Schiff's Diseases of the Liver [12 ed.] 9781119251224

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Schiff’s Diseases of the Liver

We dedicate the twelfth edition of Schiff’s Diseases of the Liver to Dr. Thomas Starzl, the inspired and inspiring pioneer in the field of liver transplantation. Dr. Starzl influenced generations of hepatologists over his long and productive career, during which his work led to the development of successful liver replacement. Dr. Starzl taught, challenged, and inspired surgeons and hepatologists while opening and advancing the field of liver transplantation against many obstacles. His brilliance and tenacity brought liver transplantation from concept to reality. As a consequence of his efforts, hope and productive lives were restored to legions of patients. The editors are among the many who now view the world of hepatology with renewed hope based on an effective treatment for hitherto unapproachable problems. We further dedicate this edition to our wives Dana, Ann, and Vanaja for their continuing support of our endeavors.

Schiff’s Diseases of the Liver TWELFTH EDITION EDITED BY

Eugene R. Schiff University of Miami, Schiff Center for Liver Diseases, Miami, FL, USA

Willis C. Maddrey University of Texas Southwestern Medical Center, Dallas, TX, USA

K. Rajender Reddy Hospital of University of Pennsylvania, Philadelphia, PA, USA

This edition first published 2018 © 2018 John Wiley & Sons Ltd. Edition History John Wiley & Sons Ltd. (11e 2012). Previous editions: LippincottWilliams & Wilkins. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Eugene R. Schiff, Willis C. Maddrey, and K. Rajender Reddy to be identified as the author(s) of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. A catalogue record for this book is available from the Library of Congress and the British Library. ISBN 9781119251224 Cover image: © ilbusca/Gettyimages Cover design by Wiley Set in 9.5/12pt Palatino LTStd by Aptara Inc., New Delhi, India

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Contents

Contributors, viii Foreword, xiii

9 The Liver in Pregnancy, 244

Nancy Reau and Yannick Bacq

Preface, xiv

Part III Consequences of Liver Disease

About the Companion Website, xvi

10 Hepatic Fibrosis, 271

Scott L. Friedman

Part I Overview: Clinical Fundamentals of Hepatology 1 History Taking and Physical Examination for

the Patient with Liver Disease, 3 Esperance A. Schaefer and Lawrence S. Friedman 2 Laboratory Tests, Noninvasive Markers of

Fibrosis, Liver Biopsy, and Laparoscopy, 17 Michael P. Curry and Lennox J. Jeffers 3 Noninvasive and Invasive Imaging

of the Liver and Biliary Tract, 38 Koushik K. Das, Matthew A. Morgan, and Gregory G. Ginsberg

Part II General Considerations 4 Physioanatomic Considerations, 73

Ian R. Wanless 5 Bilirubin Metabolism and Jaundice, 103

Allan W. Wolkoff and Paul D. Berk 6 Hepatic Histopathology, 135

Zachary D. Goodman

11 Preoperative Evaluation of the Patient with

Liver Disease, 290 Patrick S. Kamath and Mark T. Keegan 12 Management of Portal Hypertension, 304

Guadalupe Garcia-Tsao and Juan G. Abraldes 13 Renal Complications of Liver Disease and the

Hepatorenal Syndrome, 336 Xingxing S. Cheng and W. Ray Kim 14 Pulmonary Manifestations of Liver Disease, 353

Michael B. Fallon and Anil Seetharam 15 Ascites and Spontaneous Bacterial Peritonitis, 365

Vicente Arroyo and Javier Fern´andez 16 Hepatic Encephalopathy, 387

Chathur Acharya and Jasmohan S. Bajaj 17 Acute Liver Failure, 411

Robert J. Fontana and Khurram Bari 18 Acute-on-Chronic Liver Failure, 432

Florence Wong 19 Malnutrition and Liver Disease, 460

Craig McClain, Irina Kirpich, and Laura Smart

7 Mechanisms of Liver Injury, 200

Harmeet Malhi and Gregory J. Gores 8 Hepatic Manifestations of Systemic Disorders, 218

Stuart C. Gordon and Humberto C. Gonzalez

Part IV Cholestatic Disorders 20 Primary Sclerosing Cholangitis, 491

John M. Vierling

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Contents

21 Primary Biliary Cholangitis, 523

Cynthia Levy, Andres F. Carrion, and Marlyn J. Mayo 22 Autoimmune Hepatitis, 546

34 The Liver in Circulatory Failure, 935

Santiago J. Munoz, Hanisha R. Manickavasagan, and Idean Amirjazil

Gideon M. Hirschfield and Gwilym J. Webb

Part V Viral Hepatitis 23 Hepatitis A and E, 565

Kenneth E. Sherman and Shyam Kottilil 24 Hepatitis B and D, 584

Marc G. Ghany and Naveen Gara 25 Hepatitis C, 628

Michael W. Fried, Jama M. Darling, and Stanley M. Lemon

Part VI Alcohol- and Drug-induced Liver Disease 26 Alcoholic Liver Disease, 701

Mack C. Mitchell and Gyongyi Szabo 27 Drug-induced Hepatotoxicity, 740

Dominique Larrey, Jose Ursic-Bedoya, and Lucy Meunier 28 Mechanisms of Drug-induced Liver Injury, 774

Part IX Benign and Malignant Tumors; Cystic Disorders 35 Benign Tumors, Nodules, and Cystic Diseases

of the Liver, 949 Julien Calderaro and Jessica Zucman-Rossi 36 Hepatocellular Carcinoma, 977

Maddie Kubiliun and Jorge A. Marrero 37 Surgical Options in Liver Cancers, 989

Garrett R. Roll and John Paul Roberts

Part X Infectious and Granulomatous Disease 38 Amoebic and Pyogenic Liver Abscesses, 1005

Marco A. Olivera-Mart´ınez and David Kershenobich 39 Parasitic Diseases, 1013

Michael A. Dunn 40 Granulomas of the Liver, 1028

James H. Lewis

Paul B. Watkins and Merrie Mosedale

Part VII Genetic and Metabolic Disease 29 Wilson Disease, 801

Michael L. Schilsky and Aftab Ala 30 Hemochromatosis and Iron Storage Disorders, 820

Kris V. Kowdley and Priya Handa 31 Alpha-1 Antitrypsin Deficiency, 843

David H. Perlmutter 32 Nonalcoholic Fatty Liver Disease, 867

Curtis K. Argo, Zachary H. Henry, and Stephen H. Caldwell

Part VIII Vascular Diseases of the Liver 33 Vascular Liver Disease, 911

Dominique-Charles Valla

Part XI Elements of Liver Transplantation 41 Selection of Candidates and Timing of Liver

Transplantation, 1055 Meaghan Phipps, Alyson N. Fox, and Robert S. Brown Jr. 42 Immunosuppression: The Global Picture, 1065

Caroline C. Jadlowiec, Timucin Taner, and Russell H. Wiesner 43 The First Six Months Following Liver

Transplantation, 1079 K. Rajender Reddy and Manuel Mendizabal 44 Long-term Management of the Liver

Transplant Patient, 1093 Timothy M. McCashland 45 The Liver Transplant Procedure, 1107

Bijan Eghtesad, Koji Hashimoto, and John Fung

Contents 46 Recurrent Disease Following Liver

Transplantation, 1127 Haripriya Maddur and Josh Levitsky 47 The Role of Retransplantation, 1143

Peter L. Abt and Kim M. Olthoff

48 Controversies in Liver Transplantation, 1156

James F. Trotter Index, 1169

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viii

Contributors

Juan G. Abraldes

Curtis K. Argo

Robert S. Brown, Jr.

MD, MMSc Department of Medicine Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit) University of Alberta, CEGIIR Edmonton, Canada

MD, MS GI/Hepatology Department of Internal Medicine University of Virginia Health System Charlottesville, VA, USA

MD, MPH Center for Liver Disease and Transplantation Weill Cornell Medical College New York, NY, USA

Julien Calderaro Vicente Arroyo

Peter L. Abt MD Department of Surgery Division of Transplant Surgery The Hospital of the University of Pennsylvania Philadelphia, PA, USA

MD, PhD Liver Unit, Hospital Clinic IDIBAPS University of Barcelona, Spain; CIBEREHED, Spain; and EF Clif, Barcelona, Spain

MD, PhD Department of Pathology Henri Mondor University Hospital, and INSERM U955, Team 18 Institut Mondor de Recherche Biom´edicale, and Universit´e Paris-Est Cr´eteil Cr´eteil, France

Yannick Bacq Chathur Acharya MD Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and McGuire VA Medical Center Richmond, VA, USA

Aftab Ala MD, PhD, FRCP Department of Gastroenterology and Hepatology Royal Surrey County Hospital NHS Foundation Trust Guildford, Surrey, UK, and Department of Clinical and Experimental Medicine School of Biosciences and Medicine University of Surrey, Guildford, Surrey, UK

Idean Amirjazil MD Department of Medicine Hahnemann University Hospital and Drexel University College of Medicine Philadelphia, PA, USA

MD Department of Hepatogastroenterology Centre Hospitalier de Tours ˆ Hopital Trousseau Tours, France

Stephen H. Caldwell MD GI/Hepatology Department of Internal Medicine University of Virginia Health System Charlottesville, VA, USA

Jasmohan S. Bajaj MD, MS Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and McGuire VA Medical Center Richmond, VA, USA

Andres F. Carrion MD Division of Gastroenterology and Hepatology Paul L. Foster School of Medicine Texas Tech University Health Sciences Center El Paso, TX, USA

Khurram Bari

Xingxing S. Cheng

MD Department of Internal Medicine University of Cincinnati School of Medicine Cincinnati, OH, USA

MD, MS Division of Nephrology Department of Medicine Stanford University Stanford, CA, USA

Paul D. Berk MD Division of Digestive & Liver Diseases Columbia University Medical Center New York, NY, USA

Michael P. Curry MD Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA, USA

Contributors

Jama M. Darling

Lawrence S. Friedman

Zachary D. Goodman

MD University of North Carolina at Chapel Hill Chapel Hill, NC, USA

MD Harvard Medical School Tufts University School of Medicine Department of Medicine, Newton-Wellesley Hospital, and Massachusetts General Hospital Newton and Boston, MA, USA

MD, PhD Center for Liver Diseases Inova Fairfax Hospital Falls Church, VA, USA

Koushik K. Das MD Division of Gastroenterology Department of Medicine Washington University School of Medicine St. Louis, MO, USA

Michael A. Dunn MD Division of Gastroenterology, Hepatology and Nutrition and the Liver Center University of Pittsburgh Pittsburgh, PA, USA

Scott L. Friedman MD Icahn Sinai School of Medicine at Mount Sinai New York, NY, USA

John Fung MD Department of Surgery The University of Chicago Chicago, IL, USA

Bijan Eghtesad MD Department of General Surgery The Cleveland Clinic Cleveland, OH, USA

Naveen Gara MD Department of Gastroenterology Mayo Clinic Health System Mankato, MN, USA

Michael B. Fallon MD Division of Gastroenterology, Transplant and Advanced Liver Disease University of Arizona College of Medicine Phoenix, AZ, USA

´ Javier Fernandez MD, PhD Liver Unit, Hospital Clinic IDIBAPS University of Barcelona, Spain; CIBEREHED, Spain; and EF Clif, Barcelona, Spain

Robert J. Fontana MD Department of Internal Medicine University of Michigan Medical School Ann Arbor, MI, USA

Alyson N. Fox MD, MSCE Center for Liver Disease and Transplantation Columbia University Medical Center New York, NY, USA

Michael W. Fried MD University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Guadalupe Garcia-Tsao MD Department of Internal Medicine, Section of Digestive Diseases Yale University New Haven, CT, USA and Department of Medicine VA-CT Healthcare System West Haven, CT, USA

ix

Stuart C. Gordon MD Division of Hepatology Henry Ford Hospital Detroit, MI, USA

Gregory J. Gores MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

Priya Handa PhD Organ Care Research and Liver Care Network Swedish Medical Center Seattle, WA, USA

Koji Hashimoto MD Department of General Surgery The Cleveland Clinic Cleveland, OH, USA

Zachary H. Henry MD, MS GI/Hepatology Department of Internal Medicine University of Virginia Health System Charlottesville, VA, USA

Marc G. Ghany MD, MHSc Liver Diseases Branch National Institute of Diabetes, Digestive and Kidney Diseases National Institutes of Health Bethesda, MD, USA

Gideon M Hirschfield MA, MB, BChir, PhD, FRCP Centre for Liver Research and National Institute for Health Research Birmingham Liver Biomedical Research Unit University of Birmingham Birmingham, UK

Gregory G. Ginsberg MD Division of Gastroenterology Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

Caroline C. Jadlowiec MD Division of Transplant Surgery, Department of Surgery William J. von Liebig Transplantation Center Mayo Clinic Rochester, MN, USA

Humberto C. Gonzalez MD Department of Transplant Surgery Methodist University Hospital University of Tennessee Health Science Center Memphis, TN, USA

Lennox J. Jeffers MD Hepatology Section Miami Veterans Affairs Medical Center and University of Miami Leonard School of Medicine Miami, FL, USA

x

Contributors

Patrick S. Kamath

Stanley M. Lemon

Timothy M. McCashland

MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

MD University of North Carolina at Chapel Hill Chapel Hill, NC, USA

MD Department of Hepatology University of Nebraska Medical Center Nebraska Medical Center Omaha, NE, USA

Josh Levitsky Mark T. Keegan MB, MRCPI, MSc, D.ABA Department of Anesthesiology Division of Critical Care Mayo Clinic College of Medicine Rochester, MN, USA

MD, MS, FAASLD, FAST Professor of Medicine Division of Gastroenterology and Hepatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

David Kershenobich

Cynthia Levy

MD, PhD Instituto Nacional de Ciencias M´edicas y ´ Salvador Zubir´an Nutricion M´exico City, M´exico

MD, AGAF, FAASLD Division of Hepatology Schiff Center for Liver Diseases University of Miami Miller School of Medicine Miami, FL, USA

W. Ray Kim MD, MS, MBA Division of Gastroenterology & Hepatology Department of Medicine Stanford University Stanford, CA, USA

James H. Lewis

Irina Kirpich

Haripriya Maddur

PhD Departments of Medicine and Pharmacology and Toxicology University of Louisville Louisville, KY, USA

Shyam Kottilil MD, PhD Institute of Human Virology University of Maryland School of Medicine Baltimore, MD, USA

Kris V. Kowdley MD Organ Care Research and Liver Care Network Swedish Medical Center Seattle, WA, USA

MD Department of Hepatology Georgetown University Medical Center Washington, DC, USA

MD Division of Gastroenterology and Hepatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Harmeet Malhi MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

Hanisha R. Manickavasagan MD Department of Medicine Hahnemann University Hospital and Drexel University College of Medicine Philadelphia, PA, USA

Maddie Kubiliun MD Division of Digestive and Liver Disease University of Texas Southwestern Medical Center Dallas, TX, USA

Jorge A. Marrero MD, MS Division of Digestive and Liver Disease University of Texas Southwestern Medical Center Dallas, TX, USA

Dominique Larrey MD, PhD Liver and Transplantation Unit Montpellier School of Medicine and IRB-INSERM-1183 Montpellier, France

Marlyn J. Mayo MD Division of Digestive and Liver Diseases University of Texas Southwestern Dallas, TX, USA

Craig McClain MD Departments of Medicine and Pharmacology and Toxicology University of Louisville and Robley Rex Veterans Administration Medical Center Louisville, KY, USA

Manuel Mendizabal MD Hepatology and Liver Transplant Unit Hospital Universitario Austral Pilar, Provincia de Buenos Aires, Argentina

Lucy Meunier MD Liver and Transplantation Unit Montpellier School of Medicine and IRB-INSERM-1183 Montpellier, France

Mack C. Mitchell MD, FAASLD University of Texas Southwestern Medical Center Dallas, TX, USA

Matthew A. Morgan MD Department of Radiology Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

Merrie Mosedale PhD Institute for Drug Safety Sciences Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy Chapel Hill, NC, USA

Santiago J. Munoz MD, FACP, FACG, FAASLD Department of Medicine and Liver Failure Unit Hahnemann University Hospital and Drexel University College of Medicine Philadelphia, PA, USA

Contributors

Marco A. Olivera-Mart´ınez

Esperance A. Schaefer

Jose Ursic-Bedoya

MD, FACP Department of Internal Medicine Section of Gastroenterology & Hepatology University of Nebraska Medical Center Omaha, NE, USA

MD, MPH Harvard Medical School and Gastrointestinal Unit Massachusetts General Hospital Boston, MA, USA

MD Liver and Transplantation Unit Montpellier School of Medicine and IRB-INSERM-1183 Montpellier, France

Kim M. Olthoff

Michael L. Schilsky

Dominique-Charles Valla

MD Department of Surgery Division of Transplant Surgery The Hospital of the University of Pennsylvania Philadelphia, PA, USA

MD, FAASLD Departments of Medicine and Surgery, Sections of Digestive Diseases, Transplant and Immunology Yale New Haven Transplant Center Yale University Medical Center New Haven, CT, USA

MD University Paris-Diderot and Inserm UMR1149 Paris, France, and DHU UNITY and Centre National de R´ef´erence Maladies Rares – Maladies Vasculaires du Foie Service d’h´epatologie ˆ Hopital Beaujon, APHP Clichy-la-Garenne, France

David H. Perlmutter MD Washington University School of Medicine St Louis, MO, USA

Meaghan Phipps MD Columbia University Medical Center New York, NY, USA

Nancy Reau MD Section of Hepatology, Solid Organ Transplantation Rush University Medical Center Chicago, IL, USA

K. Rajender Reddy MD Division of Gastroenterology/Hepatology Department of Medicine University of Pennsylvania Philadelphia, PA, USA

John P. Roberts MD, FACS Division of Transplant Surgery University of California San Francisco San Francisco, CA, USA

Garrett R. Roll MD, FACS Department of Surgery Division of Transplant University of California San Francisco San Francisco, CA, USA

Anil Seetharam MD Division of Gastroenterology, Transplant and Advanced Liver Disease University of Arizona College of Medicine Phoenix, AZ, USA

Kenneth E. Sherman MD, PhD Department of Internal Medicine Division of Digestive Diseases University of Cincinnati College of Medicine Cincinnati, OH, USA

xi

John M. Vierling MD, FACP, FAASLD Baylor College of Medicine Baylor-St. Luke’s Medical Center Houston, TX, USA

Ian R. Wanless MD, CM, FRCPC Department of Pathology Dalhousie University Halifax, Nova Scotia, Canada

Laura Smart MD Department of Medicine University of Louisville Louisville, KY, USA

Gyongyi Szabo MD, PhD Department of Medicine University of Massachusetts Medical School Worcester, MA, USA

Timucin Taner MD, PhD Division of Transplant Surgery, Department of Surgery William J. von Liebig Transplantation Center Mayo Clinic Rochester, MN, USA

James F. Trotter MD Baylor University Medical Center Dallas, TX, USA

Paul B. Watkins MD Institute for Drug Safety Sciences Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy Chapel Hill, NC, USA

Gwilym J Webb MA, BM, BCh, MRCP Centre for Liver Research and National Institute for Health Research Birmingham Liver Biomedical Research Unit University of Birmingham Birmingham, UK

Russell H. Wiesner MD Department of Gastroenterology and Hepatology William J. von Liebig Transplantation Center Mayo Clinic Rochester, MN, USA

xii

Contributors

Allan W. Wolkoff

Florence Wong

Jessica Zucman-Rossi

MD Marion Bessin Liver Research Center Division of Gastroenterology and Liver Diseases Albert Einstein College of Medicine Bronx, NY, USA

MBBS, MD, FRACP, FRCPC Department of Medicine Division of Gastroenterology Toronto General Hospital University Health Network University of Toronto Ontario, Canada

MD, PhD INSERM UMR1162 G´enomique fonctionelle des tumeurs solides, and Universit´e Paris Descartes Labex Immuno-Oncology Sorbonne Paris Cit´e Facult´e de M´edecine Paris, France

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Foreword

Liver science and the clinical care of the liver patient is a rapidly evolving and exciting time of progress and change. Clinicians of all stripes are confronted by the challenges of staying abreast of new physiologic/molecular/cell concepts of disease while simultaneously remaining current with advances in diagnostic and treatment modalities. The liver literature is vast, rich in the variety of publications including general specialty journals, specialized research journals, review journals and a host of giveaway publications, sponsored by pharmaceutical companies. What is the busy clinician, trainee, and medical student to do? The answer often is to resort to online electronic media. This approach provides instant answers but is often lacking in the background and understanding of the basis for the answer provided. To flesh out the underlying scientific basis and to add background, scrutiny as well as perspective is the role of a comprehensive and thoughtfully curated textbook. This new twelfth edition of Schiff’s Diseases of the Liver continues its traditional role as the authoritative textbook of the liver. It is comprehensive, fact based, and uniquely timely. Each section, when appropriate, provides biochemical and physiologic background and indepth perspective of advances since the last edition. This approach lends authority to conclusions advanced by the authors and is relevant to all readers, including students, trainees, and practicing clinicians. The twelfth edition has been extensively revised, with 25 of the 48 chapters written by new authors. Two chapters have been deleted from prior editions and two new chapters added on mechanisms of drug-induced liver injury and on acute and chronic liver failure. All of the authors chosen are established and respected leaders in their field. Similar to previous editions of Schiff’s textbook, the chapters are organized thematically. The initial Overview section tackles the often-neglected aspects of history

taking and physical examination, followed by integrative chapters on laboratory tests and imaging modalities. The following section, labeled General Considerations, includes basic information and specific considerations including masterful chapters on liver histopathology and mechanisms of liver injury. The section that follows, Consequences of Liver Disease, covers portal hypertension, renal complications, pulmonary manifestation, acute liver failure, and hepatic encephalopathy. Subsequent chapters comprise specific groups of diseases, such as the cholestatic disorders, alcohol- and drug-induced liver injury, genetic and metabolic disease, and a compressive update on the viral hepatitis disorders. The paradigm in shift in treatment of hepatitis C since the advent of direct-acting antiviral agents is dramatic. The resultant cure of the majority of patients treated is extraordinary, in addition to the important public health and economic implications. Reflecting its importance in the therapeutic arsenal of hepatology, the last section, Elements of Liver Transplantation, is in actuality a mini-textbook of liver transplantation that encompasses the fundamental elements essential in caring for the transplanted patient. Rapid advances in liver science and new developments in the diagnostic approach and therapeutic care of the liver patient pose new challenges for the clinician at whatever his or her stage of life. The new twelfth edition of Schiff’s Diseases of the Liver serves as an authoritative resource. It provides a deep understanding of liver physiology and molecular/genetic background that segues seamlessly into an erudite discussion of each individual disease entity. Michael F. Sorrell MD Distinguished Professor of Medicine University of Nebraska, Omaha, NE, USA

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Preface

The twelfth edition of Schiff’s Diseases of the Liver continues to chronicle the major scientific advances in pathogenesis, diagnosis, management, treatment, and in some instances cure of hepatobiliary disorders. The rapid rollout of innovation has led to the decision that this edition will be accompanied by a subsequently expanded electronic program in order to bridge the gap of evolving knowledge until the next edition. The spectrum of liver disease is changing. The gratifying spectacular cure rates now available for hepatitis C have had major impacts on the practice of hepatology. Widespread instruction of treatment with the newer agents should markedly reduce the number of patients who progress to advanced cirrhosis, and likely will lead to a reduction in hepatocellular carcinoma, as well the need for liver transplantation. Unfortunately, hepatitis C virus vaccines are not anticipated to be available in the near future and development of effective vaccines is a major goal. It is apparent to all hepatologists that nonalcoholic steatohepatitis worldwide has come to the fore as a prominent liver disease that leads to cirrhosis and hepatocellular carcinoma. The challenges are to develop safe and effective therapies to curtail the progression of nonalcoholic steatohepatitis and hopefully reverse necroinflammation and fibrosis. Recognition of the earlier stages of steatohepatitis should provide a better therapeutic opportunity to prevent cirrhosis. Many of the cases of acute liver failure have been found to be a result of acute-on-chronic liver disease, which highlights the importance of preventing superimposed hepatic injury in patients with advanced liver disease of any etiology. Specific biomarkers are emerging which provide more accurate diagnostic and prognostic serologic parameters.

Implementation of universal vaccination for hepatitis B virus (HBV) continues throughout the world; however a definitive cure for HBV infection remains elusive. An ongoing research focus in chronic hepatitis B is to develop ways to eliminate covalently closed circular DNA and thereby block HBV integration. Prevention of reactivation of HBV in a patient receiving immunosuppressants and chemotherapy and the development of more effective HBV treatments have become areas of great interest. Liver transplantation has become a major life-saving procedure for patients who have progressive liver disease and for a minority who have acute liver failure. Surgical techniques are well advanced and live donor liver transplantation presents a life-saving option, albeit for a minority of patients. Organ allocation has been modified and is well served with the model for end-stage liver disease (MELD) score while we continue to work on optimizing immunosuppression regimens and develop new approaches to improve upon them. Aggressive monitoring of patients with cirrhosis allows early identification of hepatocellular carcinoma and increasingly effective therapies (medical and surgical) hopefully will reduce mortality from hepatocellular carcinoma. For those patients who are not candidates for ablation surgery or transplantation, more effective chemotherapeutic approaches, particularly those that relate to regulation of immune responses, is promising. Translational research focusing on inflammation and fibrosis is well under way with the hope of stopping and reversing hepatobiliary fibrosis regardless of etiology. Genomic and proteomic advances will likely better define hepatobiliary diseases and identify targets for therapy. The role of microbiomes and stem cell therapy are quickly evolving. These are only a few of the exciting advances in modern hepatology. Progress is being

Preface

achieved on many fronts. We remember the words of Leon Schiff that “fifty percent of what we say today will be wrong in ten years if we only knew which fifty percent.” Our task is to identify the 50% that will have lasting value. We would like to thank Dr. Nik Prowse, our freelance project manager, who was instrumental in facilitating the publication of this edition.

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It has been an honor and a privilege for us to participate in the creation and editing of Diseases of the Liver. Eugene R. Schiff Willis C. Maddrey K. Rajender Reddy April 2017

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About the Companion Website

Purchasing this book entitles you to access to the companion website: www.wiley.com/go/schiffsdiseasesoftheliver The website includes:

r Supplementary interactive multiple choice questions r PowerPoint slides of all figures from the book for downloading

PA R T I

Overview: Clinical Fundamentals of Hepatology

3

CHAPTER 1

History Taking and Physical Examination for the Patient with Liver Disease Esperance A. Schaefer1 & Lawrence S. Friedman2 1

Harvard Medical School and Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Tufts University School of Medicine, Department of Medicine, Newton-Wellesley Hospital, and Massachusetts General Hospital, Newton and Boston, MA, USA

2

Key concepts r The history and physical examination may provide clues to the r

r

r

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presence of liver disease in a person thought to be healthy. In a patient undergoing evaluation for liver disease, the history and physical examination help determine the underlying cause of liver injury, presence or absence of advanced hepatic fibrosis, and evidence of clinical complications of cirrhosis and portal hypertension. Common causes of liver injury in patients with liver disease of unknown cause include nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, hepatitis C, and drug-induced liver injury. The patient should be assessed carefully for excessive alcohol intake, new medication or herbal and dietary supplement use, risk factors for hepatitis C, and evidence of metabolic syndrome. In a patient with known liver disease, clinical evaluation for advanced hepatic fibrosis has particular importance, because one third of patients who present for an outpatient hepatology evaluation already have underlying cirrhosis. The skin examination is helpful when assessing a patient for advanced hepatic fibrosis; Terry’s nails, spider telangiectasias,

The liver is an organ with a broad set of critical biologic functions, a unique dual vascular supply, and several distinct cell types that contribute to its physiologic functions as well as potential pathology. Most of the key functions of the liver are carried out by the hepatocytes, which are the most abundant cell type in the liver. Hepatocytes are responsible for drug detoxification, protein synthesis (including albumin and coagulation factors), excretion of bile for digestion, and synthesis of cholesterol and fatty acids. Injury to hepatocytes and the pursuant inflammation may occur from a toxin-mediated insult such as alcohol or medications, lipotoxicity as seen in fatty liver, infectious causes such as viral hepatitis, or autoimmunity. Stellate cells are less abundant, comprising only about 5%

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decreased body hair, gynecomastia, and palmar erythema are associated with cirrhosis with a specificity of 89–97%. Assessment of liver span, tenderness, and contour provides important clinical information. Liver span is best assessed by percussion or the “scratch test.” In general, the normal liver span is less than 12 cm in the midclavicular line, and the edge is smooth and nontender. For the patient with established cirrhosis, careful attention should be paid to vital signs. A reduced mean arterial pressure is associated with renal impairment, particularly when the mean arterial pressure drops below 82 mmHg. Weight gain raises concern for the development of fluid retention and ascites, and weight loss may be associated with malnutrition or malignancy. Ascites may be suspected on physical examination by the detection of flank dullness, bulging flanks, shifting dullness, and a fluid wave. Flank dullness and bulging flanks have a sensitivity of at least 80% but a specificity of only 59% for detecting ascites.

of parenchymal cells and, in health, are the primary site of vitamin A storage. In the setting of chronic inflammation, however, stellate cells are responsible for the deposition of extracellular matrix that leads to cirrhosis. The process of progressive hepatic fibrosis, in general, proceeds over a timeframe of years to decades. This slow progression allows effective intervention if liver disease is identified and treated early in its clinical course. Unfortunately, chronic liver injury is often asymptomatic, and symptoms and signs may not manifest until advanced fibrosis or decompensated liver disease has ensued. In the evaluation of a patient with liver disease, the focus of history taking and the physical examination will be guided by the reason for which the patient has

Schiff’s Diseases of the Liver, Twelfth Edition. Edited by Eugene R. Schiff, Willis C. Maddrey and K. Rajender Reddy. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/schiffsdiseasesoftheliver

4

Part I: Overview: Clinical Fundamentals of Hepatology

presented and has been referred for consultation. Common reasons for referral to a hepatologist include elevated liver biochemical test levels, abnormal serologic test results, jaundice, known chronic liver disease, or evidence of decompensated liver disease. For all of these clinical scenarios, specific historical elements and physical examination findings may provide important insights into the ongoing disease process. In general, the clinician seeks, through history taking and physical examination, to determine the (i) etiology of liver injury, (ii) presence or absence of advanced hepatic fibrosis, and (iii) existence of clinical complications of cirrhosis and portal hypertension. The clinical objectives are to identify the cause of injury and address it early in the disease course to prevent development of advanced hepatic fibrosis, and, if cirrhosis is already present, to monitor the patient carefully for complications of end-stage liver disease.

Abnormal liver biochemical test levels or known liver disease History taking Acute and chronic liver injury has a broad spectrum of clinical presentations, and patients present to medical attention for a wide variety of reasons. Many patients are completely asymptomatic and come to medical attention after a routine physical examination or life insurance testing has demonstrated elevated liver biochemical test levels. Others, particularly those with acute hepatitis, may present with abdominal pain, nausea and vomiting, fever, or jaundice. The duration of liver injury, particularly in the absence of symptoms, is not always certain. Clues such as the time of onset of symptoms, prior normal test results, and the presence of potential risk factors may help differentiate acute injury from chronic liver disease. When evaluating a patient with abnormal serologic test results or a known history of a specific liver disease, the focus of history taking and the physical examination is both to provide clues toward the underlying etiology of liver injury (if unknown) and to assess the patient for clinical evidence of advanced hepatic fibrosis. Central to this objective is an understanding of the most common causes of liver injury and chronic liver disease. A cohort of 1040 patients in the Chronic Liver Disease Network (between the years 1999 and 2001) found that 91% of persons in the cohort had liver injury related to one of the diseases listed in Table 1.1 [1]. In a smaller cohort examined at a single center in the United Kingdom, the most common diagnoses that prompted an outpatient hepatology referral were nonalcoholic fatty liver disease (NAFLD, 29.5%), chronic hepatitis C (17.5%), alcoholic liver disease (17.5%), unspecified hepatitis (7.5%), and drug-induced liver injury (DILI, 4%). Other causes, such as Wilson

disease, α1 -antitrypsin deficiency, and congestive hepatopathy, each accounted for 40 years old Metabolic syndrome Diabetes mellitus Injection drug use High-risk sexual activity Country of birth Female gender Fatigue Pruritus History of osteoporosis History of autoimmune disease Family history of cirrhosis Diabetes mellitus Arthralgias

Pertinent physical examination findings Scarring from injection drug use Purpura Porphyria cutanea tarda Dupuytren’s contractures

BMI >29.9 Increased waist-hip ratio —

Xanthelasma and xanthomas Skin excoriations Melanosis

Skin hyperpigmentation

Primary sclerosing cholangitis

Bloody diarrhea History of inflammatory bowel disease Pruritus

Erythema nodosum

Autoimmune hepatitis

Arthralgias History of autoimmune disease

—

Drug-induced liver disease

Use of prescription drugs, herbal or dietary supplements, or over-the-counter medications

—

Celiac disease

Altered bowel habits Iron deficiency Rash

Dermatitis herpetiformis

AUDIT-C, Alcohol Use Disorders Identification Test; BMI, body mass index. Data from [1].

Risk factors for viral hepatitis should also be identified. The most common risk factors for hepatitis C virus (HCV) infection in the United States are injection drug use, blood transfusions prior to 1992 [8], and needlestick occupational exposures. Additional risk factors have also been recognized, including the sharing of snorting straws [9] and high-risk sexual behaviors, such as anal receptive intercourse [10]. All persons born in the United States between the years 1945 and 1965 are at increased risk of chronic hepatitis C relative to the remaining population, with an estimated prevalence of 3.25%, prompting the Centers for Disease Control and Prevention to recommend screening for HCV infection for all persons in this birth

cohort [11]. Coexisting hereditary hemochromatosis (HH) accelerates liver fibrosis due to HCV infection or alcohol but infrequently causes advanced fibrosis in the absence of a cofactor [12]. A strong family history of liver disease or cirrhosis raises suspicion for HH, and a personal history of arthralgias, skin discoloration, or diabetes mellitus is suggestive of underlying HH in the appropriate clinical setting. Although hepatitis B is a vaccine-preventable disease, only 32.2% of US-born persons aged 19–49 have received ≥3 doses of the hepatitis B virus (HBV) vaccine. Injection drug use and high-risk sexual behaviors remain important risk factors for HBV infection in the United States, and the

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Part I: Overview: Clinical Fundamentals of Hepatology

Box 1.1 AUDIT-C questionnaire. 1 How often do you have a drink containing alcohol? a Never b Monthly or less c 2–4 times per month d 2–3 times per week e 4 or more times a week 2 How many standard drinks containing alcohol do you have on a typical day? a 1 or 2 b 3 or 4 c 5 or 6 d 7 to 9 e 10 or more 3 How often do you have six or more drinks on one occasion a Never b Less than monthly c Monthly d Weekly e Daily or almost daily Points are assigned for each answer: a – 1, b – 2, c – 3, d – 4, e – 5. A score of ≥4 is identifies persons with alcohol abuse with sensitivity of 0.79 and specificity of 0.56 in men.

incidence of HBV infection is high in areas where injection drug use is common [13]. Foreign-born persons are also at higher risk of harboring HBV infection, with the highest rates, up to 33%, in persons of Asian descent [14]. Therefore, high-risk sexual behaviors, injection drug use, and country of origin are all important elements of a patient’s history for assessing the risk of chronic HBV infection. NAFLD has emerged as the most prevalent chronic liver condition in the United States, with estimated prevalence rates of 30–46% of adults [15] and 70% of obese or diabetic persons [16]. The clinical burden of NAFLD in the United States is staggering, and it is therefore critical to attempt to distinguish persons who have nonalcoholic steatohepatitis (NASH), and who are thus at risk for progressive inflammation, fibrosis, and cirrhosis, from those with simple steatosis (fatty liver) alone. Important risk factors for NASH include age >40 years, body mass index (BMI) ≥30, metabolic syndrome (Box 1.2), type 2 diabetes mellitus, and persistently elevated serum aminotransferase levels [17]. After drugs and toxins, viral hepatitis, and NAFLD, autoimmune and autoinflammatory liver diseases comprise most of the remaining causes of chronic liver injury. In middle-aged women with an elevated alkaline phosphatase level, primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) is a principal consideration. PBC is much more common in women than men and is associated with other autoimmune diseases, in partic¨ ular Raynaud’s disease and Sjogren’s syndrome. When

Box 1.2 The National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Three of the following five clinical characteristics must be present: 1 Abdominal obesity (waist circumference >101 cm (40 inches) in men, >89 cm (35 inches) in women) 2 Serum triglycerides >150 mg/dL 3 Serum high-density lipoprotein level 2.5 and a platelet count of 94% sensitivity and specificity at diagnosing fatty change, fibrosis, and inflammatory activity [71]. Laparoscopic appearance of the liver has also been evaluated as a prognostic indicator for treatment of chronic hepatitis C. Worse macroscopic appearance was correlated with a lower sustained virologic response (SVR).

Box 2.3 Indications for laparoscopic liver biopsy.

r r r r r

r

Biopsy in patients with coagulopathy and/thrombocytopenia Inadequate percutaneous biopsy Biopsy of discrete lesions difficult to access percutaneously Stage for primary hepatic tumors and gastric cancer Evaluation of: – Unexplained hepatomegaly – Ascites – Peritoneal disease – Unexplained portal hypertension – Budd–Chiari syndrome – The obese patient’s liver disease – Liver disease after nondiagnostic radiological evaluation – Granulomatous disease When other less invasive modalities fail to provide a diagnosis of liver disease

When routine testing does not reveal a source for ascites, laparoscopy can be an invaluable tool for diagnosis. Laparoscopy can also identify the presence of multiple causes of ascites and is useful in obtaining peritoneal biopsies to confirm the diagnosis of malignancy or infection when suspected. The diagnostic utility of laparoscopy and peritoneal disease has been demonstrated in several series and has determined the cause of ascites in up to 86% of cases of ascites of unclear etiology [72]. Special consideration should be given to the role of laparoscopy and peritoneal biopsy in those suspected of having tuberculous peritonitis. In a series of 14 patients with high protein content and elevated lymphocytes measured by paracentesis, tuberculous peritonitis was only confirmed after laparoscopy demonstrated multiple white tubercles and adhesions. Biopsy specimens demonstrated caseating granulomas [73]. Laparoscopy can be used in the management of HCC. Diagnostically, a laparoscopic view of the liver surface may demonstrate changes suggestive of malignancy, such as hypervascular nodules and hyperemic, pigmented lesions [74]. Specific laparoscopic features, including the presence of irregular regenerative nodules, a high degree of nodular regeneration, and an atrophic right lobe, have been described to predict the development of HCC in patients with hepatitis C cirrhosis. Therapeutically, laparoscopy can also be used in patients with suspected HCC to assess the extent of the primary lesion and to examine other areas for synchronous tumors. In addition, it may be helpful to perform laparoscopy in patients with an elevated α-fetoprotein and unrevealing imaging studies. Previously, patients undergoing diagnostic laparoscopic procedures were required to be admitted for observation after the procedure. Currently, outpatient diagnostic laparoscopy using conscious sedation has been demonstrated to be safe and effective. Patients should receive oxygen via a nasal cannula and should be monitored during the procedure. Intravenous access is required to provide conscious sedation. With the patient in a supine position, the abdomen is prepped and draped. A Veress needle and trocar are usually placed in the left paramedian area; however, a right paramedian or subumbilical approach can be used in patients with an enlarged left hepatic lobe, splenomegaly, or previous splenectomy and thus, the laparoscopist has to have an excellent knowledge of the anatomy of the abdominal wall prior to the insertion of the laparoscope to avoid large vessels. A local anesthetic such as 1% lidocaine is injected intradermally 2 cm above and to the left of the umbilicus. Then, a 16gauge needle is inserted through the center of the wheal to the parietal peritoneum, which usually provokes some pain. Approximately 15–20 mL of 1% lidocaine is applied to the subcutaneous tissue and fascia within a 2 cm radius.

Chapter 2: Laboratory Tests

It is important that sufficient local anesthesia be applied. A small incision is made in the center of the wheal, and the patient is asked to distend the abdominal cavity without arching the back. Aspiration with the 10 mL syringe may avoid air embolism or inadvertent entry into the intestines, both of which are rare complications. Whereas carbon dioxide used for insufflation during therapeutic laparoscopy is a peritoneal irritant and provokes pain, the nitrous oxide commonly used for diagnostic laparoscopy is better tolerated. Insufflation to an abdominal cavity pressure of 20 mmHg is accomplished by delivering 3–6 L of nitrous oxide through the Veress needle. A 20 mL syringe, half filled with saline solution, is then inserted and rotated within the abdominal cavity. Gas bubbles within the syringe indicate an unobstructed area for trocar placement. The patient is then instructed to distend the abdomen, and the trocar is inserted into the peritoneal cavity. Two distinct “pops” confirm placement. An oblique-view laparoscope is then inserted into the abdominal cavity under direct vision. The area perpendicular to the scope is inspected for insertion-related damage. With the patient in the Trendelenburg position, the bladder and other pelvic structures can be visualized. Placement of the patient in the reverse Trendelenburg position allows inspection of the right and left upper quadrants. A second trocar is inserted into the right midclavicular line to allow, via another laparoscope, inspection of the superior aspect of the right lobe and the delivery of accessory equipment, such as the biopsy needle and palpating probe. Liver specimens are obtained with a biopsy gun, or less commonly, a Tru-Cut needle from left of the falciform ligament, and the medial and lateral aspects of the right lobe to avoid sampling error. To avoid large blood vessels, a tangential approach to the liver left of the falciform ligament is recommended. Pressure is applied with a palpating probe on both the biopsy sites to tamponade the bleeding site and establish hemostasis. Towards the end of the procedure, the initial trocar site (left of the umbilicus) is observed using the laparoscopic camera on the right side to look for any bleeding while the trocar is being removed. If bleeding occurs at the initial trocar site, an Avotin pellet is inserted into the site to achieve hemostasis. After the examination is completed, the trocar and biopsy sites can be closed with Steri-Strips or by sutures if a larger incision is made to accommodate larger trocars and laparoscopes. Patients are observed for approximately 18–24 hours post procedure and discharged to resume regular activity in 3–4 days. Right shoulder pain for 6–8 hours after the procedure is common. Diagnostic laparoscopy can also be performed safely in the operating room under general anesthesia utilizing carbon dioxide in the elderly patient without compromising the cardiopulmonary system. Despite intubation of the patient, the overall time to start and complete a

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diagnostic laparoscopy in the operating room is very similar to a diagnostic laparoscopy utilizing nitrous oxide. The other advantage of an operating room and the use of carbon dioxide is that one can utilize cautery to cease a patient’s bleeding, particularly in those who have advanced liver disease. As with the percutaneous and transvenous biopsy approaches, patients should avoid nonsteroidal antiinflammatory drugs and salicylate compounds for a period of time before and after the procedure. Recommendations for patients with clotting factor and platelet count abnormalities are similar to those for percutaneous liver biopsy. Advances in technology have allowed for the use of mini-laparoscopy, in which a smaller diameter trocar (1.9 mm) is used. This technique has been noted to be extremely safe, less invasive, and well tolerated by patients [75]. When compared with conventional laparoscopy, the mini-laparoscopic technique demonstrated similar success and had the advantage of a shorter procedure time. When compared with a percutaneous approach, mini-laparoscopy has been noted to have the advantage of offering both macroscopic and histologic results that can improve the diagnosis of cirrhosis. Moreover, mini-laparoscopy appeared safe in a small study of 61 patients with a platelet count less than 50 000 /μL and/or an INR greater than 1.5; however, most patients required the application of argon plasma coagulation directly to the liver to stop post-biopsy bleeding.

Laparoscopic ultrasound Laparoscopic ultrasonography is another technologic advance that has allowed for improved visualization of the liver parenchyma, targeted biopsies, and staging of both primary and metastatic hepatic lesions. Performance of laparoscopic ultrasound can help to identify lesions not seen on conventional preoperative imaging and in this regard, has been noted to help in avoiding unnecessary laparotomy [76]. Therapeutically, laparoscopic ultrasound can be used to direct radiofrequency ablation of unresectable lesions. Although there are few to no training programs teaching the diagnostic laparoscopy method for gastroenterologists and hepatologists, laparoscopies still remain an invaluable tool in diagnosing the stage of liver, gastric, and pancreatic cancer, as well as the diagnosis of parenchymal liver disease and ascites. Other types of diagnostic procedures, such as percutaneous and transvenous biopsy, are associated with significant sampling error, particularly in this decade in patients with fatty liver or NASH. An exciting and recent technical advance involves an extension of the natural orifice transluminal endoscopic surgery (NOTES) procedure to perform a liver biopsy.

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Part I: Overview: Clinical Fundamentals of Hepatology

Complications of liver biopsy Major complications associated with a percutaneous liver biopsy are fortunately rare. Mortality is reported in 0.0088–0.3% of biopsies [77] (Box 2.4). Sixty percent of complications occur within 2 hours and 96% within 24 hours. Hospitalization is required in 1.4–3.2% of patients who undergo a percutaneous liver biopsy, with pain and hypotension being the most common reasons for admission [78]. Pain is a common complication following percutaneous liver biopsy, occurring in up to 84% of patients, including those with mild discomfort [59]. The pain is usually mild and responsive to analgesia. Severe pain should prompt concern about a more serious complication such as bleeding and if a patient is hospitalized for management of pain, radiological imaging should be performed to rule out a complication. Bleeding after liver biopsy can occur as a subcapsular bleed, intrahepatic bleed, or free intraperitoneal bleed. Subcapsular and intrahepatic bleeding is noted to occur in 18–20% of cases when ultrasound has been performed after liver biopsy. These are usually asymptomatic and the majority do not require intervention. Large hematomas may expand, cause hepatomegaly and result in a delayed drop in hematocrit. These patients usually settle with conservative management but rarely angiography is required to stop bleeding. Severe bleeding occurs in 1 in 2500–10 000 cases, usually within 2–4 hours and is evident by a change in vital signs. It requires hospitalization,

Box 2.4 Complications of percutaneous biopsy.

r

r

r r r r r r r r r

r

Pain (0.056–83%) – Pleuritic – Peritoneal – Diaphragmatic Hemorrhage – Intraperitoneal (0.03–0.7%) – Intrahepatic/subcapsular (0.59–23%) – Hematobilia (0.059–0.2%) Bile peritonitis (0.03–0.22%) Bacteremia Sepsis (0.008%) and abscess formation Pneumothorax and pleural effusion (0.08–0.28%) Hemothorax (0.18–0.49%) Arteriovenous fistula (5.4%) Subcutaneous emphysema (0.014%) Reaction to the anesthetic (0.029%) Biopsy of other organs – Lung (0.001–0.014%) – Gallbladder (0.034–0.117%) – Kidney (0.029–0.096%) – Colon (0.00038–0.044%) Mortality (0.008–0.3%)

transfusion, and intervention with either radiological embolization or surgical intervention. Rarely, surgical intervention is required. Risk factors associated with the risk of bleeding include operator experience, needle diameter, and the number of liver biopsy passes taken [59]. Hematobilia is an infrequent complication of liver biopsy, presenting with the classic triad of gastrointestinal bleeding manifesting as melena, biliary colic, and jaundice. The bleeding can be arterial or venous and is generally delayed, with a mean onset of 5 days post procedure. Endoscopy will reveal blood flowing from the ampulla of Vater and endoscopic retrograde cholangiography will demonstrate filling defects in the biliary tree and gallbladder. Angiography and embolization is required to treat the bleeding vessel. Other less common complications include transient bacteremia, biliary peritonitis, biliary pleuritis, and the formation of arteriovenous fistulae. The complication rate after transvenous liver biopsy is low and ranges from 0.13 to 6.5%. The majority of complications are mild and related to bleeding from the puncture site over the venous access. Minor complications also include cardiac arrhythmia, and pneumothorax. Major complications are reported in 0.6% of cases after a transvenous liver biopsy and include major hemorrhage from a capsular perforation. Mortality rate is reported in