Schiff's Diseases of the Liver

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.

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Contents

Contributors, viii 9 The Liver in Pregnancy, 244 Nancy Reau and Yannick Bacq Foreword, xiii

Preface, xiv Part III Consequences of Liver Disease

About the Companion Website, xvi 10 Hepatic Fibrosis, 271 Scott L. Friedman

Part I Overview: Clinical 11 Preoperative Evaluation of the Patient with Fundamentals of Hepatology Liver Disease, 290 Patrick S. Kamath and Mark T. Keegan 1 History Taking and Physical Examination for the Patient with Liver Disease, 3 12 Management of Portal Hypertension, 304 Esperance A. Schaefer and Lawrence S. Friedman Guadalupe Garcia-Tsao and Juan G. Abraldes

2 Laboratory Tests, Noninvasive Markers of 13 Renal Complications of Liver Disease and the Fibrosis, Liver Biopsy, and Laparoscopy, 17 Hepatorenal Syndrome, 336 Michael P. Curry and Lennox J. Jeffers Xingxing S. Cheng and W. Ray Kim

3 Noninvasive and Invasive Imaging 14 Pulmonary Manifestations of Liver Disease, 353 of the Liver and Biliary Tract, 38 Michael B. Fallon and Anil Seetharam KoushikK.Das,MatthewA.Morgan,and 15 Ascites and Spontaneous Bacterial Peritonitis, 365 Gregory G. Ginsberg Vicente Arroyo and Javier Fernandez´

16 Hepatic Encephalopathy, 387 Part II General Considerations Chathur Acharya and Jasmohan S. Bajaj

4 Physioanatomic Considerations, 73 17 Acute Liver Failure, 411 Ian R. Wanless Robert J. Fontana and Khurram Bari

5 Bilirubin Metabolism and Jaundice, 103 18 Acute-on-Chronic Liver Failure, 432 Allan W. Wolkoff and Paul D. Berk Florence Wong

6 Hepatic Histopathology, 135 19 Malnutrition and Liver Disease, 460 Zachary D. Goodman Craig McClain, Irina Kirpich, and Laura Smart 7 Mechanisms of Liver Injury, 200 Harmeet Malhi and Gregory J. Gores Part IV Cholestatic Disorders

8 Hepatic Manifestations of Systemic Disorders, 218 20 Primary Sclerosing Cholangitis, 491 Stuart C. Gordon and Humberto C. Gonzalez John M. Vierling vi Contents

21 Primary Biliary Cholangitis, 523 34 The Liver in Circulatory Failure, 935 Cynthia Levy, Andres F. Carrion, and Marlyn J. Mayo Santiago J. Munoz, Hanisha R. Manickavasagan, and Idean Amirjazil 22 Autoimmune Hepatitis, 546 Gideon M. Hirschfield and Gwilym J. Webb Part IX Benign and Malignant Tumors; Cystic Disorders Part V Viral Hepatitis 35 Benign Tumors, Nodules, and Cystic Diseases 23 Hepatitis A and E, 565 of the Liver, 949 Kenneth E. Sherman and Shyam Kottilil Julien Calderaro and Jessica Zucman-Rossi

24 Hepatitis B and D, 584 36 Hepatocellular Carcinoma, 977 Marc G. Ghany and Naveen Gara Maddie Kubiliun and Jorge A. Marrero

25 Hepatitis C, 628 37 Surgical Options in Liver Cancers, 989 Michael W. Fried, Jama M. Darling, and Garrett R. Roll and John Paul Roberts Stanley M. Lemon

Part X Infectious and Part VI Alcohol- and Granulomatous Disease Drug-induced Liver Disease 38 Amoebic and Pyogenic Liver Abscesses, 1005 26 Alcoholic Liver Disease, 701 Marco A. Olivera-Mart´ınez and David Kershenobich Mack C. Mitchell and Gyongyi Szabo 39 Parasitic Diseases, 1013 27 Drug-induced Hepatotoxicity, 740 Michael A. Dunn Dominique Larrey, Jose Ursic-Bedoya, and Lucy Meunier 40 Granulomas of the Liver, 1028 James H. Lewis 28 Mechanisms of Drug-induced Liver Injury, 774 Paul B. Watkins and Merrie Mosedale Part XI Elements of Liver Transplantation Part VII Genetic and Metabolic Disease 41 Selection of Candidates and Timing of Liver Transplantation, 1055 29 Wilson Disease, 801 Meaghan Phipps, Alyson N. Fox, and Michael L. Schilsky and Aftab Ala Robert S. Brown Jr.

30 Hemochromatosis and Iron Storage Disorders, 820 42 Immunosuppression: The Global Picture, 1065 Kris V. Kowdley and Priya Handa Caroline C. Jadlowiec, Timucin Taner, and Russell H. Wiesner 31 Alpha-1 Antitrypsin Deficiency, 843 David H. Perlmutter 43 The First Six Months Following Liver Transplantation, 1079 32 Nonalcoholic Fatty Liver Disease, 867 K. Rajender Reddy and Manuel Mendizabal Curtis K. Argo, Zachary H. Henry, and Stephen H. Caldwell 44 Long-term Management of the Liver Transplant Patient, 1093 Timothy M. McCashland Part VIII Vascular Diseases of the Liver 45 The Liver Transplant Procedure, 1107 Bijan Eghtesad, Koji Hashimoto, and John Fung 33 Vascular Liver Disease, 911 Dominique-Charles Valla Contents vii

46 Recurrent Disease Following Liver 48 Controversies in Liver Transplantation, 1156 Transplantation, 1127 James F. Trotter Haripriya Maddur and Josh Levitsky Index, 1169 47 The Role of Retransplantation, 1143 Peter L. Abt and Kim M. Olthoff viii

Contributors

Juan G. Abraldes Curtis K. Argo Robert S. Brown, Jr. MD, MMSc MD, MS MD, MPH Department of Medicine GI/Hepatology Center for Liver Disease and Transplantation Cirrhosis Care Clinic, Division of Department of Internal Medicine Weill Cornell Medical College Gastroenterology (Liver Unit) University of Virginia Health System New York, NY, USA University of Alberta, CEGIIR Charlottesville, VA, USA Edmonton, Canada Julien Calderaro Vicente Arroyo MD, PhD Peter L. Abt MD, PhD Department of Pathology MD Liver Unit, Hospital Clinic Henri Mondor University Hospital, and Department of Surgery IDIBAPS INSERM U955, Team 18 Division of Transplant Surgery University of Barcelona, Spain; Institut Mondor de Recherche Biomedicale,´ The Hospital of the University of CIBEREHED, Spain; and and Pennsylvania EF Clif, Barcelona, Spain Universite´ Paris-Est Creteil´ Philadelphia, PA, USA Creteil,´ France Yannick Bacq Chathur Acharya MD Stephen H. Caldwell MD Department of Hepatogastroenterology MD Division of Gastroenterology, Hepatology and Centre Hospitalier de Tours GI/Hepatology Nutrition Hopitalˆ Trousseau Department of Internal Medicine Virginia Commonwealth University and Tours, France University of Virginia Health System McGuire VA Medical Center Charlottesville, VA, USA Richmond, VA, USA Jasmohan S. Bajaj MD, MS Andres F. Carrion Aftab Ala Division of Gastroenterology, Hepatology and MD MD, PhD, FRCP Nutrition Division of Gastroenterology and Hepatology Department of Gastroenterology and Virginia Commonwealth University and Paul L. Foster School of Medicine Hepatology McGuire VA Medical Center Texas Tech University Health Sciences Center Royal Surrey County Hospital NHS Richmond, VA, USA El Paso, TX, USA Foundation Trust Guildford, Surrey, UK, and Khurram Bari Xingxing S. Cheng Department of Clinical and Experimental MD MD, MS Medicine Department of Internal Medicine Division of Nephrology School of Biosciences and Medicine University of Cincinnati School of Medicine Department of Medicine University of Surrey, Guildford, Surrey, UK Cincinnati, OH, USA Stanford University Stanford, CA, USA Idean Amirjazil Paul D. Berk MD MD Michael P. Curry Department of Medicine Division of Digestive & Liver Diseases MD Hahnemann University Hospital and Drexel Columbia University Medical Center Beth Israel Deaconess Medical Center and University College of Medicine New York, NY, USA Harvard Medical School Philadelphia, PA, USA Boston, MA, USA Contributors ix

Jama M. Darling Lawrence S. Friedman Zachary D. Goodman MD MD MD, PhD University of North Carolina at Chapel Hill Harvard Medical School Center for Liver Diseases Chapel Hill, NC, USA Tufts University School of Medicine Inova Fairfax Hospital Department of Medicine, Newton-Wellesley Falls Church, VA, USA Koushik K. Das Hospital, and Massachusetts General Hospital MD Stuart C. Gordon Newton and Boston, MA, USA Division of Gastroenterology MD Department of Medicine Division of Hepatology Washington University School of Medicine Scott L. Friedman Henry Ford Hospital St.Louis,MO,USA MD Detroit, MI, USA Icahn Sinai School of Medicine at Mount Sinai Michael A. Dunn New York, NY, USA Gregory J. Gores MD MD Division of Gastroenterology, Hepatology and John Fung Division of Gastroenterology and Hepatology Nutrition and the Liver Center MD Mayo Clinic College of Medicine University of Pittsburgh Department of Surgery Rochester, MN, USA Pittsburgh, PA, USA The University of Chicago Chicago, IL, USA Priya Handa Bijan Eghtesad PhD MD Naveen Gara Organ Care Research and Liver Care Network Department of General Surgery MD Swedish Medical Center The Cleveland Clinic Department of Gastroenterology Seattle, WA, USA Cleveland, OH, USA Mayo Clinic Health System Mankato, MN, USA Koji Hashimoto Michael B. Fallon MD MD Guadalupe Garcia-Tsao Department of General Surgery Division of Gastroenterology, Transplant and MD The Cleveland Clinic Advanced Liver Disease Department of Internal Medicine, Section of Cleveland, OH, USA University of Arizona College of Medicine Digestive Diseases Phoenix, AZ, USA Yale University Zachary H. Henry New Haven, CT, USA and MD, MS Department of Medicine Javier Fernandez´ GI/Hepatology VA-CT Healthcare System MD, PhD Department of Internal Medicine West Haven, CT, USA Liver Unit, Hospital Clinic University of Virginia Health System IDIBAPS Charlottesville, VA, USA University of Barcelona, Spain; Marc G. Ghany CIBEREHED, Spain; and MD, MHSc Gideon M Hirschfield EF Clif, Barcelona, Spain Liver Diseases Branch MA, MB, BChir, PhD, FRCP National Institute of Diabetes, Digestive and Centre for Liver Research and National Robert J. Fontana Kidney Diseases Institute for Health Research Birmingham National Institutes of Health Liver Biomedical Research Unit MD Bethesda, MD, USA University of Birmingham Department of Internal Medicine Birmingham, UK University of Michigan Medical School Ann Arbor, MI, USA Gregory G. Ginsberg MD Caroline C. Jadlowiec Alyson N. Fox Division of Gastroenterology MD Department of Medicine Division of Transplant Surgery, Department of MD, MSCE Perelman School of Medicine Surgery Center for Liver Disease and Transplantation University of Pennsylvania William J. von Liebig Transplantation Center Columbia University Medical Center Philadelphia, PA, USA Mayo Clinic New York, NY, USA Rochester, MN, USA Humberto C. Gonzalez Michael W. Fried MD Lennox J. Jeffers MD Department of Transplant Surgery MD University of North Carolina at Chapel Hill Methodist University Hospital Hepatology Section Chapel Hill, NC, USA University of Tennessee Health Science Center Miami Veterans Affairs Medical Center and Memphis, TN, USA University of Miami Leonard School of Medicine Miami, FL, USA x Contributors

Patrick S. Kamath Stanley M. Lemon Timothy M. McCashland MD MD MD Division of Gastroenterology and Hepatology University of North Carolina at Chapel Hill Department of Hepatology Mayo Clinic College of Medicine Chapel Hill, NC, USA University of Nebraska Medical Center Rochester, MN, USA Nebraska Medical Center Josh Levitsky Omaha, NE, USA Mark T. Keegan MD, MS, FAASLD, FAST MB, MRCPI, MSc, D.ABA Professor of Medicine Craig McClain Department of Anesthesiology Division of Gastroenterology and Hepatology MD Division of Critical Care Northwestern University Feinberg School of Departments of Medicine and Pharmacology Mayo Clinic College of Medicine Medicine and Toxicology Rochester, MN, USA Chicago, IL, USA University of Louisville and Robley Rex Veterans Administration Medical David Kershenobich Cynthia Levy Center Louisville, KY, USA MD, PhD MD, AGAF, FAASLD Instituto Nacional de Ciencias Medicas´ y Division of Hepatology Nutricion´ Salvador Zubiran´ Schiff Center for Liver Diseases Manuel Mendizabal Mexico´ City, Mexico´ University of Miami Miller School of Medicine MD Miami, FL, USA Hepatology and Liver Transplant Unit W. Ray Kim Hospital Universitario Austral Pilar, Provincia de Buenos Aires, Argentina MD, MS, MBA James H. Lewis Division of Gastroenterology & Hepatology MD Department of Medicine Department of Hepatology Lucy Meunier Stanford University Georgetown University Medical Center MD Stanford, CA, USA Washington, DC, USA Liver and Transplantation Unit Montpellier School of Medicine and Irina Kirpich Haripriya Maddur IRB-INSERM-1183 PhD Montpellier, France MD Departments of Medicine and Pharmacology Division of Gastroenterology and Hepatology and Toxicology Northwestern University Feinberg School of Mack C. Mitchell University of Louisville Medicine MD, FAASLD Louisville, KY, USA Chicago, IL, USA University of Texas Southwestern Medical Center Shyam Kottilil Harmeet Malhi Dallas, TX, USA MD, PhD MD Institute of Human Virology Division of Gastroenterology and Hepatology Matthew A. Morgan University of Maryland School of Medicine Mayo Clinic College of Medicine MD Baltimore, MD, USA Rochester, MN, USA Department of Radiology Perelman School of Medicine Kris V. Kowdley Hanisha R. Manickavasagan University of Pennsylvania MD Philadelphia, PA, USA MD Organ Care Research and Liver Care Network Department of Medicine Swedish Medical Center Hahnemann University Hospital and Drexel Merrie Mosedale Seattle, WA, USA University College of Medicine PhD Philadelphia, PA, USA Institute for Drug Safety Sciences Maddie Kubiliun Division of Pharmacotherapy and Experimental Therapeutics MD Jorge A. Marrero UNC Eshelman School of Pharmacy Division of Digestive and Liver Disease MD, MS Chapel Hill, NC, USA University of Texas Southwestern Medical Division of Digestive and Liver Disease Center University of Texas Southwestern Medical Dallas, TX, USA Santiago J. Munoz Center Dallas, TX, USA MD, FACP, FACG, FAASLD Dominique Larrey Department of Medicine and Liver Failure Unit MD, PhD Marlyn J. Mayo Hahnemann University Hospital and Drexel Liver and Transplantation Unit MD University College of Medicine Montpellier School of Medicine and Division of Digestive and Liver Diseases Philadelphia, PA, USA IRB-INSERM-1183 University of Texas Southwestern Montpellier, France Dallas, TX, USA Contributors xi

Marco A. Olivera-Martınez´ Esperance A. Schaefer Jose Ursic-Bedoya MD, FACP MD, MPH MD Department of Internal Medicine Harvard Medical School and Gastrointestinal Liver and Transplantation Unit Section of Gastroenterology & Hepatology Unit Montpellier School of Medicine and University of Nebraska Medical Center Massachusetts General Hospital IRB-INSERM-1183 Omaha, NE, USA Boston, MA, USA Montpellier, France

Kim M. Olthoff Michael L. Schilsky Dominique-Charles Valla MD MD, FAASLD MD Department of Surgery Departments of Medicine and Surgery, University Paris-Diderot and Inserm Division of Transplant Surgery Sections of Digestive Diseases, Transplant and UMR1149 The Hospital of the University of Immunology Paris, France, and Pennsylvania Yale New Haven Transplant Center DHU UNITY and Centre National de Philadelphia, PA, USA Yale University Medical Center Ref´ erence´ Maladies Rares – Maladies New Haven, CT, USA Vasculaires du Foie David H. Perlmutter Service d’hepatologie´ Hopitalˆ Beaujon, APHP MD Anil Seetharam Clichy-la-Garenne, France Washington University School of Medicine MD St Louis, MO, USA Division of Gastroenterology, Transplant and Advanced Liver Disease John M. Vierling Meaghan Phipps University of Arizona College of Medicine MD, FACP, FAASLD Phoenix, AZ, USA Baylor College of Medicine MD Baylor-St. Luke’s Medical Center Columbia University Medical Center Houston, TX, USA New York, NY, USA Kenneth E. Sherman MD, PhD Ian R. Wanless Nancy Reau Department of Internal Medicine Division of Digestive Diseases MD, CM, FRCPC MD University of Cincinnati College of Medicine Department of Pathology Section of Hepatology, Solid Organ Cincinnati, OH, USA Dalhousie University Transplantation Halifax, Nova Scotia, Canada Rush University Medical Center Chicago, IL, USA Laura Smart MD Paul B. Watkins K. Rajender Reddy Department of Medicine MD University of Louisville Institute for Drug Safety Sciences MD Louisville, KY, USA Division of Pharmacotherapy and Division of Gastroenterology/Hepatology Experimental Therapeutics Department of Medicine UNC Eshelman School of Pharmacy University of Pennsylvania Gyongyi Szabo Chapel Hill, NC, USA Philadelphia, PA, USA MD, PhD Department of Medicine Gwilym J Webb John P. Roberts University of Massachusetts Medical School Worcester, MA, USA MA, BM, BCh, MRCP MD, FACS Centre for Liver Research and National Division of Transplant Surgery Timucin Taner Institute for Health Research Birmingham University of California San Francisco Liver Biomedical Research Unit San Francisco, CA, USA MD, PhD University of Birmingham Division of Transplant Surgery, Department of Birmingham, UK Garrett R. Roll Surgery William J. von Liebig Transplantation Center MD, FACS Russell H. Wiesner Mayo Clinic Department of Surgery Rochester, MN, USA MD Division of Transplant Department of Gastroenterology and University of California San Francisco James F. Trotter Hepatology San Francisco, CA, USA William J. von Liebig Transplantation Center MD Mayo Clinic Baylor University Medical Center Rochester, MN, USA Dallas, TX, USA xii Contributors

Allan W. Wolkoff Florence Wong Jessica Zucman-Rossi MD MBBS, MD, FRACP, FRCPC MD, PhD Marion Bessin Liver Research Center Department of Medicine INSERM UMR1162 Division of Gastroenterology and Liver Division of Gastroenterology Genomique´ fonctionelle des tumeurs solides, Diseases Toronto General Hospital and Albert Einstein College of Medicine University Health Network Universite´ Paris Descartes Bronx, NY, USA University of Toronto Labex Immuno-Oncology Ontario, Canada Sorbonne Paris Cite´ FacultedeM´ edecine´ Paris, France xiii

Foreword

Liver science and the clinical care of the liver patient taking and physical examination, followed by integrative is a rapidly evolving and exciting time of progress chapters on laboratory tests and imaging modalities. and change. Clinicians of all stripes are confronted The following section, labeled General Considerations, by the challenges of staying abreast of new physio- includes basic information and specific considerations logic/molecular/cell concepts of disease while simultane- including masterful chapters on liver histopathology and ously remaining current with advances in diagnostic and mechanisms of liver injury. The section that follows, Con- treatment modalities. The liver literature is vast, rich in the sequences of Liver Disease, covers portal hypertension, variety of publications including general specialty jour- renal complications, pulmonary manifestation, acute nals, specialized research journals, review journals and a liver failure, and hepatic encephalopathy. Subsequent host of giveaway publications, sponsored by pharmaceu- chapters comprise specific groups of diseases, such as tical companies. What is the busy clinician, trainee, and the cholestatic disorders, alcohol- and drug-induced liver medical student to do? The answer often is to resort to injury, genetic and metabolic disease, and a compressive online electronic media. This approach provides instant update on the viral hepatitis disorders. The paradigm answers but is often lacking in the background and under- in shift in treatment of hepatitis C since the advent of standing of the basis for the answer provided. To flesh direct-acting antiviral agents is dramatic. The resultant out the underlying scientific basis and to add background, cure of the majority of patients treated is extraordinary, scrutiny as well as perspective is the role of a comprehen- in addition to the important public health and economic sive and thoughtfully curated textbook. implications. Reflecting its importance in the therapeu- This new twelfth edition of Schiff’s Diseases of the Liver tic arsenal of hepatology, the last section, Elements of continues its traditional role as the authoritative textbook Liver Transplantation, is in actuality a mini-textbook of the liver. It is comprehensive, fact based, and uniquely of liver transplantation that encompasses the funda- timely. Each section, when appropriate, provides bio- mental elements essential in caring for the transplanted chemical and physiologic background and indepth per- patient. spective of advances since the last edition. This approach Rapid advances in liver science and new developments lends authority to conclusions advanced by the authors in the diagnostic approach and therapeutic care of the and is relevant to all readers, including students, trainees, liver patient pose new challenges for the clinician at what- and practicing clinicians. The twelfth edition has been ever his or her stage of life. The new twelfth edition extensively revised, with 25 of the 48 chapters written by of Schiff’s Diseases of the Liver serves as an authoritative new authors. Two chapters have been deleted from prior resource. It provides a deep understanding of liver phys- editions and two new chapters added on mechanisms iology and molecular/genetic background that segues of drug-induced liver injury and on acute and chronic seamlessly into an erudite discussion of each individual liver failure. All of the authors chosen are established and disease entity. respected leaders in their field. Similar to previous editions of Schiff’s textbook, the Michael F. Sorrell MD chapters are organized thematically. The initial Overview Distinguished Professor of Medicine section tackles the often-neglected aspects of history University of Nebraska, Omaha, NE, USA xiv

Preface

The twelfth edition of Schiff’s Diseases of the Liver continues Implementation of universal vaccination for hepatitis to chronicle the major scientific advances in pathogenesis, B virus (HBV) continues throughout the world; however diagnosis, management, treatment, and in some instances a definitive cure for HBV infection remains elusive. An cure of hepatobiliary disorders. The rapid rollout of inno- ongoing research focus in chronic hepatitis B is to develop vation has led to the decision that this edition will be ways to eliminate covalently closed circular DNA and accompanied by a subsequently expanded electronic pro- thereby block HBV integration. Prevention of reactiva- gram in order to bridge the gap of evolving knowledge tion of HBV in a patient receiving immunosuppressants until the next edition. and chemotherapy and the development of more effective The spectrum of liver disease is changing. The grati- HBV treatments have become areas of great interest. fying spectacular cure rates now available for hepatitis Liver transplantation has become a major life-saving C have had major impacts on the practice of hepatology. procedure for patients who have progressive liver dis- Widespread instruction of treatment with the newer ease and for a minority who have acute liver failure. Sur- agents should markedly reduce the number of patients gical techniques are well advanced and live donor liver who progress to advanced cirrhosis, and likely will lead transplantation presents a life-saving option, albeit for a to a reduction in hepatocellular carcinoma, as well the minority of patients. Organ allocation has been modified need for liver transplantation. Unfortunately, hepatitis C and is well served with the model for end-stage liver dis- virus vaccines are not anticipated to be available in the ease (MELD) score while we continue to work on opti- near future and development of effective vaccines is a mizing immunosuppression regimens and develop new major goal. approaches to improve upon them. It is apparent to all hepatologists that nonalcoholic Aggressive monitoring of patients with cirrhosis steatohepatitis worldwide has come to the fore as a promi- allows early identification of hepatocellular carcinoma nent liver disease that leads to cirrhosis and hepatocellular and increasingly effective therapies (medical and surgi- carcinoma. The challenges are to develop safe and effec- cal) hopefully will reduce mortality from hepatocellular tive therapies to curtail the progression of nonalcoholic carcinoma. For those patients who are not candidates steatohepatitis and hopefully reverse necroinflammation for ablation surgery or transplantation, more effective and fibrosis. Recognition of the earlier stages of steatohep- chemotherapeutic approaches, particularly those that atitis should provide a better therapeutic opportunity to relate to regulation of immune responses, is promising. prevent cirrhosis. Translational research focusing on inflammation and Many of the cases of acute liver failure have been fibrosis is well under way with the hope of stopping found to be a result of acute-on-chronic liver disease, and reversing hepatobiliary fibrosis regardless of etiology. which highlights the importance of preventing super- Genomic and proteomic advances will likely better define imposed hepatic injury in patients with advanced liver hepatobiliary diseases and identify targets for therapy. disease of any etiology. Specific biomarkers are emerging The role of microbiomes and stem cell therapy are which provide more accurate diagnostic and prognostic quickly evolving. These are only a few of the excit- serologic parameters. ing advances in modern hepatology. Progress is being Preface xv achieved on many fronts. We remember the words of Leon It has been an honor and a privilege for us to participate Schiff that “fifty percent of what we say today will be in the creation and editing of Diseases of the Liver. wrong in ten years if we only knew which fifty percent.” Our task is to identify the 50% that will have lasting value. Eugene R. Schiff We would like to thank Dr. Nik Prowse, our freelance Willis C. Maddrey project manager, who was instrumental in facilitating the K. Rajender Reddy publication of this edition. April 2017 xvi

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 PART I Overview: Clinical Fundamentals of Hepatology

CHAPTER 1 History Taking and Physical Examination for the Patient with Liver Disease Esperance A. Schaefer1 & Lawrence S. Friedman2 1Harvard Medical School and Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA 2Harvard Medical School, Tufts University School of Medicine, Department of Medicine, Newton-Wellesley Hospital, and Massachusetts General Hospital, Newton and Boston, MA, USA

Key concepts r The history and physical examination may provide clues to the decreased body hair, gynecomastia, and palmar erythema are r presence of liver disease in a person thought to be healthy. r associated with cirrhosis with a specificity of 89–97%. In a patient undergoing evaluation for liver disease, the history and Assessment of liver span, tenderness, and contour provides important physical examination help determine the underlying cause of liver clinical information. Liver span is best assessed by percussion or the injury, presence or absence of advanced hepatic fibrosis, and evidence “scratch test.” In general, the normal liver span is less than 12 cm in r of clinical complications of cirrhosis and portal hypertension. r the midclavicular line, and the edge is smooth and nontender. Common causes of liver injury in patients with liver disease of For the patient with established cirrhosis, careful attention should be unknown cause include nonalcoholic fatty liver disease (NAFLD), paid to vital signs. A reduced mean arterial pressure is associated with alcoholic liver disease, hepatitis C, and drug-induced liver injury. The renal impairment, particularly when the mean arterial pressure drops patient should be assessed carefully for excessive alcohol intake, new below 82 mmHg. Weight gain raises concern for the development of medication or herbal and dietary supplement use, risk factors for fluid retention and ascites, and weight loss may be associated with r hepatitis C, and evidence of metabolic syndrome. r malnutrition or malignancy. In a patient with known liver disease, clinical evaluation for advanced Ascites may be suspected on physical examination by the detection hepatic fibrosis has particular importance, because one third of of flank dullness, bulging flanks, shifting dullness, and a fluidwave. patients who present for an outpatient hepatology evaluation already Flank dullness and bulging flanks have a sensitivity of at least 80% r have underlying cirrhosis. but a specificity of only 59% for detecting ascites. 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 of parenchymal cells and, in health, are the primary site of functions, a unique dual vascular supply, and several dis- vitamin A storage. In the setting of chronic inflammation, tinct cell types that contribute to its physiologic functions however, stellate cells are responsible for the deposition as well as potential pathology. Most of the key functions of extracellular matrix that leads to cirrhosis. The process of the liver are carried out by the hepatocytes, which of progressive hepatic fibrosis, in general, proceeds over are the most abundant cell type in the liver. Hepatocytes a timeframe of years to decades. This slow progression are responsible for drug detoxification, protein synthesis allows effective intervention if liver disease is identified (including albumin and coagulation factors), excretion of and treated early in its clinical course. Unfortunately, bile for digestion, and synthesis of cholesterol and fatty chronic liver injury is often asymptomatic, and symptoms acids. Injury to hepatocytes and the pursuant inflam- and signs may not manifest until advanced fibrosis or mation may occur from a toxin-mediated insult such as decompensated liver disease has ensued. alcohol or medications, lipotoxicity as seen in fatty liver, In the evaluation of a patient with liver disease, the infectious causes such as viral hepatitis, or autoimmunity. focus of history taking and the physical examination Stellate cells are less abundant, comprising only about 5% will be guided by the reason for which the patient has

presented and has been referred for consultation. Com- disease, α1-antitrypsin deficiency, and congestive hep- mon reasons for referral to a hepatologist include ele- atopathy, each accounted for <1% of new patient visits [2]. vated liver biochemical test levels, abnormal serologic Many patients with acute or chronic liver injury are test results, jaundice, known chronic liver disease, or evi- asymptomatic, and when symptoms do occur, they are dence of decompensated liver disease. For all of these often nonspecific. Presenting symptoms may include clinical scenarios, specific historical elements and physi- abdominal discomfort, anorexia, nausea, vomiting, cal examination findings may provide important insights fatigue, malaise, fever, rash, pruritus, or jaundice. Careful into the ongoing disease process. In general, the clinician questioning about risk factors for certain conditions can seeks, through history taking and physical examination, provide insight into the likely nature of the liver injury. to determine the (i) etiology of liver injury, (ii) presence Toxins, including alcohol and prescribed medications, or absence of advanced hepatic fibrosis, and (iii) existence are common causes of abnormal liver biochemical test lev- of clinical complications of cirrhosis and portal hyperten- els and chronic liver disease. DILI may occur from either sion. The clinical objectives are to identify the cause of prescription or over-the-counter medications, including injury and address it early in the disease course to prevent dietary and herbal supplements, and a careful medica- development of advanced hepatic fibrosis, and, if cirrho- tion history including prescription and nonprescription sis is already present, to monitor the patient carefully for medications, supplements, and herbal remedies should be complications of end-stage liver disease. obtained. DILI can present with either acute or chronic liver injury and can range in severity from mild hepatitis or cholestasis to acute liver failure. The estimated inci- Abnormal liver biochemical test levels dence of DILI is 19.1 cases per 100 000 population, and or known liver disease DILI accounts for 10% of all cases of acute liver failure [3]. The most common classes of drugs implicated in DILI are History taking antimicrobial agents (most notably amoxicillin-clavulanic Acute and chronic liver injury has a broad spectrum of acid, isoniazid, and nitrofurantoin) and dietary and herbal clinical presentations, and patients present to medical supplements [4], but any class of drug may be responsible. attention for a wide variety of reasons. Many patients are In alcoholic liver disease, gender and the quantity of completely asymptomatic and come to medical attention alcohol use are the primary predictors of hepatic injury after a routine physical examination or life insurance test- and fibrosis. Gender is an important risk factor for clin- ing has demonstrated elevated liver biochemical test lev- ically significant alcoholic liver disease, with women els. Others, particularly those with acute hepatitis, may developing liver injury at lower levels of daily alcohol present with abdominal pain, nausea and vomiting, fever, consumption than men. The daily threshold of alcohol or jaundice. The duration of liver injury, particularly in the intake for the development of cirrhosis is 40–60 g of alco- absence of symptoms, is not always certain. Clues such as hol in men, but only 20 g in women. With one alco- the time of onset of symptoms, prior normal test results, holic drink defined as containing 14 g of ethanol (the and the presence of potential risk factors may help differ- amount contained in 5 ounces (150 mL) of wine, 12 ounces entiate acute injury from chronic liver disease. (360 mL) of beer, or 1.5 ounces (45 mL) of 40-proof alco- When evaluating a patient with abnormal serologic test hol), the risk of alcoholic liver disease in women is asso- results or a known history of a specific liver disease, the ciated with more than one drink daily, compared with at focus of history taking and the physical examination is least two drinks daily for men [5]. The amount and type of both to provide clues toward the underlying etiology of alcohol consumed, along with the duration of alcohol use, liver injury (if unknown) and to assess the patient for clin- should be carefully assessed to determine a patient’s risk ical evidence of advanced hepatic fibrosis. Central to this for alcoholic liver disease. Patients frequently underreport objective is an understanding of the most common causes the quantity of consumption, and obtaining additional of liver injury and chronic liver disease. A cohort of 1040 history from family members or close social contacts is patients in the Chronic Liver Disease Network (between often helpful. The CAGE (attempts to cut back, annoyed the years 1999 and 2001) found that 91% of persons in about drinking, guilt regarding drinking habits, use of eye the cohort had liver injury related to one of the diseases opener) criteria have long been used as a marker of alcohol listed in Table 1.1 [1]. In a smaller cohort examined at misuse. An increasingly utilized screening test for alco- a single center in the United Kingdom, the most com- hol dependence is the Alcohol Use Disorders Identifica- mon diagnoses that prompted an outpatient hepatology tion Test (AUDIT-C), which has been shown to predict the referral were nonalcoholic fatty liver disease (NAFLD, risk of alcohol-related gastrointestinal illness, including 29.5%), chronic hepatitis C (17.5%), alcoholic liver disease liver disease [6]. AUDIT-C utilizes three questions and has (17.5%), unspecified hepatitis (7.5%), and drug-induced been validated for identifying persons with alcohol abuse liver injury (DILI, 4%). Other causes, such as Wilson or dependence [7] (Box 1.1). Chapter 1: History Taking and Physical Examination 5

Table 1.1 Clinical features of the most common causes of liver injury and chronic liver disease in a cohort of 1040 patients in the Chronic Liver Disease Network.

Cause of elevated liver Pertinent physical biochemical test levels Features from patient’s history examination findings

Hepatitis C Injection drug or intranasal cocaine use Scarring from injection drug use Blood transfusions prior to 1992 Purpura Needlestick exposure Porphyria cutanea tarda Birth between 1945 and 1965 Alcohol-related liver disease Quantification of daily alcohol intake Dupuytren’s contractures Duration of alcohol use Positive AUDIT-C questionnaire (see Box 1.1) Nonalcoholic fatty liver disease Age >40 years old BMI >29.9 Metabolic syndrome Increased waist-hip ratio Diabetes mellitus Hepatitis B Injection drug use — High-risk sexual activity Country of birth Primary biliary cholangitis Female gender Xanthelasma and xanthomas Fatigue Skin excoriations Pruritus Melanosis History of osteoporosis History of autoimmune disease Hereditary hemochromatosis Family history of cirrhosis Skin hyperpigmentation Diabetes mellitus Arthralgias Primary sclerosing cholangitis Bloody diarrhea Erythema nodosum History of inflammatory bowel disease Pruritus 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 Dermatitis herpetiformis Iron deficiency Rash

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

Risk factors for viral hepatitis should also be identi- cohort [11]. Coexisting hereditary hemochromatosis (HH) fied. The most common risk factors for hepatitis Cvirus accelerates liver fibrosis due to HCV infection or alcohol (HCV) infection in the United States are injection drug but infrequently causes advanced fibrosis in the absence use, blood transfusions prior to 1992 [8], and needlestick of a cofactor [12]. A strong family history of liver disease occupational exposures. Additional risk factors have also or cirrhosis raises suspicion for HH, and a personal his- been recognized, including the sharing of snorting straws tory of arthralgias, skin discoloration, or diabetes mellitus [9] and high-risk sexual behaviors, such as anal recep- is suggestive of underlying HH in the appropriate clinical tive intercourse [10]. All persons born in the United States setting. between the years 1945 and 1965 are at increased risk of Although hepatitis B is a vaccine-preventable disease, chronic hepatitis C relative to the remaining population, only 32.2% of US-born persons aged 19–49 have received with an estimated prevalence of 3.25%, prompting the ≥3 doses of the hepatitis B virus (HBV) vaccine. Injection Centers for Disease Control and Prevention to recommend drug use and high-risk sexual behaviors remain important screening for HCV infection for all persons in this birth risk factors for HBV infection in the United States, and the 6 Part I: Overview: Clinical Fundamentals of Hepatology

Box 1.1 AUDIT-C questionnaire. Box 1.2 The National Cholesterol Education 1 How often do you have a drink containing alcohol? Program Adult Treatment Panel III criteria a Never for the metabolic syndrome. b Monthly or less Three of the following five clinical characteristics must be present: c 2–4 times per month 1 Abdominal obesity (waist circumference >101 cm (40 inches) in d 2–3 times per week men, >89 cm (35 inches) in women) e 4 or more times a week 2 Serum triglycerides >150 mg/dL 2 How many standard drinks containing alcohol do you have on a 3 Serum high-density lipoprotein level <40 mg/dL in men or typical day? <50 mg/dL in women a 1or2 4 Blood pressure ≥130/85 mmHg b 3or4 5 Fasting plasma glucose ≥100 mg/dL c 5or6 d 7to9 e 10 or more 3 How often do you have six or more drinks on one occasion a Never symptomatic, persons with PBC commonly present with b Less than monthly fatigue (estimated frequency of 20–85%) and pruritus (20– c Monthly 75%). Other clinical features include jaundice (10–60%), d Weekly osteoporosis (35%), and an elevated serum cholesterol e Daily or almost daily level (>75%), with a correlation between the degree Pointsareassignedforeachanswer:a–1,b–2,c–3,d–4,e–5.A of cholesterol elevation and the severity of cholestasis score of ≥4 is identifies persons with alcohol abuse with sensitivity of [18,19]. From 5% to 10% of persons with PBC may have 0.79 and specificity of 0.56 in men. negative testing for antimitochondrial antibodies, thereby increasing the importance of clinical assessment. Autoimmune hepatitis, like PBC, is seen more commonly in women than men and in persons with con- incidence of HBV infection is high in areas where injection comitant autoimmune diseases. A wide spectrum of drug use is common [13]. Foreign-born persons are also at autoimmune diseases has been associated with autoim- higher risk of harboring HBV infection, with the highest mune hepatitis, most commonly autoimmune thyroiditis rates, up to 33%, in persons of Asian descent [14]. There- and type 1 diabetes mellitus [20]. The clinical presenta- fore, high-risk sexual behaviors, injection drug use, and tion of autoimmune hepatitis varies from asymptomatic country of origin are all important elements of a patient’s disease to fulminant hepatitis in 25% of cases. In patients history for assessing the risk of chronic HBV infection. with symptomatic disease, joint symptoms and fatigue NAFLD has emerged as the most prevalent chronic liver are common [21]. condition in the United States, with estimated prevalence Luminal gastrointestinal diseases may manifest with rates of 30–46% of adults [15] and 70% of obese or diabetic liver biochemical test abnormalities and evidence of persons [16]. The clinical burden of NAFLD in the United chronic liver injury. For example, up to 40% of patients States is staggering, and it is therefore critical to attempt with untreated celiac disease have elevated serum amino- to distinguish persons who have nonalcoholic steatohep- transferase levels [22]. A history of altered bowel habits, atitis (NASH), and who are thus at risk for progressive iron deficiency, weight loss, rash, or osteoporosis should inflammation, fibrosis, and cirrhosis, from those with sim- raise suspicion for underlying celiac disease. A history of ple steatosis (fatty liver) alone. Important risk factors for bloody diarrhea, rash, or known history of inflammatory NASH include age >40 years, body mass index (BMI) ≥30, bowel disease suggests the possibility of primary scleros- metabolic syndrome (Box 1.2), type 2 diabetes mellitus, ing cholangitis. and persistently elevated serum aminotransferase levels Other less common liver diseases may also be sug- [17]. gested by careful questioning. For example, a history

After drugs and toxins, viral hepatitis, and NAFLD, of pulmonary symptoms suggests α1-antitrypsin defi- autoimmune and autoinflammatory liver diseases com- ciency or sarcoidosis. In a young patient with a comor- prise most of the remaining causes of chronic liver injury. bid neurologic or psychiatric disturbance, Wilson dis- In middle-aged women with an elevated alkaline phos- ease should be considered. The neurologic features of phatase level, primary biliary cholangitis (PBC, formerly Wilson disease relate in part to basal ganglia dysfunction primary biliary cirrhosis) is a principal consideration. and include akinetic rigid syndrome similar to parkin- PBC is much more common in women than men and is sonism, psuedosclerosis with tremor, ataxia, and dysto- associated with other autoimmune diseases, in partic- nia. Dysarthria, dysphagia, incoordination, and spasticity ular Raynaud’s disease and Sjogren’s¨ syndrome. When are typical. Migraines, insomnia, seizures, and depression Chapter 1: History Taking and Physical Examination 7 may occur. Recurrent unexplained fever suggests granu- bilirubin levels exceed 2.5 mg/dL [23]. Kayser–Fleischer lomatous hepatitis in a patient with a cholestatic pattern rings, caused by deposition of copper in Descemet’s of liver biochemical test results. membranes of the cornea, and “sunflower” cataracts may occasionally be seen in patients with Wilson disease but Physical examination often require slit-lamp examination for detection. Persons The physical examination in the patient with abnormal who abuse alcohol or drugs may have poor dentition. liver biochemical test results or known liver disease seeks not only to provide clinical clues to the etiology of under- Skin lying liver injury, but also to determine whether there may Liver diseases have a myriad of cutaneous manifestations, be underlying advanced fibrosis or cirrhosis. Indeed, upto and after the general inspection of the patient, a careful one third of patients who present for an outpatient hepa- skin examination may yield important insights (Fig. 1.1). tology consultation already have underlying cirrhosis [2]. The examiner may begin with the patient’s hands and Vital signs provide initial important data, particularly nails. Palmar erythema is a result of increased circulat- in identifying risk factors for NAFLD, which is sug- ing estradiol levels and raises suspicion for cirrhosis. A gested by an elevated BMI, increased waist circumference, number of nailbed findings may be found in patients with and hypertension. Conversely, hypotension or a widened liver disease. Terry’s nails are characterized by a proximal pulse pressure is often seen in the vasodilatory state asso- white discoloration of the nail and are associated with cir- ciated with advanced cirrhosis. rhosis. Terry’s nails and palmar erythema are not sensi- Inspection of the patient begins with a determination tive for cirrhosis but are quite specific (with specificities whether the patient appears older than his or her stated of 97% and 91%, respectively) [24,25]. Blue lunules, due to age, the muscles are atrophied (e.g., temporal wasting), copper deposition, may be seen in Wilson disease. Club- suggesting the catabolic state of cirrhosis, the parotid bing of the fingernails and central cyanosis, most com- glands are enlarged, as is typical of alcoholic cirrhosis, monly associated with pulmonary disease, may be found and frank jaundice is present. Jaundice is assessed most in patients with cirrhosis, especially those with hepatopul- readily by inspection of the eyes: in patients with scleral monary syndrome [24]. Dupuytren’s contractures, charac- icterus (or, more accurately, conjunctival icterus), the terized by fibrosis of the palmar fascia that pulls oneor whites of the eyes appear yellowed due to deposition more fingers into flexion, is associated with alcohol use, of bilirubin in the conjunctivae, generally when serum although it does not correlate with the severity of liver

(B) (C)

(A) (D) (E)

Figure 1.1 Cutaneous findings in cirrhosis. (A) Palmar erythema. (B) Terry’s nails. (C) Clubbing. (D) Xanthelasma. (E) Spider telangiectasia. d(C–E: Reproduce from [24] with permission from John Wiley & Sons.) 8 Part I: Overview: Clinical Fundamentals of Hepatology disease in alcoholics [26]. Spider telangiectasias are cuta- examination, the patient should remain supine with the neous vascular lesions characterized by “spidery” ves- legs flexed at the knee to relax the anterior abdominal sels that radiate from a central arteriole and that may be musculature. seen with acute or chronic liver disease. When pressure Auscultation of the abdomen classically has involved is applied to the lesion it blanches and then fills from placing the stethoscope over all four quadrants to assess the central arteriole outward. Spider telangiectasias are bowel sound activity and additionally in the flanks and found in the distribution of the superior vena cava and back to detect bruits. The reliability of auscultation to are more often anterior than posterior on the body. Addi- determine clinical pathology from bowel sounds, how- tionally, they have been associated with clinically sig- ever, has come into question, with one study finding nificant portal hypertension in the setting of established low sensitivity and poor inter-rater reliability [30]. Nev- cirrhosis [27]. ertheless, a number of auscultatory findings have been Specific causes of chronic liver disease may have char- described in the setting of liver disease. Portosystemic acteristic cutaneous manifestations. PBC, in particular, has shunting may be associated with a low-pitched continu- associated dermatologic manifestations, and, in one series ous venous hum, and a continuous hum at the umbilicus, [28], nearly 40% of patients with PBC presented with known as the Cruveilhier–Baumgarten bruit, is thought a dermatologic complaint. Typical findings include xan- to be due to shunting in the abdominal wall due to a thelasma and xanthomas, which are yellowish deposits patent umbilical vein [31]. Auscultation has also been uti- near the inner canthus of the eyelids and on the palms lized to determine the liver span by the scratch test (see of the hands, respectively. They reflect the dyslipidemia later). Rare auscultatory findings include a harsh systolic associated with PBC, and although uncommon, they are bruit over the liver in patients with hepatocellular carci- quite specific for advanced PBC among patients with noma or alcoholic hepatitis and a peritoneal friction rub liver disease. Hyperpigmentation, excoriations, and skin (like two pieces of leather rubbing together) in patients lichenification due to pruritus and scratching are also with perihepatitis or hepatocellular carcinoma or after a common skin findings in patients with PBC and other liver biopsy. A rub over the spleen may be heard after chronic cholestatic disorders [24]. Other less common a splenic infarct. Rarely, continuous murmurs are heard skin findings related to liver disease include a slate gray with a hepatic hemangioma or an arteriovenous fistula in or bronze coloration of the skin in HH, nonpalpable the splanchnic circulation. purpura due to HCV-related mixed cryoglobulinemia, a An estimation of liver span is an important element of vesicular rash on the dorsum of the hands in porphyria the clinical examination of the patient with liver disease cutanea tarda due to HCV infection and iron overload, [29]. The liver span may vary with a person’s height and dermatitis herpetiformis related to underlying celiac and gender, and the liver size generally correlates with disease. body size and liver shape correlates with body habitus. The average liver diameter in healthy persons has been Abdomen estimated to be 7 cm in women and 10.5 cm in men [32]. Situated in the right upper quadrant, the liver may infre- In general, hepatomegaly is unlikely if the liver span by quently extend 5–6 cm across the midline to the left upper gentle percussion is less than 12 cm [29]. An enlarged quadrant. The upper convex surface is tucked under the liver may be seen in acute and chronic hepatitis, whereas diaphragm at the level of the fifth or sixth anterior rib. the liver often shrinks as fibrosis progresses and cirrhosis The lower surface is concave, with the gallbladder tucked advances. Marked enlargement of the liver may be seen in it, and generally not palpable in healthy persons. The in patients with primary or metastatic hepatic tumors liver edge runs parallel with the right costal margin. Res- (including lymphoma), alcoholic liver disease, severe piration drives the liver downward with an excursion of heart failure (with a pulsatile liver in tricuspid regurgita- 2–3 cm. There is great variability in the shape of the liver tion), and infiltrative liver diseases such as amyloidosis, [29]. myelofibrosis, and chronic myelogenous leukemia. Tech- Although abdominal imaging is often relied on to sup- niques employed to determine liver span include the port the abdominal examination findings in the clini- scratch test and percussion. The underlying principle of cal evaluation of liver disease, a number of important the scratch test is that the solid liver will transmit sound findings are best determined by simple inspection, aus- with a greater intensity than the other, hollow, viscera cultation, and palpation. Abdominal, and specifically of the abdominal cavity. The stethoscope is placed just hepatic, tenderness can only be elicited by direct exam- below the xyphoid process. The clinician begins by gently ination. Inspection of the abdomen may reveal signs of stroking the skin of the lower right abdomen in the mid- decompensated liver disease (see later), such as disten- clavicular line and advancing steadily upward until the tion, bulging flanks, or distended abdominal veins on sound heard through the stethoscope abruptly increases the anterior abdominal wall. To facilitate the abdominal in volume – the point thought to represent the lower edge Chapter 1: History Taking and Physical Examination 9 of the liver. This finding is quite reliable between examiners but may not reliably demonstrate the true location of the liver edge when compared with ultrasonography [33]. Percussion of the abdomen is commonly utilized to determine the liver span and can also be used to assess splenomegaly. To map the size of the liver, both the upper and lower borders should be percussed lightly in the midclavicular line. After the liver span is assessed in the midclavicular line, percussion may be extended into the epigastrium. In the midclavicular line, the upper border is near the right nipple and the lower border lies just under the right costal margin. Dullness to percussion that is present in the epigastrium raises concern for left hepatic lobe hypertrophy, which is often seen in cirrhosis [34]. With left hepatic lobe hypertrophy from cirrhosis, the liver span in the midsternal line will be similar to, or greater than, the liver span in the midclavicular line (Fig. 1.2). Splenomegaly also raises concern for cirrhosis and portal hypertension and is generally assessed by palpation, but percussion may also be performed. Two percussion techniques have been used: percussion in the space of Traube and elicitation of Castell’s sign. The space of Traube is defined as the sixth rib superiorly, the left midax- (A) illary line laterally, and the left costal margin inferiorly. With the patient supine, this area is expected to be resonant, or tympanitic; dullness suggests splenomegaly. Compared with ultrasonography, this maneuver has a sensitivity and specificity of 62% and 72%, respectively. To elicit Castell’s sign, the left anterior axillary line is percussed at the lowest intercostal space. The area is normally resonant. Splenomegaly is diagnosed if the percussion note becomes dull with deep inspiration, when the enlarged spleen descends. Castell’s sign has a sensitivity and specificity of 82% and 83%, respectively [35]. Palpation can often detect splenomegaly and determine the contour and tenderness of the liver edge, but the detection of the liver by palpation does not correlate closely with liver size by imaging, and in some cases a nonpalpable liver may still be enlarged [29]. When splenomegaly is (B) present, the enlarged spleen can be felt by pressing gen- Figure 1.2 Percussion of the liver in cirrhosis. (A) Image of the abdomen tly with the right hand just below the left costal mar- and chest showing location of the liver and spleen. In healthy persons, the gin in the anterior axillary line, while the examiner’s left liver descends 1–3 cm with deep inspiration. (B) In cirrhosis, there may be hand is placed in the left flank for counterpressure. The shrinking of the right lobe of the liver with enlargement of the left and patient is asked to inspire deeply, and the spleen tip is caudate lobes. This results in the finding of an enlarged liver span in the sought between the subcostal margin and the umbilicus. midsternal line and palpation of the liver edge in the epigastrium. (Reproduced from [34] with permission from Taylor and Francis, If the spleen edge is not detected, the examination may www.tandfonline.com.) be repeated with the patient in the right lateral decubitus position with the knees flexed. Conversely, in the setting of massive splenomegaly, the spleen edge may be missed To palpate the liver edge, the examiner begins palpation if palpation does not begin in the lower abdomen above in the right lower quadrant and proceeds gently upward the iliac crest. Detection of splenomegaly by palpation to the expected lower edge of the liver at the right costal implies that the spleen size is at least two- to three-fold margin. A normal liver may rest entirely below the rib above normal. cage; to assist with palpation of the liver the examiner’s 10 Part I: Overview: Clinical Fundamentals of Hepatology

Table 1.2 Findings on percussion and palpation of the liver in various conditions.

Condition Liver size Contour and firmness Tenderness

Acute hepatitis Enlarged Smooth May be quite tender Chronic hepatitis May be enlarged Firm May or may not be tender Cirrhosis Small, relatively large left lobe Firm, may be nodular Nontender Right heart failure Enlarged Firm Tender Neoplasms of the liver Enlarged Hard, nodular Nontender

left hand may be placed posteriorly beneath the patient Table 1.3 Sensitivity and specificity of various physical examination below the twelfth rib to lift the liver gently upward, and findings for the detection of cirrhosis. the patient may be asked to take a deep breath as the liver Finding Sensitivity Specificity edge descends inferiorly with deep inspiration. In healthy persons, the liver edge may be felt when the patient takes Firm liver edge 0.73 0.81 a slow, deep inspiration with relaxed abdominal muscles. Spider telangiectasias 0.46 0.89 In obese persons, the “hooking” technique may be help- Palmar erythema 0.46 0.91 ful. With the examiner to the right of the patient’s chest, Terry’s nails 0.43–0.44 0.97–0.98 both hands are placed, side by side, on the right upper Decreased body hair 0.36 0.97 Splenomegaly 0.34 0.90 quadrant below the border of liver dullness with the fin- Jaundice 0.28 0.93 gers curled around the costal margin. The liver edge is Gynecomastia 0.18–0.58 0.97–0.98 felt when the patient takes a deep breath. Riedel’s lobe is an anatomic variant of the liver in which the right lobe Data from [25]. extends in a tongue-like projection into the right lower quadrant and can be palpated in a healthy person. As noted earlier, palpation of the liver in the epigastrium is quite specific for cirrhosis but have poor sensitivity. The suggestive of advanced hepatic fibrosis. The size, contour, presence of spider telangiectases, palmar erythema, and a firmness and presence or absence of tenderness of the liver firm liver edge on palpation are among the most sensitive provide insight into the underlying disease (Table 1.2). findings. With pressure in the right upper quadrant, the examiner may also assess the patient for hepatojugular reflux suggestive of congestive hepatopathy (and exclusion of hep- Jaundice atic vein thrombosis). A pulsatile liver is characteristic of The patient with frank jaundice requires a different tricuspid regurgitation and may be seen in constrictive diagnostic formulation and clinical approach from that pericarditis. for the patient with asymptomatic elevations of the serum Although laboratory testing, imaging, and in some liver enzyme levels. Categories of diagnostic possibilities cases liver biopsy are required to confirm a diagnosis of include extrahepatic biliary obstruction, intrahepatic cirrhosis, physical examination findings may heighten biliary disease, and hemolysis or other causes of indirect clinical suspicion and identify patients for whom a (unconjugated) hyperbilirubinemia. Whether jaundice is liver biopsy may be warranted to diagnose cirrhosis. due to conjugated or unconjugated hyperbilirubinemia Several physical examination findings in patients with can be hinted at clinically by eliciting a history of darken- cirrhosis are thought to be related to impaired intrahep- ing of the urine, because unconjugated bilirubin cannot atic metabolism of androstenedione, with a resulting be excreted by the renal tubules and does not result in increase in the peripheral conversion of andostenedione dark urine. In the past, it was observed that hemolytic to estradiol and estrogen. These findings include palmar jaundice has a light yellow color on eye examination, erythema, spider telangiectasias, gynecomastia and tes- whereas hepatic jaundice is orange-yellow; however, ticular atrophy in men, and diminished body hair. The the distinction is best assessed with biochemical testing. consequence of severe hepatocellular dysfunction and When jaundice is due to direct hyperbilirubinemia, the portal hypertension are often more readily apparent and evaluation focuses on extrahepatic biliary obstruction, include ascites, caput medusae, an umbilical hernia, aster- severe hepatocellular injury, and intrahepatic cholestasis, ixis, and frank jaundice (see later). The sensitivity and including rare disorders of bilirubin metabolism such as specificity of physical findings for the clinical detection of Dubin–Johnson or Rotor syndrome (Table 1.4). Fulminant cirrhosis are summarized in Table 1.3. Most findings are Wilson disease is rare but should be considered in young Chapter 1: History Taking and Physical Examination 11

Table 1.4 Differential diagnosis of direct hyperbilirubinemia.

Cause of jaundice Historical elements Physical examination findings

Extrahepatic biliary obstruction Choledocholithiasis Epigastric or RUQ abdominal pain Fever Ascending cholangitis Fever, chills Palpable, tender gallbladder Benign biliary stricture Acholic stools Abdominal tenderness Malignant obstruction Weight loss Cachexia Pancreatic cancer Malaise, fatigue Courvoisier’s sign (see text) Anorexia Hepatomegaly Pruritus Ascites Diabetes mellitus Smoking Prior pancreatitis Severe hepatocellular injury Acute viral hepatitis Anorexia, malaise Fever Autoimmune hepatitis Rash Tender hepatomegaly Fever Reticular rash Arthralgias Acute alcoholic hepatitis History of heavy alcohol use Fever Recent binge drinking Tender hepatomegaly Ascites Drug-induced liver injury New medication use Hepatomegaly Supplement use Excoriations (if pruritus) Ischemic hepatitis Critical Illness, hypotension Critically ill patient Decompensated cirrhosis Prior history of liver disease Muscle wasting Increasing abdominal girth Ascites Pedal edema Asterixis Altered mental status Intrahepatic cholestasis } Primary biliary cholangitis Pruritus, fatigue, history of IBD Excoriations, xanthoma, xanthelasma, Primary sclerosing cholangitis erythema nodosum Familial or benign intrahepatic cholestasis Pruritis, jaundice — Infiltrative diseases Weight loss Hepatomegaly Metastatic malignancy Fatigue Palpable abdominal masses Sepsis Critical illness Critically ill patient TPN Mechanical ventilation Inherited disorders of bilirubin metabolism Dubin–Johnson syndrome Mild, chronic icterus Pruritus Jaundice Rotor syndrome Other bile transport disorders

IBD, inflammatory bowel disease; RUQ, right upper quadrant; TPN, total parenteral nutrition. persons, particularly females, with jaundice and acute pancreatic cancer [37]. On physical examination, wasting hepatic dysfunction. and cachexia may be evident. In addition to jaundice, skin For the patient presenting with the insidious onset of examination may reveal excoriations due to pruritus. A clinically evident jaundice, the clinician must harbor par- suggestive physical examination finding in patients with ticular suspicion for malignant biliary obstruction. In one pancreatic or ampullary cancer is Courvoisier’s sign – series of patients presenting with jaundice, the most com- painless and palpable distention of the gallbladder that mon cause was malignancy, followed by sepsis, alcoholic is thought to result from gradually progressive bile duct liver disease, cirrhosis, and gallstone disease [36]. A his- obstruction. To detect the enlarged gallbladder, the exam- tory of anorexia, weight loss, and vague abdominal dis- iner palpates the angle formed between the lateral edge of comfort may suggest a malignant cause. Pancreatic cancer the rectus abdominus muscle and the right costal margin. is strongly associated with smoking and diabetes mellitus, Courvoisier’s sign, however, is present only in approxi- and an attack of pancreatitis may pre-date the diagnosis of mately 13% of patients presenting with jaundice due to 12 Part I: Overview: Clinical Fundamentals of Hepatology pancreatic cancer; hepatomegaly and jaundice are more Known or suspected compensated or common physical examination findings [38]. Nor is Cour- decompensated cirrhosis voisier’s sign specific for a malignant cause of biliary obstruction. A firm umbilical mass (“Sister Mary Joseph’s The objective of the clinical evaluation of a patient with node”) indicates intra-abdominal malignancy. known cirrhosis or decompensated liver disease is not Gallbladder disease and choledocholithiasis are com- only to determine likely causes of liver injury and con- mon causes of jaundice due to extrahepatic biliary firm evidence of advanced hepatic fibrosis, but alsoto obstruction. Biliary obstruction due to choledocholithiasis assess the patient for complications of cirrhosis (Table 1.5). may be complicated by acute cholangitis, which is char- The natural progression of cirrhosis has been considered acterized clinically by the triad of fever, abdominal pain, to be one of a period of stability with few complications and jaundice (Charcot’s triad), in severe cases complicated followed by decompensation heralded by the onset of by hypotension and altered mental status (Reynolds’ pen- ascites, variceal hemorrhage, or encephalopathy, with an tad). On examination, the right upper quadrant is typ- estimated mean 2-year survival following initial decom- ically tender, and on occasion the gallbladder may be pensation. The prognosis of a patient with cirrhosis may palpable. be further stratified by the type and number of compli- The clinical evaluation of patients with intrahepatic cations. In patients with varices without bleeding, the 5- causes of jaundice parallels the evaluation of abnormal year mortality rate is relatively low at 10%; however, with liver biochemical test levels discussed earlier. A care- additional complications of portal hypertension, the mor- fully taken history of medication and supplement use is tality rate increases to 30%, and with more than one com- required to exclude DILI. The severity of icteric DILI may plication, the 5-year mortality rate approaches 90% [41]. range from asymptomatic jaundice to acute liver failure. The concept of acute-on-chronic liver failure (ACLF) has Acute viral hepatitis presents with jaundice when there been introduced to describe the abrupt onset of multi- is severe hepatocellular injury. Etiologic agents include organ dysfunction in the setting of chronic liver injury, hepatitisA,B,C,D,andEviruses,aswellasEpstein– compensated cirrhosis, or decompensated cirrhosis [42]. Barr virus, herpes simplex virus, and cytomegalovirus. When decompensated cirrhosis is further complicated by When acute hepatitis C presents clinically with jaundice, infectious complications or acute kidney injury, the 1-year immune clearance of the virus is substantially more likely mortality rate has been estimated to be 67% [43]. than when hepatitis C presents without jaundice [39]. Patients with compensated cirrhosis may have few or Symptoms of acute viral hepatitis may include anorexia, no symptoms related to liver disease or symptoms specific malaise, fever, rash, and abdominal pain. In addition to to the underlying cause of cirrhosis. When present, symp- assessing for risk factors for hepatitis B and C, a his- toms may include fatigue, muscle wasting, easy bruising tory of recent travel, unusual food exposures, and sick or bleeding, and subtle cognitive changes. With decom- contacts should be elicited. The clinical presentation of pensation, patients often present to medical attention with autoimmune hepatitis may be similar to that of acute viral overt clinical symptoms pointing to the nature of the com- hepatitis but with negative serologic testing for a viral plicating event (e.g., variceal hemorrhage, ascites). etiology. Alcoholic hepatitis is an acute and potentially severe form of alcoholic liver disease and may occur with History taking or without underlying advanced fibrosis. Like alcohol- The patient with cirrhosis may present for routine exam- related cirrhosis, alcoholic hepatitis is associated with ination or with specific clinical complaints related to excessive alcohol use over a prolonged period of time. decompensation. In the asymptomatic patient, the focus A history of a recent increase in alcohol intake or binge of the history is mainly to ensure that appropriate pre- drinking and the type of alcohol imbibed (beer and spir- ventive lifestyle measures are being followed. Abstinence its more than wine) are also risk factors for acute alco- from alcohol is recommended for all patients with cirrho- holic hepatitis [40]. In addition to jaundice, symptoms sis, irrespective of etiology, and alcohol intake should be may include fever, new-onset ascites, and abdominal pain. assessed at each visit. For patients with insulin resistance On physical examination, the patient may or may not have and obesity, which are independently linked to adverse cutaneous stigmata of liver disease but will commonly outcomes in patients with cirrhosis, weight loss and glu- have tender hepatomegaly; ascites and evidence of hep- cose control should be encouraged and monitored. atic encephalopathy may be present. Skin findings may In a patient with cirrhosis with a new complication or include palmar erythema, facial and upper body telang- worsening of a known complication, additional history iectasias, and palmar Dupuytren’s contractures. Jaundice taking should focus on the driving etiology and clinical also may signal decompensation of established cirrhosis, severity of the complication. Ascites may present with the which merits additional evaluation as discussed later. new onset of pedal or leg edema or increasing abdominal Chapter 1: History Taking and Physical Examination 13

Table 1.5 Complications of decompensated liver disease.

Complication Historical elements Physical examination findings

Ascites/edema Weight gain Bulging flanks Ankle swelling Flank dullness Increased abdominal girth Shifting dullness Fluid wave Encephalopathy Sleep–wake cycle reversal Asterixis Personality changes Mental status assessment Inattentiveness Abnormal PHES Confusion Gastrointestinal bleeding: varices, portal Weakness, lightheadedness Fecal occult blood or melena hypertensive gastropathy Melena Hematemesis Jaundice New medication use Scleral icterus Diminished urine output Jaundice Symptoms of infection Weight loss Alcohol use Decreased blood pressure, renal injury Decreased urine output Systolic blood pressure <100 mmHg Dark urine MAP <82 mmHg Lightheadedness Orthostatic hypotension Coagulopathy Epistaxis Ecchymoses Gum bleeding Easy bruising Spontaneous bacterial peritonitis Fevers, chills Fever Abdominal pain Abdominal tenderness Diminished urine output Encephalopathy Evidence of gastrointestinal bleeding

MAP, mean arterial pressure; PHES, Psychometric Hepatic Encephalopathy Score.

girth. In a patient with the new onset of ascites, poten- because it may signal the development of ACLF. Care- tial contributors include excessive or recurrent alcohol ful questioning regarding any possible triggers, such as use, poor glucose control, increased sodium intake, new medications or supplements, alcohol use, evidence heart or renal failure, or interval development of portal of infection, abdominal pain, decreased urine output, vein thrombosis. In a patient already on diuretic therapy, or increased abdominal girth, should heighten clinical recurrent ascites suggests medication nonadherence, poor concern. dietary sodium restriction, or progressive decompensation. Spontaneous bacterial peritonitis is a feared compli- Physical examination cation of decompensated cirrhosis, with clinical suspicion Careful assessment for objective evidence of complica- raised by abdominal pain and fever, although deteriora- tions of cirrhosis should be undertaken to guide manage- tion in liver function may be the only manifestation. ment. For patients already receiving medical care for liver In a patient with new overt hepatic encephalopathy, disease, the physical examination may also detect evi- careful assessment for potential precipitants is required, dence of adverse events resulting from the medical man- including use of new or sedating medications, infections, agement of liver disease. gastrointestinal bleeding, electrolyte imbalance (particu- Determination of the vital signs is of great value. Given larly hypokalemia), dehydration, or new renal impair- the mortality associated with infectious complications of ment. The clinician should review all drugs, including liver disease, fever in a patient with cirrhosis merits urgent over-the-counter medications, taken by the patient and evaluation, particularly if ascitic fluid is evident on clin- ask about a recent history of fever, abdominal pain, ical examination. The patient’s blood pressure, includ- melena, hematochezia, pedal edema, increasing abdom- ing orthostatic vital signs, should be assessed; cirrhosis inal girth, and diminished urine output. itself results in a vasodilatory state that may cause rela- The new onset of jaundice in a previously well- tive hypotension and that can be potentiated by medica- compensated patient with cirrhosis is a cause for concern tions such as nonselective beta receptor antagonists used 14 Part I: Overview: Clinical Fundamentals of Hepatology to prevent variceal bleeding. Nonselective beta recep- the most superior margin of abdominal dullness with the tor antagonists may increase mortality in patients with patient in the supine position is identified. The transition decompensated cirrhosis [44], and it has been suggested point between tympany and dullness represents the intra- that beta receptor antagonists be discontinued when sys- abdominal air–fluid boundary. The patient is then asked tolic blood pressure falls below 90 mmHg or mean arte- to turn toward the examiner and assume a right lateral rial pressure falls below 82 mmHg, the serum sodium is decubitus position, and the area of dullness is again per- less than 130 mEq/L, or acute kidney injury has devel- cussed. If intra-abdominal free fluid is present, the area of oped [45]. dullness will shift toward the umbilicus. This maneuver Careful monitoring of weight is also important in the should be performed with the patient on the left side as assessment of the patient with cirrhosis. Rapid weight well to confirm the presence of ascites. Finally, the exam- gain raises concern for volume retention and the devel- iner may attempt to elicit a fluid wave (Fig. 1.3). The fluid opment of ascites, whereas weight loss in a patient with wave requires either a second examiner or the participa- cirrhosis without ascites raises concern for malnutrition tion of the patient, who places the ulnar surface of one or the development of malignancy. For the patient with or both hands firmly in the midline to hold subcutaneous ascites, regular monitoring of weight is required to assess adipose tissue in place. The examiner then taps one flank the adequacy of the diuretic regimen and of dietary with one hand while the other hand is placed gently on the sodium restriction. contralateral flank. Detection of an impulse by the exam- The clinician should assess the patient with cirrhosis for iner’s second hand is considered to be a positive sign for scleral icterus or frank jaundice. Although there are lim- the presence of fluid. ited objective measures, subjective assessment should be These physical examination maneuvers all have mod- made of muscle mass or diminishing strength. The parotid erately good sensitivity but limited specificity, as detailed glands may be enlarged (as may the lacrimal glands) in Table 1.6 [46]. Diffuse abdominal tenderness in a patient especially in patients with alcoholic cirrhosis. The pun- with ascites raises clinical concern for spontaneous bacte- gent odor of fetor hepaticus, caused by the portosystemic rial peritonitis. shunting of sulfur-containing thiols, may be detected The neurologic examination assumes additional impor- when the patient exhales. A skin examination may reveal tance in the evaluation of the patient with cirrhosis, ecchymoses due to coagulopathy or an increasing num- because the development of overt hepatic encephalopa- ber of spider telangiectasias suggestive of worsening por- thy portends decompensation and poor survival and tosystemic shunting. Normally, the superficial veins of the abdominal wall are barely visible, but in a patient with cirrhosis, venous prominence may reflect inferior vena cava or portal vein obstruction. Pronounced dilatation of the periumbilical veins produces the pattern known as caput medusae. The direction of blood flow in the engorged veins may suggest the site of venous obstruction. Normal flow is away from the umbilicus, and portal hypertension does not alter the direction of flow. On the other hand, obstruction of the inferior vena cava causes upward flow from the lower abdomen, and obstruction of the superior vena cava causes downward flow from the upper abdomen. Blood flow can be assessed by compressing an abdominal wall vein with two fingers several centimeters apart and removing one finger to observe the rate of refilling; the maneuver is repeated with release of the other finger, and the direction of flow is thus determined. A number of maneuvers may be utilized to detect ascites on physical examination. On inspection, bulging flanks may indicate the presence of ascites. Percussion of the abdomen in the supine position detects flank dull- Figure 1.3 The fluid wave test for the detection of ascites. While an assistant (either a second clinician or the patient) places one hand firmly in ness if fluid is present laterally in the dependent areas. the patient’s abdominal midline, the examiner holds one hand still on the In obese patients, it may be challenging to detect bulging patient’s right flank, while the other hand taps or presses firmly but gently flanks and flank dullness, but shifting dullness maybe on the left flank. Detection of an impulse in the right flank indicates the detectable in these persons. To assess for shifting dullness, presence of fluid. Chapter 1: History Taking and Physical Examination 15

Table 1.6 Sensitivity and specificity of physical examination findings for substantial deficits are identified. Despite the reassuring the detection of ascites. clinical examination, covert hepatic encephalopathy can have important impact on quality of life and activities Finding Sensitivity Specificity of daily living. Formal neuropsychological testing is the Flank dullness 0.84 0.59 most robust assessment for covert hepatic encephalopa- Bulging flank 0.81 0.59 thy, although bedside pen-and-paper tests are often used Shifting dullness 0.77 0.72 in practice. The best-validated neuropsychological testing Fluid wave 0.62 0.9 is the battery of tests that comprise the Psychometric Hep- atic Encephalopathy Score (PHES), but the widespread Data from [46]. clinical utility of the PHES has been limited due to its time- intensive nature and the lack of availability of the tools within the test itself [47]. One component of the PHES, the characteristic neurologic findings are seen in patients serial “dotting” test, has been translated into applications with Wilson disease. Hepatic encephalopathy has a broad for a personal computer or mobile device (e.g., the Stroop spectrum of clinical manifestations from mild cognitive test), potentially increasing the feasibility of its routine impairment to coma. Overt hepatic encephalopathy is use in clinical practice. This test, administered alone, often readily apparent in a patient who is agitated, con- has a 68% sensitivity and 98.3% specificity for detecting fused, or somnolent. The West Haven criteria, developed covert or grade I hepatic encephalopathy [48]. The man- in 1977 for the clinical assessment of encephalopathy, agement of covert hepatic encephalopathy is an area of remain widely used in assessing the severity of overt ongoing investigation; although increased vigilance for hepatic encephalopathy (Table 1.7). 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CHAPTER 2 Laboratory Tests, Noninvasive Markers of Fibrosis, Liver Biopsy, and Laparoscopy Michael P. Curry1 & Lennox J. Jeffers2 1Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA 2Hepatology Section, Miami Veterans Affairs Medical Center and University of Miami Leonard School of Medicine, Miami, FL, USA

Key concepts r r Laboratory tests are commonly used as noninvasive tests to screen for Liver biopsy continues to serve as the gold standard in the diagnosis liver dysfunction, monitor known liver disease, determine the severity r and management of liver disease. r of liver cirrhosis and assess response to treatment. Percutaneous liver biopsy is a safe procedure, with a low mortality The most commonly used tests include serum aminotransferases, rate. Safety of the procedure can be enhanced with the addition of r bilirubin, alkaline phosphatase, albumin and prothrombin time. r ultrasound guidance. Elevation in serum aminotransferases indicates a hepatocellular injury In those with contraindications to percutaneous liver biopsy, the pattern, and elevations in alkaline phosphatase and bilirubin indicate transjugular approach is an alternative that offers the added benefit cholestatic liver injury. These patterns can help determine specific of portosystemic pressure gradient measurement. Endoscopic r disease states and guide additional investigations. ultrasound transgastric biopsy is a novel technique that can yield Noninvasive biomarkers of liver fibrosis provide an assessment of liver large cores of liver tissue and has the added advantage of diagnostic r fibrosis and have been validated in chronic viral hepatitis. r upper endoscopy. Noninvasive biomarkers of liver fibrosis are limited by a variable Diagnostic laparoscopy affords the clinician the ability to observe the degree of indeterminate results. gross appearance of the liver, perform directed biopsies, and obtain peritoneal tissue when indicated.

Introduction currently approved by the Healthcare Financing Admin- istration for Medicare reimbursement [1]. Thus, a limited Laboratory evaluation of the hepatobiliary system has an set of blood tests has been considered to be the “classic important role in the diagnosis, monitoring, and assess- liver tests” and include the serum enzyme activities ALT, ment of patients with hepatobiliary diseases. Guidelines AST, ALP,the concentration of total bilirubin, and ALB [3]. produced by the National Academy of Clinical Bio- Serum liver enzyme activities can be divided into markers chemistry (NCAB) and the American Association for of hepatocellular injury (ALT and AST) and cholestasis the Study of Liver Disease (AASLD) have recommended (alkaline phosphatase and serum bilirubin concentra- that the following tests be used to evaluate patients with tion). These do not truly measure the liver function and known or suspected liver disease: aspartate aminotrans- are biochemical measures of liver injury or cholestasis. ferase (AST), alanine aminotransferase (ALT), alkaline Other blood tests that are commonly used to assess the phosphatase (ALP), total bilirubin, direct bilirubin, liver function include serum ALB and prothrombin time total protein, and albumin (ALB) [1]. A survey of 10 (PT) and reflect the synthetic function of the liver. public hospitals and 13 private laboratory networks in Liver tests provide health care providers with a nonin- Australia and New Zealand identified the following tests vasive method to screen for the presence of, and monitor as part of a liver function test profile: ALP, ALT, AST, the course of liver injury. No one liver test enables the γ-glutamyltransferase (GGT), ALB, total protein, total clinician to accurately assess the total functional capacity bilirubin, and globulins [2]. A panel of all of these tests is of the liver. These laboratory tests measure only a limited

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 18 Part I: Overview: Clinical Fundamentals of Hepatology number of functions of the liver. In addition, they are 1. 2 increasingly used to investigate asymptomatic individuals or those with nonspecific symptoms. Isolated abnor- 1 malities of liver function tests (LFTs) in asymptomatic individuals is becoming an increasingly recognized chal- 0.8 lenge for the clinician due to the routine incorporation of liver tests in automated blood chemistry panels. 0.6 Liver tests are also used alone or in combination with clinical parameters to assess the severity of liver dysfunc- 0.4

tion. Many of the predictive models for determining an limits Upper reference individual patient’s prognosis, including the Child–Pugh 0.2

(CP) score for cirrhosis, Maddrey’s discriminant function old) males 25–35 years to (Relative (DF) for alcoholic hepatitis, and the model for end-stage 0 0204060 80 liver disease (MELD) score for prognosis and prioritiza- Age (years) tion of liver transplant candidates, rely on assessments of various liver tests such as prothrombin time, serum biliru- Figure 2.1 Age and gender effect on upper limits of normal for ALT bin, and albumin [4–6]. In addition, serial liver test assess- (circles, males; squares, females). (Reproduced from [1] with permission from the American Association for Clinical Chemistry.) ments are used to monitor the response of treatment in patients with known liver disease, such as is the case with the treatment of autoimmune hepatitis and primary bil- to reduced nicotinamide adenine dinucleotide (NAD). iary cholangitis. NADH can absorb light at 340 nm and thus the loss of absorptivity, measured spectromorphometrically, yields a measurable result. Tests used for detection of injury The current upper limit of normal (ULN) for ALT and to hepatocytes AST is usually set at around 40 IU/L by most laboratories, although there are slight variations among different Aminotransferases laboratories. AST is higher than ALT in children until The activity of serum aminotransferases (AST and ALT) in approximately age 15 years in males and age 20 years the liver is ∼7000- and 3000-fold higher than serum activi- in females. In adults, ALT activity is higher than AST ties, respectively, and they are sensitive indicators of liver activity and both are higher in males than in females. At cell injury. Both ALT and AST are present in the serum at approximately 60 years of age AST and ALT activity is low concentrations of 30–40 IU/L. AST is predominantly equal with no gender difference (Fig. 2.1). Because upper found in the heart, liver, skeletal muscle, kidney, brain, limit references vary little between ages 25 and 60, there pancreas, lung, leukocytes, and erythrocytes, whereas is no need for age-adjusted reference limits in this popu- ALT is predominantly found in the liver and the kidney lation. However, separate adjusted limits are needed for with lesser amounts in the heart and skeletal muscle. children and older adults [8]. The current ULN were com- ALT is more specific marker for liver tissue injury than puted in the 1980s when ALT testing was introduced as a AST [1,7]. ALT is exclusively found in the cytoplasm of surrogate marker for screening for non-A, non-B hepatitis the cell while AST is present in both mitochondria and among blood donors. As with most clinical laboratory cytoplasm. ALT and AST concentration in bile are very tests, the normal range was the mean of values from a low and almost nonexistent in urine and it is believed that “healthy group of individuals” ± 2 SD (97.5th percentile) the enzymes are cleared from the blood by the reticuloen- [9]. The ULN reference was established before testing was dothelial system. These enzymes catalyze the transfer of available for hepatitis C and the “healthy population” α-amino groups from aspartate and alanine to the α-keto likely also included some patients with nonalcoholic fatty group of ketoglutaric acid to generate oxalacetic and liver disease (NAFLD). In the past there has been a wide pyruvic acids, which are important contributors to the range of ULN for ALT with two-fold degree of variability citric acid cycle. Both AST and ALT require pyridoxal-5′- between laboratories. The reasons for the marked vari- phosphate (P-5′-P) for maximal activity, and deficiency ation have included the use of different equipment and in P-5′-P affects ALT greater than AST. The most specific reagents by different laboratories. However, it is impor- method for measuring ALT and AST activity in the serum tant to stress that there is more variation between labo- relies on the formation of pyruvic acid and oxaloacetic ratories than between analyzers, and that the reference acid, the product of aminotransferase, and coupling with populations from which ULN is defined have often been lactate and maleate, a reaction that results in the reduction poorly characterized and may have included persons with of oxidized nicotinamide adenine dinucleotide (NADH) liver disease [10]. A multinational study found very minor Chapter 2: Laboratory Tests 19

Table 2.1 The level of ALT is independently and highly associated with male sex and BMI, and weakly associated with age and with negatively associated with smoking [13].

Variable Regression coefficient Standard error T-value Significance

Male 0.118 0.107 10.9 0.0001 gender BMI 0.177 0.018 9.34 0.0001 Age 0.012 0.015 2.39 0.02 Smoker −0.242 0.108 −2.21 0.03 R2 0.216

differences between three models of auto-analyzers for a for men and 22 IU/L for women [10]. In addition to deter- reference sample with an ALT activity of 39.7 IU/L. Thus mining the ULN for ALT to define the presence or absence differences in laboratory procedures explain only part of of liver disease, an elevation in serum ALT has been asso- the difference in reference limits between laboratories. ciated with poor outcomes. In a large, population-based In a separate study of 11 academic centers used by the study from South Korea, serum ALT activity measured Nonalcoholic Steatohepatitis Clinical Research Network at baseline has been correlated with subsequent mortal- (NASH CRN), the primary factors identified in variability ity. There is a 2.9-fold increase in liver-related mortality of the ALT ULN were attributed to the different character- for those men with an ALT of 20–29 IU/L and a 9.5-fold istics of the reference cohorts used by the individual labo- increase in mortality in those with ALT of 30–39 IU/L ratories to define their own reference ranges rather than when compared with men who had an ALT of <20 IU/L. interanalyzer variation [10,11]. In addition, aminotrans- In patients with liver disease, ALT and AST are released ferase levels will fluctuate over time. In a study of 1864 from the hepatocyte into the serum, resulting in increased individuals who had two assessments of ALT and AST, a levels. The differential diagnosis of elevated ALT and AST mean of 18 days apart, approximately one third of indi- is broad and includes disorders such as acute and chronic viduals with an initial abnormal ALT or AST were reclas- hepatitis (viral, ischemic, drug and toxin-induced), cir- sified as having a normal test on follow-up [12]. Thishas rhosis of all causes, heart failure and venous outflow caused some to question the validity of the ULN for serum obstruction, granulomatous disease, malignant infiltra- aminotransferases. Piton et al. demonstrated that ALT tion and biliary obstruction. Increases in ALT and AST was independently associated with male gender and body are among the first laboratory abnormality in patients mass index (BMI) and that these two factors accounted with an acute hepatitis. In patients who develop jaun- for 22% of the ALT variability [13]. They proposed that dice as a consequence of the liver injury, the bilirubin the ULN in clinical practice and clinical research should increase usually occurs approximately 1 week after first be redefined based on gender and BMI (Table 2.1). Simi- elevation in ALT and AST. The degree of elevation in larly, a retrospective study of Italian blood donors calcu- ALT and AST can provide some insight into the etiol- lated the ALT ULN in a population of patients with the ogy of the liver injury. Marked elevations in ALT and lowest risk for subclinical disease by stratifying patients AST to values of >15 times ULN are typically seen with with normal BMI (<25 kg/m2); normal serum triglyc- an acute hepatitis caused by viral infection, drug- or erides (<200 mg/dL), cholesterol (<22 mg/dL), glucose toxin-induced hepatitis (acetaminophen toxicity, poison- (<105 mg/dL) and absence of concurrent medications to ing due to ingestion of Amanita phalloides), autoimmune 30 IU/L for males and 19 IU/L for female at the 95th hepatitis, ischemic hepatitis (or other vascular events such percentile [9]. The authors hypothesize that undiagnosed as Budd–Chiari syndrome or sinusoidal obstruction syn- hepatitis C virus (HCV) infection has played an impor- drome (SOS), HELLP (hemolysis, elevated liver enzymes, tant role in the previous overestimates of ALT thresholds and low platelet count) syndrome and fatty liver of preg- for liver disease. In order to determine an ALT ULN that nancy. Moderate elevations in ALT and AST to values would differentiate individuals with hepatitis HCV infec- >6 < 15 times ULN are seen in patients with chronic liver tion from those with the lowest risk of having liver dis- disease such as chronic viral hepatitis, hepatic conges- ease, Ruhl et al. used the National Health and Nutrition tion caused by heart failure, Wilson disease, and some Examination Survey (NHANES) data collected between cases of autoimmune hepatitis. Mild elevations of ALT 1999 and 2008 to identify individuals without HCV and at and AST <6 ULN are typically seen in patients with alco- lowest risk for liver disease by excluding those with hep- holic hepatitis, nonalcoholic hepatitis, hemochromatosis, atitis B virus (HBV), diabetes, alcohol consumption, and chronic viral hepatitis, cirrhosis, and malignant infiltra- obesity and determined that the ULN ALT was 29 IU/L tion of the liver, bile duct obstruction, and cholangitis. 20 Part I: Overview: Clinical Fundamentals of Hepatology

There are rare cases of acute bile duct obstruction caused Lactate dehydrogenase by stone impaction at the lower end of the common bile Lactate dehydrogenase (LDH) is a ubiquitous cytoplasmic duct in which ALT and AST can be elevated to >15 ULN. enzyme. There are five isoenzymes that are measurable by In most forms of liver disease the ALT is higher than electrophoresis. LDH reversibly catalyzes the conversion the AST, but there are a few instances when the AST is of lactate and NAD to pyruvate and NADH. Serum LDH higher than the ALT. Serum AST is typically elevated to activity is very high in patients with ischemic hepatitis a level of 2–6 times ULN in severe alcoholic hepatitis. and an ALT/LDH ratio of 1.5 differentiates viral hepati- In 70% of patients with alcoholic hepatitis the AST : ALT tis from ischemic hepatitis with a sensitivity of 94% and a ratio is higher than 2 and ratios >3 are highly suggestive specificity of 84% [16–18]. of alcoholic liver disease [14]. This increased ratio of AST to ALT is possibly related to a deficiency of ′P-5 -P in Enzymes for detection of cholestasis patients with alcoholic liver disease. P-5′-P is a necessary component in the synthesis of ALT and a deficiency may Alkaline phosphatase result in lower ALT levels. Additionally, researchers have The term cholestasis is derived from the Greek words identified the presence of AST–immunoglobulin (Ig) com- chole, which means bile, and stasis, meaning standing still. plex (macro-AST) in patients with chronic liver disease. Cholestasis occurs because of either a defect in bile syn- The presence of AST–IgA complex was more frequently thesis, bile secretion, or from obstruction to bile flow [19]. seen in patients with alcoholic liver disease than in those Serum ALP activity is the traditional indirect marker of with chronic hepatitis and liver cirrhosis, suggesting that cholestasis. Other enzymes that reflect cholestasis include AST–IgA complex might explain the reversed ALT : AST 5′-nucleotidase and γ-glutamyltransferase (GGT). ALP ratio in alcoholic hepatitis [15]. Elevation in AST and ALT and 5′-nucleotidase are found in the bile canalicular mem- can also be seen in conditions other than liver disease. brane while GGT is located in the endoplasmic reticulum AST is elevated in patients with myocardial infarction and and the bile duct epithelial cells. Human ALP can be clas- in those with significant muscle injury such as myositis, sified into at least four tissue-specific isoenzymes accord- rhabdomyolysis, or after vigorous exercise. Typically AST ing to the specificity of the tissue. These are placental ALP is greater than ALT with a ratio of 3 : 1 but this approaches (or Regan isoenzyme), intestinal ALP, liver/bone/kidney 1 : 1 over time as AST has a shorter half-life than ALT. ALP, and germ cell ALP. The enzymes are distinguish- able by a variety of structural, biochemical and immuno- Glutamate dehydrogenase logic methods. Serum ALP activity is derived primarily from the canalicular membranes of the hepatocytes, bone Glutamate dehydrogenase is present in the liver, heart, osteoblasts, the brush border of the intestinal epithelial muscle, and kidneys. It is a mitochondrial enzyme that cells, the first trimester placenta, and the proximal convo- catalyzes the reversible deamination of glutamate to α- luted tubules of the kidney [20]. Little is known about the ketoglutarate plus free ammonia by using NAD or NADP function of ALP in most tissues. as a cofactor. It is predominantly found in the centrilobu- The distribution of the enzyme in the serum varies with lar hepatocytes and has been studied as a marker of liver age. The normal serum range is 20–140 IU/L. In children, injury as well as mitochondrial injury in patients with serum ALP activity level is up to 3 times higher than that acute acetaminophen poisoning, where it performs better seen in young adults and correlates with bone growth. than initial ALT in predicting acute liver injury. It is not Bone ALP makes up about half of the total ALP activity routinely used in clinical practice. in adults. In the 15- to 50-year-old age group, the mean ALP is higher in men than in women. In those older than Isocitrate dehydrogenase 60 years, the enzyme activity is higher in women and can Isocitrate dehydrogenase is a cytoplasmic enzyme present be 1.5 times that seen in younger adults (Fig. 2.2). Addi- in the liver, heart, kidneys and skeletal muscle. Increased tionally, ALP activity also increases significantly in late activity in the serum isocitrate dehydrogenase is seen pregnancy, reaching up to 3–4 times the normal value, in patients with acute and chronic liver injury dis- due to an influx of placental phosphatase [21]. Increases seminated malignant disease without hepatic involve- in serum ALP activity due to an influx of intestinal ALP ment. Heterozygous somatic mutations in the ICDH1 and can also be seen after ingestion of fatty meals in patients ICDH2 genes are associated with a number of differ- with blood groups O and B. ent tumor types, including intrahepatic cholangiocarci- Elevation in ALP is not totally specific for cholestasis, noma. Measurement of isocitrate dehydrogenase activity and a mild elevation (2–3 times ULN) can be seen with in the serum does not offer any diagnostic advantage over almost any type of liver disease. Elevations in ALP activ- aminotransferase activity and it is not used routinely in ity greater than 4 times the ULN are seen in patients with clinical practice. cholestatic liver disease, infiltration of the liver and rapid Chapter 2: Laboratory Tests 21

6 sinusoidal membrane, where it catalyzes the hydrolysis of nucleotides such as adenosine 5′-phosphate and ino- 5 sine 5′-phosphate. It has also been found in the cytoplasm. It is normally present at low concentrations in childhood 4 and increases through adolescence, reaching a plateau at the age of 50 years. 3 Despite its widespread distribution in the body, increased serum levels of 5′-nucleotidase activity are seen 2 patients with cholestasis similar to ALP activity. Bile acids

Upper reference limits Upper reference acting as detergents likely solubilize and disrupt canalicu- 1 lar membranes, releasing ALP and 5′-nucleotidase which

(Relative to males 25–35 years old) males 25–35 years to (Relative is reflected in the parallel increase in these enzymes in 0 the serum of patients with cholestatic liver disease. There 0204060 80 is little or no increase in 5′-nucleotidase in patients with Age (years) bone disease and thus the test can be used to confirm the Figure 2.2 Age and gender effect on upper limits of normal for ALP liver origin of an elevated ALP in patients with suspected (circles, males; squares, females). (Reproduced from [1] with permission liver disease. from the American Association for Clinical Chemistry.) Gamma-glutamyltransferase bone turnover. In clinical practice the differentiation of the γ-Glutamyltransferase (GGT), previously called γ- source of ALP elevation is determined by obtaining addi- glutamyltranspeptidase, is located on the plasma mem- ′ tional enzyme testing with the 5 -nucleotidase or GGT, by branes of most cells, including kidney, pancreas, spleen, measurement of the isoenzymes using electrophoresis, or heart, brain, and seminal vesicle, but is predominantly by subjecting the ALP to chemical or heat inactivation. The found in hepatocytes in the endoplasmic reticulum. The measurement of an elevated serum ALP with a heat-stable primary role of GGT is the extracellular metabolism of fraction suggests that the ALP is from placenta or a tumor. glutathione, the major thiol antioxidant in mammalian However this latter method is rarely used in present day cells. It is present in the human serum and the reference clinical practice. range is similar across all ages, but there are gender Only liver ALP is found in the serum of patients with differences, with a higher ULN for men (51 IU/L) than for liver disease. The mechanism by which liver disease women (33 IU/L). Normal levels are seen in childhood results in an increase in the serum activity of ALP is and in pregnancy. Liver injury, cholestasis, excessive alco- related to de novo synthesis of ALP in the liver and the hol intake, obesity, and the use of medications including regurgitation into the sinusoidal blood [21]. The method phenytoin and phenobarbital result in increases serum by which ALP reaches the serum is unclear but it possi- activity of GGT due to secretion into the circulation [23]. bly occurs because of solubilization of liver membrane- Abnormal values for GGT are seen in the same spectrum bound enzymes by bile acids [22]. ALP elevations occur of diseases as ALP and 5′-nucleotidase. The clinical utility in the setting of both intra- and extrahepatic cholesta- of a GGT test is to confirm the liver specificity of elevated sis and the level of serum ALP activity does not help ALP activity and in determining the possible intake of distinguish between these two entities. The serum activ- excessive alcohol, as serum activity of GGT is significantly ity of ALP is similar in intrahepatic cholestasis caused increased in patients with alcoholic hepatitis over that of by drug-induced hepatitis, viral hepatitis, primary biliary ALP [23]. In recent years, variability in GGT activity has cholangitis, granulomatous liver disease, or small duct been associated with BMI waist circumference, smoking, primary sclerosing and in extrahepatic cholestasis caused heart rate, blood pressure, and serum levels of glucose, by pancreatic cancer, choledocholithiasis, large duct scle- ferritin, and triglycerides. In addition, there is now strong rosing cholangitis, or common hepatic/bile duct obstruc- epidemiological evidence that GGT is a positive and inde- tion. Other nonhepatic conditions, such as extrahepatic pendent risk factor for cardiovascular disease (CVD) and cancers, congestive heart failure, intra-abdominal infec- CVD mortality. The association between increased GGT tions, osteomyelitis, hyperthyroidism, and inflammatory activity and increased risk of vascular disease appears bowel disease, can result in elevation in ALP activity. to be the same for cardiac events and cerebrovascular events such as stroke. There is the possibility that this ′ 5 -Nucleotidase association is related to the underlying association of 5′-Nucleotidase is found in the liver, intestines, brain, GGT with nonalcoholic fatty liver disease, which is itself heart, blood vessels, and pancreas. In the liver, the a major risk factor for CVD and commonly associated enzyme is associated with the bile canalicular and with GGT activity [24]. 22 Part I: Overview: Clinical Fundamentals of Hepatology

Bilirubin The terms direct- and indirect-reacting bilirubins are Bilirubin, a tetrapyrrole pigment, is an end-product of based on the original van den Bergh method of measuring heme degradation. Approximately 70–90% of bilirubin is unconjugated bilirubin [26]. This method is still used derived from the degradation of hemoglobin in senescent in some clinical chemistry laboratories to determine red blood cells [25]. Other sources of bilirubin include the serum bilirubin level. In this assay, bilirubin reacts myoglobin, cytochromes, catalase, peroxidase, and tryp- with diazo reagents and splits into two relatively stable tophan pyrrolase. Bilirubin produced in the periphery azodipyrroles that absorb maximally at 540 nm. The is water insoluble and is transported to the liver in the direct fraction is that which reacts with diazo reagents plasma tightly bound to albumin. The initial steps lead- in 1 minute in the absence of alcohol [26]. This fraction ing to the formation of bilirubin occurs in the reticuloen- provides an approximate determination of the amount dothelial cells, primarily in the spleen and liver. Trans- of conjugated bilirubin in the serum. The total serum fer of bilirubin from the blood to the bile involves four bilirubin level is the amount that reacts in 30 minutes steps, including hepatocellular uptake, intracellular bind- after the addition of alcohol. The indirect fraction is ing, conjugation, and biliary excretion. the difference between the total and the direct biliru- r Uptake: Albumin-bound bilirubin passes through the bin level, and provides an estimate of the amount of endothelial cell fenestrae to reach the hepatocyte sur- unconjugated bilirubin in serum. With the van den Bergh face where it is taken up into the hepatocyte by biliary method, the normal serum bilirubin concentration is transporters and diffusion. Although several potential usually less than 1 mg/dL (17 μmol/L). Total serum transporters have been identified, none has yet been bilirubin concentrations are between 0.2 and 0.9 mg/dL cloned. (3.4–15.3 μmol/L) in 95% of a healthy population, and r Intracellular binding: In the hepatocyte, bilirubin is cou- less than 1 mg/dL (17 μmol/L) in 99%. Direct-reacting pled to glutathione-S-transferases, previously called bilirubin slightly overestimates the conjugated bilirubin ligandins. concentration because a fraction of unconjugated biliru- r Conjugation: Bilirubin is then solubilized by means of bin (about 10–15%) also gives a direct van den Bergh conjugation to glucuronic acid by a specific uridine reaction [26]. diphosphate (UDP)-glucuronosyltransferase to biliru- Advances in methodology have shown that the diazo bin monoglucuronide and diglucuronide. method does not accurately reflect the values of the r Biliary excretion: The bilirubin conjugates are then indirect- and direct-reacting fractions of bilirubin, particu- actively transported from the hepatocyte into canalicu- larly at low total serum bilirubin concentrations [27]. More lar bile by an adenosine triphosphate (ATP)-dependent accurate and sensitive quantification of bilirubin requires transport process that is the rate-limiting step in hepatic chromatographic analysis such as HPLC and reflectance bilirubin excretion. This process is mediated by a pro- fluorimetry. tein in the bile canalicular membrane called multidrug The bilirubin normally present in serum represents a resistance-associated protein 2 (MRP2). balance between the input from production and the hep- The conjugated bilirubins drain from the bile duct into atic removal of the pigment. Hyperbilirubinemia may the duodenum and are carried distally through the intes- therefore result from (i) overproduction of bilirubin, tine. In the distal ileum and colon, the conjugated biliru- (ii) impaired uptake, conjugation, or excretion of bilirubin, bins are hydrolyzed to unconjugated bilirubin by bacterial or (iii) regurgitation of unconjugated or conjugated biliru- glucuronidases. The unconjugated bilirubin is reduced bin from damaged hepatocytes or bile ducts (Table 2.2). by normal intestinal bacteria to form a group of col- One may anticipate that an increase in unconjugated orless tetrapyrroles called urobilinogens. Approximately bilirubin in the serum results from overproduction or 80–90% of these products are excreted in feces, either from impairment of uptake or conjugation, whereas an unchanged or oxidized to orange derivatives called uro- increase in the conjugated moiety is caused by decreased bilins. The remaining 10–20% of the urobilinogens are pas- excretion or backward leakage of the pigment. sively absorbed, enter the portal venous blood, and are Total serum bilirubin level is not a sensitive indi- re-excreted by the liver. A small fraction, usually less than cator of hepatic dysfunction and may not accurately 3 mg/dL, escapes hepatic uptake, filters across the renal reflect the degree of liver damage. Hyperbilirubinemia glomerulus, and is excreted in urine. may not be detected in instances of moderate to severe hepatic parenchymal damage or a partially or briefly Measurement of serum bilirubin obstructed common bile duct. This lack of sensitivity is Bilirubin is measured in blood by (i) the “diazo reaction,” partly explained by observations obtained in healthy per- (ii) direct spectrophotometry, (iii) oxidative, enzymatic, sons given infusions of unconjugated bilirubin and in and chemical methods, (iv) high-performance liquid chro- patients with uncomplicated hemolysis. These observa- matogaphy (HPLC), and (v) transcutaneous methods. tions suggest that the capacity of the human liver to