Drug-InducedHepatotoxicityContributors

S. Anuras, M.Z. Badr, A.S. Basile, S.A. Belinsky, L.M. BlendisR.G. Cameron, J.G. Conway, F.A. de la Iglesia, M.U. DianzaniE. Farber, G. Feuer, RJ. Fingerote, P.E. Ganey, A.K. GhoshalK.G. Ishak, Y. Israel, E.A. Jones, K. Kitani, CD. KlaassenJ.S. Leeder, G.A. Levy, I.R. Mackay, D.K. Monteith, A.B. OkeyB.K. Park, M. Pirmohamed, W.F. Pool, E.A. Roberts, E. RubinR.W. Sallie, D.C. Snover, R.G. Thurman, F. Trevisani, D.H. Van ThielR.R. Varma, R.M. Walker, J.B. Watkins III, P.G. WellingT.F. Woolf, H.J. Zimmerman, M.J. Zuckerman

Editors

R.G. Cameron, G. Feuer, and F.A. de la Iglesia

With a Foreword by M. James Phillips

Springer

Contents

CHAPTER 1

Orientation in Liver Toxicity by DrugsE. FARBER. With 1 Figure 1

A. Introduction 1B. Agents and Processes 1C. Responses to Injury as Multitier or Multigrid Patterns 2

I. Quantitative Versus Qualitative Changes 3II. Patterns of Liver Toxicity 4

1. Tier One: Patterns of Interactionsof Agents with Liver 4

2. Tier Two: Patterns of Biological Responsesto Cell Injury 8

3. Tier Three: Cellular and Intracellular Responses 104. Tier Four: Cellular and Tissue Physiology 19

D. Conclusion 21References 21

CHAPTER 2

Clinical Studies and Role of Necrosis in HepatotoxicityR.G. CAMERON and L.M. BLENDIS. With 7 Figures 25

A. Zonal Necrosis as a Response to Acetaminophen 25I. Zonality: Specific Hepatocytes Die as a Group 25

II. Ethanol Plus Acetaminophen:Extension of Zone of Necrosis 28

III. Constitutive Bases of Zonal Responses 301. Perivenous Localization

of Acetaminophen-Metabolizing enzyme CYP 2E1 32IV. Zonal Hepatocellular Necrosis: Historical Perspective 33

B. Regeneration in Response to Zonal Necrosisof Acetaminophen Overdose 33

I. Regeneration of Periportal and Mid-zonal Hepatocytesto Restore the Perivenous Zone 33

XIV Contents

C. Clinical Implications of "Adaptive" Perivenous Necrosis 38References 39

CHAPTER 3

Subcellular Biochemical and Pathological Correlatesin Experimental Models of HepatotoxicityG. FEUER and F.A. DE LA IGLESIA. With 5 Figures 43

A. Introduction 43B. Organization of the Liver Cell 44C. Liver Cell Injury 45D. Subcellular Organelle Pathology 46

I. Endoplasmic Reticulum 461. Membrane Structure 462. Cytochrome P450 System 483. Proliferation and Induction 484. Structure-Activity Relationships 505. Membrane-Bound Phospholipids 51

II. Golgi Apparatus 52III. Intracellular Membrane Dynamics 54IV. Mitochondria 55V. Lysosomes 56

VI. Peroxisomes 57E. Biochemical Pathology of Subcellular Changes 59

I. Cell Respiration 59II. Protein Metabolism 60

III. Lipid Metabolism 61IV. Bile Secretion 62

F. Latent Hepatotoxicity Models 63G. Conclusions 64References 65

CHAPTER 4

Molecular Biology of Hepatic Drug ReactionsR.W. SALLIE and E.A. JONES. With 6 Figures 75

A. Introduction 75B. General Considerations 75C. DNA Damage 77

I. Drugs and DNA Metabolism 77II. DNA Replication and Repair Pathways 78

D. Inhibition of DNA Replication 79I. Inhibition of DNA Polymerases 79

II. Inhibition of DNA Ligase 80

Contents XV

III. Chain Termination 81IV. Inhibition of DNA Repair 81V. Alterations in Purine/Pyrimidine Metabolism 83

VI. Alterations in DNA Processing Post Synthesis 83E. Damage to RNA 84F. Interference with Protein Synthesis 85G. Apoptosis 86H. Future Developments 92I. Summary and Conclusions 93

References 94

CHAPTER 5

In Vitro Models of Liver ToxicityR.G. THURMAN, P.E. GANEY, S.A. BELINSKY, J.G. CONWAY,

and M.Z. BADR. With 4 Figures 99

A. Introduction 99I. Metabolism of Foreign Compounds

Can Cause Zone-Specific Hepatotoxicity 99II. Advantages and Disadvantages of Whole Cell Models 100

B. Techniques Used to Study Zone-Specific Hepatotoxicityin the Isolated Perfused Liver 101

I. Metabolite Measurements in Tissue and Perfusate 103II. Microlight Guides 104

III. Miniature Oxygen Electrodes 105IV. Trypan Blue Exclusion 106

C. Applying In Vitro Models to the Study of Liver Toxicology 106I. Monooxygenation in Periportal and Pericentral Zones

of the Liver Lobule 106II. Conjugation Reactions in Periportal and Pericentral

Regions of the Liver Lobule 1071. Sulfation 1072. Glucuronidation 109

III. Oxygen as a Determinantof Zone-Specific Hepatotoxicity I l l

D. Conclusions 113References 113

CHAPTER 6

Cytochromes P450 and Liver InjuryJ.S. LEEDER and A.B. OKEY. With 4 Figures 119

A. Drug Biotransformation, Cytochromes P450 and the Liver 119I. Drug Biotransformation by the Liver 119

II. General Drug Biotransformation Processes 119

XVI Contents

III. Phase I Reactions 120IV. Introduction to the Cytochromes P450 120

B. Cytochromes P450 and Drug Biotransformation 121I. Human Hepatic Cytochromes P450 121

II. Sources of Variability in P450 Expression and Activity . . . . 1251. P450 Genetics and Polymorphisms 1262. P450 Induction 1273. P450 Inhibition 1294. Liver Disease: Effects on Drug Biotransformation 130

II. Reaction Mechanism 130III. Drug Biotransformation and Drug Toxicity 132

1. Cytochrome P450 and Bioactivation 1322. Activation/Detoxification Balance 1323. "Probe Drugs" for Determining P450 Activities

in Humans In Vivo 134C. Mechanisms of P450-Mediated Liver Injury 135

I. Reactive Metabolites 1351. Noncovalent Interactions 1362. Covalent Adduct Formation 137

II. P450s as Targets of Immune Effectors 138D. Specific Drugs/P450s and Liver Injury 139

I. Acetaminophen 139II. Halothane 141

III. Tienilic Acid 142IV. Dihydralazine 143V. Diclofenac 144

E. Conclusions 144References 145

CHAPTER 7

Mechanisms of Drug-Induced CholestasisJ.B. WATKINS III and C D . KLAASSEN 155

A. Definition of Cholestasis 155B. Mechanisms of Canalicular Bile Formation 156

I. Transport of Bile Acids 156II. Transport of Inorganic Ions and Glutathione 157

III. Other Mechanisms 157C. Mechanisms of Cholestasis 158

I. Alterations in Basolateral Membrane Function 158II. Alterations in Canalicular Membrane Function 158

III. Alterations in Intracellular Events 1591. Binding to Intracellular Proteins

and Conjugation Enzymes 1592. Cytoskeleton 159

Contents XVII

IV. Permeability Changes in the Biliary Tree 1601. Altered Permeability of the Junctional Complex 1612. Altered Permeability of the Canalicular Membrane 1613. Alterations in Membrane Proteins 1624. Alterations in Membrane Composition and Function . . . 164

D. Drugs and Other Chemicals Inducing Cholestasis 165I. a-Naphthylisothiocyanate 165

II. Androgenic and Estrogenic Steroids 166III. Bile Acids 168IV. Chlorpromazine and Other Phenothiazines 169V. Cyclosporine 170

VI. Miscellaneous Cholestatic Agents 170References 171

CHAPTER 8

Fatty Liver and DrugsM.U. DIANZANI. With 1 Figure 185

A. General Mechanisms for Fatty Liver 185B. Drugs Provoking Fatty Liver 187

I. Drugs Provoking Fatty Liver by IncreasingFFA Supply to the Liver 187

II. Drugs Provoking Fatty Liverby Intrahepatic Mechanisms 1881. Drugs Increasing Intrahepatic FFA Synthesis 1882. Drugs Provoking Fatty Liver by Decreasing

Fatty Acid Oxidation 1923. Drugs Blocking Lipoprotein Secretion 192

III. Drugs Decreasing Fat Infiltration in the Liver 200References 202

CHAPTER 9

Choline Deficiency: An Important Modelfor the Study of HepatotoxicityA.K. GHOSHAL. With 2 Figures 211

A. Introduction 211B. Hepatotoxicity by Dietary Manipulation - Not by Addition

but by Depletion 212C. Absence of Choline in an Otherwise Complete Diet -

An Excellent Model for the Study of Liver Cell Deathand Liver Cancer 213

XVIII Contents

I. Choline Deficiency Model and Cell Death 215II. Choline Deficiency and Liver Cancer 216

D. Lipotrope Deficiency Versus Choline Deficiency 217E. Step by Step Development of Liver Aberration 217F. Hypothesis of Choline Deficiency Induced Hepatocarcinoma 218G. Conclusions 218References 218

CHAPTER 10

Immune Mechanisms and Liver ToxicityI.R. MACKAY. With 3 Figures 221

A. Introduction and Overview of Drug-Mediated Hepatotoxicity 221B. Functional Aspects of the Immune System 222

I. Immune Repertoire 222II. Major Histocompatibility Complex 223

III. Afferent Limb of the Immune Response 224IV. Efferent Limb of the Immune Response 225V. Regulation and Dysregulation of Immune Responses 226

C. Genetic Determinants of Adverse Drug Reactions 227D. Liver in Relation to Adverse Drug Reactions 228

I. Intrahepatic Metabolism of Drugsby Microsomal Enzymes 2281. Cytochrome P450 Oxidases (CYP450) 2282. UDP Glucuronosyl Transferases 2283. Carboxyl Esterases 228

II. Intrahepatic Immune Processes 2291. Initiation of Immune-Mediated Drug Reactions

in the Liver 2292. Regulatory and Dysregulation

of Intrahepatic Immune Reactions 229III. Infrequency of Hepatic Hypersensitivity

Drug Reactions 230IV. Immunopathology of Hepatic Hypersensitivity

Drug Reactions 230V. Drug-Altered Neoantigen - The Halothane Paradigm 232

1. Halothane Hepatitis 2322. Immunological Investigations of Halothane Hepatitis . . . 2333. Detection of Antibodies to TFA Conjugates 233

VI. Native Liver Antigens - The Liver-Kidney Microsomal(LKM) System 2341. Hepatitis with Anti-LKM-2 2352. Identification of LKM as Cytochrome P450 Species 235

Contents XIX

3. Antibodies to CYP 1A2 in Drug-Induced Hepatitis 2364. Inhibition of Enzyme Function by Anti-LKM 2375. Origins of Anti-LKM Reactivity ' 237

VII. Drug-Induced Hepatitis with Reactions to Autoantigens . . . 238E. Experimental Models of Drug-Induced Immune-Mediated

Disease 239F. Laboratory Investigation of Immune-Mediated

Hepatic Drug Reactions 240I. General Laboratory Investigations 240

II. Drug-Specific Immunological Investigations 2401. Detection of T-Cell-Mediated Reactions 241

III. Pharmacological Idiosyncrasy 242References 242

CHAPTER 11

Hepatic EncephalopathyA.S. BASILE 249

A. Introduction 249I. Clinical Manifestations of Hepatic Encephalopathy 249

II. Neuropathological Changes in Hepatic Encephalopathy . . . 2511. Anatomy 2512. Electrophysiology 251

B. Involvement of Neurotoxins in the Pathogenesisof Hepatic Encephalopathy 252

I. Ammonia 2531. Glial Interactions 2532. Electrophysiological Changes 2543. Changes in Oxidative Metabolism 2564. Summary 256

II. Synergistic Neurotoxins 257C. Neurotransmitter Involvement in the Pathogenesis

of Hepatic Encephalopathy 258I. y-Aminobutyric Acid 258

1. Electrophysiology 2582. Neurochemistry and Pharmacology 2583. Behavior 2604. Summary 260

II. Excitatory Amino Acids 261III. Aromatic Amino Acids

and Monoamine Neurotransmitters 263D. Conclusions 265References 265

XX Contents

CHAPTER 12

Liver Drug Reactions and PregnancyF. TREVISANI and D.H. VAN THIEL 273

A. The Liver in Normal Pregnancy 273I. Liver Histology 273

II. Liver Perfusion and Function 274B. Effects of Pregnancy on the Risk of Experiencing

a Drug-Induced Hepatic Injury 276I. Specific Pre-Marketing Risk/Benefit Evaluation of Drugs . . 276

II. Risk of Exposure to Hepatotoxic Drugs 276III. Pharmacokinetics 278

1. Absorption 2782. Distribution 2783. Hemodynamics and Drug Clearance 2794. Maternal-Placental-Fetal Unit 279

IV. Liver Vulnerability 280C. Liver Drug Reactions Occurring During Pregnancy 282

I. Antibiotics 282II. Antiemetics 283

III. Anesthetics and Analgesics 283IV. Anticonvulsants 284V. Other Agents 284

D. Clinical Presentation and Diagnostic Approachto Hepatic Injury in Pregnancy 285

E. Treatment 286F. Prevention 287References 288

CHAPTER 13

Pediatric Hepatic Drug ReactionsE.A. ROBERTS 293

A. Classification of Drug Hepatotoxicity 293B. Specific Drugs Causing Hepatotoxicity in Children 294

I. Acetaminophen 294II. Phenytoin 296

III. Valproic Acid 297IV. Isoniazid 301V. Halothane 302

VI. Carbamazepine 303VII. Phenobarbital 304

VIII. Antineoplastic Drugs 304IX. Pemoline 306

Contents XXI

X. Sulfonamides 306XI. Aspirin 307

XII. Propylthiouracil 307XIII. Erythromycin 308XIV. Methotrexate 308XV. Estrogens: Oral Contraceptive Pill 310

XVI. Ketoconazole 310XVII. Haloperidol 310

XVIII. Amiodarone 310XIX. Nitrofurantoin 311XX. Retinoids 311

XXI. Azathioprine 311XXII. Cocaine 312

References 312

CHAPTER 14

Reye's SyndromeR.R. VARMA 323

A. Introduction 323B. Clinical Features 324C. Laboratory Features 326D. Diagnostic Criteria for Population Surveys 327E. Liver Morphology 328F. Brain Morphology 328G. Liver Histology and Electron Microscopy in Reye's Syndrome . . . . 329H. Pathophysiology 330I. Aspirin and Reye's Syndrome 332J. Animal Models 334

K. Reye's Syndrome in Adults 335L. Treatment 335M. Sequelae 336References 337

CHAPTER 15

Drug Hepatotoxicity in the ElderlyK. KITANI. With 7 Figures 341

A. Introduction 341B. Clinical Information 341

I. Idiosyncratic Hepatotoxicity. The Swedish Experience 341II. Dose-Dependent Hepatotoxicity 343

XXII Contents

C. Age-Related Alterations in Hepatic Detoxifying Functions:Discrepancies Between Human and Animal Data 343

I. Phase I Drug Metabolism 344II. Phase II Metabolism 346

1. Glucuronidation and Sulfation:Acetaminophen Conjugation 346

2. Glutathione S-Transferases 347III. Oxidant and Antioxidant Variables 350

1. Lipid Peroxidation 3512. Glutathione 3513. Antioxidant Enzymes 351

D. Morbidity and Frailty as Major Factors for Lowered DrugClearances in the Elderly: A Possible Role in Hepatotoxicity 353

E. Adverse Drug Reactions in the Liver in Old Animals:Mini Review 354

I. Hepatocyte Susceptibility to Chlorpromazineand Erythromycin Estolate 355

II. Acetaminophen Hepatotoxicity: An Exampleof Variability of the Results in Studies Using Rodents 355

III. Ethanol Metabolism in the Liver and Its Hepatotoxicity:Another Controversy 358

IV. Hepatotoxicities by Other Toxicants 361F. Conclusions and Suggestions for Future Studies 361References 362

CHAPTER 16

Effect of Liver Disease on Drug Metabolism and PharmacokineticsP.G. WELLING and W.F. POOL. With 6 Figures 367

A. Introduction 367B. Function and Structure of the Liver 368C. Types and Severity of Liver Disease 369

I. Changes in Hepatic Function 369II. Changes in Hepatic Vasculature 369

III. Changes in Renal Function 370IV. Ascites 370

D. Pharmacodynamic Factors 370E. Pharmacokinetic Factors 371

I. Linear Pharmacokinetic Models 3711. One-Compartment Model, Intravenous Dosing 3712. First-Order Absorption and Elimination 3733. Repeated Dosing with Linear Pharmacokinetics 374

II. Nonlinear Pharmacokinetic Models 376

Contents XXIII

III. Impact of Liver Disease 3771. Distribution Volume 3792. Elimination Half-Life 3793. Protein Binding 3804. Presystemic Clearance 380

F. Markers of Liver Disease Relevant to Drug Metabolismand Pharmacokinetics 381

G. Examples of Effects of Liver Disease on the Pharmacokineticsof Some Drug Therapeutic Classes 382

I. Cardiovascular Agents 383II. Drugs Acting on the Central Nervous System 384

III. Antimicrobial Agents 385IV. Other Drugs 386

H. Conclusions 387References 388

CHAPTER 17

Liver Reactions to TacrineT.F. WOOLF, W.F. POOL, R.M. WALKER, and D.K. MONTEITH.

With 2 Figures 395

A. Introduction 395B. Clinical Experience 395C. Metabolism of Tacrine in Humans 397D. Preclinical Toxicology 399E. Metabolism of Tacrine in Animals 401F. Cytotoxicity Studies 402G. In Vitro Metabolism Studies 403H. Conclusions 405References 406

CHAPTER 18

Mechanisms of HypertransaminemiaM. PIRMOHAMED and B.K. PARK. With 7 Figures 411

A. Introduction 411B. Overview of Liver Transaminase Monitoring 411

I. Significance of the Different Tests Used to MonitorLiver Function 411

II. Spectrum of Drug-Induced Hepatotoxicityand Hypertransaminemia 413

XXIV Contents

III. Clinical Correlates of Transaminase Measurement 4141. Sensitivity and Specificity of Hypertransaminemia 4142. Correlation Between Severity of Hepatic Injury

and Degree of Hypertransaminemia 4153. Clinical Significance of Minor Degrees

of Hypertransaminemia 416C. Classification of the Causes of Hypertransaminemia 419D. Mechanisms of Acute Hepatic Injury

Leading to Hypertransaminemia 419I. Role of Drug Metabolism 419

II. Evidence for the Formation of Chemically ReactiveMetabolites 421

III. Acute Chemical Hepatotoxicity 4221. Acetaminophen Hepatotoxicity 4222. Carbon Tetrachloride Hepatotoxicity 424

IV. Acute Idiosyncratic Hepatotoxicity 4251. Metabolic Idiosyncrasy Causing Hypertransaminemia . . . 4252. Immune-Mediated Drug-Induced

Hypertransaminemia 426E. Mechanisms of Chronic Hepatic Injury Causing

Hypertransaminemia 431I. Chronic Chemical Hypertransaminemia 431

II. Chronic Idiosyncratic Drug-InducedHypertransaminemia 432

F. Diagnosis of Drug-Induced Hypertransaminemia 433I. Distinction Between Drug- and Non-Drug-Induced

Etiologies 433II. Distinction Between Direct and Immune-Mediated

Acute Idiosyncratic Toxicity 433G. Conclusions 434References 435

CHAPTER 19

Diagnostic Tools and Clinical PathologyD.C. SNOVER 441

A. General Features and Clinical Evaluationof Drug-Induced Liver Diseases 441

B. General Mechanisms of Drug Reactions 442I. Toxic Reactions 442

II. Idiosyncratic Reactions 443III. Tumor Formation 443IV. Vascular Reactions • 444V. Interactions 445

Contents XXV

C. General Biochemical and Histological Types of Drug Reactions . . . 445I. Hepatocellular Reactions 445

II. Cholestatic Reactions 447III. Mixed Hepatocellular-Cholestatic 448IV. Tumors 448V. Vascular Lesions 448

D. Clinical Evaluation and Diagnosis of Hepatic Drug Reactions 449I. History 450

II. Laboratory Findings 450III. Histopathological Findings 451

E. Some Specific Illustrative Drug Reactions 451I. Unsuspected Acetaminophen Overdose

Caused by Consumption of Nyquil 451II. Suspected Fatal Isoniazid Toxicity

Disproven by Autopsy Examination 452III. Toxicity Due to Health Food ("Hot Stuff") 452

F. Summary of the Clinical Approach to Drug Toxicity 453References 453

CHAPTER 20

Antimicrobial DrugsH.J. ZIMMERMAN and K.G. ISHAK. With 7 Figures 457

A. Antibiotics 457I. Aminoglycosides 457

II. Cephalosporins 457III. Chloramphenicol 457IV. Clindamycin 458V. Colimycin 458

VI. Erythromycin 459VII. Fusidic Acid 460

VIII. Roxithromycin 460IX. Tetracyclines 461X. Troleandomycin 461

XI. Penicillin 462B. Synthetic Antimicrobials 463

I. Organic Arsenicals 463II. Quinolones 467

III. Sulfonamides 468IV. Sulfamethoxazole-Trimethoprim 468V. Sulfasalazine 468

VI. Sulfones 468VII. Nitrofurantoin 469

VIII. Furazolidone 469

XXVI Contents

C. Antituberculous Drugs 469I. /7-Aminosalicylic Acid 469

II. Isoniazid 470III. Rifampin 470

D. Antifungal Agents • • • • 471I. Griseofulvin 471

II. Ketoconazole 471III. Other Imidazoles 471IV. Flucytosine 471

E. Antiviral Agents 472F. Antiprotozoal Agents 472

I. Anthelmintics 472References 473

CHAPTER 21

Hepatotoxicity of Cardiovascular DrugsR.G. CAMERON, F.A. DE LA IGLESIA, and G. FEUER. With 9 Figures . . . . 477

A. Introduction 477B. a-Methyldopa 478

I. Hepatitis 479II. Fatty Change 481

III. Hepatic Necrosis 482IV. Cholestasis 482V. Cirrhosis 483

C. Amiodarone 483I. Alcoholic-Type Hepatitis 484

II. Phospholipid Fatty Liver 487III. Reye's Syndrome-Like Disease 488

D. Aprindine 488I. Hepatitis 488

E. Hydralazine and Dihydralazine 489I. Hepatitis 490

F. Papaverine 491I. Hepatitis 492

G. Procainamide 492I. Hepatitis 492

II. Cholestasis 493H. Quinidine 493

I. Hepatitis 494II. Granulomatous Hepatitis 494

I. Lipid-Regulating Agents 495I. Classes of Lipid-Regulating Agents 495

II. Hyperlipoproteinemia and Liver Structure 496III. Nicotinic Acid 498

Contents XXVII

IV. Fibrates 498V. Statins 500

J. Miscellaneous Cardiovascular Drugs 501K. Modulation of Hepatotoxicity 502L. Conclusions 502References 504

CHAPTER 22

Analgesic HepatopathyM.J. ZUCKERMAN and S. ANURAS 515

A. Introduction 515B. Acetaminophen 515

I. Epidemiology 5151. Incidence of Hepatotoxicity 5152. Hepatotoxicity in Alcoholics 5163. Hepatotoxicity in Therapeutic Settings 517

II. Pathogenesis 5181. Hepatotoxic Dose and Blood Level 5182. Mechanism 5183. Factors Influencing Hepatotoxicity 519

III. Clinical Manifestations and Laboratory Findings 5191. Clinical Course 5192. Pathology 5203. Prognosis 521

IV. Treatment 5221. General Management 5222. Specific Therapy 5233. Fulminant Hepatic Failure 524

V. Prevention 525C. Nonsteroidal Antiinflammatory Drugs 526

I. Epidemiology 526II. Pathogenesis 529

III. Clinical Manifestations and Laboratory Findings 5311. General Observations 5312. Specific NSAIDs 532

IV. Treatment 534V. Prevention 535

D. Narcotic Analgesics 536References 537

CHAPTER 23

Steroids and Other HormonesH.J. ZIMMERMAN and K.G. ISHAK. With 7 Figures 543

XXVIII Contents

A. Gonadal Steroids and Their Derivatives 543B. Anabolic Steroids 543

I. Cholestasis 5441. Structural Characteristics of Icterogenic Steroids 5442. Incidence 5443. Clinical Features 5454. Biochemical Features 5465. Histopathology 5466. Prognosis 5467. Mechanism 547

II. Peliosis Hepatis 548III. Neoplasms 549

1. Nodular Regenerative Hyperplasia 5492. Hepatocellular Adenoma 5493. Hepatic Carcinoma 5504. Other Neoplasms 550

C. Female Sex Hormones and the Contraceptive Steroids 551I. Estrogenic Hormones and Related Drugs 551

II. Progestational Steroids 552III. Adverse Effects of Contraceptive Steroids on the Liver . . . 553IV. Syndrome of Contraceptive Steroid Jaundice 554

1. Clinical Features 5542. Biochemical Features 5543. Histologic Characteristics 5544. Prognosis 5545. Susceptibility 554

V. Tumors Associated with Oral Contraceptives 5551. Hepatocellular Adenoma 5552. Focal Nodular Hyperplasia 5583. Hepatocellular Carcinoma 558

VI. Vascular Lesions 5601. Effect on Hemangiomas and Related Lesions 5602. Sinusoidal Dilatation 5603. Peliosis Hepatis 5604. Hepatic Vein Thrombosis 5615. Rupture of the Liver 5626. Other Vascular Changes 563

VII. Disturbed Porphyrin Metabolism 563VIII. Mechanisms of Injury by Contraceptive Steroids 563

IX. Cholelithiasis 564D. Drugs Related to Sex Hormones 565

I. Antiestrogens 5651. Clomiphene 5652. Cyclofenil 5653. Tamoxifen 565

Contents XXIX

II. Antihypophysial Drugs 5651. Danazol 5652. Octreotide 566

E. Glucocorticoids 566F. Oral Hypoglycemic Agents 566

I. Sulfonylureas 566II. Clinical Syndrome 567

III. Prognosis 568IV. Biguanide 569V. Other Oral Hypoglycemic Agents 569

G. Antithyroid Drugs 569I. Form of Injury 570

II. Clinical Features 570III. Prognosis 570IV. Mechanism 571V. Comment 571

References 571

CHAPTER 24

Hepatotoxicity of Immunomodulating AgentsR.J. FINGEROTE and G.A. LEVY 581

A. Introduction 581B. Immunostimulatory Agents 582

I. Classification 5821. Immune-System-Derived Biologicals 5832. Immunostimulatory Pharmaceutical Agents 583

II. Hepatotoxicity of Specific Immunostimulatory Agents 5831. Interleukin-2 5832. Interferons 585

C. Immunosuppressive Agents 588I. Classification 588

1. Antilymphocyte Products 5892. Immunophilin-Binding Agents 5893. Cytotoxic Agents 5894. Sterols 5905. Immunosuppressive Antibiotics 5906. Arachidonic Acid Metabolites 590

II. Hepatotoxic Effectsof Specific Immunosuppressive Agents 5911. Methotrexate 5912. Corticosteroids 5943. Azathioprine 595

XXX Contents

4. Cyclosporine 5985. FK-506 601

D. Conclusion 602References 602

CHAPTER 25

Alcohol-Induced Liver InjuryY. ISRAEL and E. RUBIN 611

A. Epidemiology 611B. Liver Dysfunction in Alcoholic Liver Disease 612

I. Hemodynamic Alterations 612II. Liver Failure 613

C. Alcoholic Liver Injury: Morphological Studies 615I. Hepatocytes 615

II. Inflammation 616III. Collagen Deposition 616IV. Nonparenchymal Cells (EM Studies) 616

1. Ito Cells 6162. Endothelial Cells 6163. Kupffer Cells 616

D. Clustering 617I. Fatty Liver 617

II. Alcoholic Hepatitis 617III. Alcoholic Cirrhosis 617

E. Pathogenesis of Alcohol-Induced Liver Injury 617I. Liquid Diet Model 617

II. Cytochrome P450 2E1 618III. Acetaldehyde Adducts 619IV. Hepatocyte Ballooning and Hepatomegaly 620V. Hepatic Oxygen Consumption 621

VI. Liver Hypoxia 622VII. Intragastric Infusion Model 623

VIII. Modulation of Alcohol-Induced Liver Injury 624IX. Glutathione 626X. Micropig Model of Alcoholic Liver Injury 627

XI. Baboon Model of Alcoholic Liver Injury 627References 528

CHAPTER 26

Antiepileptic DrugsH.J. ZIMMERMAN and K.G. ISHAK. With 10 Figures 637

Contents XXXI

A. Phenytoin 637I. Type of Hepatic Injury 637

II. Clinical Manifestations 638III. Biochemical Features 640IV. Histopathology 640V. Prognosis 641

VI. Mechanism 643VII. Other Hydantoins 645

1. Mephenytoin 6452. Acetylurea Derivatives 6453. Oxazolidinediones 6464. Barbiturates and Primidone 646

B. Carbamazepine 646I. Susceptibility 646

II. Clinical Features 647III. Biochemical Features 647IV. Histopathology 648V. Prognosis 648

VI. Mechanism 648C. Valproic Acid 649

I. Incidence of Injury 649II. Susceptibility 650

III. Clinical Features 650IV. Biochemical Features 652V. Histopathology 652

VI. Prognosis 654VII. Mechanism of Injury 654

VIII. Prevention 657References 657

Subject Index 663