Drug-InDuceD LIver DIsease

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Drug-InDuceD LIver DIsease

Second Edition

Edited by

Neil Kaplowitz

Keck School of Medicine, University of Southern California Los Angeles, California, USA

Laurie D. DeLeve

Keck School of Medicine, University of Southern California Los Angeles, California, USA

Kaplowitz_978-0849398964_TP.indd2 2 6/6/07 4:00:05 PM

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New York, NY 10017

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Library of Congress Cataloging-in-Publication Data Drug-induced liver disease / edited by Neil Kaplowitz, Laurie D. DeLeve.

– 2nd ed.

p. ; cm.

Includes bibliographical references and index.

ISBN-13: 978-0-8493-9896-4 (hb : alk. paper) ISBN-10: 0-8493-9896-7 (hb : alk. paper) 1. Hepatotoxicology.

2. Liver–Effect of drugs on.

3. Drugs–Side effects.

I. Kaplowitz, Neil. II. DeLeve, Laurie D., 1955-

[DNLM: 1. Liver Diseases–chemically induced. 2. Liver–drug effects. 3. Pharmaceutical Preparations–adverse effects. WI 700 D7943 2007]

RC848.H48D78 2007 616.3’6–dc22

2007014965 Visit the Informa Web site at

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To our loving families and to the memory of Hy Zimmerman, who inspired us with his intellect and dedication

in pioneering this ﬁeld.

We are proud to follow in his footsteps.

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Preface to the Second Edition

The high productivity of the pharmaceutical industry has provided exciting, efficacious new drugs. However, with efficacy always comes the potential for toxicity, and the growth in new pharmaceuticals has been accompanied by several new drugs linked to liver toxicity. At the same time, epidemiological studies have found that drugs are now the most common causes of liver failure. This has led to a resurgence of interest in drug-induced liver disease in general and has spurred an influx of clinical researchers into this area. Basic research in this area has also thrived over the last decade, due to innovations in biomedical research that have given us tools that have provided new insights into the mechanisms of drug toxicity.

The time was therefore ripe to compile a volume with contributions from scientists around the world with expertise in pathogenesis and clinical presentation, as well as authorities on the various categories of drugs and toxins of importance to this ﬁeld.

We have been gratified by the outstanding reviews of the first edition. However, we believe that in this fast-moving field, a book would only remain of value if it can be revised in a timely enough fashion to keep abreast of recent developments. In the second edition, 16 out of the 36 chapters have new authors or cover new topics. New topics include pharmacogenomics and toxicogenomics, causality assessment, risk factors for drug-induced liver disease, management of drug-induced liver disease, and mushroom poisoning.

Pharmacogenomics and toxicogenomics are new ﬁelds that provide the hope for rational strategies for the pharmaceutical industry in weeding out toxic drugs earlier in development, but may also devise novel approaches to prevent drug toxicity in the susceptible few without exclusion of new drugs efﬁcacious for the many. The new chapters “Causality Assessment”

and “Risk Factors for Drug-Induced Liver Disease” expand the Diagnosis and Management section and provide more background on the fundamentals of the ﬁeld. We have also added a chapter on management to address issues as such liver transplantation and the use of steroids and ursodeoxycholic acid, and we have addressed therapy in individual chapters as well.

The second edition is divided into four sections. Section I focuses on mechanisms of hepatotoxicity, often illustrated by examples of speciﬁc drugs. The newly expanded Section II reviews general principles of clinical presentation, histopathology, predisposition to toxicity, diagnosis, and management. Each chapter in Section III examines a class of drugs, toxins, or drugs used within a clinical specialty. This section provides a systematic review of the major xenobiotics associated with drug-induced liver disease and also serves as a reference for clinicians dealing with a possible case of drug-induced liver disease. Section IV contains a completely rewritten chapter on drug toxicity from a regulatory perspective.

We are pleased with the second edition, which has allowed us to improve and expand coverage of the ﬁeld and to update the rapidly advancing knowledge of pathogenesis. We believe this volume will be a great value to hepatologists, physicians in all ﬁelds of medicine, toxicologists and pharmacologists, and scientists working in preclinical and clinical drug development in both academia and industry.

Neil Kaplowitz Laurie D. DeLeve

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Preface to the First Edition

With the ever-increasing exposure to pharmaceuticals, more and more examples of drug- induced liver disease have been identiﬁed in recent years. At the same time, the basic science of hepatic pharmacology, toxicology, and immunology have exploded in the past 5 to 10 years with exciting new developments and insights. We are now poised at the very end of the 20th century with the opportunity to re-evaluate this important topic as we look to the promise of understanding, predicting, preventing, and healing a common problem in clinical medicine that is of importance to all branches of medicine and to anyone who prescribes pharmaceutical or alternative medications. Therefore, the editors believe that an authoritative, up-to-date volume with contributions by experts in basic pathogenesis, clinical pathology, and use of various categories of agents will be of great interest to a broad spectrum of medicine. In this regard, we have drawn upon worldwide expertise with about one-third of the chapters written by authors outside the United States.

Innovations in methodology have had a major impact on research in drug-induced liver injury, and this has led to a greater understanding of the mechanisms involved. A few examples should illustrate the progress that has been made and is described in this book. The explosion of information on apoptosis has provided insight into the subtleties of drug-induced cell death.

The use of molecular biological techniques has permitted the cloning of numerous genes encoding for P450 isoenzymes. This has made possible the expression of recombinant P450 enzymes and specific P450 antibodies. The availability of recombinant enzymes and specific inhibiting antibodies has facilitated studies to determine the contribution of individual P450 isoenzymes to the metabolism of specific drugs. Until quite recently, cholestasis was thought to be due to either mechanical obstruction of bile flow or cell toxicity that impeded the handling of bile. Improved techniques for isolating membrane vesicles and the cloning and characterization of hepatocyte membrane transporters have allowed the elucidation of a novel mechanism of cholestasis: drug-induced impairment of bile acid transporters in otherwise intact hepatocytes.

As more investigators have taken advantage of relatively new methods to isolate pure nonparenchymal cells, there has been a rapid rise in information on the contribution of Kupffer cells, sinusoidal endothelial cells, and stellate cells to a variety of liver diseases, including drug- and toxin-induced liver injury. The concept of the mitochondrion as a major target of drug-induced toxicity was only raised in the early 1980s. Since then, toxicity of an ever- increasing number of drugs has been linked to selective toxicity to the mitochondrion.

Although reference is made in these examples to chapters on mechanisms in Section I, Section III reiterates many of these processes in the context of individual drugs that have been linked to one of these modes of toxicity.

This book has been divided into three major sections. Section I examines hepatotoxicity from the perspective of the mechanisms, across categories of drugs, so that the principles involved can be explored in depth. Examples of drugs to which these mechanisms apply is provided, but the main focus is on the mechanism. Because the authors are experts who are writing about the current state-of-the-art in their own ﬁeld, this information is useful to both clinicians who want to gain understanding of the fundamental principles as we understand them today, as well as to knowledgeable clinicians and investigators who wish to read about the newest advances.

Section II provides a general outline of the clinical presentation, histopathology, and management of drug-induced hepatotoxicity. Chapter 12 systematically reviews the clinical

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presentation and pathological picture of the types of liver injury that can be induced by drugs and toxins. Chapter 14 reviews the factors that predispose an individual to drug toxicity, suggests strategies for monitoring patients at risk for toxicity, and provides information on preventive measures. The information provided in this section provides a basic framework for any clinician who might be confronted with xenobiotic-induced hepatotoxicity.

Section III systematically reviews speciﬁc toxins implicated in drug-induced hepatotoxicity. Each chapter examines the toxicity induced by drugs or toxins within a speciﬁc pharmacological class or by drugs used within a clinical specialty. The current understanding of the mechanism of toxicity, risk factors for developing toxicity, histological characteristics, clinical manifestations, and management are discussed for each category of drugs. This section is of value to gastroenterologists and hepatologists who want a systematic review of drug- induced liver disease. It also serves as a reference for clinicians in a variety of specialties who are confronted with a patient with liver disease that might be attributable to drug therapy.

Neil Kaplowitz Laurie D. DeLeve

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Contributors

Rau´l J. Andrade Liver Unit, Hospital Virgen de la Victoria, Ma´laga, Spain

Leslie Z. Benet Department of Biopharmaceutical Sciences, University of California-San Francisco School of Pharmacy, San Francisco, California, U.S.A.

Alain Berson E´quipe Mitochondries, INSERM, U773, Centre de Recherche Biome´dicale Bichat Beaujon, Faculte´ de Me´decine Xavier Bichat, Universite´ Paris 7 Denis Diderot, Paris, France Sidharth S. Bhardwaj Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Urs A. Boelsterli Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, U.S.A.

Thomas D. Boyer Liver Research Institute, University of Arizona, Tucson, Arizona, U.S.A.

Sam A. Bruschi Department of Medicinal Chemistry, University of Washington School of Pharmacy, Seattle, Washington, U.S.A.

Raquel Camargo Liver Unit, Hospital Virgen de la Victoria, Ma´laga, Spain

Naga P. Chalasani Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Shivakumar Chitturi Department of Gastroenterology and Hepatology, Australian National University Medical School at the Canberra Hospital, Australian Capital Territory, Australia Anthony S. Dalpiaz Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.

Timothy J. Davern Gastroenterology Division and Liver Transplant Program, University of California, San Francisco, California, U.S.A.

Laurie D. DeLeve Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

Franc¸ois Durand Service d’He´patologie, Hospital Beaujon, Clichy, France

Geoffrey C. Farrell Department of Gastroenterology and Hepatology, Australian National University Medical School at the Canberra Hospital, Australian Capital Territory, Australia Bernard Fromenty E´quipe Mitochondries, INSERM, U773, Centre de Recherche Biome´dicale Bichat Beaujon, Faculte´ de Me´decine Xavier Bichat, Universite´ Paris 7 Denis Diderot, Paris, France Miren Garcı´a-Corte´s Liver Unit, Hospital Virgen de la Victoria, Ma´laga, Spain

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Carol R. Gardner Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, U.S.A.

F. Peter Guengerich Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A.

Hartmut Jaeschke Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.

Gary C. Kanel Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

Neil Kaplowitz Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

J. Gerald Kenna AstraZeneca Safety Assessment, R&D Alderley Park, Macclesﬁeld, Cheshire, U.K.

Dominique Larrey Service d’He´pato-Gastroente´rologie et Transplantation, Hoˆpital Saint Eloi, Montpellier, France

Debra L. Laskin Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, U.S.A.

William M. Lee University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Steven J. Leeder Division of Pediatric Pharmacology and Medical Toxicology, Children’s Mercy Hospital and Clinics, Kansas City, Missouri, U.S.A.

James H. Lewis Georgetown University Medical Center, Washington, D.C., U.S.A.

Chunze Li Merck & Co., Inc., West Point, Pennsylvania, U.S.A.

Lawrence U. Liu Division of Liver Diseases and Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, New York, U.S.A.

Ma Isabel Lucena Departmento de Farmacologia Clinica, Hospital Virgen de la Victoria, School of Medicine, Ma´laga, Spain

Willis C. Maddrey Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, U.S.A.

Abdellah Mansouri E´quipe Mitochondries, INSERM, U773, Centre de Recherche Biome´dicale Bichat Beaujon, Faculte´ de Me´decine Xavier Bichat, Universite´ Paris 7 Denis Diderot, Paris, France Harihara M. Mehendale Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, U.S.A.

Peter J. Meier University of Basel, Basel, Switzerland

Richard H. Moseley Ann Arbor Veterans Affairs Healthcare System and Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, U.S.A.

Sidney D. Nelson Department of Medicinal Chemistry, University of Washington School of Pharmacy, Seattle, Washington, U.S.A.

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George Ostapowicz University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Christiane Pauli-Magnus University Hospital Basel, Basel, Switzerland

Dominique Pessayre E´quipe Mitochondries, INSERM, U773, Centre de Recherche Biome´dicale Bichat Beaujon, Faculte´ de Me´decine Xavier Bichat, Universite´ Paris 7 Denis Diderot, Paris, France Munir Pirmohamed Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, U.K.

Adrian Reuben Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, U.S.A.

Mark Russo Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, U.S.A.

Thomas D. Schiano Division of Liver Diseases and Recanati/Miller Transplantation Institute, The Mount Sinai Medical Center, New York, New York, U.S.A.

John R. Senior Ofﬁce of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, U.S.A.

Hilde Spahn-Langguth German University in Cairo, New Cairo City, Egypt

Ulrich Spengler Department of General Internal Medicine, Rheinische Friedrich Wilhelms Universita¨t Bonn, Bonn, Germany

Andrew A. Stolz Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

Dwain L. Thiele Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, U.S.A.

Keith G. Tolman Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.

Dominique Valla Service d’He´patologie, Hopital Beaujon, Clichy, France

Sumita Verma Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

Paul B. Watkins Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, U.S.A.

Contributors xv

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PART I MECHANISMS OF LIVER INJURY

1 Drug-Induced Liver Disease

Neil Kaplowitz

Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A.

INTRODUCTION

The goal of this chapter is to provide a broad overview of the subject of this book and to introduce a number of concepts that will be expanded upon in subsequent chapters. Drug-induced liver disease represents an important problem for the following major reasons: (1) approximately 1000 drugs have been implicated in causing liver disease at least on rare occasions (1); (2) in the United States drug-induced liver disease is the most common cause of acute liver failure, accounting for one-third to one-half of cases (2,3); although acetaminophen accounts for the bulk of these, other drugs are still a more frequent cause of acute liver failure than viral hepatitis and other causes (4);

(3) in addition, drug-induced liver disease represents an important diagnostic/therapeutic challenge for physicians caring for patients presenting with liver disorders, since it can mimic all forms of acute or chronic liver disease (5); the frequency and economic impact of this problem is a major challenge for the pharmaceutical industry and regulatory bodies, especially since the toxic potential of some drugs is not evident in preclinical and phase 1 to 3 clinical testing.

The incidence of drug-induced liver injury is not well established in the general population.

In a population-based cohort study in France the incidence was 14 cases per 100,000 (0.014%) inhabitants (6), whereas an inpatient study from Switzerland found a higher incidence (1.4%) (7).

CLINICAL OVERVIEW

Drug-induced liverdiseases can mimic all forms of acute and chronic hepatobiliary diseases (Table 1) (5,8). However, the predominant clinical presentations resemble acute icteric hepatitis (hepatocellular jaundice) or cholestatic liver disease. The former is of grave signiﬁcance as the mortality approximates 10% irrespective of the speciﬁc drug (1,5,9,10). This is referred to as Hy’s Law after the late Hy Zimmerman, who noted that mortality from drug-induced hepatocellular jaundice ranged from 10% to 50%. Hy Zimmerman also noted that in most cases at risk for fatal outcome, aside from jaundice alanine aminotransferase (ALT) and aspartate aminotransferase were between 8 and 100!

upper limit of normal (ULN) and alkaline phosphatase (Alk. Ptase) !3!ULN. Over the years the validity of Hy’s Law has held up in specific examples (Table 2) and is further verified in recent registries (9–11). This type of reaction is accompanied by systemic symptoms, jaundice, markedly elevated serum transaminases, ALT!ULN/Alk. Ptase.!ULNR5, and in the more severe cases, coagulopathy and encephalopathy indicative of acute (fulminant) liver failure. It is noteworthy that the height of the transaminases does not reliably predict severity except perhaps in the case of acute intrinsic toxins, e.g., acetaminophen. Cholestatic disease, although not usually life threatening, presents with jaundice, disproportionate increased Alk. Ptase, ALT!ULN/Alk. Ptase.!ULN%2, and pruritus; cholestatic reactions tend to resolve very slowly (i.e., months vs. weeks for hepatitis) The author of this chapter has relationships with the following corporations: Abbott, Adams Respiratory Therapy, Allergan, Amgen, Astra Zeneca, Avera, BG Medicine, Biogen, Boehringer/Ingelhem, Cadence, Daiichi Sankyo, DOV, Elan, Enanta, Encysive, GSK, Gtx, Incyte, ISIS, Janssen, Johnson & Johnson, Maxygen, Merck, Millenium, Ono, Pfizer, Rigel, Roche, Sankyo, TAP, Threshold, Teva, and Wyeth.

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and on rare occasion lead to vanishing bile duct disease and biliary cirrhosis (12,13). Mixed injury patterns with intermediate ALT/Alk. Ptase. can resemble atypical hepatitis or granulomatous hepatitis. Individual drugs tend to exhibit a consistent pattern or clinicopathological signature of the reaction (Table 1) with characteristic latency and clinical presentation. However, some drugs may show several patterns: e.g., nimesulide can cause a short-latency, hypersensitivity-mediated cholestatic injury and a delayed idiosyncratic acute hepatitis-like reaction (14). Thus, although one pattern may predominate, crossover to other patterns is not unusual.

Drug-induced liver disease can be predictable (high incidence and dose-related) or unpredictable (low incidence and may or may not be dose-related). Unpredictable reactions, also referred to as idiosyncratic, can be viewed as either immune-mediated hypersensitivity or nonimmune reactions. Most potent predictable hepatotoxins are recognized in the animal testing or clinical phase of drug development. Those that slip through are almost always unpredictable. Latency between the initiation of therapy and the onset of liver disease is a component of the signature of reactions to speciﬁc drugs and provides some clues as to the pathogenesis. Early onset within a few days (particularly if no previous exposure) is strong evidence for direct toxicity of the drug or its metabolite, which is characteristic of predictable reactions; acetaminophen overdose is an example (15).

Unpredictable reactions manifested as overt or symptomatic disease usually occur with intermediate (one to eight weeks) or long latency (up to 12 months). Intermediate latency is characteristic of hypersensitivity reactions, but can be seen with nonimmune idiosyncrasy as well. The hypersensitivity reactions tend to be associated with fever, rash, and eosinophilia and a rapid positive rechallenge (5,8). Hepatotoxicity of sulindac (16), phenytoin (17), and amoxicillin–clavulanic acid (18) are typical examples. Most cases of cholestatic liver injury and chronic hepatitis caused by drugs are of the hypersensitivity type. It is important to recognize that these reactions may occur up to three to four weeks after a one to two week course of medication (e.g., amoxicillin–clavulanic acid). In contrast, the long-latency type of idiosyncratic reaction is characteristically not associated with features of hypersensitivity and the response to rechallenge is variable and delayed. Thus, one assumes that these events reﬂect TABLE 1 Spectrum of Hepatic Manifestations of Drug-Induced Liver Disease

Acute hepatitis Acetaminophen, isoniazid, troglitazone, bromfenac Chronic hepatitis^a Nitrofurantoin, methyldopa, diclofenac, minocycline,

dantrolene

Acute cholestasis Amoxicillin clavulanic acid, erythromycins, sulindac, chlorpromazine, angiotensin-converting enzyme inhibitors Mixed hepatitis/cholestasis or atypical hepatitis Phenytoin, sulfonamides

Chronic cholestasis^a Chlorpromazine, numerous others on rare occasion Non-alcoholic steatohepatitis Amiodarone, tamoxifen

Fibrosis/cirrhosis Methotrexate

Microvesicular fatty liver Valproic acid, nucleoside reverse transcriptase inhibitors

Veno-occlusive disease Busulfan, cyclophosphamide

Peliosis hepatitis Azathioprine, hormones

Adenoma and hepatocellular carcinoma Hormones

aDrugs that cause chronic disease more frequently cause acute disease.

TABLE 2 Drugs that Cause Hepatocellular Jaundice and Confirm Hy’s Law

1978 Later Probable

Iproniazid Phenylbutazone Bromfenac

Isoniazid Ketoconazole Troglitazone

Phenytoin Ticrynafen Trovafloxacin

Halothane Valproic acid Nefazodone

Cinchophen Enflurane

Dantrolene Pemoline

Nitrofurantoin Labetalol

Diclofenac Sulindac 1978 refers to first edition of Zimmerman’s textbook.

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some type of late-onset change in the metabolism of the drug or the response to injury (repair or regeneration). Drugs associated with variable, long latency include isoniazid (19) and troglitazone (20). This type of idiosyncratic reaction is extremely challenging with respect to understanding the pathogenesis and predicting the problem in individual cases. Table 3 provides a list of drugs that are associated with idiosyncratic allergic and nonallergic reactions.

A few can cause either allergic or nonallergic reactions, e.g., diclofenac and nevirapine.

Low-frequency unpredictable reactions, either immune-mediated or not, often occur on a background, higher rate of mild, asymptomatic, and usually transient liver injury, which is detected as abnormal biochemical tests, particularly serum ALT. Generally, the biochemical abnormality deﬁned as ALTO3!ULN may occur 10 to 20 times more frequently than overt disease. In almost all instances, the ALT returns to normal despite continued drug use. Thus, in the majority of patients with increased ALT some type of adaptation or “tolerance” occurs and in the minority progression to overt, severe injury occurs, which may reﬂect a failure to adapt.

This issue is further complicated by the uncertain explanation for the very long latency in some of the idiosyncratic reactions.

It should be emphasized that acute or chronic hepatitis induced by drugs subsides upon discontinuation of the drug without long-term sequelae with rare exception. A few reported cases of autoimmune hepatitis triggered by hypersensitivity drug reactions have continued on without the drug, but it is questionable as to whether this was drug-induced liver disease or underlying autoimmune chronic hepatitis. Scarring may persist after severe subacute or chronic injury but is of little consequence after removal of the drug cholestalic reactions are cholestatic reactions are not infrequently associated with loss of interlobular bile ducts. However, the development of cirrhosis or effects on longevity are exceedingly rare.

PATHOGENESIS

Hepatotoxicity of drugs can be principally metabolism-dependent, parent drug-dependent, or a combination of both (Fig. 1). Metabolism takes place largely in the liver, which accounts for its susceptibility to drug-induced injury (8). The metabolites may be electrophilic chemicals or free radicals that deplete glutathione (GSH), covalently bind to proteins, lipids, or nucleic acids, or induce lipid peroxidation. The consequences include hepatocellular necrosis, apoptosis, or sensitization to cytokines or inﬂammatory mediators produced by nonparenchymal cells.

Alternatively, the reactive metabolites may covalently bind to or alter liver proteins such as cytochrome P450s (CYPs) leading to sensitization and immune-mediated injury. The immune phenomena nevertheless are metabolism dependent. Thus, the rare occurrence of immune- mediated liver disease is often superimposed on a higher frequency of mild injury (abnormal ALT) suggesting that the drug has a mild toxic potential (e.g., phenytoin or halothane) but in rare individuals this toxic potential leads to more severe toxicity initiated by metabolism steps, TABLE 3 Drugs Associated with Idiosyncratic Hepatitis

Nonallergic Allergic

Acarbose Leflunomide Allopurinol Erythromycins^a

Benoxaprofen^b Nefazodone^b Diclofenac Sulfonamides^a

Bosentan Nevirapine Dihydralazine Sulindac^a

Bromfenac^b Pemoline Halothane Tricyclics^a

Dantrolene Pyrazinamide Methyldopa

Diclofenac Terbinafine^a Minocycline

Disulfiram Tolcapone Nevirapine

Felbamate Troglitazone^b Nitrofurantoin

Flutamide^b Trovafloxacin^b Phenytoin

Isoniazid Valproic acid Propylthiouracil

Isotretinoin Zafirlukast ACE inhibitors^a

Ketoconazole Zileuton Augmentinw^a

Labetalol Phenothiazines^a

aCholestatic/mixed.

bWithdrawn from the market.

Drug-Induced Liver Disease 3

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but also heavily influenced by genetic and/or environmental factors that determine either an immune response or idiosyncratic reaction. Genetic polymorphisms of enzymes involving drug activation or detoxification have been implicated in the susceptibility to hypersensitivity reactions to sulfonamides (21,22), anticonvulsants (17,23), and tacrine (24). Presumably genetic polymorphisms of either major histocompatibility complex (MHC) I-dependent antigen presentation in hepatocytes or MHC II-dependent antigen presentation in macrophages, which have scavenged necrotic or apoptotic hepatocytes directly killed by the drug, may further contribute to determine the rare occurrence of these hypersensitivity reactions (25) which most often have an incidence of 1:1000 or less. Parent drug-dependent toxicity occurs as a result of the properties of the parent drug (or metabolite) to accumulate in organelles [weak bases such as amiodarone accumulate in mitochondria (26)], undergo nonspecific redox cycling (quinones cycle electrons from NADPH to O2generating (O2K)), or specifically inhibit enzymes or transporters (nucleoside reverse transcriptase inhibitors block mitochondrial DNA poly- merase (27)) or cyclosporin A inhibits canalicular transporters (28). In these cases, if the parent drug’s chemical properties account for direct toxicity, factors that enhance its availability (decreased metabolism or export) may increase susceptibility.

Regardless of whether toxicity within a target liver cell (e.g., hepatocyte, sinusoidal endothelial cell, or bile duct cell) is parent drug- or metabolite-dependent, the ultimate severity of the liver disease in vivo may depend greatly on the subsequent downstream participation of toxic mediators released from various cell types and the recruitment of inﬂammatory cells as well as intracellular and tissue repair and regenerative responses. The toxic mediators include chemicals, such as NO and reactive oxygen metabolites, and the balance of cytokines that promote injury [e.g., tumor necrosis factor-a (TNFa), Interleukin-1 (IL-1), Interferon-g (IFNg), Interleukin-12 (IL-12), Interleukin-18 (IL-18)), or prevent injury (IL-4, IL-10, IL-13, monocyte chemotactic protein-1 (MCP-1)]. Thus, toxin may somewhat injure hepatocytes but then sensitize to the effects of an imbalance in injurious versus protective cytokines (Fig. 2). For example, the toxicity of carbon tetrachloride (CCl4) is abrogated in vivo by neutralizing TNF (29); the toxicity of acetaminophen is markedly enhanced in MCP-1 chemokine receptor

Drug Metabolite

Toxicity (mild) Mitochondria

DNA

Covalent binding GSH depletion

Reactive O₂ “Danger”

Immune response

Overt liver injury Inflammatory/

toxic

mediators Repair

Recovery Adaptation

Haptenization

FIGURE 1 Pathogenesis of drug-induced liver diseases. Upstream events in the hepatocytes affect viability of individual cells but sensitize to downstream processes leading to clinically overt organ damage. The latter involves a balance of effects of cytokines, chemokines, and inflammatory mediators, mainly produced by nonparenchymal cells and the effects on repair processes a such as regeneration.

Protection IL-4IL-10 IL-13 MCP-1

Injury IL-12 TNFαIFNγ IL-12 Toxin Sensitize

hepatocytes TNFα _Lethal IFNγ

T(–) MCP-1 IL-10, 13

FIGURE 2 Role of cytokine balance in determining susceptibility to toxins. Drugs or metabolites may directly injure hepatocytes to a minor extent, but may markedly sensitize to the lethal effects of TNFa and IFNg.

The latter are modulated by cytokines that promote or inhibit their production or actions. Abbreviations: TNFa, tumor necrosis factor a;

IFNg, interferon g.

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knockouts associated with an enhanced TNFa response (30) and may be abrogated by inactivating Kupffer cells (31), although this is controversial. Similarly IL-10 null mice are sensitized to acetaminophen (32), whereas natural killer/natural killer cell with T cell receptor cell depletion, knockout of IFNg, and Fas/Fas ligand deﬁciency protect against acetaminophen (33). Thus, the direct and indirect inﬂuence of toxins on the production and balance of mediators, and genetic polymorphisms in these responses may play a major role in unmasking the overt toxic potential of a drug culminating in overt idiosyncratic toxicity.

Another important factor that contributes to the extent of liver injury is the capacity of the liver to regenerate (Fig. 3). Thus, for example, TNFa will promote regeneration by acting on Kupffer cells (autocrine) to release IL-6, which will trigger, along with hepatocyte growth factor, regeneration. Interference with IL-6 (knockout) worsens CCl4injury, and conversely, exogenous IL-6 treatment diminishes liver injury in wild-type mice (34). TNF also acts on hepatocytes through NF-kB signaling to promote survival gene transcription. If the toxin interferes with the latter pathway, TNFa-induced apoptosis may occur.

RISK FACTORS

Regardless of whether hepatotoxicity is predictable (frequent) or unpredictable (rare), hypersensitivity-mediated or idiosyncratic, metabolism dependent or parent drug-dependent, the interplay of genetic and environmental risk factors inﬂuences susceptibility (Fig. 4) (35). Age, gender, concomitant drugs, and underlying diseases (e.g., hepatitis C virus, hepatitis

Toxin Hepatocyte

injury HGF

Regeneration IL-6

LPS Kupffer cell activation

TNFα

Acute liver failure Pro- or anti-

apoptosis Anti-

apoptosis

FIGURE 3 Role of cytokines and regeneration in toxin-induced liver disease. TNF activates NF-kB in nonparenchymal cells, leading to IL-6 production, and in hepatocytes, or with the regenerative response, worsening of the overt liver injury.

Toxic potential of drug - Reactive metabolite - Acylglucuronide - Mitochondrial effects

Genetic factors - Drug metabolism - Detoxification - Transport - Others

Environmental factors - Ethanol

- Other drugs - Age

- Underlying disease

FIGURE 4 Risk of hepatotoxicity. The ultimate development of hepatotoxicity is determined by the interplay of the toxic potential of the drug or its metabolites and the susceptibility of the host as determined by genetic and environmental factors, both of which influence gene expression.

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B virus, HIV) have been most frequently identiﬁed. Table 4 lists examples of drugs and associated risk factors.

With the advent of new technologies in genomics and proteomics, one can anticipate that new insights into the mechanisms of susceptibility and liver injury from drugs will be forthcoming (36). Some of the genetic factors to consider are listed in Table 5. Polymorphisms (CYPs, cytokines, MHC, etc.) and rare heterozygous mutations (b-oxidation, bile salt export pump) will need to be assessed.

DIAGNOSIS

Establishing a diagnosis of drug-induced liver disease in an individual case is mainly based upon circumstantial evidence aided by the signature type of reactions (if known) with respect to latency and clinical characteristics as well as exclusion of other more plausible alternative causes. Additional information can be gained from the response to removal of the drug—rapid improvement in cytotoxic reactions and slow improvement in cholestatic reactions.

A rechallenge with recrudescence of liver abnormalities is the most definitive evidence, but hardly ever justified and not always positive in idiosyncratic cases. A practical approach is to consider the diagnosis probable/possible if the signature latency and pattern of disease fit and other causes are excluded (viral hepatitis, ischemic hepatitis, biliary disease). The remaining cases are unlikely or unrelated depending on the completeness of the workup and the strength of the evidence in favor of an alternative diagnosis. This ad hoc approach is equivalent to diagnosing as yes, no, or maybe.

The presence of autoantibodies to specific forms of CYP has been associated with hypersensitivity reactions to certain drugs (25,37,38). Although uncertain but intriguing significance with respect to pathophysiology, their presence may be helpful in the diagnosis of drug-induced liver disease in these special cases (Table 6). However, testing for these autoantibodies is mainly a research tool at present. Furthermore, sensitivity and specificity of the presence of these autoantibodies is uncertain and autoantibodies to certain CYPs have been TABLE 4 Risk Factors for Drug-Induced Hepatotoxicity

Drug Factors

Methotrexate Chronic alcohol, obesity, diabetes, chronic hepatitis, psoriasis

Isoniazid HBV, HCV, HIV, alcohol, older age, female, slow acetylator, rifampin, pyrazinamide Acetaminophen Chronic alcohol, fasting, isoniazid

Valproate Young age, anticonvulsants, genetic defects of mitochondrial b-oxidation and respiratory chain enzymes

Diclofenac Female, osteoarthritis

Anticonvulsants Genetic defect in detoxification

Sulfonamides HIV, slow acetylator, genetic defect in defense Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus.

TABLE 5 Possible Genetic Determinants of Risk 1. Drug metabolism (e.g., CYP polymorphisms) 2. Detoxification (e.g., GSH-related, epoxide hydrase) 3. Apoptosis and survival genes

4. Signal transduction (kinases and phosphatases) 5. MHC I and II

6. Cytokines/chemokines and receptors 7. Inflammatory mediators (Cox, NOS, etc.) 8. Regeneration/repair

9. Transporters (BSEP, MRP2, etc.)

10. Mitochondrial b-oxidation and respiratory chain 11. Structural integrity (e.g., cytokeratin 8/18)

Abbreviations: Cox, cyclooxygenase; NOS, nitric oxide synthase; BSEP, bile salt export pump; MRP2, multidrug resistance associated protein family; MHC, major histocompatibility complex; CYP, cytochrome P450s; GSH, glutathione.

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observed in patients taking drugs without evidence of hepatotoxicity, limiting their diagnostic value.

Several groups have attempted to generate quantitative systems designed to generate a numerical score that reﬂects the probability of a drug as the cause for liver disease (39–42).

The Roussel-Uclaf casuality assessment method scoring system appears to be the most accurate (43,44) and puts numerical weight on the factors discussed above (Table 7) to generate a composite score that reﬂects the probability that liver injury is drug-induced. The advantage is that this system is less subjective than the ad hoc approach. This type of scoring system performs well when validated against well-documented cases of drug-induced liver disease.

Specialists, the pharmaceutical industry, and regulatory bodies should be encouraged to use this scale. It also would be reasonable to apply the scoring system to individual case reports submitted to medical journals. Although it is not perfect and may not discriminate between multiple concurrently used candidate toxins, it does provide consistency and focuses the attention of the evaluator on most of the critical parameters that need to be considered in estimating the probability of causality.

DRUG DEVELOPMENT

Drug development involves a preclinical and clinical phase. Preclinical assessment is centered on animal testing using very high doses. Although animal testing is probably very reliable in screening out potent, predictable toxins, it is far less reliable in identifying a propensity for unpredictable toxicity. Experience has suggested that there are numerous false positives and false negatives. A better understanding of the mechanisms of unpredictable hepatotoxicity may eventually lead to the establishment of appropriate animal models that recapitulate the factors that determine susceptibility in humans. This will most likely be achieved with the use of transgenic and knockout mice to set up conditions that mimic human susceptibility. At present, some suggestion of hepatotoxicity at high doses in animals may at least warrant more careful or extensive assessment in the clinical phases of drug development.

During phases I to III of drug testing the likelihood of encountering overt hepatotoxicity (i.e., jaundice and high transaminases) depends on the frequency of the reaction. Most idiosyncratic reactions occur in 1 in 1000 or more individuals and acute liver failure in 1 in 10,000 or more. Typically in clinical development, drugs are tested in 1500 to 2500 individuals.

Exclusion of an overt reaction with 95% conﬁdence, if the true incidence is 1:1000, would require 3000 treated patients, assuming all were exposed for the appropriate duration (e.g., six to nine months). This is usually not attained in clinical trials. Therefore, if one is not fortunate TABLE 6 Autoantibodies in Drug-Induced Liver Disease

Autoantibody target Drug

CYP 2C9^a Tienilic acid

CYP 1A2^b Dihydralazine

CYP 3A^b Anticonvulsants

CYP 2E1 Halothane

mEH Germander

aAlso referred to as anli-LKM2 autoantibody.

bAlso referred to as anti-LM autoantibody.

Abbreviations: CYP, cytochrome P450; mEH, microsomal epoxide hydrolase.

TABLE 7 Causality Assessment 1. Latency

2. Rate of resolution (dechallenge) 3. Risk factors (age, alcohol, pregnancy)

4. Exclusion of other causes (viral hepatitis, ischemia, biliary tract disease, alcohol) 5. Concomitant drugs

6. Track record (PDR, case reports) 7. Rechallenge

Abbreviation: PDR, Physicians Desk Reference.

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enough to identify overt hepatitis in one or two cases in the study population, the appearance of lesser signals needs to be the focus for scrutiny. It is very rare indeed to identify acute liver failure from idiosyncratic hepatotoxins in drug development. The rule of threes indicates that to identify (not miss) acute liver failure with 95% conﬁdence that has a true incidence of 1 in 10,000 would require 30,000 study patients.

Since the probability of identifying overt or life-threatening liver injury in clinical trials is so low, one must focus on the incidence of asymptomatic ALT and bilirubin elevations (45).

The most sensitive parameter appears to be the incidence of ALTO3!ULN in drug-treated versus placebo control-treated patients. Depending on the study population, the incidence of 3!ALT in controls may vary from 0.1% to nearly 1.0%. Thus, an incidence of 2% to 3% or greater in the drug-treated patients would be unequivocal cause for closer scrutiny. Although this is a sensitive indicator, it is not entirely specific since there are drugs, e.g., statins, tacrine, aspirin, etc., that are associated with an increased incidence of 3!ALT, but have proved relatively safe in postmarketing experience (?false-positive signal). More specificity is gained by examining the height of the transaminases. An ALT increase of eightfold or greater is a more specific signal since this rarely occurs in controls. Even more specific is conjugated hyperbilir- ubinemia (R1.5-fold) associated with elevated ALT.

The experience with troglitazone exempliﬁes the issue of identiﬁcation of a signal. In a cohort of 2500 study patients, ALTO3!ULN occurred in nearly 2% (vs. !1% in controls);

ALTO8!ULN occurred in 0.6% (vs. none of controls); and two cases with overt jaundice were observed (46). Thus, all the criteria for a hepatic signal were present at the time of approval of the drug. A similar premarketing experience was observed with bromfenac (47), which was also withdrawn postmarketing.

A critical issue is what is the appropriate regulatory response to the occurrence of a signal? In some cases, particularly when the drug is not crucial, approval is denied. If the drug is critical, warnings and education of physicians and patients are very important and there may be justification for recommending monitoring ALT (see below) and/or restrictions on the use of the drug. Two recent examples are bosentan and ximelagatran, which had unequivocal signals for idiosyncratic hepatotoxicity, perhaps stronger than troglitazone (Table 8). Bosentan was approved with monitoring because the disease being treated is fatal, i.e., pulmonary hyperten- sion, and no other efficacious treatment is available, and therefore a favorable risk-benefit analysis. Ximelagatran, a thrombin inhibitor, was not approved because several cases of very severe hepatotoxicity were seen and alternative anticoagulants are available. A number of antituberculous, HIV and cancer drugs have remained on the market because benefit outweighs risks.

POSTMARKETING MONITORING

The background incidence of drug-induced mild, reversible liver injury provides the rationale for monitoring or surveillance. From this background of mild injury a minority of individuals will emerge with overt disease. Thus, by stopping the medications at the ﬁrst sign of mild injury one should prevent serious consequences. Although this seems a logical approach, a number of problems must be considered. First, the approach applies only to delayed reactions.

TABLE 8 Comparison of Idiosyncratic Hepatotoxins in Clinical Trials

Troglitazone Bosentan Ximelagatran

nZ 2500 658 6948

ALTO3!ULN 1.8% 12 14% 7.8%

ALTO10!ULN 0.6% 2 7% 1.9%

ALTO3! and bili O2! 0.5%

ALTO8! and bili O3! 0.08% 0.3% 0.1%

Fatal acute liver failure 0 0 0.01 0.04%^a

a3 cases (one confounded by HBV).

Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal; HBV, hepatitis B virus.

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Hypersensitivity reactions occur relatively early and evolve rapidly so educating patients about symptoms is crucial in early cessation of the offending drug. Second, one is sacriﬁcing potentially very important therapy to a much larger number of patients than would actually develop overt disease; third, compliance with such approaches is known to be very poor;

fourth, the rate of development of overt disease from the first appearance of elevated ALT needs to be gradual for monthly monitoring to be efficacious in preventing life-threatening disease. Testing more frequently than monthly is not practical, although the future development of a fingerstick ALT test that could be applied in a fashion similar to monitoring glucose might change this by improving compliance and allowing more frequent monitoring. In any case, monthly monitoring for delayed idiosyncratic reactions is the best approach available, but the efficacy of the approach is assumed and not proven. Furthermore, this should not substitute for the need to educate patients about symptoms of hepatotoxicity, such as fever, rash, malaise, fatigue, anorexia, gastrointestinal complaints, abdominal pain, dark urine; jaundice, pruritus, etc., and the need to report them to the physicians to ensure expeditious cessation of offending agents. Despite monthly monitoring, some adverse events may appear rapidly in the few weeks after a normal test.

Ultimately, the most difficult challenge to the application of monitoring is cost-effective- ness—monthly monitoring is expensive and one needs to weigh this quantitatively against the morbidity and mortality of adverse liver events. There is no clear answer to the question of what incidence of serious adverse idiosyncratic hepatitis warrants monitoring, how frequently it should be performed, and for how long. Furthermore, the postmarketing occurrence of adverse events must be weighed against the benefit of the drug. Risk/benefit assessment is ill defined but ultimately becomes the crucial factor in recommending monitoring ALT versus removal of the drug from the market. In the case of the nonsteroidal anti-inflammatory drug, bromfenac, continued use of the drug in the face of infrequent, delayed idiosyncratic severe hepatotoxicity (47) could not be justified since many alternative treatments were available.

In the case of troglitazone, the decision to withdraw was delayed and more complicated owing to the important and unique therapeutic properties of the drug in managing a serious medical condition, albeit with beneﬁts that would not be evident for many years (i.e., the effect of long-term control of blood sugar on complications of diabetes). It was decided that the implementation of monthly monitoring would likely protect the users and the drug was continued. Although this strategy may have worked to some extent, the issue of compliance with monitoring and the possibility of occasional “rapid risers” meant that the population could not be completely protected. At the same time, several new drugs in this class were approved and after a year of postmarketing experience with the alternative new agents, it was concluded that these agents were much less likely to induce severe hepatotoxicity, leading to the withdrawal of troglitazone.

A major issue in postmarketing surveillance is the frequency of serious adverse events compared to the background in the general population. Reliable data on the occurrence of hospitalization for idiopathic hepatitis and acute liver failure are very limited. However, several databases (Medicaid, HMO) suggest that hospitalization for cryptic acute hepatitis occurs in about 1:50,000 to 1:100,000 adult individuals in the general population each year (48–50). Acute liver failure is estimated to occur in up to 3000 individuals annually in the United States. About 10% to 20% of these cases are idiopathic with a resulting annual incidence of one to two cases per million individuals in the population. Thus, when a new drug is marketed and more than a few cases of unexplained acute liver failure are reported, concern should be raised. In the example of troglitazone, at least 30 to 40 cases of acute liver failure were reported to the FDA in the ﬁrst year on the market from a population of about one million taking the drug. This was a much higher rate than predicted. Such a postmarketing signal may be less apparent when far fewer individuals are exposed.

However, the current MedWatch system for reporting adverse events, with all its attendant problems regarding poor compliance and accurate causality assessment, has been reasonably successful in rapidly identifying problems with numerous drugs leading to withdrawal or severe restrictions of use.

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CONCLUSIONS

The liver is a particular target for drugs because of its role in clearing and metabolizing chemicals. The parent drug or more frequently the metabolites may either affect critical functions, or sensitize to the effects of cytokines or inﬂammatory cells, or elicit an immune response. This often occurs in an unpredictable fashion, implying that environmental and genetic factors alter the susceptibility to these adverse events. A wide range of liver diseases can occur as adverse events but the individual drug tends to induce a characteristic signature reaction with respect to latency and clinicopathological manifestations. Hepatotoxicity from drugs poses a major challenge in drug development and postmarketing surveillance.

The future identiﬁcation of the pathogenesis of idiosyncratic reactions represents the major challenge in this ﬁeld and will likely advance rapidly with the application of methods of toxicogenomics and pharmacogenomics in the preclinical and clinical arenas.

REFERENCES

1. Zimmerman H. Drug Hepatotoxicity. 2nd ed. Philadelphia, PA: Lippincott, 1999.

2. Ostapowicz G, Fontana RB, Larson AM, et al. Etiology and outcome of acute liver failure in the USA:

preliminary results of a prospective multi-center study (abstr). Hepatology 1999; 30(4):221A.

3. Shakil A, Kramer D, Mazariegos G, et al. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transplant 2000; 16:163–9.

4. Larsen A, Polson J, Fontana R, et al. Acetaminophen-induced acute liver failure: results of a U.S.

Multicenter, prospective study. Hepatology 2005; 42:1364–72.

5. Zimmerman H. Drug-induced liver disease. In: Schiff E, Sorrell M, Maddrey W, eds. Schiff’s Diseases of the Liver. 8th ed. Philadelphia, PA: Lippincott-Raven, 1999:973–1064.

6. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population- based study. Hepatology 2002; 36:451–5.

7. Meier Y, Cavallaro M, Roos M, et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 2005; 61:135–43.

8. Kaplowitz N. Drug metabolism and hepatotoxicity. In: Kaplowitz N, ed. Liver and Biliary Diseases.

2nd ed. Baltimore, MD: Williams & Wilkins, 1996:103–20.

9. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.

Hepatology 2005; 42:481–9.

10. Andrade R, Lucena M, Fernandez M, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129:512–21.

11. Lewis JH. “Hy’s law”, the “Rezulin rule” and other predictors of severe drug-induced hepatotoxicity:

putting risk-beneﬁt perspective. Pharmacoepidemiol Drug Saf 2006; 15:221–9.

12. Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol 1997; 26:31–5.

13. Degott C, Feldmann G, Larrey D, et al. Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia. Hepatology 1992; 15:244–51.

14. Van Steenberen W, Peeters P, DeBondt J, et al. Nimesulide-induced acute hepatitis: evidence from six cases. J Hepatol 1998; 29:135–41.

15. Pham T-V, Lu S, Kaplowitz N. Acetaminophen hepatotoxicity. In: Taylor MB, ed. Gastrointestinal Emergencies. 2nd ed Baltimore, MD: Williams & Wilkins, 1997:371–88.

16. Tarazi E, Harter JG, Zimmerman HJ, et al. Sulindac-associated hepatic injury. Analysis of 91 cases reported to the food and drug administration. Gastroenterology 1993; 104:569–74.

17. Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 1988; 82:1826–32.

18. Larrey D, Vial T, Micaleff A, et al. Hepatitis associated with amoxycillin-clavulanic acid combination.

Report of 15 cases. Gut 1992; 33:368–71.

19. Thompson N, Caplin M, Hamilton M, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995; 8:1384–8.

20. Murphy E, Davern T, Shakil O, et al. Troglitazone-induced fulminant hepatic failure. Dig Dis Sci 2000;

45:549–53.

21. Rieder M, Uetrecht J, Shear N, et al. Diagnosis of sulfonamide hypersensitivity reactions by in vitro

“rechallenge” with hydroxylamine metabolites. Ann Intern Med 1999; 110:286–9.

22. Rieder M, Shear N, Kanee A, et al. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther 1991; 49:13–7.

23. Gennis M, Vemusi R, Burns E, et al. Familial occurrence of hypersensitivity to phenytoin. Am J Med 1991; 91:631–4.

24. Becquemont L, Lecoeur S, Simon T, et al. Glutathione S-transferase q genetic polymorphism might inﬂuence tacrine in Alzheimer’s patients. Pharmacogenetics 1997; 7:251–3.

(28)

25. Robin M, LeRoy M, Descatoire V, Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J Hepatol 1997; 26(1):23–30.

26. Berson A, DeBeco V, Letteron P, et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998; 114:764–74.

27. Brinkman K, Hofstede H, Burger D, et al. Adverse effects of reverse transcriptase inhibitors:

mitochondrial toxicity as common pathway. AIDS 1998; 12:1735–44.

28. Kowdley K, Keefe E. Hepatotoxicity of transplant immunosuppressive agents. Gastroenterol Clin North Am 1995; 24:991–1001.

29. Czaja M, Xu J, Alt E. Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology 1995; 108:1849–54.

30. Hogaboam C, Bone-Larson C, Steinhauser M, et al. Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C–C chemokine receptor 2. Am J Pathol 2000; 156:1245–52.

31. Laskin D, Gardner C, Price V, Jollow D. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995; 21:1045–50.

32. Bourdi M, Masubuchi Y, Reilly TP, et al. Protection against acetaminophen induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 2002; 35:289–98.

33. Liu Z-X, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004; 127:1760–74.

34. Cressman P, Greenbaum L, DeAngelis R, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deﬁcient mice. Science 1996; 274:1379–83.

35. DeLeve L, Kaplowitz N. Prevention and therapy of drug-induced hepatic injury. In: Wolfe M, ed.

Therapy of Digestive Disorders Philadelphia, PA: WB Saunders/Harcourt Brace & Company, 2000:334–48.

36. Nuwayser E, Bittner M, Trent J, et al. Microarrays and toxicology: the advent of toxicogenomics. Mol Carcinog 1999; 24:153–9.

37. Beaune P, Lecoeur S. Immunotoxicology of the liver: adverse reactions to drugs. J Hepatol 1997;

26(Suppl. 2):37–42.

38. Neuberger J. Immune mechanisms in drag hepatotoxicity. Clin Liver Dis 1998; 2:471–82.

39. Maria V, Victorino R. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26:664–9.

40. Benichou C. Criteria of drug induced liver disorders: report of an international consensus meeting.

J Hepatol 1990; 11:272–6.

41. Danan G, Benichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46:1323–30.

42. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs II. An original model or validation of drug causality assessment methods: case reports with positive rechallenge.

J Clin Epidemiol 1993; 46:1331–6.

43. Lucena M, Camargo R, Andrade R, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33:123–30.

44. Kaplowitz N. Causality assessment versus guilt by association in drug hepatotoxicity. Hepatology 2001; 33:308–10.

45. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005; 4:489–99.

46. Watkins P, Whitcomb R. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998;

338:916–7.

47. Moses P, Schroeder B, Alkhatib O, et al. Severe hepatotoxicity associated with bromfenac sodium. Am J Gastroenterol 1999; 94:1393–6.

48. Walker A, Cavanaugh R. The occurrence of new hepatic disorders in a deﬁned population. Post Mark Surveill 1992; 6:107–17.

49. Carson J, Strom B, Duff A, et al. Safety of nonsteroidal anti-inﬂammatory drugs with respect to acute liver disease. Arch Intern Med 1993; 153:1331–6.

50. Dun M-S, Walker A, Kronlund K. Descriptive epidemiology of acute liver enzyme abnormalities in the general population of central Massachusetts. Pharmacoepidemiol Drug Saf 1999; 8:275–83.

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Drug-InDuceD LIver DIsease