorders of The Thyroid Gland

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SECTION 7 Thyroid/Parathyroid

121 Disorders of the Thyroid Gland

T4 (FT4I) T3 (FT3I), T4 (FT4I)

Normal Low Normal High

Subclinical Subclinical Fig. 121.2 Algorithm for using the

test. Its greatest clinical value is in managing patients with well-

THYROTOXICOSIS BOX 121.1 Etiology of Thyrotoxicosis 121

Thyroid Storm BOX 121.2 Causes of Primary (Thyroid) Hypothyroidism

causes include lymphocytic hypophysitis, tumors, infarctions,

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