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FOURTH EDITION
Handbook of
Liver Disease
LAWRENCE S. FRIEDMAN, MD
The Anton R. Fried, MD, Chair
Department of Medicine
Newton-Wellesley Hospital
Assistant Chief of Medicine
Massachusetts General Hospital
Professor of Medicine
Harvard Medical School
Tufts University School of Medicine
Newton, Massachusetts
PAUL MARTIN, MD, FRCP, FRCPI

Chief, Division of Gastroenterology and Hepatology
University of Miami Miller School of Medicine
Miami, Florida
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HANDBOOK OF LIVER DISEASE, FOURTH EDITION ISBN: 978-0-323-47874-8

Copyright © 2018 by Elsevier, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information
or methods they should be mindful of their own safety and the safety of others, including parties for whom
they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration, and
contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge
of their patients, to make diagnoses, to determine dosages and the best treatment for each individual
patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability, negli-
gence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained
in the material herein.
Previous editions copyrighted 2012, 2004, and 1998.
Library of Congress Cataloging-in-Publication Data
Names: Friedman, Lawrence S. (Lawrence Samuel), 1953- editor. | Martin, Paul,

M.D., editor.
Title: Handbook of liver disease / [edited by] Lawrence S. Friedman, Paul
Martin.
Description: Fourth edition. | Philadelphia, PA : Elsevier, [2018] | Includes
bibliographical references and index.
Identifiers: LCCN 2017024152 | ISBN 9780323478748 (pbk. : alk. paper)
Subjects: | MESH: Liver Diseases | Handbooks
Classification: LCC RC845 | NLM WI 39 | DDC 616.3/62—dc23 LC record
available at https://lccn.loc.gov/2017024152
Senior Content Strategist: Sarah Barth

Content Development Specialist: Meghan Andress
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Claire Kramer
Design Direction: Amy Buxton
Printed in China.
Last digit is the print number: 9 8 7 6 5 4 3 2 1

In memory of Emmet B. Keeffe
CONTRIBUTORS
Sanath Allampati, MD Ji Young Bang, MBBS, MPH

Assistant Professor Interventional Endoscopist
Department of Internal Medicine Center for Interventional Endoscopy
West Virginia University Florida Hospital
Morgantown, West Virginia Orlando, Florida
Helen M. Ayles, MBBS, MRCP, Petros C. Benias, MD

DTM&H, PhD Director of Endoscopic Surgery
Professor of Infectious Diseases and Northwell Health System
International Health Hofstra University
Clinical Research Department Manhassett, New York
London School of Hygiene and Tropical
Medicine Marina Berenguer, MD, PhD
London, England Professor
Director of Research Hepatology and Liver Transplantation Unit
ZAMBART Project La Fe University and Polytechnic Hospital
University of Zambia School of Medicine Valencia, Spain
Lusaka, Zambia
Emily D. Bethea, MD
Bruce R. Bacon, MD Fellow in Gastroenterology
James F. King MD Endowed Chair in Gastrointestinal Division
Gastroenterology Massachusetts General Hospital
Professor of Internal Medicine Chief Medical Resident
Division of Gastroenterology and Department of Medicine
Hepatology Brigham and Women’s Hospital
Saint Louis University School of Medicine Boston, Massachusetts
St. Louis, Missouri
Kalyan Ram Bhamidimarri, MD, MPH
Sarah Lou Bailey, BSc, MBChB, MRCP Assistant Professor of Clinical Medicine
Clinical Research Fellow Departments of Medicine and Hepatology
Faculty of Infectious and Tropical Diseases University of Miami
London School of Hygiene and Tropical Miami, Florida
Medicine
London, England Christopher L. Bowlus, MD
Professor and Chief
William F. Balistreri, MD Division of Gastroenterology and Hepatology
Director University of California, Davis
Pediatric Liver Care Center Sacramento, California
Department of Gastroenterology,
Hepatology, and Nutrition
Children’s Hospital Medical Center
Cincinnati, Ohio
vii
viii CONTRIBUTORS
Andres Cardenas, MD, MMSc, PhD, Michael P. Curry, MD

AGAF, FAASLD Director of Hepatology
Consultant-Institute of Digestive Diseases Department of Medicine
and Metabolism Beth Israel Deaconess Medical Center
Institut de Investigacions Biomèdiques Associate Professor of Medicine
August Pi i Sunyer (IDIBAPS) Department of Medicine
Hospital Clinic Harvard Medical School
University of Barcelona Boston, Massachusetts
Barcelona, Spain
Albert J. Czaja, MD, FACP, FACG,
Andres F. Carrion, MD AGAF, FAASLD
Direct of Hepatology Professor Emeritus of Medicine
Assistant Professor of Medicine Division of Gastroenterology and
Division of Gastroenterology and Hepatology
Hepatology Mayo Clinic College of Medicine
Texas Tech University Health Sciences Rochester, Minnesota
Center
El Paso, Texas Teresita Gomez de Castro, MD
Pontifical Catholic University of Chile
Steve S. Choi, MD Santiago, Chile
Assistant Professor
Division of Gastroenterology Andrew S. deLemos, MD
Department of Medicine Clinical Assistant Professor of Medicine
Duke University University of North Carolina School of
Director, Hepatology Medicine
Department of Medicine Center for Liver Disease and Transplantation
Durham Veterans Affairs Medical Center Carolinas HealthCare System
Durham, North Carolina Charlotte, North Carolina
Sanjiv Chopra, MBBS, MACP Adrian M. Di Bisceglie, MD, FACP

Professor of Medicine Professor of Internal Medicine and
Harvard Medical School Chairman
Chief, James Tullis Internal Medicine Firm Department of Internal Medicine
Beth Israel Deaconess Medical Center Saint Louis University School of Medicine
Editor-in-Chief, Hepatology Section, St. Louis, Missouri
UpToDate
Boston, Massachusetts Anna Mae Diehl, MD
Raymond T. Chung, MD Divison of Gastroenterology
Director of Hepatology and Vice Chief Department of Medicine
Division of Gastroenterology Duke University
Massachusetts General Hospital Durham, North Carolina
Boston, Massachusetts
Robert J. Fontana, MD
Jeremy F.L. Cobbold, PhD, MRCP Professor of Medicine
Clinical Lecturer in Hepatology Department of Internal Medicine
Imperial College London University of Michigan
London, England Ann Arbor, Michigan
CONTRIBUTORS ix
Lawrence S. Friedman, MD Michael G. House, MD, FACS

The Anton R. Fried, MD, Chair Associate Professor
Department of Medicine Department of Surgery
Newton-Wellesley Hospital Indiana University School of
Assistant Chief of Medicine Medicine
Massachusetts General Hospital Indianapolis, Indiana
Harvard Medical School Christine E. Waasdorp Hurtado,
Professor of Medicine MD, MSCS
Tufts University School of Medicine Associate Professor of Pediatrics
Newton, Massachusetts Section of Pediatric Gastroenterology,
Hepatology, and Nutrition
Pere Ginès, MD Children’s Hospital Colorado
Chairman University of Colorado School of Medicine
Liver Unit Colorado Springs, Colorado
Hospital Clinic
Professor Ira M. Jacobson, MD
School of Medicine Director of Hepatology
University of Barcelona NYU Langone Medical Center
Barcelona, Spain New York, New York
Norman D. Grace, MD Kris V. Kowdley, MD, FACP

Staff Physician Director, Swedish/Providence Liver Care
Division of Gastroenterology, Hepatology, Network
and Endoscopy Swedish Liver Center and Organ Transplant
Department of Medicine Seattle, Washington
Brigham and Women’s Hospital
Professor of Medicine Michelle Lai, MD, MPH
Tufts University School of Medicine Assistant Professor
Lecturer on Medicine Department of Medicine
Harvard Medical School Harvard Medical School
Boston, Massachusetts Beth Israel Deaconess Medical Center
Steven-Huy B. Han, MD, AGAF,
FAASLD Jay H. Lefkowitch, MD
Professor of Medicine and Surgery Professor of Pathology and Cell Biology
David Geffen School of Medicine at Columbia University Medical Center
University of California, Los Angeles New York, New York
Los Angeles, California
Chatmanee Lertudomphonwanit, MD
Gideon M. Hirschfield, MB BChir, PhD, Division of Gastroenterology and
FRCP Hepatology
Professor of Autoimmune Liver Disease Department of Pediatrics
Centre for Liver Research Faculty of Medicine
National Institute for Health Research Ramathibodi Hospital
Biomedical Research Unit Mahidol University
University of Birmingham Bangkok, Thailand
Birmingham, England
x CONTRIBUTORS
James H. Lewis, MD Mack C. Mitchell, MD

Professor of Medicine and Director of Professor
Hepatology Department of Internal Medicine
Division of Gastroenterology University of Texas Southwestern Medical
Georgetown University Medical Center Center
Washington, District of Columbia Dallas, Texas
Keith D. Lillemoe, MD, FACS Kevin D. Mullen, MD, FRCPI, FAASLD

Chief of Surgery Professor of Medicine
Department of Surgery Director of Digestive Diseases
Massachusetts General Hospital West Virginia University
W. Gerald Austen Professor of Surgery Morgantown, West Virignia
Boston, Massachusetts Santiago J. Muñoz, MD
Director of Hepatology
Vincent Lo Re III, MD, MSCE Medical Director, Liver Transplantation
Associate Professor of Medicine and Hahnemann University Hospital
Epidemiology Professor of Medicine
Department of Medicine Drexel University College of Medicine
Division of Infectious Diseases Philadelphia, Pennsylvania
Department of Biostatistics and
Epidemiology Brent A. Neuschwander-Tetri, MD
Perelman School of Medicine Professor of Internal Medicine
University of Pennsylvania Division of Gastroenterology and
Philadelphia, Pennsylvania Hepatology
Saint Louis University School of Medicine
Hanisha Manickavasagan, MD St. Louis, Missouri
Department of Internal Medicine
Drexel University College of Medicine Kelvin T. Nguyen, MD
Philadelphia, Pennsylvania Gastroenterology Fellow
Vatche and Tamar Manoukian Division of
Paul Martin, MD, FRCP, FRCPI Digestive Diseases
Professor of Medicine David Geffen School of Medicine at
Chief, Division of Gastroenterology and University of California, Los Angeles
Hepatology Los Angeles, California
University of Miami Miller School of
Medicine Kavish R. Patidar, DO
Miami, Florida Division of Gastroenterology, Hepatology,
and Nutrition
Marlyn J. Mayo, MD Virginia Commonwealth University
Associate Professor Richmond, Virginia
Department of Internal Medicine
University of Texas Southwestern Medical Patricia Pringle, MD
Center Fellow
Dallas, Texas Divison of Gastroenterology
Massachusetts General Hospital
CONTRIBUTORS xi
Nicholas J. Procaccini, MD, JD, MS Ronald J. Sokol, MD

Hepatologist Professor and Vice Chair of Pediatrics
Swedish Liver Center and Organ Arnold Silverman MD Chair in Digestive
Transplant Health
Gastroenterologist Director of Colorado Clinical and
Swedish Gastroenterology Translational Sciences Institute
Swedish Medical Center Chief, Section of Pediatric Gastroenterology,
Seattle, Washington Hepatology, and Nutrition
Children’s Hospital Colorado
James Puleo, MD University of Colorado School of Medicine
Albany Gastroenterology Consultants Aurora, Colorado
Albany, New York
Erin Spengler, MD
K. Rajender Reddy, MD, FACP Assistant Professor of Medicine
Professor of Medicine University of Wisconsin
Division of Internal Medicine Madison, Wisconsin
University of Pennsylvania
Philadelphia, Pennsylvania Elena M. Stoffel, MD
Assistant Professor of Medicine
Hugo R. Rosen, MD, FACP Division of Gastroenterology
Waterman Endowed Chair in Liver Research Department of Medicine
Professor of Medicine and Immunology University of Michigan Health System
Division Head, Gastroenterology and Ann Arbor, Michigan
Hepatology
University of Colorado School of Medicine John A. Summerfield, MD, FRCP,
Aurora, Colorado FAASLD
Consultant in Gastroenterology
Arun J. Sanyal, MD St. Mary’s Hospital
Division of Gastroenterology, Hepatology London, England
and Nutrition
Virginia Commonwealth University Elliot B. Tapper, MD
Richmond, Virginia Assistant Professor
Division of Gastroenterology and
Michael L. Schilsky, MD Hepatology
Professor University of Michigan
Departments of Medicine and Surgery Ann Arbor, Michigan
Yale University School of Medicine
New Haven, Connecticut Tram T. Tran, MD
Medical Director, Liver Transplant
Stuart Sherman, MD Professor of Medicine
Professor of Medicine and Radiology Cedars Sinai Medical Center
Director of Endoscopic Retrograde David Geffen School of Medicine at
Cholangiopancreatography University of California, Los Angeles
Department of Medicine Los Angeles, California
Indiana University School of Medicine
Indianapolis, Indiana Carmen Vinaixa, MD
Consultant
Digestive Medicine, Hepatology
La Fe University and Polytechnic Hospital
Valencia, Spain
xii CONTRIBUTORS
Gwilym J. Webb, BM BCh, MA, MRCP Florence S. Wong, MD, FRACP,

Clinical Research Fellow FRCP(C)
National Institute for Health Research Professor
Birmingham Liver Biomedical Research Department of Medicine
Unit Division of Gastroenterology
University of Birmingham University of Toronto
Birmingham, England Toronto, Ontario, Canada
Douglas M. Weine, MD Wei Zhang, MD, PhD

Gastroenterologist Internal Medicine Resident
Riverview Medical Center Department of Internal Medicine
Red Bank, New Jersey Saint Louis University School of Medicine
St Louis, Missouri
Jacqueline L. Wolf, MD
Associate Professor
Department of Gastroenterology/Medicine
Beth Israel Deaconess Medical Center
PREFACE
This fourth edition of Handbook of Liver Disease is the first for which Emmet B. Keeffe did not
serve as a coeditor because of his untimely death as the third edition was published in 2012. A
tribute to Emmet follows this Preface and the Acknowledgments. Succeeding Emmet as coeditor
is Paul Martin, an accomplished editor and hepatologist in his own right.
The field of hepatology has continued to progress at a remarkable pace as the contents of the
book illustrate. This is best exemplified by the paradigm-changing advances in the treatment of
hepatitis C, which has been transformed from interferon-based therapy to the use of combina-
tions of highly effective, direct-acting antiviral agents. Hepatitis C is now relatively easy to treat—
and to cure—and the major challenge to eradication of the virus is the expense of the available
drugs. The development of viral resistant mutations during treatment appears to be a less imposing
obstacle. Reflecting the extraordinary pace of scientific developments in the field of viral hepatitis,
the book now offers four, rather than two, chapters on the topic, with expanded attention to each
virus.
Progress in other areas of hepatology has been no less impressive. Primary biliary cholangitis
(formerly primary biliary cirrhosis) has a new name, more accurately reflecting the spectrum of
disease, as well as a new treatment—obeticholic acid—for nonresponders or incomplete respond-
ers to ursodeoxycholic acid. Nonalcoholic fatty liver disease has emerged as the preeminent chal-
lenge, both epidemiologically and therapeutically, as hepatitis C is anticipated to come under
control. There is much new information as well on autoimmune liver diseases, drug- and alcohol-
induced liver disease, cirrhosis and portal hypertension, metabolic disorders of the liver, biliary
disorders, and hepatobiliary neoplasms, among other topics, that is reflected in the fourth edition.
Liver transplantation continues to have a central role in the practice of hepatology as advances
proceed steadily toward new approaches to hepatic replacement and regeneration.
We are delighted to welcome a number of highly regarded new senior authors and their
junior associates to the Handbook. The infusion of “new blood” ensures the vitality and currency
of the book. Among the new authors are Erin Spengler and Robert J. Fontana (Acute Liver
Failure), Kelvin T. Nguyen and Steven-Huy B. Han (Hepatitis A and Hepatitis E), Tram T. Tran
(Hepatitis B and Hepatitis D), Elliot B. Tapper and Michael P. Curry (Hepatitis Caused by
Other Viruses), James H. Lewis (Drug-Induced and Toxic Liver Disease), Kavish R. Patidar and
Arun J. Sanyal (Ascites and Spontaneous Bacterial Peritonitis), Andres Cardenas and Pere
Ginès (Hepatorenal Syndrome), Michael L. Schilsky (Wilson Disease and Related Disorders),
Andres F. Carrion and Kalyan Ram Bhamidimarri (Liver Transplantation), and Ji Young Bang
and Stuart Sherman (Cholelithiasis and Cholecystitis). We are equally grateful to our outstanding
returning authors and coauthors.
As in the past, the goal of the Handbook is to provide a concise, accurate, up-to-date, and
readily accessible (in print or online) reference for students of the liver and particularly for busy
practitioners who need reliable information in “real time.” We continue to use an outline format
with many lists, tables, and color figures to convey information efficiently and effectively without
compromising the depth and richness of the field. Our continued mission is to provide a resource
that will be valuable to practicing gastroenterologists and hepatologists, as well as to internists,
family practitioners, other specialists, and students and trainees in gastroenterology and hepatol-
ogy or internal medicine.
—Lawrence S. Friedman
—Paul Martin
xiii
ACKNOWLEDGMENTS
We are grateful to all the authors for sharing their expertise and for staying true to the unique
format of the book. We feel fortunate to be able to learn from the foremost authorities in the field
of hepatology. We particularly appreciate the support, advice, and assistance of Suzanne Toppy
and Sarah Barth, our acquisitions editors, Meghan Andress, our content development specialist,
and Claire Kramer, our project manager, without whom this book would not have been possible.
We thank our friend and esteemed colleague Bruce R. Bacon for his inspiring foreword. We are
appreciative of our colleagues at Newton-Wellesley Hospital and the University of Miami School
of Medicine for their support, and particularly our assistants, Alison Sholock and Maria del Rio,
who provided invaluable and tireless editorial assistance. Finally, we are grateful to our families,
especially our wives, Mary Jo Cappuccilli and Maria T. Abreu, for their steadfast support during
the preparation of this fourth edition.
xv
SPECIAL TRIBUTE
This book is dedicated to the memory of Emmet B. Keeffe, who cocreated the Handbook of
Liver Disease and served as coeditor for the first three editions. Emmet worked tirelessly on the
book, was a superb editor, and had a total mastery of the field of hepatology. He had a talent
for clear, organized, and informative exposition, and an impressive feel for what was important
to practitioners and to patients. He dealt with authors—and with his coeditor—in a direct yet
respectful manner and delighted in discussing the ins and outs of liver disease and the finer points
of English grammar. He was passionate about medicine and scholarship.
Emmet had a remarkably successful and productive academic career, but he is most
remembered as a loving and devoted husband, father, and grandfather; a compassionate and
effective physician; and a warm and generous friend who had no hint of pretense or formality.
Emmet’s professional life was a reflection of his love of people, dedication to the service of others,
and devotion to the generation and communication of new knowledge.
A consummate “quadruple-threat”—an academician with strengths as a clinician, clinical
investigator, educator, and administrator—Emmet’s contributions spanned the breadth of
gastroenterology and hepatology, from flexible sigmoidoscopy to liver transplantation, and he
brought enlightenment to numerous areas. His particular interest was in the treatment and
prevention of viral hepatitis. Emmet helped develop and lead three successful liver transplantations
programs at Oregon Health and Science University, at California Pacific Medical Center, and at
Stanford Medical Center. He held numerous leadership and editorial positions, including the
presidencies of the American Society for Gastrointestinal Endoscopy from 1995 to 1996 and
of the American Gastroenterological Association from 2004 to 2005. He also served as chair of
the American Board of Internal Medicine (ABIM), Subspecialty of Gastroenterology and as a
member of the ABIM Board of Directors in 2007. In addition to serving as coeditor of Handbook
of Liver Disease, Emmet was editor-in-chief of the journal Digestive Diseases and Sciences at the
time of his death.
Emmet had numerous friends around the world who admired his warmth, compassion,
empathy, work ethic, integrity, grace, and wisdom. He was a natural leader who led by example
and consensus building and was generous in his praise of others, yet always humble about
his own accomplishments, which were prodigious. He was an international ambassador of
gastroenterology and hepatology and truly beloved by all who knew him. The Handbook of Liver
Disease is but one of his legacies.
xvii
FOREWORD
I am pleased and honored to have been asked to prepare a Foreword for the fourth edition of
Handbook of Liver Disease. This handbook has become an incredibly valuable resource for all levels
of medical providers who deal with patients who have liver disease. It is easy to use and not overly
detailed; nonetheless, all the essentials are present. Reading through the forewords from previous
editions of the book shows an interesting array of dramatic adjectives describing the progress
that has been made in the field of hepatology. For example, the changes have been described as
“astronomical” and “stunning.” That seems still to be the case in light of continued new develop-
ments. For the young hepatologists in the field, it might be hard for them to consider a time when
we as hepatologists could only identify problems but not do anything about them. Furthermore,
I can remember when it was jokingly said that all we had in our armamentarium was furosemide
and lactulose. Now, in 2017, the diagnostic and therapeutic advances have been phenomenal. One
need only compare the exhibit area at the annual meeting of the American Association for the
Study of Liver Diseases (AASLD) over the years. In 1977, there were only 11 exhibitors, whereas
in 2017 in Washington, DC, there were 85 exhibitors. Indeed, hepatology has become a very suc-
cessful growth area.
Perhaps the greatest developments in hepatology over the past 30 years have come in the field
of viral hepatitis. In certain parts of the world, hepatitis B vaccination has significantly reduced
the frequency of vertical transmission of the hepatitis B virus and in turn has reduced the risk
of hepatocellular carcinoma (HCC) in young adults. In much of the United States, hepatitis D
(delta) is rarely seen now, and identification of a case of hepatitis E is rare. However, the most dra-
matic example of progress in hepatology has been in the field of hepatitis C. The progress from the
discovery of the hepatitis C virus (HCV) in the late 1980s to the ability to cure more than 90% to
95% of patients—and in some studies up to 100%—is truly remarkable. The new treatment regi-
mens do not include interferon, are well tolerated, are safe, are highly effective, and usually require
only 12 weeks of oral treatment. Unfortunately, the biggest current problem related to viral hepati-
tis, and particularly hepatitis C, is the increase in transmission of HCV associated with the opioid
abuse problem in the United States. Also, the frequency of vertical transmission from mother to
child is increasing slightly, and, unfortunately, the call for screening in baby boomers has not been
vigorously received. Development of a hepatitis C vaccine has been slow, and some observers have
opined that with treatment success approaching 100% with direct-acting antiviral agents, the need
for a vaccine is not as great as once thought. At any rate, the availability of hepatitis C treatment
regimens, with at least seven regimens by the end of 2017, has been a great achievement.
The explosion of successful therapies for hepatitis C has not been equaled for hepatitis B, but
many of the scientists, clinicians, and investigators who had been working in hepatitis C are now
working on treatments that will lead to cure of hepatitis B. Perhaps by the time the next edition of
the Handbook has been prepared, we will have curative, direct-acting antiviral agents being tested
for use in patients with hepatitis B.
The other major growth area in hepatology is nonalcoholic steatohepatitis (NASH). Although
there may be three to five million Americans with hepatitis C and approximately two million
with hepatitis B, it has been estimated that there may be as many as 25 million Americans with
nonalcoholic fatty liver disease (NAFLD). Clinical trials are rapidly being initiated, and numerous
new agents are being tested, some alone and some in combination. Most patients with NAFLD
or NASH have insulin resistance, and it seems likely that two or more mechanisms for defining
treatment may be necessary for success. It is also likely that the need for treatment may be long-
term and perhaps lifelong. Therefore expense will be a major consideration for access to these
treatments, and health care providers will have to be careful about this issue.
xxv
xxvi FOREWORD
A significant number of patients who have elevated liver biochemical test levels are receiving
medications known to cause liver dysfunction. The Drug-Induced Liver Injury Network (DILIN)
has increased our attention to these disorders and has helped remind us of the need to focus on
this area. Accordingly, all patients with abnormal liver enzyme levels must have their medication
lists reviewed.
The autoimmune-mediated liver diseases include autoimmune hepatitis (AIH), primary bili-
ary cholangitis (PBC), primary sclerosing cholangitis (PSC), and the overlap syndromes. The new
findings in these disease states include recognition that overlap syndrome can develop in patients
who initially present with AIH and progress to include PBC, or present with PBC and progress
to include AIH. Occasionally, treatment needs to be adjusted. Also, the first new treatment in
decades approved for patients with PBC is obeticholic acid, which is helpful in about one half
of the patients who have had an inadequate or incomplete response to standard treatment with
ursodeoxycholic acid. No new treatments have come about in AIH or in PSC, although trials of
obeticholic acid in PSC are in progress.
In the area of inherited liver diseases, the changes and advances have not been as great in the
past few years as they were in the 1990s, when new genes were being discovered. Most patients
who have hereditary hemochromatosis with significant iron overload have two copies of a single
mutation (C282Y). This is in stark contrast to the more than 600 disease-causing mutations found
in the Wilson disease gene. This indicates that almost all patients with Wilson disease are com-
pound heterozygotes.
Complications of chronic liver disease such as variceal bleeding, hepatic encephalopathy, fluid
retention (ascites and edema), and hepatorenal syndrome are usually managed effectively and,
when these problems occur, are often the precursors to liver transplantation. A dreaded complica-
tion of cirrhosis is the development of HCC, but current guidelines and recommendations for
monitoring and standardized evaluation have led to outcomes that are acceptable. Most mid-to-
large academic health centers now have teams of medical oncologists, hepatologists, transplant
surgeons, pathologists, and interventional radiologists who meet regularly to discuss the manage-
ment of patients with HCC. This multidisciplinary approach is necessary for successful outcomes
in these complicated patients.
Therefore the developments in diagnosis and treatment for a variety of liver diseases have
undergone tremendous advances since the publication of the previous edition of Handbook of
Liver Disease. The changes that have developed in our field have led to improved care and better
outcomes for our patients. We look with excitement to the future to see even greater changes that
will further enhance the care that we provide.
Finally, I cannot resist adding a comment about Dr. Emmet B. Keeffe, to whom this edition
of Handbook of Liver Disease is dedicated. I vividly remember several years ago visiting Emmet
at Stanford. At the time, he was recovering from valvular heart surgery. It was mid-morning on
a sunny day, and we sat outside enjoying a cup of coffee at a small shop. As if it were yesterday, I
remember Emmet saying to me, “You know, Bruce, I found out with the recovery from this sur-
gery that there is a life outside the hospital. Having some recovery time like this reminds me that
we need to take time to take care of ourselves.” This was vintage Emmet Keeffe and a valuable
lesson for all of us as we go about our busy lives.
Congratulations to Drs. Friedman and Martin on an excellent fourth edition of the Handbook
of Liver Disease.
—Bruce R. Bacon
C H A P T E R 1
Assessment of Liver Function and
Diagnostic Studies
Paul Martin, MD, FRCP, FRCPI n Lawrence S. Friedman, MD
KEY POINTS

1 Reflecting the liver’s diverse functions, the colloquial term liver function tests (LFTs) includes
true tests of hepatic synthetic function (e.g., serum albumin), tests of excretory function
(e.g., serum bilirubin), and tests that reflect hepatic necroinflammatory activity (e.g., serum
aminotransferases) or cholestasis (e.g., alkaline phosphatase [ALP]).
2 A
bnormal liver biochemical test results are often the first clues to liver disease. The
widespread inclusion of these tests in routine blood chemistry panels uncovers many
patients with unrecognized hepatic dysfunction.
3 N
ormal or minimally abnormal liver biochemical test levels do not preclude significant liver
disease, even cirrhosis.
4 Laboratory testing can assess the severity of liver disease and its prognosis; sequential
testing may allow assessment of the effectiveness of therapy.
5 A
lthough liver biopsy had been the gold standard for assessing the severity of liver
disease, as well as for confirming the diagnosis for some causes, fibrosis is increasingly
assessed by noninvasive means, most notably by ultrasound elastography, especially in
chronic viral hepatitis.
6 Various imaging studies are useful in detecting focal hepatic defects, the presence of

portal hypertension, and abnormalities of the biliary tract.
Routine Liver Biochemical Tests

SERUM BILIRUBIN
1. J aundice
■ Often the first evidence of liver disease
■ Clinically apparent when serum bilirubin exceeds 3 mg/dL; patient may notice dark urine
or pale stool before conjunctival icterus
2. M
etabolism
■ Bilirubin is a breakdown product of hemoglobin and, to a lesser extent, heme-containing
enzymes; 95% of bilirubin is derived from senescent red blood cells.
■ A fter red blood cell breakdown in the reticuloendothelial system, heme is degraded by the
enzyme heme oxygenase in the endoplasmic reticulum.
■ Bilirubin is released into blood and tightly bound to albumin; free or unconjugated bilirubin
is lipid soluble, is not filtered by the glomerulus, and does not appear in urine.
1
2 HANDBOOK OF LIVER DISEASE
■ U nconjugated bilirubin is taken up by the liver by a carrier-mediated process, attaches to

intracellular storage proteins (ligands), and is conjugated by the enzyme uridine diphos-
phate (UDP)–glucuronyl transferase to form a diglucuronide and, to a lesser extent, a
monoglucuronide.
■ Conjugated bilirubin is water soluble and thus appears in urine.
■ W hen serum levels of bilirubin glucuronides are elevated, some binding to albumin occurs
(delta bilirubin), leading to absence of bilirubinuria despite conjugated hyperbilirubinemia;
this phenomenon explains delayed resolution of jaundice during recovery from acute liver
disease until albumin-bound bilirubin is catabolized.
■ Conjugated bilirubin is excreted by active transport across the canalicular membrane into
bile.
■ Bilirubin in bile enters the small intestine; in the distal ileum and colon, bilirubin is hy-
drolyzed by beta-glucuronidases to form unconjugated bilirubin, which is then reduced by
intestinal bacteria to colorless urobilinogens; a small amount of urobilinogen is reabsorbed
by the enterohepatic circulation and mostly excreted in the bile, with a smaller proportion
undergoing urinary excretion.
■ Urobilinogens or their colored derivatives urobilins are excreted in feces.
3. Measurement of serum bilirubin
a. van den Bergh reaction
■ Total serum bilirubin represents all bilirubin that reacts with diazotized sulfanilic acid
to form chromogenic pyrroles within 30 minutes in the presence of alcohol (an acceler-
ating agent).
■ Direct serum bilirubin is the fraction that reacts with the diazo reagent in an aqueous
medium within 1 minute and corresponds to conjugated bilirubin.
■ Indirect serum bilirubin represents unconjugated bilirubin and is determined by
subtracting the direct reacting fraction from the total bilirubin level.
b. More specific methods (e.g., high-pressure liquid chromatography) demonstrate that the
van den Bergh reaction often overestimates the amount of conjugated bilirubin; however,
the van den Bergh method remains the standard test.
4. Classification of hyperbilirubinemia
a. Unconjugated (bilirubin nearly always <7 mg/dL)
■ O verproduction (presentation to liver of bilirubin load that exceeds hepatic capac-
ity for uptake and conjugation): Hemolysis, ineffective erythropoiesis, resorption of
hematoma
■ Defective uptake and storage of bilirubin: Gilbert syndrome (idiopathic unconjugated
hyperbilirubinemia)
b. Conjugated
■ Hereditary: Dubin-Johnson and Rotor syndromes, bile transport protein defects
■ Cholestasis (Bilirubin is not a sensitive test of hepatic dysfunction.)
– Intrahepatic: Cirrhosis, hepatitis, primary biliary cholangitis, drug induced
– Extrahepatic biliary obstruction: Choledocholithiasis, stricture, neoplasm, biliary
atresia, sclerosing cholangitis
c. Very high bilirubin levels
■ >30 mg/dL: Usually signifies hemolysis plus parenchymal liver disease or biliary ob-
struction; urinary excretion of conjugated bilirubin may help prevent even higher levels
of hyperbilirubinemia; renal failure contributes to hyperbilirubinemia.
■ >60 mg/dL: Seen in patients with hemoglobinopathies (e.g., sickle cell disease) in whom
obstructive jaundice or acute hepatitis develops.
d. The diagnostic approach to the evaluation of an isolated serum bilirubin level is shown in
Fig. 1.1.
ASSESSMENT OF LIVER FUNCTION AND DIAGNOSTIC STUDIES 3
Elevated serum bilirubin
Fractionate
bilirubin
≥15% direct Mostly indirect
Dubin-Johnson Evaluate for

syndrome, Rotor hemolysis
syndrome,
or bile transport defect
Negative Positive
Review medications Hemolytic

(e.g., rifampin) disorder
No causative
medications
Gilbert syndrome;
rarely Crigler-Najjar
syndrome, type 1 or 2
Fig. 1.1 Algorithm for the approach to a patient with an isolated elevation of the serum bilirubin level.
5. U
rine bilirubin and urobilinogen
■ Bilirubinuria indicates an increase in serum conjugated (direct) bilirubin.
■ Urinary urobilinogen (rarely measured now) is found in patients with hemolysis (increased
production of bilirubin), gastrointestinal hemorrhage, or hepatocellular disease (impaired
removal of urobilinogen from blood).
■ Absence of urobilinogen from urine suggests interruption of the enterohepatic circulation
of bile pigments, as in complete bile duct obstruction.
■ Urobilinogen detection and quantification add little diagnostic information to the evalua-
tion of hepatic dysfunction.
SERUM AMINOTRANSFERASES (Table 1.1)

1. These intracellular enzymes are released from injured hepatocytes and are the most useful
marker of hepatic injury (inflammation or cell necrosis).
a. A
spartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT])
■ Found in cytosol and mitochondria
■ Found in liver as well as skeletal muscle, heart, kidney, brain, and pancreas
TABLE 1.1 n Causes of Elevated Serum Aminotransferase Levelsa

Mild Elevation (<5× normal) Marked Elevation (>15× normal)
Hepatic: ALT predominant Acute viral hepatitis (A–E, herpes)

Chronic viral hepatitis DILI
Acute viral hepatitis (A–E, EBV, CMV) Ischemic hepatitis
NAFLD Autoimmune hepatitis
Hemochromatosis Wilson disease
DILI Acute bile duct obstruction
Autoimmune hepatitis Acute Budd-Chiari syndrome
Alpha-1 antitrypsin deficiency Hepatic artery ligation
Wilson disease
Celiac disease
Glycogenic hepatopathy
Hepatic: AST predominant
Alcohol-related liver injury (AST/ALT >2:1)
Cirrhosis
Nonhepatic
Strenuous exercise
Hemolysis
Myopathy
Thyroid disease
Macro-AST

aAlmost any liver disease may be associated with ALT levels 5 times to 15 times normal.
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; DILI, drug-induced liver injury;
EBV, Epstein-Barr virus; NAFLD, nonalcoholic fatty liver disease.

b. A
lanine aminotransferase (ALT, serum glutamic pyruvic transaminase [SGPT])
■ Found in cytosol
■ Highest concentration in liver (more sensitive and specific than AST for liver inflammation
and hepatocyte necrosis)
2. C
linical usefulness
■ Normal levels of ALT are up to ~30 U/L in men and up to ~19 U/L in women.
■ Levels increase with body mass index (and particularly with trunk fat) and correlate with
serum triglyceride, glucose, insulin, and leptin levels and possibly inversely with serum vi-
tamin D levels. There is controversy as to whether levels correlate with the risk of coronary
artery disease and mortality.
■ Levels may rise acutely with a high caloric meal or ingestion of acetaminophen 4 g/day;
coffee appears to lower levels.
■ Aminotransferase elevations are often the first biochemical abnormalities detected in pa-
tients with viral, autoimmune, or drug-induced hepatitis; the degree of elevation may cor-
relate with the extent of hepatic injury but is generally not of prognostic significance.
■ In alcoholic hepatitis, the serum AST is usually no more than 2 to 10 times the upper limit
of normal, and the ALT is normal or nearly normal, with an AST:ALT ratio >2; relatively
low ALT levels may result from a deficiency of pyridoxal 5-phosphate, a necessary cofactor
for hepatic synthesis of ALT. In contrast, in nonalcoholic fatty liver disease, ALT is typically
higher than AST until cirrhosis develops.
■ Aminotransferase levels may be higher than 3000 U/L in acute or chronic viral hepatitis
or drug-induced liver injury; in acute liver failure or ischemic hepatitis (shock liver), even
higher values (>5000 U/L) may be found.
Elevated ALT
History and physical

examination
Obesity, diabetes mellitus,

Consider NAFLD
hyperlipidemia
Risk factors for viral Serologic tests for viral

hepatitis hepatitis: HBsAg, anti-HCV
Autoimmune features Serum IgG level, ANA, SMA
Tests for
Miscellaneous Hemochromatosis: Fe, TIBC, ferritin
considerations Wilson disease: Cu, ceruloplasmin
AAT deficiency: AAT level
Celiac disease: transglutaminase antibody
Imaging and liver biopsy
based on findings and
course
Fig. 1.2 Algorithm for the approach to a patient with a persistently elevated serum alanine aminotrans-
ferase level. AAT, Alpha-1 antitrypsin; ANA, antinuclear antibodies; anti-HCV, antibody to hepatitis C virus; Cu,
copper; Fe, iron; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; NAFLD, nonalcoholic fatty liver
disease; SMA, smooth muscle antibodies; TIBC, total iron binding capacity.
■ M ild-to-moderate elevations of aminotransferase levels are typical of chronic viral hepatitis,

autoimmune hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease, and
celiac disease.
■ In obstructive jaundice, aminotransferase values are usually lower than 500 U/L; rarely,
values may reach 1000 U/L in acute choledocholithiasis or 3000 U/L in acute cholecystitis,
followed by a rapid decline to normal.
3. The approach to the patient with a persistently elevated ALT level is shown in Fig. 1.2.
4. Abnormally low aminotransferase levels have been associated with uremia and chronic hemodialysis;
chronic viral hepatitis in this population may not result in aminotransferase elevation.
SERUM ALKALINE PHOSPHATASE

1. Hepatic ALP is one of several ALP isoenzymes found in humans and is bound to the hepatic
canalicular membrane; various laboratory methods are available for its measurement, and
comparison of results obtained by different techniques may be misleading.
2. This test is sensitive for detection of biliary tract obstruction (a normal value is highly
unusual in significant biliary obstruction); interference with bile flow may be intrahepatic or
extrahepatic.
■ A n increase in serum ALP results from increased hepatic synthesis of the enzyme, rather
than leakage from bile duct cells or failure to clear circulating ALP; because it is synthe-
sized in response to biliary obstruction, the ALP level may be normal early in the course of
acute cholangitis when the serum aminotransferases are already elevated.
■ Increased bile acid concentrations may promote the synthesis of ALP.
■ Serum ALP has a half-life of 17 days; levels may remain elevated up to 1 week after relief
of biliary obstruction and return of the serum bilirubin level to normal.
3. Isolated elevation of alkaline phosphatase
■ This may indicate infiltrative liver disease: Tumor, abscess, granulomas, or amyloidosis.
■ High levels are associated with biliary obstruction, sclerosing cholangitis, primary biliary
cholangitis, immunoglobulin (Ig) G4–associated cholangitis, acquired immunodeficiency
syndrome, cholestatic drug reactions, and other causes of vanishing bile duct syndrome; in
critically ill patients with sepsis, high levels may result from secondary sclerosing cholangitis
from ischemia with rapid progression to cirrhosis.
■ Nonhepatic sources of ALP are bone, intestine, kidney, and placenta (different isoenzymes);
elevations are seen in Paget disease of the bone, osteoblastic bone metastases, small bowel
obstruction, and normal pregnancy.
■ A hepatic origin of an elevated ALP level is suggested by simultaneous elevation of either
serum gamma-glutamyltranspeptidase (GGTP) or 5ʹ-nucleotidase (5NT).
■ Hepatic ALP is more heat stable than bone ALP. The degree of overlap makes this test less
useful than GGTP or 5NT.
■ The diagnostic approach to an isolated elevated ALP level is shown in Fig. 1.3.
4. Mild elevations of serum ALP are often seen in hepatitis and cirrhosis.
5. Low serum levels of ALP may occur in hypothyroidism, pernicious anemia, zinc deficiency,
congenital hypophosphatasia, and fulminant Wilson disease.
GAMMA-GLUTAMYLTRANSPEPTIDASE
1. Although present in many different organs, GGTP is found in particularly high concentra-
tions in the epithelial cells lining biliary ductules.
2. It is a very sensitive indicator of hepatobiliary disease but is not specific. Levels are elevated in
other conditions, including renal failure, myocardial infarction, pancreatic disease, and diabetes
mellitus.
3. GGTP is inducible, and thus levels may be elevated by ingestion of phenytoin or alcohol
in the absence of other clinical evidence of liver disease.
4. Because of its long half-life of 26 days, GGTP is limited as a marker of surreptitious alcohol
consumption.
5. Its major clinical use is to exclude a bone source of an elevated serum ALP level.
6. Many patients with isolated serum GGTP elevation have no other evidence of liver disease;
an extensive evaluation is usually not warranted. Patients should be retested after avoiding
alcohol and other hepatotoxins for several weeks.
5’-NUCLEOTIDASE
1. 5 NT is found in the liver in association with canalicular and sinusoidal plasma membranes.
2. Although 5NT is distributed in other organs, serum levels are believed to reflect hepatobiliary
release by the detergent action of bile salts on plasma membranes.
3. Serum 5NT levels correlate well with serum ALP levels; an elevated serum 5NT level in
association with an elevated ALP level is specific for hepatobiliary dysfunction and is su-
perior to GGTP in this regard.
Elevated alkaline
phosphatase
History and physical examination

(especially pruritus, cholestasis, drugs,
pregnancy, renal disease, bony symptoms)
Normal
GGTP or 5'- Extrahepatic
nucleotidase source
Elevated
Hepatobiliary
disease
Abdominal US
AMA, ACE level,
Normal
serologic tests for
hepatitis, alpha
fetoprotein
Gallstones Cholecystectomy and

bile duct exploration,
if indicated
Focal lesion(s)
CT and/or MRI, biopsy
Biliary tract
abnormalities
Cholangiography
(MRCP, ERCP, THC)
Primary
Above negative;
sclerosing
elevation persists
cholangitis
Liver biopsy Colonoscopy
Fig. 1.3 Algorithm for the approach to a patient with isolated serum alkaline phosphatase elevation. ACE,
Angiotensin-converting enzyme; AMA, antimitochondrial antibodies; CT, computed tomography; ERCP, en-
doscopic retrograde cholangiopancreatography; GGTP, gamma-glutamyltranspeptidase; MRCP, magnetic
resonance cholangiopancreatography; MRI, magnetic resonance imaging; THC, transhepatic cholangio-
graphy; US, ultrasonography.
LACTATE DEHYDROGENASE
Measurement of lactate dehydrogenase (LDH) and the more specific isoenzyme LDH5 adds little
to the evaluation of suspected hepatic dysfunction. High levels of LDH are seen in hepatocellular
necrosis, ischemic hepatitis, cancer, and hemolysis. The ALT/LDH ratio may help differentiate
acute viral hepatitis (≥1.5) from ischemic hepatitis and acetaminophen toxicity (<1.5).
SERUM PROTEINS
Most proteins circulating in plasma are produced by the liver and reflect its synthetic capacity.
1. Albumin
■ Albumin accounts for 75% of serum proteins.
■ Its half-life is approximately 3 weeks.
■ The concentration in blood depends on the albumin synthetic rate (normal, 12 g/day) and
plasma volume.
■ Hypoalbuminemia may result from expanded plasma volume or decreased albumin syn-
thesis. It is frequently associated with ascites and expansion of the extravascular albumin
pool at the expense of the intravascular albumin pool. Hypoalbuminemia is common in
chronic liver disease (an indicator of severity); it is less common in acute liver disease. It is
not specific for liver disease and may also reflect glomerular or gastrointestinal losses.
2. Globulins
a. Globulins are often increased nonspecifically in chronic liver disease.
b. The pattern of elevation may suggest the cause of the underlying liver disease.
■ Elevated IgG: Autoimmune hepatitis
■ Elevated IgM: Primary biliary cholangitis
■ Elevated IgA: Alcoholic liver disease
3. Coagulation factors
a. Most coagulation factors are synthesized by the liver, including factors I (fibrinogen), II
(prothrombin), V, VII, IX, and X and have much shorter half-lives than that of albumin.
■ Factor VII decreases first in liver disease because of its shortest half-life, followed by
factors X and IX.
■ Factor V is not vitamin K dependent, and its measurement can help distinguish vitamin
K deficiency from hepatocellular dysfunction in a patient with prolonged prothrombin
time. Serial measurement of factor V levels has been used to assess prognosis in acute liver
failure; a value <20% of normal portends a poor outcome without liver transplantation.
■ Measurement of factor II (des-gamma-carboxyprothrombin) has also been used to as-
sess liver function. Elevated levels are found in cirrhosis and hepatocellular carcinoma
(HCC) and in patients taking warfarin, a vitamin K antagonist. Administration of vi-
tamin K results in normalization of des-gamma-carboxyprothrombin in patients taking
warfarin but not in those with cirrhosis.
b. The prothrombin time is useful in assessing the severity and prognosis of acute liver
disease. The one-stage prothrombin time described by Quick measures the rate of conversion
of prothrombin to thrombin after activation of the extrinsic coagulation pathway in the pres-
ence of a tissue extract (thromboplastin) and calcium (Ca++) ions. Deficiency of one or more
of the liver-produced factors results in a prolonged prothrombin time.
c. Prolongation of the prothrombin time in cholestatic liver disease may result from vitamin
K deficiency.
■ Explanations for a prolonged prothrombin time apart from hepatocellular disease or
vitamin K deficiency include consumptive coagulopathies, inherited deficiencies of a
coagulation factor, or medications that antagonize the prothrombin complex.
■ V itamin K deficiency as the cause of a prolonged prothrombin time can be excluded

by administration of vitamin K 10 mg; intravenous administration can cause severe
reactions, and the oral route is preferable, if possible. (Subcutaneous administration
is not recommended because of erratic absorption.) Correction or improvement of
the prothrombin time by at least 30% within 24 hours implies that hepatic synthetic
function is intact.
■ The international normalized ratio (INR) is used to standardize prothrombin time de-
terminations performed in different laboratories; however, the results are less consistent
in patients with liver disease than in those taking warfarin unless liver-disease controls
are used.
■ The prothrombin time and INR correlate with the severity of liver disease but not with
the risk of bleeding because of counterbalancing decreases in levels of anticoagulant
factors (e.g., proteins C and S, antithrombin) and enhanced fibrinolysis in patients with
liver disease.
Assessment of Hepatic Metabolic Capacity

Various drugs that undergo purely hepatic metabolism with predictable bioavailability have been
used to assess hepatic metabolic capacity. Typically, a metabolite is measured in plasma, urine, or
breath following intravenous or oral administration of the parent compound. These tests are not
widely used in practice.
ANTIPYRINE CLEARANCE
1. Antipyrine is metabolized by cytochrome P-450 oxygenase with good absorption after oral
administration and elimination entirely by the liver.
2. In chronic liver disease, good correlation exists between prolongation of the antipyrine half-life
and disease severity as assessed by the Child-Turcotte-Pugh score (see Chapter 11).
3. Clearance of antipyrine is less impaired in acute liver disease and obstructive jaundice than in
chronic liver disease.
4. Disadvantages of this test include its long half-life in serum, which requires multiple blood
sampling, poor correlation with in vitro assessment of hepatic microsomal capacity, and al-
teration of antipyrine metabolism by increased age, diet, alcohol, smoking, and environmental
exposure.
AMINOPYRINE BREATH TEST

1. This test is based on detection of [14C]O2 in breath 2 hours after an oral dose of [14C]dimethyl
aminoantipyrine (aminopyrine), which undergoes hepatic metabolism.
2. E xcretion is diminished in patients with cirrhosis as well as those with acute liver disease.
3. The test has been used to assess prognosis in patients with alcoholic hepatitis and in cirrhotic
patients who are undergoing surgery.
4. A limitation of the aminopyrine breath test is its lack of sensitivity in hepatic dysfunction
resulting from cholestasis or extrahepatic obstruction.
CAFFEINE CLEARANCE
1. Caffeine clearance after oral ingestion can be assessed by measuring levels in either saliva or
serum; the accuracy appears similar to the [14C]aminopyrine breath test, without the need for
a radioisotope.
2. Results are clearly abnormal in clinically severe liver disease, but the test is insensitive in mild
hepatic dysfunction.
3. Caffeine clearance decreases with age or cimetidine use and increases with cigarette
smoking.
GALACTOSE ELIMINATION CAPACITY

1. Galactose clearance from blood as a result of hepatic phosphorylation can be determined
after either intravenous or oral administration; serial serum levels of galactose are ob-
tained 20 to 50 minutes after an intravenous bolus, with correction for urinary galactose
excretion.
2. At plasma concentrations >50 mg/dL, removal of galactose reflects hepatic functional
mass, whereas at concentrations lower than this plasma level, clearance reflects hepatic
blood flow.
3. [14C]galactose is distributed in extracellular water and is affected by changes in volume.
4. Galactose clearance is impaired in acute and chronic liver disease as well as in patients with
metastatic hepatic neoplasms but is typically unaffected in obstructive jaundice.
5. The oral galactose tolerance test incorporates [14C]galactose with measurement of breath
[14C]O2; the results of this breath test correlate with [14C]aminopyrine testing.
6. [14C]galactose testing is no more accurate than standard liver biochemical tests in assessing
prognosis in patients with chronic liver disease.
LIDOCAINE METABOLITE
1. Monoethylglycinexylidide (MEGX), a product of hepatic lidocaine metabolism, is easily
measured by a fluorescence polarization immune assay 15 minutes after administration of an
intravenous dose of lidocaine.
2. The test may offer prognostic information about the likelihood of life-threatening complications
in cirrhotic patients.
3. The test has also been used to assess the viability of donor liver allografts.
4. The test is easy to perform and has few adverse reactions, although it may be unsuitable for
some cardiac patients. Test results may be affected by simultaneous use of certain drugs me-
tabolized by cytochrome P-450 3A4 and high bilirubin levels; test results are affected by age
and body mass index and are higher in men than in women.
Other Tests of Liver Function

SERUM BILE ACIDS
1. Bile acids are synthesized from cholesterol in the liver, conjugated to glycine or taurine, and
excreted in the bile. Bile acids facilitate fat digestion and absorption within the small intestine.
They recycle through the enterohepatic circulation; secondary bile acids form by the action of
intestinal bacteria.
2. Detection of elevated serum bile acid levels is a sensitive marker of hepatobiliary dysfunction.
3. Various methods are available to assay individual and total bile acids; assaying an individual
bile acid is probably as useful as measuring total bile acid concentration.
4. Numerous different bile acid tests have been described, including fasting and postprandial
levels and determination of levels after a bile acid load, either oral or intravenous.
5. Normal bile acid levels in the presence of hyperbilirubinemia suggest hemolysis or Gilbert
syndrome.
UREA SYNTHESIS
1. Hepatic metabolism of nitrogen from protein results in urea production. Urea is distributed in
total body water and is excreted in urine or diffuses into the intestine, where urease-producing
bacteria hydrolyze it to CO2 and ammonia.
2. The rate of urea synthesis can be calculated from the urinary urea excretion and blood urea
nitrogen after estimation of body water, with correction for gastrointestinal hydrolysis of
urea.
3. The rate of urea synthesis is significantly reduced in cirrhosis and correlates with the Child-
Turcotte-Pugh score, although it is insensitive for detection of well-compensated cirrhosis.
BROMSULPHALEIN
Clearance of bromsulphalein (BSP) after an intravenous bolus was formerly used to measure
hepatic function. The most accurate information was obtained by the 45-minute retention test and
initial fractional rate of disappearance. BSP testing fell out of favor because of reports of severe
allergic reactions, lack of accuracy in distinguishing hepatocellular from obstructive jaundice, and
the availability of simpler tests of liver function.
INDOCYANINE GREEN
This dye is removed by the liver after intravenous injection. A blood level can be obtained 20
minutes after administration, or levels can be determined by skin sensors. Compared with BSP,
the hepatic clearance of indocyanine green is more efficient, and it is nontoxic. Its accuracy in
assessing liver dysfunction is no better than standard Child-Turcotte-Pugh scoring. Its major role
had been as a measure of hepatic blood flow.
NONINVASIVE SERUM MARKERS OF FIBROSIS

Various tests have been described to determine the extent of fibrosis in patients with chronic liver
disease, thereby avoiding the need for liver biopsy.
Direct Markers
These markers include serum hyaluronate, procollagen III N-peptide, and matrix metallopro-
teinases. They are generally accurate in confirming cirrhosis and excluding severe liver disease in
patients with minimal fibrosis.
Indirect Markers
Various formulas have been described that incorporate serum markers of fibrosis or routine labo-
ratory tests, such as platelet count, INR, and serum aminotransferases.
■ Examples include FibroSure, Fibrospect, and AST-to-platelet ratio index (APRI).
■ F ibroSure is used most commonly in the United States and includes α2-macroglobulin,
haptoglobin, apolipoprotein A1, bilirubin, and GGTP; it is most useful for excluding fibrosis
(low score) or suggesting cirrhosis (high score); intermediate scores can reflect a varying
degree of fibrosis.
Liver Biopsy
Despite advances in serologic testing and imaging, liver biopsy remains the definitive test in a
number of settings: To confirm the diagnosis of specific liver diseases such as Wilson disease,
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would justify. In this way he contrived to eke out a humble but
respectable subsistence, and after gaining the good will of his
employer by his faithful and honest exertions, he scraped together
sufficient money to enable him to set up an establishment of his own,
where a flaming board proclaimed that Richard Dashall executed
sign, house and chaise painting, in all its varieties, “in the most neat
and expeditious manner possible;” assisted by two or three active
young apprentices in all his handicrafts. In due course of time he
joined to his fortunes a pretty little lady of a wife, and conjointly they
reared up and educated a numerous progeny. So ends the history of
poor Dick Dashall; and it is that of many an honest and industrious
young fellow, who is cast forth like a weed upon the ocean of life, to
sink or to swim as the chance may be.
The Fata Morgana.
Travels, Adventures, and Experiences of Thomas
Trotter.
CHAPTER XIII.
Messina.—Trade of the place.—The Fata Morgana.—Embark for
Naples.—The Sicilian pilot.—The Faro of Messina.—Scylla
and Charybdis.—Exaggerations of the ancient writers.—Fatal
adventure of a Neapolitan diver.
We found Messina quite a lively, bustling place, with a harbor full

of all sorts of Mediterranean craft. Several American vessels lay at
the quay, loading with oranges and lemons for Boston. These fruits
constitute the chief trade of the place, and give employment to a
great part of the population of the city and neighborhood. Every
orange and lemon is carefully wrapped in a paper before being
packed. The paper absorbs the moisture which exudes from the fruit,
and prevents the rotting. Labor, however, is so cheap in this country
that all this preparation adds but little to the cost of the cargoes.
Another article exported is barilla, a sort of alkali, or potash, made by
burning sea-weed. The barilla is used by our manufacturers for
bleaching cotton cloth.
The city is very handsomely built, and has several fine squares,
ornamented with statues and fountains. It has suffered severely from
earthquakes at different times, and was once nearly destroyed; but
its admirable situation for commerce has caused it to be rebuilt after
every catastrophe. It stands just within the narrow strait which
divides Sicily from the Italian coast, and has a very safe harbor,
formed by a strip of land running out into the sea, in the shape of an
elbow, which appears almost the work of art. In the interior, the city is
enclosed by steep, rocky hills, which rise immediately from the walls,
and shut out all prospect of the country; but the view toward the sea
is very grand. The strait is six or eight miles wide in this part, though
in the clear and transparent atmosphere of these regions, it does not
appear to be more than three or four. The mountains of Calabria rise
up majestically from the blue sea, dark, craggy, and frowning, with
now and then a fleecy white cloud melting away on their summits.
Feluccas, with latine sails, are gliding up and down the straits; and
the white walls of Reggio rise from the water’s edge on the opposite
side.
This is the spot on which that remarkable phenomena, called the
Fata Morgana, has been observed. On the Italian side of the strait
the inhabitants are sometimes astonished to behold in the air the
images of castles, towns, palaces, houses, ships, &c. Being unable
to account for these appearances, they ascribe them to magic; and
these airy phantoms are supposed to be the work of a fairy named
Morgana. The true cause is a certain rarefaction of the air, which
brings into view objects far below the horizon; and the phenomena is
not difficult to explain by the principles of optics. This appearance is
not uncommon, near the shore, in all parts of the world. Lighthouses,
towers, ships, &c., appear stretched up to three or four times their
actual height. The sailors call this looming up. None of these
apparitions, however, are so remarkable as the Fata Morgana.
On the 7th of March I went on board an Italian brig bound to
Naples. It was a dead calm by the time we got out of the harbor, so
we drifted back again and dropped anchor. Next morning the calm
continued, and on looking across the water, we saw little specks of
white cloud, hanging motionless on the sides of the mountains,—a
sure sign that no wind was stirring there. The sea was as smooth as
glass, and I expected a long delay; but presently a light breeze came
down the strait. Though this was ahead, we determined to take
advantage of it. We therefore got out the boats and warped out of
the harbor, when we set our sails and beat up the straits to the north.
Italian sailors are not very expert in the nicer arts of seamanship,
and we made very little headway by our tacking. About the middle of
the afternoon we dropped anchor, close to the Sicilian shore. There
was a little village, with a pretty church at the water’s edge. The
coast exhibited low sand-hills, with patches of green soil. After lying
at anchor two or three hours, the wind hauled round, and we set sail
again. About sunset we reached the mouth of the strait, where the
extreme end of Sicily approaches close to the Italian shore. This is
called the Faro of Messina. Here we set the pilot ashore, after an
immense bawling and vociferation, occasioned by a dispute as to the
amount of his fee. The Italians can seldom bargain to the amount of
a shilling, without making a clamor and din as if it were a matter of
life and death. The pilot wanted about twenty cents more than the
captain was willing to pay. They plunged at once into a noisy dispute;
—argued, contradicted, bawled, sputtered, grinned, stamped their
feet, and flourished their arms like a couple of bedlamites. The
sailors took part in the squabble; every ragged rogue put in his oar,
and had something to say, till the hurly-burly became outrageous.
The pilot was a queer looking fellow, with a red cap, tattered
unmentionables, japanned with tar, a beard like a shoebrush, and a
bluff, burly face, all bronzed by the sun, and weather-beaten—in
short, the very picture of an old Triton; and so I called him from the
moment he first met my eyes. I never laughed more heartily than at
the sight of this squabble; but at length they agreed to split the
difference, and old Triton paddled ashore, tolerably well satisfied.
The sun was going down as we passed out the strait. We had but
a small breeze before, but almost in an instant we were assailed by
violent gusts of wind that obliged us to take in our canvass. The
captain pointed toward the rocky shore, and said to me, “There is
Scylla.” I looked in the direction, and saw a huge, craggy rock not far
from the shore, against which the waves were dashing. Here were
Scylla and Charybdis, so famous in classical history, and so terrible
to the mariners of old times. Homer, in his Odyssey, thus describes
them:
“Dire Scylla there a scene of horror forms,
And here Charybdis fills the deep with storms:
When the tide rushes in her rumbling caves,
The rough rock roars, tumultuous boil the waves;
They toss, they foam, a dire confusion raise,
Like waters bubbling o’er a fiery blaze.”
The ancients, who were timid and unskilful in their navigation,
give us exaggerated accounts of the dangers of the sea. Scylla they
imagined to be a horrid monster, who sat on the seashore, and
devoured the crews of such vessels as came within her reach.
Charybdis was a fearful whirlpool, which swallowed up both ships
and men. Very little of this description is true. Scylla is no monster,
but only a steep, craggy rock, which is dangerous enough should a
vessel run against it, but it is so easily seen that none but a very
unskilful navigator need be afraid of it. Charybdis is no whirlpool, but
only a spot where the winds and currents, drawing through the
narrow strait between Italy and Sicily, cause a rough, chopping sea,
with sudden and violent gusts. These, indeed, were great dangers to
the small craft used by the ancients, but American sailors would
laugh at them.
Some writers are of opinion that there was in reality a dangerous
whirlpool in the strait, and that it has been destroyed by one of those
violent earthquakes that have so often shaken the earth and sea in
this quarter. It is my opinion, however, from a view of the coast on
both sides, that no such alteration has taken place, and that the spot
was no more dangerous in ancient times than it is at present. The
marvellous part of the description is owing to the fictions and
exaggerations of the ancient poets. But, at any rate, the water is very
deep in the strait, and, like many other places in different parts of the
world, it has the popular reputation of being bottomless. There was a
man at Messina, famous for his exploits in swimming and diving, like
our “Sam Patch.” He used to dive to immense depths in the water,
and could walk on the bottom of the sea, if we are to believe his own
story, for nobody ever went down with him to ascertain the truth. The
king of Naples tempted him to dive into the gulf of Charybdis, by
throwing a golden cup into the sea. He plunged in after it, but was
not seen again till some days afterwards, when his body was found
on the shore, thirty or forty miles distant.
CHAPTER XIV.
A calm among the Lipari islands.—Manners of the crew.—Stromboli.
—A natural lighthouse.—A gale of wind.—Fright of the crew
and danger of the vessel.—Loss of the topmasts, and narrow
escape from shipwreck.—Arrival at Lipari.
Next morning, as I went on deck, I found the wind had died away,
and left us becalmed among the Lipari islands. We were close to the
island of Stromboli, which looked like the top of a mountain rising out
of the water, with the smoke constantly pouring out at the top. All
these islands are volcanic, and send forth flame and smoke
occasionally, but Stromboli is constantly burning. Notwithstanding
this, there are several thousand inhabitants upon it, who live chiefly
by fishing. They pass a strange life, constantly pent up between fire
and water. All day we lay becalmed, and I amused myself with
looking at these curious islands through a spy-glass, and watching
the odd behavior of the crew. They were picturesque-looking
mortals, as all the Mediterranean sailors are: exceedingly ragged,
noisy, and good-humored. When they were not telling stories, or
cutting capers, they were sure to be eating. Indeed, there was very
little time during the voyage that their jaws were not in motion. The
principal food was bread and vegetables. There was a pile of greens
on the deck nearly as big as a haycock: it was a species of fennel,
which the Italians eat raw. The sailors munched it by handfuls as
they went about their work. There was no meat in all the ship’s
stores, but now and then a mess of fish was served up to the crew.
They drank freely of red wine, but I never saw any one of them
intoxicated.
The calm continued through the day and the following night. After
dark, the summit of Stromboli began to grow red, and all night long it
shot up streams of fire, giving a light that might be seen a great way
off. This island is a natural lighthouse, loftier and more efficient than
any work ever constructed by man. Volcanoes, with all their danger,
are not without their uses.
A little after sunrise, a light breeze sprung up from the north, and
by ten o’clock it blew pretty fresh. This was a head wind again, but
we preferred it to a calm, as we were enabled to make some
progress northward, by tacking. In a few hours, the clouds rose thick
in the northwest, and the wind increased to a gale, with a violent
chopping sea. We took in sail as fast as possible, but nothing could
surpass the confusion and fright of the sailors. They ran fore and aft,
as if out of their wits, and instead of pulling the ropes, did little else
but cross themselves, fall on their knees, and pray to the Virgin Mary.
I began to feel alarmed, though I had seen worse weather than this
—and there was really no danger to the vessel with proper care—
yet, with a crew half frightened to death, any accident might be the
destruction of us all. The captain bawled to the sailors, who paid no
attention to him, but bawled to one another, and cried, “Santissima
Vergine! San Gennaro! Santa Rosolio!” and the names of forty other
saints, male and female. My apprehensions became serious when I
saw matters growing worse, instead of better. The crew did nothing
which they should have done, and the vessel pitched, rolled, and
floundered about, at the mercy of the winds and waves. The gale
came on in harder gusts than ever; the sea dashed over the bows;
and amid the roaring of the storm and the cries of the frightened
wretches around me, I began to think it was all over with us. There
was, however, one savage-looking fellow among the crew, whose
looks gave me some hope: he was a real caitiff in appearance, and
was evidently born to be hanged; therefore I concluded he could
never be drowned.
Meantime, the masts were bending like twigs under the gale; the
rigging was slack and crazy—worse than ever was seen on the
clumsiest wood-thumper in Penobscot Bay. I saw it was impossible
the spars could hold on much longer, unless the wind went down.
Presently the foretopmast snapped short, just above the cap, and
went over the side with an awful crash! The main-topmast followed
almost immediately, and left us little better than a mere hulk. It is
impossible to describe the scene of confusion and terror that
followed. The miserable crew lost all courage and self-possession.
They threw themselves upon their knees, and called upon the saints
to save them. Had they behaved with the least coolness and
discretion in the beginning of the gale, they might have guarded
against this disaster. For my part, I almost gave myself over for lost;
and as to my gallows-looking friend, I am quite certain that he lost for
a time all hopes of dying by a rope. In fact, there was not a man in
the whole crew but would have given his whole ragged wardrobe for
the chance of a dry death. The vessel was now entirely
unmanageable, and fell off with her broadside to the wind. A heavy
sea came rolling on, and how we escaped being thrown on our
beam-ends, I hardly know; but the vessel continued to roll and labor,
with the sea dashing over the deck, to such a degree that I expected
every moment would be our last. By good fortune at length she fell
off still further, and brought her stern to the wind. The crew recovered
from their fright sufficiently to attempt doing something to save their
lives. With great exertions they got the wrecked spars clear, and set
a little sail on the lower masts. By this help we began to scud before
the wind. Having once more the vessel under some control, we
gathered courage; but the gale was as furious as ever, and the sea
increased in violence. We continued to scud for an hour and a half,
when the cry of “terra! terra!” raised by the whole crew, announced
the discovery of land, ahead. Such had been the hurly-burly,
confusion, and terror on board, from the beginning of the gale, that
not a man of the crew could guess where we were, or what land was
in sight. Some thought it was Stromboli, and others imagined it to be
the coast of Sicily. I now began to have more fear of the land than of
the water, and wished for sea-room. Had there been any shoals in
this quarter, we should infallibly have been shipwrecked; but
fortunately there were none, as all the coasts have bold shores.
The land was high and mountainous, and we presently made it
out to be the island of Lipari, about thirty miles from Stromboli. We
steered as close to the island as we dared, and ran under the lee,
where the height of the land broke the force of the gale. In this
shelter we cast anchor, and found ourselves tolerably safe, with the
probability that the gale would blow over in a few hours. I thanked
Heaven for our escape; but formed a resolution never to trust myself
at sea with Italian sailors again, as long as I had any other means of
pursuing my rambles. In the midst of all these dangers, I would have
given more for a couple of Yankee cabin boys than for the whole
twenty lubbers of our valiant crew.
(To be continued.)
THE PILOT.
The curling waves with awful roar
A little boat assailed,
And pallid fear’s distracting power
O’er all on board prevailed,—
Save one, the captain’s darling child,

Who steadfast viewed the storm,
And, fearless, with composure smiled
At danger’s threatening form.
“And fear’st thou not?” a seaman cried,

“While terrors overwhelm?”
“Why should I fear?” the child replied,
“My father’s at the helm.”
Thus when our earthly hopes are reft,

Our earthly comforts gone,
We still have one sure anchor left—
God helps, and He alone.
He to our cries will lend an ear,

He gives our pangs relief,
He turns to smiles each trembling tear,
To joy each torturing grief.
Turn, turn to Him, ’mid sorrows wild,

When terrors overwhelm,
Remembering, like the fearless child,
Our Father’s at the helm.
Merry’s Life and Adventures.
CHAPTER XIII.
Sick-room incidents and reflections.
In my last chapter I concluded the story which Raymond told me,

and which I entitled the “School of Misfortune.” At the time, I
supposed he only related it for my amusement, but I have since
believed that he had a farther design; which was, to show me that
wealth, used to puff up the heart with pride, is a source of positive
evil; and that poverty, sickness, misfortune, humiliation—provided
they make the heart tender toward mankind, and open new springs
of sympathy in the soul—are like kind and gentle schoolmasters,
teaching us the true art of happiness. I believe now, that Raymond
intended to impress this great lesson on my heart, as well because it
is useful to all, as because he probably foresaw approaching events,
in relation to my own circumstances, which might make it specially
needful to me.
There is nothing which more shows the advantages of civilization,
than the care and kindness bestowed upon the sick, among
Christian nations. With savages, the sick person is usually left to
himself, where, like a wild beast, he must await, in solitude, the result
of his disease. There is little sympathy offered to him—there is no
kind hand to wipe the cold sweat from his brow; no watchful friend at
his bedside to supply every want, and alleviate, as far as may be,
every pain. Sickness with the savage is solitary and desolate; with
Christians, though it has its pains, it has its alleviations. I suffered
much during the period of my confinement, as well from my broken
limb as the fever that raged in my veins. After this was past, I also
suffered from excessive languor.
But still, in the midst of all this, and though my mind was pained
with shame and mortification, for the folly which had brought these
evils upon me, I had a sense of peace and happiness shining
through it all. This was wholly derived from the kindness of my
friends. When Raymond sat by my bed, his benignant eye resting
upon me, I felt an indescribable degree of delightful emotion,
composed, I believe, partly of gratitude, and partly of a confidence
that all that could be done, would be done, in my behalf. Often, as I
awoke from my sleep, and saw him patiently watching by me, the
tears would gush to my eyes; but they were not tears of
unhappiness. I think he perceived my emotion, and I believe he
understood my feelings. One thing is certain—that sick-bed was the
best schoolmaster of my life; it brought me Raymond’s wise counsel;
it brought me wholesome shame for my folly; it taught me my
dependence on others. It also taught me one other lesson—and that
is, never to distrust the kindness and virtue of my fellow-men. It
seemed to open a window into the human heart, letting light and
sunshine in, where people are too apt to see nothing but selfishness
and darkness.
This latter lesson was enforced by many circumstances. Not only
was my bosom touched by the kindness of Raymond, but also by
that of my uncle. Twice each day did he come to see me, and he
always treated me with more tenderness than seemed to belong to
his nature. He was a hale man himself, and it was his boast that he
had never had a sick day in his life. Indeed, he had little sympathy
for sickness, and usually expressed himself in terms of contempt
toward everybody that chanced to be less robust than himself. When
I was at the height of my fever, he insisted that all I wanted, in order
to make me well again, was some roast beef and raw brandy! Still,
he did not interfere with the course prescribed by the physician, and
took pains to see that every thing was done for me that was deemed
useful or necessary.
My companions of the village often sent to inquire after me, and
Bill Keeler frequently stole in just to look at me, and say, “God bless
you, Bob!” All these things went to my heart; but nothing affected me
more than an event which I must notice with some detail.
The schoolmaster of the village was one of those men who seek
to accomplish every object by some indirect means. He was what is
called a cunning man, and was, withal, exceedingly fond of power, in
the exercise of which he was capricious, tyrannical and unjust. At
first he treated me with the greatest attention, and in fact picked me
out as one of his favorites, upon whom he lavished his smiles and
his praises. He had great faith in flattery, and believed that any
person, young or old, might be caught by it; and while it seemed to
be his object to propitiate me, he laid it on pretty thick. I was well
enough pleased with this for a time, though I had a sort of distrust of
the man who could condescend to such means, and enter into such
schemes of policy; and even though I yielded to his views, in many
things, I had still no respect for, or confidence in, him.
There was in the school a boy by the name of William Bury, son of
a poor Irishman, that lived in the village. He was remarkably small of
his age, but exceedingly active, and withal lively and intelligent. At
the same time he was shrewd and witty, and, perceiving the weak
points of the schoolmaster’s character, occasionally made them the
target of his wit. As the master rendered each boy in the school a
spy upon his fellows, he knew everything that was said and done;
and poor Bill Bury was often punished for the freedom with which he
indulged his tongue.
In process of time, Will and myself became the antipodes of the
school: I was the favorite, and he the reprobate. Whatever he did
was wrong: whatever I did was right. Under such circumstances, it
was natural that we should be rivals, and it was, no doubt, a part of
the plan of the politic schoolmaster, to keep us thus divided, that he
might rule the more effectually.
During this state of things, several of the school boys were one
day skating upon a river that ran along the western border of the
town—Will and myself being of the number. It had been filled with
heavy rains, and was now of considerable width and depth. In the
deepest part there was a breathing-hole in the ice, which, of course,
we all sought to avoid. As I was swiftly skating toward this place, with
the intention of turning aside as I approached it, one of my skates
struck a small stick, which brought me down, and—carried forward
by the impetus of my course—I was instantly plunged into the
opening of the ice. I sunk beneath the surface of the water for a
moment, but then rose, and caught hold of the ice, which, however,
broke in my hands as I grasped it.
It was but a few seconds before I was completely chilled; but, by
this time, the boys around had raised a shout of terror, and several of
them had gathered at a little distance, and were soon either silent
with dismay, or raising idle screams for help. Among the number I
noticed Bill Bury, and though I had been accustomed to speak lightly
of him, I confess that at that fearful moment my only hope rested in
him. Looking at me intently for a moment, and then casting a
searching glance around, he sped away like an arrow. in the space
of a minute, he returned, bringing a rail which he had plucked from a
neighboring fence. Calling aloud for all around to give place, he laid
the rail down upon the ice, and dexterously slid it across the
opening, pushing it so close as to bring it within my reach. I was,
however, so benumbed, that, in attempting to take hold of it, I lost my
grasp of the ice, and sunk senseless beneath the wave.
Will hesitated not an instant, but plunged into the water, and, as I
rose, he caught me in his arms. Grasping me tight by the right arm,
while he held on to the rail by the left, he supported himself and me;
at the same time he commanded the boys to get two more rails.
These were brought and laid across the opening, and thus support
was furnished for two of them to come and lift us out.
In this way my life was saved: I owed it to the courage, skill, and
devotedness of Will Bury—my rival, and, as I had esteemed him, my
enemy. I was not so base as to overlook his generous conduct, or to
permit the relation in which we stood to abate my praises of his
noble action. But the schoolmaster, being one of those people who
have always a selfish object in everything they say and do, fearing
that his entire system of tactics would be broken up if Will and I
should become friends, took a different course. He indeed praised
Will for an act that no one, it would seem, could fail to admire; but, at
the same time, he sought every occasion, from that day, to ruin him
in my estimation. At the same time he tried, in many cunning and sly
ways, to poison Will’s mind with jealousy of me.
It was not long, therefore, before we were again in antagonist
positions, and at last an open breach took place between us. In
process of time, Will went to learn a trade of a carpenter, at the
distance of a mile or two, and then I seldom saw him. Whenever we
met we did not speak to each other. This was the state of things,
when the accident happened which laid me on a bed of sickness.
While I was recovering, I often thought of Will Bury, and my heart
reproached me keenly for permitting my better feelings to be turned
against him. In short, I yearned to see him, and it was while I was
one day thinking about him, that I saw him come softly to the door
and ask Raymond how I was. I instantly called him to my bedside,
and I never felt a warmer emotion than when he came, and I threw
my arms around his neck. He, too, was much affected, and tears—
the first I ever saw the gay-hearted fellow shed—fell upon my cheek.
From that day we were friends; and I thus learned to put a just value
upon a generous heart—though it may belong to a poor boy.
(To be continued.)
A Little Child’s Joy.
What joy it is, from day to day,
To skip and sing, and dance and play—
To breathe the air, to feel the sun,
And o’er the spangled meadows run.
What joy to move my limbs about,

To hoop and halloo, call and shout,
Among the woods, and feel as free
As any bird upon a tree.
What joy, when hungry, ’tis to eat,

What pleasure in our daily meat;
How sweet, when sleep the eyelids close,
To sink in calm and soft repose.
What joy, as morn begins to break,

Refreshed and vigorous to wake—
To feel, amid the dews and flowers,
New life bestowed on all my powers.
But who bestows this constant joy

On every little girl or boy?
’Tis God, our Father, bright and wise,
Whose goodness every joy supplies.
Then let me love and praise the Lord,

And strive to know his holy Word;
To do no wrong, and think no ill,
And evermore perform his will.
The Mammoth.
In several of the United States persons have frequently found the

bones of a huge animal, called the Mammoth, or Mastodon. One
skeleton, nearly complete, has been found, and set up in Peale’s
Museum, in Philadelphia.
There is no such creature to be found now, on the earth, as a
Mastodon—nor has there been, since the memory of man. It seems
that it must have resembled an Elephant, but was twice as large.
In Siberia, a few years ago, a fisherman discovered the body of a
Mastodon, imbedded in the ice: the skin was nearly entire, and it was
covered with woolly hair. After about two years, this body thawed
out, and fell to the ground from the elevated place in which it was
first discovered. The flesh, as well as skin, gradually disappeared,
but the bones were secured, and being taken to St. Petersburgh, in
Russia, were set up in a museum, where they are still to be seen.
The remains of many other animals, now extinct, are found in
different countries, as well as traces of vegetables, such as are not
met with now on the face of the earth. This is a very interesting
subject, and I propose hereafter to say more about it.

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HANDBOOK OF LIVER DISEASE, FOURTH EDITION ISBN: 978-0-323-47874-8

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Routine Liver Biochemical Tests

■ U nconjugated bilirubin is taken up by the liver by a carrier-mediated process, attaches to

Elevated serum bilirubin

≥15% direct Mostly indirect

Dubin-Johnson Evaluate for

Review medications Hemolytic

SERUM AMINOTRANSFERASES (Table 1.1)

TABLE 1.1 n Causes of Elevated Serum Aminotransferase Levelsa

Mild Elevation (<5× normal) Marked Elevation (>15× normal)

Hepatic: ALT predominant Acute viral hepatitis (A–E, herpes)

History and physical

Obesity, diabetes mellitus,

Risk factors for viral Serologic tests for viral

Autoimmune features Serum IgG level, ANA, SMA

■ M ild-to-moderate elevations of aminotransferase levels are typical of chronic viral hepatitis,

SERUM ALKALINE PHOSPHATASE

History and physical examination

Gallstones Cholecystectomy and

Liver biopsy Colonoscopy

■ V itamin K deficiency as the cause of a prolonged prothrombin time can be excluded

Assessment of Hepatic Metabolic Capacity

AMINOPYRINE BREATH TEST

GALACTOSE ELIMINATION CAPACITY

Other Tests of Liver Function

NONINVASIVE SERUM MARKERS OF FIBROSIS

We found Messina quite a lively, bustling place, with a harbor full

Save one, the captain’s darling child,

“And fear’st thou not?” a seaman cried,

Thus when our earthly hopes are reft,

HANDBOOK OF LIVER DISEASE, FOURTH EDITION ISBN: 978-0-323-47874-8

■ U nconjugated bilirubin is taken up by the liver by a carrier-mediated process, attaches to

TABLE 1.1 n Causes of Elevated Serum Aminotransferase Levelsa

■ M ild-to-moderate elevations of aminotransferase levels are typical of chronic viral hepatitis,

■ V itamin K deficiency as the cause of a prolonged prothrombin time can be excluded