Section I. Introduction

Chapter 1. The Liver: General Aspects and Epidemiology

• Abbreviated History of Hepatology
• Liver Anatomy and Physiology
• Liver Cells
• Liver Zonation Allows Functional Plasticity
• Global Liver Epidemiology

Chapter 2. Structure and Ultrastructure of the Normal and Diseased Liver

• Introduction
• Normal Liver Cell Types
• Pathology of the Diseased Liver
• Concluding Remarks

Section II. Liver Pathophysiology

Chapter 3. Hepatic Apoptosis and Necrosis: Mechanisms and Clinical Relevance

• Introduction of Hepatic Injury
• Apoptosis and Necrosis
• Mechanism of Liver Injury and Disease Relevance
• Therapeutic Strategies for Liver Injury
• Summary

Chapter 4. Autoimmune Hepatitis

• Selection and Presentation of Indigenous Foreign Antigens
• Breaking Immune Tolerance of Self-Antigens
• Neoantigens and Epitope Spread
• Implicated Self-Antigens
• Cell Mediators of Liver Injury
• Molecular Mechanisms of Immune-Mediated Liver Injury
• Overview

Chapter 5. Pathogenesis of Idiosyncratic Drug Induced Liver Injury

• Epidemiology of Idiosyncratic Drug Induced Liver Injury
• Factors Contributing to the Development of Idiosyncratic Drug Induced Liver Injury
• Individual Host Factors
• Expression and Polymorphisms of Hepatocyte Transporters
• Adaptive Immune System
• Genetic Variations and Polymorphisms in Human Leukocyte Antigen
• Defective Adaptation
• Conclusion

Chapter 6. Acetaminophen

• Introduction
• Acetaminophen Metabolism
• Mitochondrial Protein Adducts and Acetaminophen Hepatotoxicity
• Mitochondrial Oxidative and Nitrosative Stress
• Amplification of Mitochondrial Oxidative Stress: Role of c-Jun N-Terminal Kinase
• Mitochondrial Permeability Transition and DNA Damage
• Mode of Hepatocyte Cell Death After Acetaminophen Toxicity
• Sterile Inflammation and Acetaminophen Hepatotoxicity
• Clinical Biomarkers in Acetaminophen Hepatotoxicity

Chapter 7. Liver Regeneration

• Introduction
• Normal Turnover (Homeostasis) of the Liver
• Liver Regeneration After Partial Hepatectomy
• Molecular Mechanisms of Liver Regeneration After Partial Hepatectomy
• Liver Regeneration After Different Models of Hepatic Injury
• Nomenclature and Niche of Hepatic Progenitor Cells
• Hepatic Progenitor Cells Activation in Human Liver Diseases
• Oval Cells/Hepatic Progenitor Cells Contribution to Liver Regeneration
• Signaling Pathways Regulating Hepatic Progenitor Cells Activation and Differentiation
• TWEAK/Fn14 Signaling
• Fibroblast Growth Factor 7
• Stromal-Cell-Derived Factor 1
• Hedgehog Signaling
• Wnt and Notch Signaling
• Contribution of Bone Marrow Cells to Liver Regeneration

Chapter 8. Nitric Oxide in Liver Ischemia-Reperfusion Injury

• Introduction
• Mechanisms of Liver Ischemia-Reperfusion Injury
• Mechanisms of Nitric Oxide on Liver Ischemia-Reperfusion Injury
• Potential Therapeutic Effect of Nitric Oxide on Liver Ischemia-Reperfusion Injury
• Summary

Chapter 9. The Immune System and Viral Hepatitis

• Introduction
• Immune Response and Viral Hepatitis
• Immune Response to Hepatitis A Virus and Hepatitis E Virus
• Immune Response to Hepatitis C Virus and Hepatitis B Virus
• Lipid Metabolism and Hepatitis C Virus: Immune Control
• Heme Metabolism and Immune Modulation During Viral Hepatitis
• Final Remarks

Chapter 10. The Pathophysiology of Alcoholic Liver Disease

• Highlights
• Introduction
• Steatosis
• Oxidative Stress
• Inflammasomes
• Macrophages
• Neutrophilic Infiltration of the Liver
• Role of Complement in Alcoholic Hepatitis Pathogenesis
• Role of Hypoxia
• The Effect of Nutrition on Alcoholic Liver Disease
• Epigenetic Changes in Gene Expression in Alcoholic Liver Disease
• Histone Acetylation and Methylation in Experimental Alcoholic Liver Disease
• Microarray Analysis
• Lipopolysaccharides and Toll-Like Receptor 4 and the Blood Alcohol Cycle
• Balloon Cell Change and Mallory-Denk Body Formation
• Cell Cycle Arrest in Alcoholic Hepatitis
• Liver Fibrosis in Alcoholic Liver Disease

Chapter 11. Cytokines in Steatohepatitis

• Introduction
• Tumor Necrosis Factor
• Interleukins
• Interferons
• Conclusive Remarks

Chapter 12. Redox Signaling in NASH

• Introduction
• Characteristics of the Pathogenesis of Nonalcoholic Fatty Liver Disease
• Conclusion

Chapter 13. Amebic Liver Abscess

• Introduction
• Prevalence of Amebic Liver Abscess
• Clinical Manifestations
• Pathology
• Experimental Hepatic Amebiasis
• Humoral Response
• Cellular Response
• Diagnosis
• Chemotherapy
• Surgical Treatment
• Vaccination

Chapter 14. Role of Cytokines and Reactive Oxygen Species in the Amebic Liver Abscess Produced by Entamoeba histolytica

• Introduction
• Animal Models of Amebiasis
• Role of Cytokines in the Amebic Liver Abscess
• Reactive Oxygen Species in the Pathogenesis of the Amebic Liver Abscess
• Conclusions

Chapter 15. Epigenetics in Liver Disease: Involvement of Oxidative Stress

• Introduction
• Oxidative Stress, Alcohol, and Epigenetics
• Nonalcoholic Fatty Liver Disease
• Conclusions

Chapter 16. Role of Oxidative and Nitrosative Stress in Hepatic Fibrosis

• Introduction
• Oxidative Stress: Concept and Formation
• Oxidative Stress and Redox Signaling in Liver Fibrosis
• Nitrosative Stress in Liver Fibrosis
• Conclusions

Chapter 17. Oxidative and Nitrosative Stress in Chronic Cholestasis

• Introduction
• Liver Injury
• Oxidative Stress
• Nitrosative Stress
• Oxidative and Nitrosative Stress: An Interplay?
• Mitochondrial Oxidative Changes
• Conclusions

Chapter 18. Cholestasis, Contraceptives, and Free Radicals

• Cholestasis
• Liver Effects of Contraceptives: Cholestasis and Oxidative Stress
• Other Hepatic Effects by Contraceptives
• Conclusions

Chapter 19. Is Human Cirrhosis a Reversible Disease?

• Introduction
• Chronic Liver Disease
• Fibrosis and Cirrhosis
• Fibrosis and Cirrhosis Regression
• Cirrhotic Hepatitis B
• Cirrhotic Hepatitis C
• Alcohol Cirrhosis
• Reversibility of Fibrosis and Cirrhosis
• Alcohol Cirrhosis
• Nonalcoholic Liver Disease and Fibrosis
• Autoimmune Cirrhosis
• Antifibrotic Therapy

Chapter 20. Obesity and Hepatocellular Carcinoma

• Introduction
• Obesity and Hepatocellular Carcinoma Incidence
• Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma Incidence
• Hepatocellular Carcinoma in Noncirrhotic Liver With Nonalcoholic Fatty Liver Disease
• Molecular Mechanisms of Hepatocarcinogenesis in Obesity-Related Hepatocellular Carcinoma
• Adiponectin and Leptin
• Endoplasmic Reticulum Stress
• Oxidative Stress
• Genetic Factor (Patatin-Like Phospholipase Domain-Containing 3)
• Epigenetic Changes (HDAC8, MicroRNAs)
• Peroxisome Proliferator-Activated Receptor Alpha
• Farnesoid X receptor
• Phosphatase and Tensin Homolog and P-Akt/Mammalian Target of Rapamycin Complex Pathway
• Tumor Necrosis Factor Alpha and Interleukin-6
• Insulin-Like Growth Factors
• C-Jun Amino Acid-Terminal Kinases
• Gut Microbiome
• Toll-Like Receptor 4
• Obesity-Related Hepatocellular Carcinoma Prevention and Therapy
• Exercise
• Statins
• Metformin
• Probiotics
• Summary
• Disclosure Statement

Chapter 21. Oxidative Stress as a Mechanism for Hepatocellular Carcinoma

• Hepatocellular Carcinoma and Oxidative Stress

Chapter 22. Nuclear Factor-Kappa B Actions During the Development of Hepatocellular Carcinoma

• Introduction
• Nuclear Factor-Kappa B Activation and Function
• Nuclear Factor-Kappa B Activation and Liver Carcinogenesis
• Nuclear Factor-Kappa B Activation During Hepatocarcinogenesis in Animal Models
• Conclusion

Chapter 23. The Role of Senescence in Hepatic Diseases

• Introduction
• Pathways of Senescence
• Oxidative Stress and Liver Cell Senescence
• Hepatic Diseases and Senescence
• Conclusion

Chapter 24. Exercise, Liver Steatosis, and Free Radicals

• The Role of Oxidative Stress in Nonalcoholic Fatty Liver Disease
• Hepatic Redox Modulation Induced by Acute and Chronic Exercise
• Exercise Mitigates Nonalcoholic Fatty Liver Disease-Induced Liver Oxidative Stress
• Conclusions

Chapter 25. The Metabolic Syndrome, Oxidative Stress, and the Liver

• Introduction
• Definition of Metabolic Syndrome
• Epidemiology of Metabolic Syndrome and Nonalcoholic Fatty Liver Disease
• Oxidative Stress
• The Metabolic Syndrome and Oxidative Stress
• Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Oxidative Stress
• Conclusions

Chapter 26. Liver Diseases in the Elderly

• Changes Found in the Aged Liver
• Liver Diseases in the Elderly
• Summary

Chapter 27. Cytokines in Hepatic Injury

• Macrophage Heterogeneity, Cytokines, and Liver Injury
• Cytokines and Basic Liver Pathophysiology
• Cytokines in Various Hepatic Injuries
• Conclusions

Chapter 28. Nrf2: A Key Regulator of Redox Signaling in Liver Diseases

• Introduction
• General Principles of Nrf2 Signaling
• Role of Nrf2 in Liver Diseases
• Conclusion

Chapter 29. Redox Regulation by HGF/c-Met in Liver Disease

• Introduction
• Hepatocyte Growth Factor/c-Met Redox Regulation and Liver Diseases
• Conclusion

Section III. Liver Metabolism

Chapter 30. Hepatic Metabolism in Liver Health and Disease

• Introduction
• Hepatic Carbohydrates Metabolism
• Hepatic Lipid Metabolism
• Hepatic Protein Metabolism
• Hepatic Drug Metabolism

Chapter 31. Cytochrome P450 and Oxidative Stress in the Liver

• Introduction
• Microsomal Mixed Function Oxidase and Cytochrome P450 Metabolism
• Mixed Function Oxidase Activity
• CYP2E1-Reactive Oxygen Species and Ethanol-Induced Liver Injury
• Conclusions and Perspectives

Chapter 32. Drug Hepatic Clearance in Spinal Cord Injury

• Background: Clinical and Experimental Observations on Pharmacokinetic Alterations Due to Spinal Cord Injury
• Effects of Experimental Spinal Cord Injury on Phenacetin and Naproxen Clearance in Rats
• What Do We Know About Spinal Cord Injury-Induced Changes in Liver Function and Drug Disposition

Section IV. Cirrhosis and Its Complications

Chapter 33. Complications of Cirrhosis: Introduction

• Introduction
• Complications of Cirrhosis
• Concluding Remarks

Chapter 34. Portal Hypertension-Molecular Mechanisms

• Introduction
• Physiology of Portal Pressure
• Pathophysiology of Portal Hypertension
• Molecular Mechanisms of Portal Hypertension
• Summary

Chapter 35. Gastroesophageal Varices

• Definition and Clinical Significance
• Pathophysiology of Portosystemic Collateral Circulation
• Development of Portosystemic Collaterals: Preexistent and De Novo
• Assessment of Varices
• Rationale for the Management of Varices
• Clinical Scenarios for the Treatment of Portal Hypertension

Chapter 36. Ascites

• Pathogenesis
• Pathophysiological Bases for the Treatment of Ascites
• Management of Cirrhotic Ascites
• Conclusions

Chapter 37. Reactive Nitrogen and Oxygen Species in Hepatic Encephalopathy

• Introduction
• Hepatic Encephalopathy
• Manganese
• Ammonia
• Other Pathogenic Mechanisms Generating Reactive Nitrogen and Oxygen Species in the Brain
• Conclusions

Chapter 38. Hepatorenal Syndrome

• Introduction
• Pathophisiology of HRS
• Diagnosis
• Differential Diagnosis
• Precipitating Factors
• Treatment of HRS

Chapter 39. Hepatopulmonary Syndrome and Portopulmonary Hypertension

• Hepatopulmonary Syndrome
• Portopulmonary Hypertension
• Summary

Section V. Methods in Liver Disease

Chapter 40. Experimental Models of Liver Damage Mediated by Oxidative Stress

• Introduction
• Carbon Tetrachloride Is a Useful Model to Induce Acute and Chronic Liver Damage
• Acetaminophen Intoxication as Model of Acute Liver Injury
• Models of Cholestasis
• Ischemia/Reperfusion Liver Injury Models Serve to Improve Liver Transplantation Surgery
• Concanavalin A Is a Good Model That Mimics Autoimmune Hepatitis
• Liver Damage Induced by Alcohol in Rats
• d-Galactosamine and Lipopolysaccharides Induce Liver Damage Through Activating the Immune System
• Thioacetamide Produces Chronic Liver Injury Through Free Radical Attack to Macromolecules
• Dimethyl or Diethyl Nitrosamine Produces Necrosis, Fibrosis, and Cancer
• Dietary Models Used to Acquire a Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis Phenotype
• Gold Thioglucose+High-Fat Diet
• Concluding Remarks

Chapter 41. Monitoring of Liver Fibrogenesis and Biochemical Diagnosis of Fibrosis

• Introduction
• Current Biomarkers of Hepatic Fibrogenesis
• Class I Fibrosis Biomarkers
• Class II Fibrosis Biomarkers
• Development of Innovative Biomarkers
• NX-Des-y-carboxyprothrombin
• Conclusion

Chapter 42. In Vitro Models of HCC

• Introduction
• General Overview and Traits of a Multistage Malignant Process
• Cell Models for the Study of Hepatocellular Carcinoma Initiation Stage
• Cell Models for the Study of Hepatocellular Carcinoma Promotion Stage
• Cell Models for the Study of Hepatocellular Carcinoma Progression Stage
• Comparative Analysis of Hepatocellular Carcinoma Cell Lines
• Frequency of Use for Research Purposes
• Pharmacological Studies in Hepatocellular Carcinoma Cell Lines
• Studies With Antioxidants
• Combination of Antioxidants With Different Drugs in Hepatocellular Carcinoma Cell Lines
• Conclusions

Section VI. Therapies in Liver Disease

Chapter 43. The Liver, Oxidative Stress, and Antioxidants

• Introduction
• Oxidative Stress
• The Overproduction of Free Radicals in Biological Systems
• Antioxidants
• Nuclear Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway in Liver Diseases
• Antioxidants From Natural Sources and Some of Its Hepatoprotective Effects
• Conclusion

Chapter 44. Herbal Drugs on the Liver

• Introduction
• Plants as Hepatoprotective Agents
• Polyherbal (Multiingredient) Formulations as Hepatoprotective Agents
• Problems With Polyherbal Formulations
• Chemistry of Hepatoprotective Herbal Drugs
• The Mechanism(s) of Action
• Active Phytochemicals as Hepatoprotective Agents
• Development of Hepatoprotective Herbal Drugs

Chapter 45. Silymarin for Liver Disease

• The History of Milk Thistle
• Biochemistry
• Pharmacokinetics
• Pharmacological Studies
• Alcohol-Induced Liver Disease
• Nonalcoholic Fatty Liver Disease
• Viral Hepatitis
• Toxic and Iatrogenic Liver Disease
• Mushroom Poisoning
• Hepatocellular Carcinoma
• Conclusion

Chapter 46. Naringenin and the Liver

• Introduction
• Knowing Naringenin
• Pharmacokinetics of Naringenin
• The Naringenin in Fibrogenic Signaling Pathways
• Beneficial Effects of Naringenin in Liver Diseases
• Pharmaceutical Technology of Naringenin
• Safety and Toxicity of Naringenin
• Conclusions and Perspectives

Chapter 47. Antioxidant, Antiinflammatory, and Antifibrotic Properties of Quercetin in the Liver

• Introduction
• Structure-Activity Relationship of Quercetin
• Metal-Chelating Activity of Quercetin
• Pharmacokinetics of Quercetin
• Hepatoprotective Effects of Quercetin
• Quercetin and Inflammation
• Quercetin in the Treatment of Hepatocellular Carcinoma
• Pharmaceutical Technology of Quercetin
• Toxicological Effects
• Conclusions and Perspectives

Chapter 48. Coffee and the Liver

• Introduction
• Chemical Composition of Coffee
• Beneficial Effects of Coffee on Liver Disease

Chapter 49. Hepatoprotective Properties of Curcumin

• Introduction
• Antiinflammatory Properties of Curcumin in the Liver
• Antifibrotic Properties of Curcumin in the Liver
• Anticancer Properties of Curcumin in the Liver
• Antiviral Properties of Curcumin in the Liver
• Antiheavy Metal Properties of Curcumin in the Liver
• Antisteatosis Properties of Curcumin in the Liver
• Conclusions and Perspectives

Chapter 50. Retinoids in Liver Function

• What Is a Retinoid?
• Dietary Intake and Intestinal Absorption of Retinoids
• Cellular Formation of Retinal and Retinoic Acid
• Hepatic Retinoids and Liver Diseases
• Effect of Retinoids on Iron Metabolism
• Effect of Retinoids on Insulin Resistance in Liver
• Activation of AMPK by Retinoids
• Identification of the Responsive Genes of All-trans Retinoic Acid
• Retinoid Metabolism in Nonalcoholic Fatty Liver Disease

Chapter 51. Stevia as a Putative Hepatoprotector

• Introduction
• Conclusions and Perspectives

Chapter 52. Are N-Acetylcysteine and Resveratrol Effective Treatments for Liver Disease?

• Introduction
• Overview of NAC and Resveratrol: Chemical Properties and Pharmacokinetic Aspects
• Pharmacodynamic Properties and Clinical Applications
• Effects of NAC and Resveratrol in Liver Diseases
• Side-Effects and Toxicology of NAC and Resveratrol
• NAC and Resveratrol Formulations
• Conclusions and Perspectives

Chapter 53. Does Nutrition Matter in Liver Disease?

• Introduction
• Malnutrition as a Consequence of Liver Disease
• Evaluation of Nutrition Status in Liver Disease
• Nutritional Treatment of Liver Disorders
• Conclusion and Perspectives

Chapter 54. One-Carbon Metabolism in Liver Health and Disease

• Introduction
• Hepatic One-Carbon Metabolism
• S-Adenosylmethionine Treatment in Liver Disease

Chapter 55. Ursodeoxycholic Acid for the Treatment of Liver Diseases

• History of Ursodeoxycholic Acid
• Physicochemical Properties and Pharmacokinetics of UDCA
• Pharmacological Activities of UDCA
• Mechanisms of UDCA Action
• Clinical Use and Efficacy of UDCA

Chapter 56. Current Treatment of Chronic Hepatitis C

• Interferon-Free Treatment Regimens
• Unresolved Issues
• Conclusions

Chapter 57. An Adenosine Derivative Compound as a Hepatoprotective Agent

• Introduction
• Concluding Remarks and Perspectives

Chapter 58. Nitric Oxide and the Liver

• Introduction
• Sources and Regulation of NO in the Liver
• NO Signaling in Liver
• Pathophysiology
• Conclusion: NO and the Liver

Chapter 59. Repopulation of Cirrhotic Liver by Hepatic Stem/Progenitor Cells: A Promising Strategy Alternative to Liver Transplantation

• Introduction
• Emergence of Cell Therapy for Liver Diseases
• Hepatocytes Transplantation
• Stem Cell-Based Therapy for Liver Cirrhosis
• Stem Cells Repopulation in Cirrhotic Liver Through Different Routes/Sites
• Immunobiology of hHSPCs Transplantation
• Alternative Strategies for the Development of Bioartificial Liver Using hHSPCs Repopulation
• Stem Cells Imaging and Tracking: From Bench to Bedside
• Concluding Remarks

Chapter 60. Gene Therapy for Liver Disease

• Introduction
• Mechanisms of Liver-Directed Gene Therapy
• Delivery Systems for Gene Therapy
• Viral Vectors
• Nonviral Vectors
• Conclusions

Chapter 61. Role of Oxidative Stress in Liver Transplantation

• Introduction
• Role of Oxidative Stress in Ischemia-Reperfusion Associated With Liver Transplantation
• Strategies to Decrease Oxidative Stress in I/R Associated With Liver Transplantation
• Future Directions in Researching on Oxidative Stress in Ischemia-Reperfusion Injury Associated With Liver Transplantation