Drug-Induced Hepatotoxicity

1: Orientation in Liver Toxicity by Drugs.- A. Introduction.- B. Agents and Processes.- C. Responses to Injury as Multitier or Multigrid Patterns.- I. Quantitative Versus Qualitative Changes.- II. Patterns of Liver Toxicity.- 1. Tier One: Patterns of Interactions of Agents with Liver.- 2. Tier Two: Patterns of Biological Responses to Cell Injury.- 3. Tier Three: Cellular and Intracellular Responses.- 4. Tier Four: Cellular and Tissue Physiology.- D. Conclusion.- References.- 2: Clinical Studies and Role of Necrosis in Hepatotoxicity (With 7 Figures).- A. Zonal Necrosis as a Response to Acetaminophen.- I. Zonality: Specific Hepatocytes Die as a Group.- II. Ethanol Plus Acetaminophen: Extension of Zone of Necrosis.- III. Constitutive Bases of Zonal Responses.- 1. Perivenous Localization of Acetaminophen-Metabolizing enzyme CYP 2E1.- IV. Zonal Hepatocellular Necrosis: Historical Perspective.- B. Regeneration in Response to Zonal Necrosis of Acetaminophen Overdose.- I. Regeneration of Periportal and Mid-zonal Hepatocytes to Restore the Perivenous Zone.- C. Clinical Implications of “Adaptive” Perivenous Necrosis.- References.- 3: Subcellular Biochemical and Pathological Correlates in Experimental Models of Hepatotoxicity (With 5 Figures).- A. Introduction.- B. Organization of the Liver Cell.- C. Liver Cell Injury.- D. Subcellular Organelle Pathology.- I. Endoplasmic Reticulum.- 1. Membrane Structure.- 2. Cytochrome P450 System.- 3. Proliferation and Induction.- 4. Structure-Activity Relationships.- 5. Membrane-Bound Phospholipids.- II. Golgi Apparatus.- III. Intracellular Membrane Dynamics.- IV. Mitochondria.- V. Lysosomes.- VI. Peroxisomes.- E. Biochemical Pathology of Subcellular Changes.- I. Cell Respiration.- II. Protein Metabolism.- III. Lipid Metabolism.- IV. Bile Secretion.- F. Latent Hepatotoxicity Models.- G. Conclusions.- References.- 4: Molecular Biology of Hepatic Drag Reactions (With 6 Figures).- A. Introduction.- B. General Considerations.- C. DNA Damage.- I. Drugs and DNA Metabolism.- II. DNA Replication and Repair Pathways.- D. Inhibition of DNA Replication.- I. Inhibition of DNA Polymerases.- II. Inhibition of DNA Ligase.- III. Chain Termination.- IV. Inhibition of DNA Repair.- V. Alterations in Purine/Pyrimidine Metabolism.- VI. Alterations in DNA Processing Post Synthesis.- E. Damage to RNA.- F. Interference with Protein Synthesis.- G. Apoptosis.- H. Future Developments.- I. Summary and Conclusions.- References.- 5: In Vitro Models of Liver Toxicity (With 4 Figures).- A. Introduction.- I. Metabolism of Foreign Compounds Can Cause Zone-Specific Hepatotoxicity.- II. Advantages and Disadvantages of Whole Cell Models.- B. Techniques Used to Study Zone-Specific Hepatotoxicity in the Isolated Perfused Liver.- I. Metabolite Measurements in Tissue and Perfusate.- II. Microlight Guides.- III. Miniature Oxygen Electrodes.- IV. Trypan Blue Exclusion.- C. Applying In Vitro Models to the Study of Liver Toxicology.- I. Monooxygenation in Periportal and Pericentral Zones of the Liver Lobule.- II. Conjugation Reactions in Periportal and Pericentral Regions of the Liver Lobule.- 1. Sulfation.- 2. Glucuronidation.- III. Oxygen as a Determinant of Zone-Specific Hepatotoxicity.- D. Conclusions.- References.- 6: Cytochromes P450 and Liver Injury (With 4 Figures).- A. Drug Biotransformation, Cytochromes P450 and the Liver.- I. Drug Biotransformation by the Liver.- II. General Drug Biotransformation Processes.- III. Phase I Reactions.- IV. Introduction to the Cytochromes P450.- B. Cytochromes P450 and Drug Biotransformation.- I. Human Hepatic Cytochromes P450.- II. Sources of Variability in P450 Expression and Activity.- 1. P450 Genetics and Polymorphisms.- 2. P450 Induction.- 3. P450 Inhibition.- 4. Liver Disease: Effects on Drug Biotransformation.- II. Reaction Mechanism.- III. Drug Biotransformation and Drug Toxicity.- 1. Cytochrome P450 and Bioactivation.- 2. Activation/Detoxification Balance.- 3. “Probe Drugs” for Determining P450 Activities in Humans In Vivo.- C. Mechanisms of P450-Mediated Liver Injury.- I. Reactive Metabolites.- 1. Noncovalent Interactions.- 2. Covalent Adduct Formation.- II. P450s as Targets of Immune Effectors.- D. Specific Drugs/P450s and Liver Injury.- I. Acetaminophen.- II. Halothane.- III. Tienilic Acid.- IV. Dihydralazine.- V. Diclofenac.- E. Conclusions.- References.- 7: Mechanisms of Drug-Induced Cholestasis.- A. Definition of Cholestasis.- B. Mechanisms of Canalicular Bile Formation.- I. Transport of Bile Acids.- II. Transport of Inorganic Ions and Glutathione.- III. Other Mechanisms.- C. Mechanisms of Cholestasis.- I. Alterations in Basolateral Membrane Function.- II. Alterations in Canalicular Membrane Function.- III. Alterations in Intracellular Events.- 1. Binding to Intracellular Proteins and Conjugation Enzymes.- 2. Cytoskeleton.- IV. Permeability Changes in the Biliary Tree.- 1. Altered Permeability of the Junctional Complex.- 2. Altered Permeability of the Canalicular Membrane.- 3. Alterations in Membrane Proteins.- 4. Alterations in Membrane Composition and Function.- D. Drugs and Other Chemicals Inducing Cholestasis.- I. a-Naphthylisothiocyanate.- II. Androgenic and Estrogenic Steroids.- III. Bile Acids.- IV. Chlorpromazine and Other Phenothiazines.- V. Cyclosporine.- VI. Miscellaneous Cholestatic Agents.- References.- 8: Fatty Liver and Drugs (With 1 Figure).- A. General Mechanisms for Fatty Liver.- B. Drugs Provoking Fatty Liver.- I. Drugs Provoking Fatty Liver by Increasing FFA Supply to the Liver.- II. Drugs Provoking Fatty Liver by Intrahepatic Mechanisms.- 1. Drugs Increasing Intrahepatic FFA Synthesis.- 2. Drugs Provoking Fatty Liver by Decreasing Fatty Acid Oxidation.- 3. Drugs Blocking Lipoprotein Secretion.- III. Drugs Decreasing Fat Infiltration in the Liver.- References.- 9: Choline Deficiency: An Important Model for the Study of Hepatotoxicity (With 2 Figures).- A. Introduction.- B. Hepatotoxicity by Dietary Manipulation - Not by Addition but by Depletion.- C. Absence of Choline in an Otherwise Complete Diet — An Excellent Model for the Study of Liver Cell Death and Liver Cancer.- I. Choline Deficiency Model and Cell Death.- II. Choline Deficiency and Liver Cancer.- D. Lipotrope Deficiency Versus Choline Deficiency.- E. Step by Step Development of Liver Aberration.- F. Hypothesis of Choline Deficiency Induced Hepatocarcinoma.- G. Conclusions.- References.- 10: Immune Mechanisms and Liver Toxicity (With 3 Figures).- A. Introduction and Overview of Drug-Mediated Hepatotoxicity.- B. Functional Aspects of the Immune System.- I. Immune Repertoire.- II. Major Histocompatibility Complex.- III. Afferent Limb of the Immune Response.- IV. Efferent Limb of the Immune Response.- V. Regulation and Dysregulation of Immune Responses.- C. Genetic Determinants of Adverse Drug Reactions.- D. Liver in Relation to Adverse Drug Reactions.- I. Intrahepatic Metabolism of Drugs by Microsomal Enzymes.- 1. Cytochrome P450 Oxidases (CYP450).- 2. UDP Glucuronosyl Transferases.- 3. Carboxyl Esterases.- II. Intrahepatic Immune Processes.- 1. Initiation of Immune-Mediated Drug Reactions in the Liver.- 2. Regulatory and Dysregulation of Intrahepatic Immune Reactions.- III. Infrequency of Hepatic Hypersensitivity Drug Reactions.- IV. Immunopathology of Hepatic Hypersensitivity Drug Reactions.- V. Drug-Altered Neoantigen - The Halothane Paradigm.- 1. Halothane Hepatitis.- 2. Immunological Investigations of Halothane Hepatitis.- 3. Detection of Antibodies to TFA Conjugates.- VI. Native Liver Antigens - The Liver-Kidney Microsomal (LKM) System.- 1. Hepatitis with Anti-LKM-2.- 2. Identification of LKM as Cytochrome P450 Species.- 3. Antibodies to CYP 1A2 in Drug-induced Hepatitis.- 4. Inhibition of Enzyme Function by Anti-LKM.- 5. Origins of Anti-LKM Reactivity.- VII. Drug-induced Hepatitis with Reactions to Autoantigens.- E. Experimental Models of Drug-induced Immune-Mediated Disease.- F. Laboratory Investigation of Immune-Mediated Hepatic Drug Reactions.- I. General Laboratory Investigations.- II. Drug-Specific Immunological Investigations.- 1. Detection of T-Cell-Mediated Reactions.- III. Pharmacological Idiosyncrasy.- References.- 11: Hepatic Encephalopathy.- A. Introduction.- I. Clinical Manifestations of Hepatic Encephalopathy.- II. Neuropathological Changes in Hepatic Encephalopathy.- 1. Anatomy.- 2. Electrophysiology.- B. Involvement of Neurotoxins in the Pathogenesis of Hepatic Encephalopathy.- I. Ammonia.- 1. Glial Interactions.- 2. Electrophysiological Changes.- 3. Changes in Oxidative Metabolism.- 4. Summary.- II. Synergistic Neurotoxins.- C. Neurotransmitter Involvement in the Pathogenesis of Hepatic Encephalopathy.- I. y-Aminobutyric Acid.- 1. Electrophysiology.- 2. Neurochemistry and Pharmacology.- 3. Behavior.- 4. Summary.- II. Excitatory Amino Acids.- III. Aromatic Amino Acids and Monoamine Neurotransmitters.- D. Conclusions.- References.- 12: Liver Drug Reactions and Pregnancy.- A. The Liver in Normal Pregnancy.- I. Liver Histology.- II. Liver Perfusion and Function.- B. Effects of Pregnancy on the Risk of Experiencing a Drug-Induced Hepatic Injury.- I. Specific Pre-Marketing Risk/Benefit Evaluation of Drugs.- II. Risk of Exposure to Hepatotoxic Drugs.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Hemodynamics and Drug Clearance.- 4. Maternal-Placental-Fetal Unit.- IV. Liver Vulnerability.- C. Liver Drug Reactions Occurring Düring Pregnancy.- I. Antibiotics.- II. Antiemetics.- III. Anesthetics and Analgesics.- IV. Anticonvulsants.- V. Other Agents.- D. Clinical Presentation and Diagnostic Approach to Hepatic Injury in Pregnancy.- E. Treatment.- F. Prevention.- References.- 13: Pediatric Hepatic Drug Reactions.- A. Classification of Drug Hepatotoxicity.- B. Specific Drugs Causing Hepatotoxicity in Children.- I. Acetaminophen.- II. Phenytoin.- III. Valproic Acid.- IV. Isoniazid.- V. Halothane.- VI. Carbamazepine.- VII. Phenobarbital.- VIII. Antineoplastic Drugs.- IX. Pemoline.- X. Sulfonamides.- XI. Aspirin.- XII. Propylthiouracil.- XIII. Erythromycin.- XIV. Methotrexate.- XV. Estrogens: Oral Contraceptive Pill.- XVI. Ketoconazole.- XVII. Haloperidol.- XVIII. Amiodarone.- XIX. Nitrofurantoin.- XX. Retinoids.- XXI. Azathioprine.- XXII. Cocaine.- References.- 14: Reye’s Syndrome.- A. Introduction.- B. Clinical Features.- C. Laboratory Features.- D. Diagnostic Criteria for Population Surveys.- E. Liver Morphology.- F. Brain Morphology.- G. Liver Histology and Electron Microscopy in Reye’s Syndrome.- H. Pathophysiology.- I. Aspirin and Reye’s Syndrome.- J. Animal Models.- K. Reye’s Syndrome in Adults.- L. Treatment.- M. Sequelae.- References.- 15: Drug Hepatotoxicity in the Elderly (With 7 Figures).- A. Introduction.- B. Clinical Information.- I. Idiosyncratic Hepatotoxicity: The Swedish Experience.- II. Dose-Dependent Hepatotoxicity.- C. Age-Related Alterations in Hepatic Detoxifying Functions: Discrepancies Between Human and Animal Data.- I. Phase I Drug Metabolism.- II. Phase II Metabolism.- 1. Glucuronidation and Sulfation: Acetaminophen Conjugation.- 2. Glutathione S-Transferases.- III. Oxidant and Antioxidant Variables.- 1. Lipid Peroxidation.- 2. Glutathione.- 3. Antioxidant Enzymes.- D. Morbidity and Frailty as Major Factors for Lowered Drug Clearances in the Elderly: A Possible Role in Hepatotoxicity.- E. Adverse Drug Reactions in the Liver in Old Animals: Mini Review.- I. Hepatocyte Susceptibility to Chlorpromazine and Erythromycin Estolate.- II. Acetaminophen Hepatotoxicity: An Example of Variability of the Results in Studies Using Rodents.- III. Ethanol Metabolism in the Liver and Its Hepatotoxicity: Another Controversy.- IV. Hepatotoxicities by Other Toxicants.- F. Conclusions and Suggestions for Future Studies.- References.- 16: Effect of Liver Disease on Drug Metabolism and Pharmacokinetics (With 6 Figures).- A. Introduction.- B. Function and Structure of the Liver.- C. Types and Severity of Liver Disease.- I. Changes in Hepatic Function.- II. Changes in Hepatic Vasculature.- III. Changes in Renal Function.- IV. Ascites.- D. Pharmacodynamic Factors.- E. Pharmacokinetic Factors.- I. Linear Pharmacokinetic Models.- 1. One-Compartment Model, Intravenous Dosing.- 2. First-Order Absorption and Elimination.- 3. Repeated Dosing with Linear Pharmacokinetics.- II. Nonlinear Pharmacokinetic Models.- III. Impact of Liver Disease.- 1. Distribution Volume.- 2. Elimination Half-Life.- 3. Protein Binding.- 4. Presystemic Clearance.- F. Markers of Liver Disease Relevant to Drug Metabolism and Pharmacokinetics.- G. Examples of Effects of Liver Disease on the Pharmacokinetics of Some Drug Therapeutic Classes.- I. Cardiovascular Agents.- II. Drugs Acting on the Central Nervous System.- III. Antimicrobial Agents.- IV. Other Drugs.- H. Conclusions.- References.- 17: Liver Reactions to Tacrine (With 2 Figures).- A. Introduction.- B. Clinical Experience.- C. Metabolism of Tacrine in Humans.- D. Preclinical Toxicology.- E. Metabolism of Tacrine in Animals.- F. Cytotoxicity Studies.- G. In Vitro Metabolism Studies.- H. Conclusions.- References.- 18: Mechanisms of Hypertransaminemia (With 7 Figures).- A. Introduction.- B. Overview of Liver Transaminase Monitoring.- I. Significance of the Different Tests Used to Monitor Liver Function.- II. Spectrum of Drug-induced Hepatotoxicity and Hypertransaminemia.- III. Clinical Correlates of Transaminase Measurement.- 1. Sensitivity and Specificity of Hypertransaminemia.- 2. Correlation Between Severity of Hepatic Injury and Degree of Hypertransaminemia.- 3. Clinical Significance of Minor Degrees of Hypertransaminemia.- C. Classification of the Causes of Hypertransaminemia.- D. Mechanisms of Acute Hepatic Injury Leading to Hypertransaminemia.- I. Role of Drug Metabolism.- II. Evidence for the Formation of Chemically Reactive Metabolites.- III. Acute Chemical Hepatotoxicity.- 1. Acetaminophen Hepatotoxicity.- 2. Carbon Tetrachloride Hepatotoxicity.- IV. Acute Idiosyncratic Hepatotoxicity.- 1. Metabolie Idiosyncrasy Causing Hypertransaminemia.- 2. Immune-Mediated Drug-induced Hypertransaminemia.- E. Mechanisms of Chronic Hepatic Injury Causing Hypertransaminemia.- I. Chronic Chemical Hypertransaminemia.- II. Chronic Idiosyncratic Drug-induced.- Hypertransaminemia.- F. Diagnosis of Drug-induced Hypertransaminemia.- I. Distinction Between Drug- and Non-Drug-Induced Etiologies.- II. Distinction Between Direct and Immune-Mediated Acute Idiosyncratic Toxicity.- G. Conclusions.- References.- 19: Diagnostic Tools and Clinical Pathology.- A. General Features and Clinical Evaluation of Drug-induced Liver Diseases.- B. General Mechanisms of Drug Reactions.- I. Toxic Reactions.- II. Idiosyncratic Reactions.- III. Tumor Formation.- IV. Vascular Reactions :.- V. Interactions.- C. General Biochemical and Histological Types of Drug Reactions.- I. Hepatocellular Reactions.- II. Cholestatic Reactions.- III. Mixed Hepatocellular-Cholestatic.- IV. Tumors.- V. Vascular Lesions.- D. Clinical Evaluation and Diagnosis of Hepatic Drug Reactions.- I. History.- II. Laboratory Findings.- III. Histopathological Findings.- E. Some Specific Illustrative Drug Reactions.- I. Unsuspected Acetaminophen Overdose Caused by Consumption of Nyquil.- II. Suspected Fatal Isoniazid Toxicity Disproven by Autopsy Examination.- III. Toxicity Due to Health Food (“Hot StufF”).- F. Summary of the Clinical Approach to Drug Toxicity.- References.- 20: Antimicrobial Drugs (With 7 Figures).- A. Antibiotics.- I. Aminoglycosides.- II. Cephalosporins.- III. Chloramphenicol.- IV. Clindamycin.- V. Colimycin.- VI. Erythromycin.- VII. Fusidic Acid.- VIII. Roxithromycin.- IX. Tetracyclines.- X. Troleandomycin.- XI. Penicillin.- B. Synthetic Antimicrobials.- I. Organic Arsenicals.- II. Quinolones.- III. Sulfonamides.- IV. Sulfamethoxazole-Trimethoprim.- V. Sulfasalazine.- VI. Sulfones.- VII. Nitrofurantoin.- VIII. Furazolidone.- C. Antituberculous Drugs.- I. p-Aminosalicylic Acid.- II. Isoniazid.- III. Rifampin.- D. Antifungal Agents.- I. Griseofulvin.- II. Ketoconazole.- III. Other Imidazoles.- IV. Flucytosine.- E. Antiviral Agents.- F. Antiprotozoal Agents.- I. Anthelmintics.- References.- 21: Hepatotoxicity of Cardiovascular Drugs (With 9 Figures).- A. Introduction.- B. a-Methyldopa.- I. Hepatitis.- II. Fatty Change.- III. Hepatic Necrosis.- IV. Cholestasis.- V. Cirrhosis.- C. Amiodarone.- I. Alcoholic-Type Hepatitis.- II. Phospholipid Fatty Liver.- III. Reye’s Syndrome-Like Disease.- D. Aprindine.- I. Hepatitis.- E. Hydralazine and Dihydralazine.- I. Hepatitis.- F. Papaverine.- I. Hepatitis.- G. Procainamide.- I. Hepatitis.- II. Cholestasis.- H. Quinidine.- I. Hepatitis.- II. Granulomatous Hepatitis.- I. Lipid-Regulating Agents.- I. Classes of Lipid-Regulating Agents.- II. Hyperlipoproteinemia and Liver Structure.- III. Nicotinic Acid.- IV. Fibrates.- V. Statins.- J. Miscellaneous Cardiovascular Drugs.- K. Modulation of Hepatotoxicity.- L. Conclusions.- References.- 22: Analgesie Hepatopathy.- A. Introduction.- B. Acetaminophen.- I. Epidemiology.- 1. Incidence of Hepatotoxicity.- 2. Hepatotoxicity in Alcoholics.- 3. Hepatotoxicity in Therapeutic Settings.- II. Pathogenesis.- 1. Hepatotoxic Dose and Blood Level.- 2. Mechanism.- 3. Factors Influencing Hepatotoxicity.- III. Clinical Manifestations and Laboratory Findings.- 1. Clinical Course.- 2. Pathology.- 3. Prognosis.- IV. Treatment.- 1. General Management.- 2. Specific Therapy.- 3. Fulminant Hepatic Failure.- V. Prevention.- C. Nonsteroidal Antiinflammatory Drugs.- I. Epidemiology.- II. Pathogenesis.- III. Clinical Manifestations and Laboratory Findings.- 1. General Observations.- 2. Specific NSAIDs.- IV. Treatment.- V. Prevention.- D. Narcotic Analgesics.- References.- 23: Steroids and Other Hormones (With 7 Figures).- A. Gonadal Steroids and Their Derivatives.- B. Anabolic Steroids.- I. Cholestasis.- 1. Structural Characteristics of Icterogenic Steroids.- 2. Incidence.- 3. Clinical Features.- 4. Biochemical Features.- 5. Histopathology.- 6. Prognosis.- 7. Mechanism.- II. Peliosis Hepatis.- III. Neoplasms.- 1. Nodular Regenerative Hyperplasia.- 2. Hepatocellular Adenoma.- 3. Hepatic Carcinoma.- 4. Other Neoplasms.- C. Female Sex Hormones and the Contraceptive Steroids.- I. Estrogenic Hormones and Related Drugs.- II. Progestational Steroids.- III. Adverse Effects of Contraceptive Steroids on the Liver.- IV. Syndrome of Contraceptive Steroid Jaundice.- 1. Clinical Features.- 2. Biochemical Features.- 3. Histologie Characteristics.- 4. Prognosis.- 5. Susceptibility.- V. Tumors Associated with Oral Contraceptives.- 1. Hepatocellular Adenoma.- 2. Focal Nodular Hyperplasia.- 3. Hepatocellular Carcinoma.- VI. Vascular Lesions.- 1. Effect on Hemangiomas and Related Lesions.- 2. Sinusoidal Dilatation.- 3. Peliosis Hepatis.- 4. Hepatic Vein Thrombosis.- 5. Rupture of the Liver.- 6. Other Vascular Changes.- VII. Disturbed Porphyrin Metabolism.- VIII. Mechanisms of Injury by Contraceptive Steroids.- IX. Cholelithiasis.- D. Drugs Related to Sex Hormones.- I. Antiestrogens.- 1. Clomiphene.- 2. Cyclofenil.- 3. Tamoxifen.- II. Antihypophysial Drugs.- 1. Danazol.- 2. Octreotide.- E. Glucocorticoids.- F. Oral Hypoglycemic Agents.- I. Sulfonylureas.- II. Clinical Syndrome.- III. Prognosis.- IV. Biguanide.- V. Other Oral Hypoglycemic Agents.- G. Antithyroid Drugs.- I. Form of Injury.- II. Clinical Features.- III. Prognosis.- IV. Mechanism.- V. Comment.- References.- 24: Hepatotoxicity of Immunomodulating Agents.- A. Introduction.- B. Immunostimulatory Agents.- I. Classification.- 1. Immune-System-Derived Biologicals.- 2. Immunostimulatory Pharmaceutical Agents.- II. Hepatotoxicity of Specific Immunostimulatory Agents.- 1. Interleukin-2.- 2. Interferons.- C. Immunosuppressive Agents.- I. Classification.- 1. Antilymphocyte Products.- 2. Immunophilin-Binding Agents.- 3. Cytotoxic Agents.- 4. Sterols.- 5. Immunosuppressive Antibiotics.- 6. Arachidonic Acid Metabolites.- II. Hepatotoxic Effects of Specific Immunosuppressive Agents.- 1. Methotrexate.- 2. Corticosteroids.- 3. Azathioprine.- 4. Cyclosporine.- 5. FK-506.- D. Conclusion.- References.- 25: Alcohol-Induced Liver Injury.- A. Epidemiology.- B. Liver Dysfunction in Alcoholic Liver Disease.- I. Hemodynamic Alterations.- II. Liver Failure.- C. Alcoholic Liver Injury: Morphological Studies.- I. Hepatocytes.- II. Inflammation.- III. Collagen Deposition.- IV. Nonparenchymal Cells (EM Studies).- 1. Ito Cells.- 2. Endothelial Cells.- 3. Kupffer Cells :.- D. Clustering.- I. Fatty Liver.- II. Alcoholic Hepatitis.- III. Alcoholic Cirrhosis.- E. Pathogenesis of Alcohol-Induced Liver Injury.- I. Liquid Diet Model.- II. Cytochrome P450 2E1.- III. Acetaldehyde Adducts.- IV. Hepatocyte Ballooning and Hepatomegaly.- V. Hepatic Oxygen Consumption.- VI. Liver Hypoxia.- VII. Intragastric Infusion Model.- VIII. Modulation of Alcohol-Induced Liver Injury.- IX. Glutathione.- X. Micropig Model of Alcoholic Liver Injury.- XI. Baboon Model of Alcoholic Liver Injury.- References.- 26: Antiepileptic Drugs (With 10 Figures).- A. Phenytoin.- I. Type of Hepatic Injury.- II. Clinical Manifestations.- III. Biochemical Features.- IV. Histopathology.- V. Prognosis.- VI. Mechanism.- VII. Other Hydantoins.- 1. Mephenytoin.- 2. Acetylurea Derivatives.- 3. Oxazolidinediones.- 4. Barbiturates and Primidone.- B. Carbamazepine.- I. Susceptibility.- II. Clinical Features.- III. Biochemical Features.- IV. Histopathology.- V. Prognosis.- VI. Mechanism.- C. Valproic Acid.- I. Incidence of Injury.- II. Susceptibility.- III. Clinical Features.- IV. Biochemical Features.- V. Histopathology.- VI. Prognosis.- VII. Mechanism of Injury.- VIII. Prevention.- References.