Drug-Induced Liver Disease

Dedication

Preface to the Third Edition

List of Figures

List of Tables

List of Contributors

Part I: Mechanisms of Liver Injury

Chapter 1. Drug-Induced Liver Injury: Introduction and Overview

Introduction

Clinical Overview

Pathogenesis

Diagnosis

Drug Development

Postmarketing Monitoring

Conclusions

References

Chapter 2. Cytochrome P450 Activation of Toxins and Hepatotoxicity

Introduction

Cytochrome P450 Enzymes

Contexts of Toxicity

Bioactivation Reactions

Strategies for Screening in Drug Development

The Issue of Human-Specific Metabolites

Conclusions

References

Chapter 3. Mechanistic Role of Acyl Glucuronides

Introduction

Overview of Major Types of Chemical ReactivitIES of Acyl Glucuronides

Biochemical Aspects of Acyl Glucuronidation

Synthesis, Isolation, and Characterization of Acyl Glucuronides

Stability of Acyl Glucuronides

Reversible Binding of Acyl Glucuronides to Proteins

Covalent Binding of Acyl Glucuronides to Proteins

Stereochemical Aspects of Acyl Glucuronides

Predictability of the Covalent Binding of Acidic Drugs

In Vitro Reactivity Screens Utilizing Nucleophilic Trapping Agents

Potential Toxicological Significance of the Reactive Acyl Glucuronides

Acknowledgment

References

Chapter 4. Oxidant Stress, Antioxidant Defense, and Liver Injury

Introduction

The Major Reactive Oxygen and Nitrogen Species in the Liver and their Sources

Pathophysiological Consequences of Oxidative Stress

Antioxidants

Drug-Induced Oxidative Stress in the Liver

References

Chapter 5. Hepatotoxicity Due to Mitochondrial Injury

Introduction

Overview of Mitochondria

Mitochondrial Permeability Transition

Mitochondria and Drug-Induced Hepatic Steatosis

Conclusion

Acknowledgments

References

Chapter 6. Mechanisms of Cell Death and Relevance to Drug Toxicity

Introduction

Classification of Cell Death

Apoptosis

Autophagy

Necrosis: A Programmed Process?

Cell Death in DILI

Conclusions

References

Chapter 7. Role of Membrane Transport in Hepatotoxicity and Pathogenesis of Drug-Induced Cholestasis

Introduction

Bile Formation

Clinical Features of Drug-Induced Cholestasis

Hepatocellular Drug Uptake and Intracellular Drug Concentrations

Mechanisms of BSEP Inhibition

Impact of Elevated Intracellular Bile Salt Levels on Transporter Expression

Susceptibility Factors for Drug-Induced Cholestasis

Conclusions

References

Chapter 8. Liver Sinusoidal Endothelial Cells and Liver Injury

Introduction

Liver Sinusoidal Endothelial Cells

Capillarization, Pseudocapillarization, and Drug Metabolism

Liver Sinusoidal Endothelial Cells and Fibrosis

Bone Marrow Liver Sinusoidal Endothelial Progenitor Cells and Liver Regeneration

Manifestations of Liver Sinusoidal Endothelial Cell Injury

Lesions of Heterogeneous Perfusion

Peliosis Hepatis

Sinusoidal Obstruction Syndrome

Acetaminophen

Gemtuzumab Ozogamicin

Oxaliplatin

Conclusions

References

Chapter 9. Macrophages and Kupffer Cells in Drug-Induced Liver Injury

Introduction

Innate Immune Activation in DILI

Interactions Between Hepatic Macrophages and Other Cells in the Liver During DILI

Danger Signals Generated in Drug-Induced Liver Injury and Their Signaling Pathways

Additional Damps/Pamps Involved in Macrophage Activation in DILI

Complement and Macrophage Activation

Diagnosis and Treatment of Drug-Induced Liver Injury: Can Macrophages Be a Target?

Genetic Susceptibility to DILI

Conclusions

References

Chapter 10. Role of Inflammation in Drug-Induced Liver Injury

Introduction

Inflammation as a Progression Factor in Intrinsic DILI

Inflammation in Idiosyncratic DILI Responses

Exogenously Imposed Inflammation as a Susceptibility Factor for Drug-Induced Liver Injury

Conclusions

Acknowledgments

References

Chapter 11. Role of the Adaptive Immune System in Idiosyncratic Drug-Induced Liver Injury

Introduction

Clinical Characteristics of IDRS

Evidence Suggesting that IDILI is Immune Mediated

Alternative Hypotheses

Toward a Unifying Hypothesis for IDILI

Conclusions

Acknowledgments

References

Chapter 12. Role of Tissue Repair and Death Proteins in Liver Injury

Introduction

Two-Stage Model of Toxicity

Tissue Repair Follows a Dose Response

Dose-Responsive Tissue Repair for Mixtures of Hepatotoxicants

Tissue Repair as a Determinant of the Final Outcome of Toxicity

Relationship Between Higher Initiation of Liver Injury and Tissue Repair

Factors Affecting Tissue Repair

Progression of Liver Injury

Regression of Injury

Significance of Tissue Repair

Significance of Death Proteins in the Spread of Liver Injury

Conclusions

References

Chapter 13. Genetic Factors in the Pathogenesis of Drug-Induced Liver Injury

Introduction

Methods and Approaches Used to Identify Genetic Factors in DILI

Genetic Factors Predicting DILI Susceptibility

Conclusions

References

Part II: Diagnosis and Management

Chapter 14. Clinical Manifestations and Management of Drug-Induced Liver Diseases

Introduction

Susceptibility Factors: Drug-Induced Liver Injury

Clinical Recognition of a Suspected or Probable DILI

Clinical and Laboratory Manifestations

Manifestations of DILI

Nonspecificity of Clinical and Laboratory Manifestations of DILD

Signals of Severe Drug-Induced Liver Injury: The Importance of Hy’s Law

The Important Issue of Drug-Induced Autoimmune Hepatitis

Drugs of Special Interest

Management and Treatment of DILD

Rechallenge

References

Chapter 15. Histopathological Evaluation of Drug-Induced Liver Disease

Introduction

Role of Pathological Evaluation in DILD

Patterns of Injury in DILd

Using Liver Biopsy to Evaluate DILD

Conclusions

Acknowledgments

References

Chapter 16. Risk Factors for Drug-Induced Liver Disease

Introduction

Host-Related Risk Factors

Environmental Risk Factors

Compound-Related Risk Factors

Conclusions

Acknowledgments

References

Chapter 17. Biomarkers for Drug-Induced Liver Injury

Introduction

Current Status of Hepatocellular DILI Biomarkers

The Road to Better DILI Biomarkers

Metabolomics

Transcriptomics

Proteomics

Example of an Application of Novel Biomarkers to a Clinical Trial: Heparins

Serum Protein Adducts

Anti-Liver Antibodies

Lymphocyte Transformation Test

Conclusions

References

Chapter 18. Causality Assessment

Introduction

Diagnosis in the Clinical Setting

Minimal Elements for Drug-Induced Liver Injury Diagnosis and Publishing

Causality Assessment

Conclusions

References

Part III: Hepatotoxicity of Specific Drugs

Chapter 19. Mechanisms of Acetaminophen-Induced Liver Disease

Introduction

Reactive Metabolite Formation

Protein Covalent Binding

Toxicity Occurs in Two Phases

Alterations in Calcium Metabolism

Oxidative Stress and Toxicity

Mitochondrial Permeability Transition

Antioxidant Defense Mechanisms

Cell Signaling and Mitochondrial Permeability Transition

Hepatic Inflammation

Genomics, Proteomics, and Metabolomics

Conclusions

Acknowledgments

References

Chapter 20. Acetaminophen: Pathology and Clinical Presentation of Hepatotoxicity

Introduction

Pharmacology of Acetaminophen

Availability of Acetaminophen and Considerations on Regulation

Clinical Presentation of Acetaminophen Toxicity

Definitions of Toxicity

Biomarkers of Toxicity

Patient Variability and Acetaminophen Toxicity

Acknowledgments

References

Chapter 21. Mechanisms Underlying the Hepatotoxicity of Nonsteroidal Antiinflammatory Drugs

NSAID Hepatotoxicity: A Paradigm of IDILI

Toxicokinetic Determinants of NSAID Hepatotoxicity: Disposition and Metabolism

Toxicodynamic Determinants of NSAID Hepatotoxicity: Cellular and Molecular Mechanisms

Patient-Specific Determinants of Susceptibility to NSAID Hepatotoxicity

Conclusions

References

Chapter 22. Nonsteroidal Antiinflammatory Drugs and Leukotriene Receptor Antagonists

Introduction

Incidence of NSAID-Induced Hepatic Injury

Effect of Rheumatic Diseases on the Liver

Clinical and Biochemical Spectrum of NSAID-Induced Hepatic Injury

Hepatic Injury Due to Individual NSAIDs

Hepatic Injury Due to DMARDS

Hepatotoxicity of Leukotriene Receptor Antagonists

Hepatotoxicity of Agents Used in the Treatment of Gout

Monitoring for NSAID and Other Antiinflammatory Drug-Induced Hepatic Injury

References

Chapter 23. Mechanism, Pathology, and Clinical Presentation of Hepatotoxicity of Anesthetic Agents

Introduction

Clinical Features of Volatile Anesthetic-Induced Hepatotoxicity

Metabolism of Volatile Anesthetics

Adaptive Immune Responses in Patients with AnesthetIc-Induced Liver Injury

Animal Models

Hydrochlorofluorocarbon Refrigerants

Mechanism of Volatile Anesthetic-Induced Liver Injury and Basis of Individual Susceptibility

Conclusions

References

Chapter 24. Anticonvulsant Agents

Introduction

Carbamazepine

Oxcarbazepine

Phenytoin

Phenobarbital

Valproic Acid

Felbamate

Lamotrigine

Management

References

Chapter 25. Hepatotoxicity of Psychotropic Drugs and Drugs of Abuse

Introduction

Epidemiological Aspects of Psychotropic Hepatotoxicity

Identification of Drug-Induced Liver Injury Caused by Psychotropic Agents

Factors that Contribute to the Hepatotoxicity of Psychotropic Agents

Antidepressants

Neuroleptic Agents

Anxiolytic Agents

Psychostimulating Agents

Thymoregulating Agents

Herbal Medicines

Illegal and Recreational Compounds

Conclusions

References

Chapter 26. Hepatotoxicity of Antimicrobials and Antifungal Agents

Introduction

Antibacterial Agents

Antifungal Agents

Conclusions

References

Chapter 27. Hepatotoxicity of Antitubercular Drugs

Introduction

Incidence of Hepatotoxicity

Mechanism of Hepatotoxicity

Hepatotoxicity of Individual Drugs

Hepatotoxicity with Multidrug Antitubercular Therapy

Risk Factors for Antitubercular Therapy Hepatotoxicity

Clinical, Biochemical, and Histological Features

Management, Including Referral for Liver Transplant

Alternative Therapy for Underlying Tuberculosis and Reintroduction of Antitubercular Therapy

Antitubercular Therapy in Patients with Underlying Liver Disease

Hepatotoxicity of Antitubercular Therapy in Liver Transplant Recipients

Recommendations for Monitoring Patients While on ATT

Conclusions

References

Chapter 28. Hepatotoxicity of Antiviral Agents

Introduction

Antiretroviral Drugs

Incidence and Risk Factors for HAART-Related DILI: The Drug and the Host

Clinical Presentations of HAART-Related DILI and their Mechanisms

Hepatitis Treatments

Herpesviridae Treatment

Influenza Virus Treatments

References

Chapter 29. Hepatotoxicity of Cardiovascular and Antidiabetic Drugs

Introduction

Cardiovascular Drugs

Antidiabetic Drugs

Other Agents

Conclusions

References

Chapter 30. Cancer Chemotherapy

Introduction

Hepatic Metabolism of Anticancer Drugs

Liver Toxicity and Hematopoietic Stem Cell Transplantation

Hepatotoxicity by Anticancer Therapy

Selected Anticancer Drugs and Modalities

Conclusions

References

Chapter 31. Hepatotoxicity of Immunosuppressive Drugs

Classification of Immunosuppressive Agents

Hepatotoxicity of Immunosuppressives in Current Clinical Practice

Conclusions

References

Chapter 32. Hepatotoxicity Related to Methotrexate

Introduction

Acute DILI

Methotrexate-Associated Chronic Liver Disease

Pathogenesis of Methotrexate-Associated Chronic Liver Disease

Monitoring for Methotrexate-Associated Chronic Liver Disease

Conclusions

References

Chapter 33. Adverse Effects of Hormones and Hormone Antagonists on the Liver

Introduction

Oral Contraceptive Steroids

Anabolic Androgenic Steroids

Estrogen Receptor Antagonists

Antiandrogens

Corticosteroids

Antithyroid Drugs

Conclusions

References

Chapter 34. Mushroom Poisoning: A Clinical Model of Toxin-Induced Centrilobular Necrosis

Introduction

Amanita: The Mushrooms

The Toxins

Amanita Poisoning: Manifestations

Liver Lesions

Prognosis

Management

Conclusions

Acknowledgment

References

Chapter 35. Hepatotoxicity of Herbals and Dietary Supplements

Introduction

Epidemiology of and Expenditure on Herbals and Dietary Supplements

Origin and Production of Herbals and Botanicals for Medicinal Purposes

Regulation of Dietary Supplements

The Use of Herbal Products to Treat Liver Disease

Liver Injury Caused by Herbals and Dietary Supplements

Causality Assessment for Hepatotoxicity Due to Herbals and Dietary Supplements

Limitations of Causality Assessment for Hepatotoxicity Due to Herbals and Dietary Supplements

Herbal Products Associated with Liver Injury

Dietary Supplements Associated with Liver Injury

Natural Toxins

Conclusions

References

Chapter 36. Occupational and Environmental Hepatotoxicity

Introduction

Types of Injuries

Types of Exposures

Susceptibility to Injury

Testing for Occupational Hepatotoxicity

Mechanisms of Injury

Hepatotoxic Chemicals

Halogenated Aromatic Hydrocarbons

Halogenated Aliphatic Hydrocarbons

Chlorinated Ethylenes

N-Substituted Amides

Organochlorine Pesticides, Insecticides, and Herbicides

Miscellaneous Hepatotoxins

Hydraulic Fracturing

Conclusions

References

Chapter 37. Chronic Liver Disease from Drugs

Introduction

Autoimmune Hepatitis Triggered by Drugs

Vanishing Bile Duct Syndrome Associated with Drugs

Liver Cirrhosis Associated with Drugs

Incidence of Chronic Liver Test Abnormalities After DILI

Possible Long-Term Consequences of DILI on the Liver

Conclusions

References

Part IV: Future Directions

Chapter 38. Regulatory Perspectives

Introduction

Regulatory and Scientific Challenges in the Assessment of Drug-Induced Liver Injury Risk

Assessment of DILI Risk in Clinical Trials

Identification and Characterization of DILI Risk in the Postmarket: A Life Cycle Approach

Evaluation of Postmarketing DILI Cases

Postmarketing DILI Surveillance Tools

Risk Management of DILI

DILI and the FDAs Role in the Safe Use of Drugs and Biological Agents

Future Directions Surrounding DILI: Interface between Science and Regulation

References

Chapter 39. Drug-Induced Liver Injury Research Networks

Introduction

Prospective Studies of DILI

Prospective DILI Registries

Retrospective Pharmacoepidemiological Studies of DILI

Acknowledgments

References

Chapter 40. LiverTox: A Website on Drug-Induced Liver Injury

Introduction

Introductory Sections

Drug Records

Interactive Section

Conclusions

Acknowledgments

References

Index