Zakim and Boyer's Hepatology: A Textbook of Liver Disease E-Book

Get The Authoritative, Up-to-date Information You Need On Liver Disease From The 7th Edition Of The Most Trusted Reference Worldwide. Covering Both Basic Science And Recent Clinical Developments, This Revised Edition By Drs. Arun J. Sanyal, Thomas D. Boyer, Norah A. Terrault, And Keith D. Lindor, Provides An In-depth, Comprehensive Look At The Pathophysiology, Diagnostic, And Treatment Information Related To The Liver. More Than 1,100 Figures And Tables, Many New And In Full Color, Highlight Completely Updated Content Throughout. Expert, International Authorship And Comprehensive, Easy-to-access Information Makes This Edition The Gold Standard In The Field Of Hepatology. Expert Consultt Ebook Version Included With Purchase. This Enhanced Ebook Experience Allows You To Search All Of The Text, Figures, Videos, And References From The Book On A Variety Of Devices. Includes New Information On The Rapid Changes In Treatment Paradigms For Acute Liver Failure, The Latest Treatments For Primary Biliary Cholangitis, Full Coverage Of The Gut Microbiome And Its Role In Liver Disease, The Newest Developments In Drug-induced Liver Injury, And Changes In Hepatitis C Virus Treatment And Hot-button Concerns About Access To Care. New Summary Boxes At The End Of Each Chapter And A Newly Streamlined Table Of Contents Make It Easier To Find And Understand The Information You're Looking For. Hundreds Of Brand-new Illustrations Clearly Present Key Aspects Of Liver Disease. Front Cover Expert Consult page Zakim and Boyer's Hepatology Copyright Page Contributors Preface Table Of Contents I Basics 1 Anatomy and Cellular Functions of the Liver Abbreviations Introduction Gross Anatomy Development of the Liver Microscopic Architecture Portal Tracts and the Biliary System The Biliary Tree Cholangiocytes Peribiliary Glands Portal Tract Mesenchyme Lobular and Acinar Functional Units Hepatocytes Plasma Membrane Nucleus Endoplasmic Reticulum, Ribosomes, and Golgi Apparatus Mitochondria Lysosomes Peroxisomes Cytoplasmic Contents Cytoskeleton and Cytomatrix The Hepatic Sinusoid Sinusoidal Endothelial Cells Kupffer Cells Stellate Cells Liver-Associated Lymphocytes Innervation Heterogeneity Conclusion References References 2 Bile Acids and Bile Flow Abbrevations Introduction Pathways of Bile Acid Synthesis From Cholesterol Bile Acid Conjugation Formation of Secondary Bile Acids Regulation of Bile Acid Synthesis Defects in Bile Acid Synthesis Causing Metabolic Liver Disease and Syndromes of Fat-Soluble Vitamin Malabsorption Defects Involving Reactions to the Steroid Nucleus Cholesterol 7α-Hydroxylase Deficiency Oxysterol 7α-Hydroxylase Deficiency 3β-Hydroxy-Δ5 C27-Steroid Oxidoreductase Deficiency Δ4-3-Oxosteroid 5β-Reductase (AKR1D1) Deficiency Defects Involving Reactions Leading to Side Chain Modification Sterol 27-Hydroxylase Deficiency: Cerebrotendinous Xanthomatosis 2-Methylacyl CoA Racemase Deficiency Side Chain Oxidation Defect in the 25-Hydroxylation Pathway Peroxisomal Disorders Bile Acid-CoA Conjugation Defects Other Disorders Influencing Bile Acid Synthesis and Metabolism Bile Acids as Signaling Integrators of Metabolism Enterocyte Bile Acid Physiology Muscle and Brown Adipose Tissue Metabolism Bile Acid Changes After Bariatric Surgery Bile Acid Signaling as a Treatment for Nonalcoholic Steatohepatitis Conclusion References References 3 Intestinal Microbiome and the Liver Abbreviations Historical Perspective and Technology Development General Principles and the Conceptual Construct: the Gut-Liver Axis in Homeostasis and Implications for Liver Diseases Intestinal Barrier How Does the Host Maintain Homeostasis With Continued Exposure to an Enormous Microbial Load? Interactions of the Liver With the Intestinal Microbiome How Is the Intestinal Microbiome Related to Liver Disease? Mucosal and Liver Tolerance Liver and Pattern Recognition Receptors Microbiota, Hepatic Inflammation, and Fibrosis The Intestinal Microbiota as a Mediator of Hepatic Inflammation The Intestinal Microbiota as a Mediator of Hepatic Fibrosis Germ-Free Models: Implications for the Intestinal Microbiome, the Intestine, and the Liver Role of the Intestinal Microbiome in Specific Liver Diseases Obesity and the Intestinal Microbiome The Intestinal Microbiome and Nonalcoholic Fatty Liver Disease Human Studies Functional and Mechanistic Insights From the Intestinal Microbiome in NAFLD The Intestinal Microbiome and Alcoholic Liver Disease Intestinal Dysbiosis in Alcoholic Liver Disease Corollaries of Intestinal Dysbiosis in Alcoholic Liver Disease The Intestinal Microbiome and Autoimmune Liver Diseases Primary Sclerosing Cholangitis and the Intestinal Microbiome Autoimmune Hepatitis and the Intestinal Microbiome The Intestinal Microbiome in Cirrhosis and Associated Complications Intestinal Dysbiosis in Experimental Fibrosis and Cirrhosis Intestinal Dysbiosis and Cirrhosis in Clinical Practice Clinical and Metabolic Corollaries of Intestinal Dysbiosis in Cirrhosis The Intestinal Microbiome and Hepatocellular Carcinoma The Intestinal Microbiome and Liver Transplant The Intestinal Microbiome and Liver Regeneration Interventions to Modulate the Intestinal Microbiome Conclusion References References 4 The Liver as an Immune Organ Abbreviations Introduction Immune Cell Populations and Their Function in the Liver Neutrophils Monocytes and Macrophages Dendritic Cells Natural Killer Cells and Natural Killer T Cells T-Cell Populations B Cells Functions of the Immune System in the Liver Innate Immunity Pattern Recognition Receptors Chemokines, Cytokines, and Interferons Antigen Presentation and Adaptive Immunity Inflammation and Innate Immunity in Liver Diseases Immune Response in Viral Hepatitis Hepatitis C Virus Hepatitis B Virus Hepatitis D Virus Hepatitis A Virus and Hepatitis E Virus Autoimmunity in Liver Diseases Liver Fibrosis and Immune Response Inflammation and Immunity in Liver Cancer Conclusion References References 5 The Liver’s Response to Injury Abbreviations Introduction Hepatic Inflammation as a Driver of Hepatic Fibrosis Cell Types That Participate in Inflammation and Fibrosis Hepatocytes Hepatic Stellate Cells Macrophages Natural Killer Cells and Natural Killer T Cells T and B Lymphocytes Key Pathways in Hepatic Inflammation and Fibrosis Cell Death–Triggered Inflammation and Fibrosis Toll-like Receptor Pathway Chemokines in Liver Inflammation and Fibrosis MicroRNAs in Hepatic Inflammation and Fibrosis MicroRNAs as Modulators of Liver Inflammation MicroRNAs as Modulators of Liver Fibrosis Conclusion References References 6 Stem Cells and Hepatocyte Transplantation Abbreviations Introduction Preclinical and Background Studies Enabling Clinical Translation Integration of Hepatocytes in the Recipient’s Liver Occlusion of the Portal Veins With Donor Cells Breeching the Endothelial Barrier Integration Into Hepatic Chords Remodeling of Liver Initial Clinical Studies Hepatocyte Transplantation for Acute Liver Failure Hepatocyte Transplantation for Metabolic Liver Disease Patient Selection for Hepatocyte Transplantation Challenges and Solutions Regarding Hepatocyte Transplantation Sources of Hepatocytes and Hepatocyte-Like Cells Identifying the Correct Niche Signals for Hepatocytes Alternative Sources of Hepatocytes Embryonic Stem Cells Induced Pluripotent Stem Cells Directly Reprogrammed Hepatocyte-Like Cells Adult Hepatic Progenitor Cells Organoid Culture of Hepatocyte Cells Assessment of Hepatic Viability and Function Before Transplant Methods for Storage of Cells After Isolation and Before Transplant Tracking Donor Cells and Assessment of Cell Function After Transplant Optimal Immunosuppressive Therapy Engraftment and Long-Term Repopulation of Recipient Liver With Donor Cells Conclusion References References II Management and Assessment of Liver Disease 7 Approach to Jaundice and Abnormal Liver Function Test Results Abbreviations Introduction Historical Perspective: 100 Years of Liver Function Tests Liver Functions Tests: Anatomic, Physiologic, and Pathologic Basis Tests That Assess the Function of Biliary Organic Anion Transport Bilirubin Urinary Bilirubin and Urobilinogen Bile Acids Tests That Assess Hepatobiliary Injury Aminotransferases Alkaline Phosphatase γ-Glutamyl Transpeptidase Other Enzymes Tests That Assess Hepatic Synthetic Function Albumin Prothrombin Time and International Normalized Ratio Clinical Approach to Abnormal Liver Function Test Results Epidemiology and Outcome of Liver Function Tests With Abnormal Results When and Whom to Evaluate Further Normal Reference Range and Definition of Abnormal Liver Enzyme Levels Establishing Abnormal Results Identification of Pattern of Abnormalities: A Clue to the Underlying Cause Cholestatic and Hepatocellular Injury Jaundice Acute-on-Chronic Liver Function Test Abnormalities Liver Function Test Results and Severity of Liver Injury: An Association Estimation of Fibrosis Based on Mathematical Scores Noninvasive Biomarkers of Fibrosis Isolated Biomarkers Fibrosis Biomarker Panels Correlations Between Liver Function Test Results and Clinical Features Patients With Abnormal Liver Function Test Results: What to Ask and Assess Clinical Examination: What to Look for Signs of Chronic Liver Disease Signs of Underlying Cause Clinical Signs of Portal Hypertension Clinical Signs of Hepatic Insufficiency (Liver Failure) Further Testing: Which Tests, as Well as When to Perform Them and What to Look for Laboratory Tests Imaging Liver Biopsy When a Diagnosis Is Not Established: How to Monitor Patients Conclusion References References 8 Noninvasive Assessment of Disease Progression Abbreviations Introduction The Value and Meaning of Fibrosis Staging and the Role of Liver Biopsies Approach to Noninvasive Testing Pathophysiology of Common Serologic Tests for Liver Fibrosis AST/ALT Ratio AST/Platelet Ratio and Fibrosis-4 Indexes Nonalcoholic Fatty Liver Disease Fibrosis Score FibroMeter FibroSure/FibroTest HepaScore FibroSpect Enhanced Liver Fibrosis Score Radiologic Tests for Liver Fibrosis Ultrasound Computed Tomography and Magnetic Resonance Imaging Vibration-Controlled Elastography Magnetic Resonance Elastography Acoustic Radiation Force Impulse Elastography Disease-Specific Considerations Hepatitis C Hepatitis B Nonalcoholic Fatty Liver Disease Cholestatic Diseases Alcoholic Liver Disease Other Liver Diseases Conclusion References References 9 Molecular and Genetics-Based Diagnostics Abbreviations Introduction Monogenic Liver Diseases Hereditary Hemochromatosis Wilson Disease α1-Antitrypsin Deficiency Cystic Fibrosis–Associated Liver Disease Familial Intrahepatic Cholestasis Hereditary Hyperbilirubinemias Polygenic Liver Diseases Intrahepatic Cholestasis of Pregnancy as Example Gallstone Disease Common ABC Transporter Risk Variants Drug-Induced Liver Injury Chronic Viral Hepatitis Fatty Liver Disease Liver Cirrhosis Next-Generation Sequencing References References 10 Imaging in Assessment of Liver Disease and Lesions Abbreviations Introduction Diffuse Liver Disease Active Inflammation Chronic Hepatitis and Cirrhosis Focal Hepatic Lesions Imaging Modalities Ultrasound Computed Tomography Magnetic Resonance Imaging Hepatobiliary-Specific Contrast Agents Benign Lesions Solid Hemangioma Imaging Focal Nodular Hyperplasia Imaging Liver Cell Adenoma Imaging Cystic Cystic Bile Duct Hamartoma Imaging Hepatic Abscess Imaging Miscellaneous Focal Fat/Fatty Sparing Sarcoidosis Imaging Neoplastic Lesions Continuum of Hepatic Lesions in Chronic Liver Disease Imaging Intrahepatic Cholangiocarcinoma Imaging Biliary Cystadenoma/Carcinoma Imaging Biliary IPBN Imaging Hepatic Metastases Hypovascular Metastases Imaging. Hypervascular Metastases Imaging. Lymphoma Imaging Conclusion References References 11 Evaluation of the Hepatic Mass Abbreviations Introduction Imaging Modalities Hemangioma Focal Nodular Hyperplasia Hepatic Adenoma Hepatic Cysts Bile Duct Hamartomas Biliary Cystadenoma Hepatic Abscess Hepatocellular Carcinoma Cholangiocarcinoma Metastases Conclusion References References 12 Assessment of Liver Histology Abbreviations Introduction Clinical-Pathologic Correlations Tissue Preparation and Stains Approach to Microscopy Morphologic Lesions of Hepatitis Acute Hepatitis Chronic Hepatitis Fatty Liver Diseases Metabolic Liver Diseases Cholestatic Lesions Acute Cholestasis Chronic Cholestasis Granulomatous Inflammation in Liver Disease Hepatic Parenchymal Manifestations of Vascular Lesions Outflow Veins/Right-Sided Cardiac Dysfunction Inflow Vessels Portal Vein Hepatic Artery Arteriovenous Malformations: Hereditary Hemorrhagic Telangiectasia (HHT) Hepatic Sinusoids Mass Lesions Benign Hepatic Lesions/Tumors Malignant Tumors Drug-Induced Liver Injury (DILI) Liver Transplant Pathology Pediatric Liver Biopsies Liver Biopsies in Systemic Disease Conclusion References References 13 Critical Care Management of Patients With Liver Disease Abbreviations Introduction Sepsis/Septic Shock Altered Mental Status Upper GI Bleeding General Critical Care Issues Mechanical Ventilation of the Patient With Liver Disease ICU Jaundice and Liver Function Test (LFT) Abnormalities (see Chapter 57) Hypoxic/Ischemic Hepatitis (Shock Liver) Acute Acalculous Cholecystitis Prophylaxis for Venous Thromboembolic Disease (VTE) Primary SBP Prophylaxis Acid-Base and Electrolyte Disorders in Cirrhosis Procedure Risk of Bleeding in Liver Disease Prognostication Conclusion References References III Clinical Consequences of Chronic Liver Disease 14 Neurologic Consequences of Liver Disease Abbreviations Introduction Historical Background Pathogenesis of Hepatic Encephalopathy Ammonia Inflammation Microbiota Neuromodulators Manganese Deposition Spectrum and Nomenclature of Hepatic Encephalopathy Spectrum of Neurocognitive Impairment in Cirrhosis Importance of Hepatic Encephalopathy Overt Hepatic Encephalopathy Covert Hepatic Encephalopathy Diagnosis of Hepatic Encephalopathy Diagnosis of Overt Hepatic Encephalopathy Physical Examination in Patients With Overt Hepatic Encephalopathy Brain Imaging for the Diagnosis of Hepatic Encephalopathy Abdominal Imaging Miscellaneous Imaging Ammonia Levels for the Diagnosis of Overt Hepatic Encephalopathy Clinical Classification of Hepatic Encephalopathy Into Normal and Overt Hepatic Encephalopathy Diagnosis of Covert Hepatic Encephalopathy Neuropsychological Examination and Psychometric Testing for the Diagnosis of Covert Hepatic Encephalopathy Paper and Pencil Tests Neurophysiologic Tests Limitations of Currently Available Psychometric and Neurophysiologic Tests Computerized Tests Management and Treatment of Hepatic Encephalopathy Goals for the Management of Hepatic Encephalopathy Nonabsorbable Disaccharides Antibiotics Neomycin Rifaximin Metronidazole, Vancomycin, and Paromomycin Probiotics Management of Acute Overt Hepatic Encephalopathy Nonabsorbable Disaccharides Antibiotics Neomycin Rifaximin Probiotics Management of Covert Hepatic Encephalopathy Nonabsorbable Disaccharides Antibiotics Probiotics Secondary Prevention of Overt Hepatic Encephalopathy Other Therapies l-Ornithine-l-Aspartate Sodium Benzoate l-Orthinine Phenylacetate and Glycerol Phenylbutyrate Flumazenil Branched-Chain Amino Acid–Enriched Formulations Dopaminergic Agents Zinc Repletion Disaccharidase Inhibitors Albumin Newer Agents Hepatic Encephalopathy Resistant to Therapy or Persistent Hepatic Encephalopathy Liver Support Systems Closure of Portosystemic Shunts Nutrition Liver Transplantation References References 15 Ascites and Hyponatremia Abbreviations Introduction Epidemiology Pathogenesis Sinusoidal Hypertension Plasma Volume Expansion Clinical Features Diagnosis Differential Diagnosis Associated Conditions Disease Complication: Spontaneous Bacterial Peritonitis Epidemiology Clinical Picture Diagnosis Treatment Prophylaxis Treatment of Ascites Sodium Restriction Diuretics Complications Contraindications Large-Volume Paracentesis Complications Contraindications Transjugular Intrahepatic Portosystemic Shunt Complications Contraindications Peritoneovenous Shunt and Other Shunting Devices Treatment of Conditions Associated With Ascites Treatment of Hyponatremia Treatment of Hepatic Hydrothorax Prognosis and Natural History Conclusion References References 16 Portal Hypertension Related to Bleeding Abbreviations Anatomy of the Portal Venous System Physiologic Principles of the Portal Circulation Portal Hypertension Definition Pathogenesis of Portal Hypertension Physiologic Principles of Portal Hypertension Increased Intrahepatic Resistance Increased Splanchnic Blood Flow and the Hyperdynamic Circulatory State Portosystemic Collateral Circulation in Portal Hypertension Clinical Features of Portal Hypertension Portosystemic Collaterals Splenomegaly Assessment of Portal Venous System Upper Gastrointestinal Endoscopy Capsule Endoscopy CT Scan Magnetic Resonance Imaging Ultrasonography Endoscopic Ultrasound Ultrasound Transient Elastography Ultrasound Real-Time Shear Wave Elastography Measurement of Portal Venous Pressure Hepatic Vein Pressure Gradient Measurement Direct Transhepatic Portal Venous Pressure Measurement Measurement of Variceal Pressure and Flow Measurement of Portal Venous and Hepatic Artery Blood Flow Classification of Diseases Causing Portal Hypertension Portal Hypertension Secondary to Increased Portal Venous Blood Flow Splanchnic Arteriovenous Fistula Splenomegaly Portal Hypertension Secondary to Increased Resistance to Portal Blood Flow Extrahepatic Portal Vein Thrombosis Idiopathic Portal Hypertension Schistosomiasis Alcoholic Liver Disease Nonalcoholic Cirrhosis Fibrocystic Liver Disease Nodular Regenerative Hyperplasia of the Liver Partial Nodular Transformation of the Liver Hematologic Disease Hepatocellular Carcinoma Metastatic Carcinoma to the Liver Hereditary Hemorrhagic Telangiectasia Sarcoidosis Cystic Fibrosis Cardiac Disease Portal Hypertension–Related Bleeding Selection of Patients to Screen for Esophageal Varices Risk Factors and Natural History of Portal Hypertension–Related Bleeding Portal Hypertensive Gastropathy and Gastric Vascular Ectasia Bleeding From Other Sites in the Gastrointestinal Tract Diagnosis of Portal Hypertension–Related Bleeding Treatment Options for Portal Hypertension–Related Bleeding Pharmacologic Treatment Vasopressin Analogs Somatostatin Analogs β-Adrenergic Blocking Drugs Combined α- and β-Adrenergic Blockers Nitrates Drugs That Decrease Intrahepatic Vascular Resistance Endoscopic Therapy Sclerotherapy Endoscopic Variceal Ligation Cyanoacrylate Glue Injection Detachable Snares and Clips Radiologic Procedures Transjugular Intrahepatic Portosystemic Shunts (TIPS) Balloon-Occluded Retrograde Transvenous Obliteration of Varices (BRTO) Balloon Tamponade Esophageal Stents Surgical Management of Portal Hypertension Decompressive Shunts Portocaval Shunts Selective Shunts Partial Portosystemic Shunts Mensenterico–Portal Venous Bypass Approach to the Patient With Portal Hypertension–Related Bleeding Esophageal Variceal Bleeding Preprimary Prophylaxis of Variceal Bleeding Primary Prophylaxis: Prevention of First Variceal Bleed Small Esophageal Varices. Large Esophageal Varices. Control of Acute Esophageal Variceal Bleeding General Measures Specific Measures Secondary Prophylaxis: Prevention of Recurrent Esophageal Variceal Bleeding Gastric Varices Portal Hypertensive Gastropathy and Gastric Vascular Ectasia Ectopic Varices Conclusion References References 17 Renal Failure in Cirrhosis Abbreviations Introduction Measurement of Renal Function The Concept of Acute Kidney Injury The RIFLE Diagnostic Criteria for Acute Kidney Injury The Acute Kidney Injury Network (AKIN) Diagnostic Criteria for Acute Kidney Injury The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines The Diagnostic Criteria of the ADQI and the International Ascites Club (IAC) for Acute Kidney Injury in Cirrhosis The Application of the Various AKI Diagnostic Criteria to Cirrhotic Patients The RIFLE Diagnostic Criteria The AKIN Diagnostic Criteria The ADQI-IAC Diagnostic Criteria for Acute Kidney Injury How Well Do These Various Diagnostic Criteria of AKI Serve Cirrhotic Patients? Revised Consensus Recommendations of the IAC on the Diagnosis of Acute Kidney Injury in Cirrhosis The Diagnostic Criteria for Hepatorenal Syndrome Pathophysiology of Acute Kidney Injury and Hepatorenal Syndrome Splanchnic and Systemic Arterial Vasodilatation of Advanced Cirrhosis and Ascites The Consequences of Splanchnic and Systemic Arterial Vasodilatation The Role of Portal Hypertension Independent of Hemodynamic Changes Renal Changes in Advanced Cirrhosis Cardiac Insufficiency The Role of Inflammation Approach to a Patient With Cirrhosis Who Presents With Renal Dysfunction Differential Diagnoses of Acute Kidney Injury Prerenal Azotemia Intrinsic Renal Diseases Non–Volume Responsive Functional Acute Kidney Injury Including Hepatorenal Syndrome Treatment of AKI General Measures Albumin Vasoconstrictors Terlipressin Norepinephrine Midodrine Nonpharmacologic Treatments Liver Transplant Prevention of Hepatorenal Syndrome–Acute Kidney Injury The Use of Albumin in Patients With Bacterial Infection Antibiotic Prophylaxis Against Infection Patients With Alcoholic Hepatitis Prophylaxis Against Circulatory Dysfunction Avoidance of Nephrotoxic Drugs Judicious Use of Diuretics Chronic Kidney Disease in Cirrhosis Conclusion References References 18 Cardiopulmonary Complications of Cirrhosis Abbreviations Introduction Definition and Diagnosis of Cirrhotic Cardiomyopathy Electrocardiography Echocardiography Tissue Doppler Imaging Stress Testing Serologic Markers Natural History and Epidemiology Pathogenesis of Cirrhotic Cardiomyopathy Cardiomyocyte Membrane Alterations Nitric Oxide and Carbon Monoxide Alterations Inflammatory Mediators: Tumor Necrosis Factor α Signaling and Endocannabinoids Clinical Features Management of Cirrhotic Cardiomyopathy Pulmonary Vascular Complications in Liver Disease The Spectrum of Pulmonary Abnormalities in Liver Disease Hepatopulmonary Syndrome Definition Epidemiology Pathogenesis Clinical Features Diagnosis Therapy Prognosis and Natural History Portopulmonary Hypertension Definition Epidemiology Pathogenesis Clinical Features Diagnosis Treatment Liver Transplant Prognosis and Natural History Coexistence of Hepatopulmonary Syndrome and Portopulmonary Hypertension Conclusion References References 19 The Hemostatic and Hematopoietic System in Liver Disease Abbreviations Introduction The Hemostatic System: Normal Physiology and Pathophysiology in Liver Disease Bleeding in Cirrhosis Patients Epidemiology Therapy Thrombosis in Cirrhosis Patients Epidemiology Therapy Other Abnormalities in the Hematopoietic System in Liver Disease Erythrocytes Platelets Leukocytes Conclusion References References 20 Acute Liver Failure Abbreviations Introduction Causes and Epidemiology Hepatotropic Viruses Hepatitis A Hepatitis B Hepatitis D Hepatitis C Hepatitis E Non–Hepatitis A-E Viruses Systemic Viral Infections Drug-Induced Acute Liver Failure Acetaminophen Biologic Toxins Metabolic Causes of Acute Liver Failure Autoimmune Acute Liver Failure Ischemic Causes of Acute Liver Failure Diffuse Malignant Infiltration of the Liver Pathogenesis of the Syndrome of Acute Liver Failure Early Presentation of the Acute Injury Failure of Liver Function Failure of Hepatobiliary Excretion Failure to Metabolize Toxic Substances Failure of Intermediary Metabolism Failure of Biosynthetic Function of the Liver Effects of Acute Liver Failure on Extrahepatic Systems Microcirculatory Dysfunction Cardiovascular Consequences Pulmonary Consequences Renal and Electrolyte Disturbances Hematologic Disturbances Breakdown of Host Immune Defenses Gastrointestinal Consequences Neurologic Consequences Hepatic Encephalopathy Intracranial Hypertension and Cerebral Edema Management of Acute Liver Failure General Management Initial Evaluation and Triage Therapies for Liver Injury N-Acetylcysteine for Acetaminophen Overdose N-Acetylcysteine for Nonacetaminophen Acute Liver Failure Other Cause-Specific Therapies Management of Fluids, Electrolytes, and Acid-Base Abnormalities Management of Nutrition Prevention and Management of Specific Complications of Acute Liver Failure Bleeding Cardiovascular Derangements Pulmonary Complications and Ventilatory Support Prevention and Management of Infection Management of Acute Kidney Injury Multiorgan System Failure Hepatic Encephalopathy, Cerebral Edema, and Intracranial Hypertension Methods to Protect the Liver From Injury and Promote Liver Regeneration Orthotopic Liver Transplantation Assessment of Prognosis: When to Initiate Orthotopic Liver Transplantation Evaluation References References 21 Acute-on-Chronic Liver Failure Abbreviations Introduction Definition Precipitating Events Prevalence Natural History Economic Burden Pathophysiology Extrahepatic Organ Failure Renal Failure Hepatic Encephalopathy Cardiovascular Dysfunction Respiratory Failure Coagulation Dysfunction Prognostic Models Potential Prognostic Biomarkers Management of ACLF General Measures Liver Support Devices Potential Hepatic Regenerative Therapy Liver Transplantation Conclusion References References IV Specific Diseases 22 Epidemiology and Pathogenesis of Alcoholic Liver Disease Abbreviations Introduction Epidemiology of Alcoholic Liver Disease Ethanol Metabolism Alcoholic Fatty Liver Alcoholic Steatohepatitis Infiltration of Neutrophils Activation of Kupffer Cells and Infiltrating Macrophages Activation of Natural Killer T Cells Activation of Adaptive Immunity Inflammatory Mediators (Cytokines and Chemokines) Alcoholic Hepatitis Alcoholic Fibrosis and Cirrhosis Alcoholic Liver Cancer Risk Factors for Alcoholic Liver Disease Animal Models of Alcoholic Liver Disease Chronic Ethanol Feeding “Second-Hit” Model Chronic-Plus-Binge Ethanol Feeding High-Fat Diet (HFD) and Ethanol Feeding Comorbid Conditions Therapeutic Targets Conclusion References References 23 Natural History and Cofactors of Alcoholic Liver Disease Abbreviations Introduction Pattern, Dosage, and Types of Alcohol Consumption and Risk of Alcoholic Liver Disease Sex Dietary Factors and Risk of Alcoholic Liver Disease Genetic Risk Factors for Alcoholic Liver Disease Genes Influencing Alcohol Metabolism Cytokine-Related Genes and Endotoxin Receptor PNPLA3 and Alcoholic Liver Disease Oxidative Stress–Related Genes Natural History of Alcoholic Liver Disease Alcoholic Fatty Liver Alcoholic Hepatitis Alcoholic Cirrhosis Special Considerations for Factors Influencing the Natural History of Alcoholic Liver Disease Hepatitis C Hepatitis B Obesity and Nonalcoholic Fatty Liver Disease Toxicity of Acetaminophen and Other Drugs Obstructive Sleep Apnea Conclusion References References 24 Prevention and Management of Alcoholic Liver Disease Abbreviations Prevention of Alcoholic Liver Disease Primary Prevention Secondary Prevention Screening for Alcohol Consumption Tertiary Prevention Treatment of Alcoholic Liver Disease Diagnosis of Alcoholic Hepatitis Assessment of Disease Severity Modified Discriminant Function Score Model for End-Stage Liver Disease Score Child-Turcotte-Pugh Score Glasgow Alcoholic Hepatitis Score Age, Bilirubin Concentration, International Normalized Ratio, Creatinine Concentration Lille Score Comparison of Scoring Systems Liver Histology Emerging Scoring Systems Treatment of Severe Episodes of Alcoholic Hepatitis Corticosteroids Efficacy of Corticosteroids in Alcoholic Hepatitis Treatment Current Status of Corticosteroid Therapy in the Management of Alcoholic Hepatitis Mechanism of Action Use of Corticosteroids in Practice Contraindications for Corticosteroid Therapy Infections in Patients Receiving Corticosteroid Therapy Pentoxifylline Current Status of Pentoxifylline in the Treatment of Alcoholic Hepatitis Tumor Necrosis Factor α Inhibitors Antioxidants Hepatic Mitogens and Growth Factors Propylthiouracil Albumin Dialysis and Miscellaneous Therapies General Management Measures Management of Alcohol Withdrawal Management of Complications of Cirrhosis Management of Malnutrition Enteral Supplementation Parenteral Supplementation Alcohol Abstinence Behavioral Therapies Pharmacologic Therapies Emerging Pharmacologic Treatments Gut-Liver Axis Inflammatory Cascade Oxidative Stress Apoptosis and Liver Regeneration Liver Transplant in Alcoholic Hepatitis Controversy Surrounding Liver Transplant in Alcoholic Hepatitis Six Months’ Abstinence Rule Beneficial Efficacy of Early Liver Transplant in Alcoholic Hepatitis Selection Criteria and Impact on the Donor Pool Barriers to Liver Transplant in Alcoholic Hepatitis Treatment of Mild Episodes of Alcoholic Hepatitis Treatment of Alcoholic Cirrhosis Alcohol Abstinence and Monitoring Management of Cirrhosis and Its Complications Pharmacologic Treatments Antioxidants Propylthiouracil Colchicine Management of Malnutrition Enteral Supplementation Liver Transplant for Alcoholic Cirrhosis Alcohol Consumption and Dependence Evaluation for Comorbidities Psychosocial Evaluation Posttransplant Recidivism Graft and Patient Outcomes Conclusion References References 25 Pathogenesis of Nonalcoholic Fatty Liver Disease Abbreviations Introduction Making Foie Gras Nonalcoholic Fatty Liver Disease: An Adiposopathy Nonalcoholic Fatty Liver Disease and Insulin Resistance: The Chicken and Egg Paradox Oxidative Stress: Overburning Fat Lipotoxicity: The Ugly and the Beast Endoplasmic Reticulum Stress: A Tree Born Crooked Cannot Straighten Its Trunk Autophagy: The Ouroboros Housekeeper Sterile Inflammation: When the Aggressor Is Fat Dysbiota: The Unwanted Guests Cell Death: A Cry for Help Fibrogenesis: To Heal or to Scar Conclusion References References 26 Epidemiology, Natural History, and Evaluation of Nonalcoholic Fatty Liver Disease Abbreviations Introduction Epidemiology Prevalence Causes of and Conditions Associated With Nonalcoholic Fatty Liver Disease Natural History of Nonalcoholic Fatty Liver Disease Progression to Advanced Liver Fibrosis and Cirrhosis in Nonalcoholic Fatty Liver Disease Nonalcoholic Fatty Liver Disease and the Risk of Hepatocellular Carcinoma Modifiers of Progression of Nonalcoholic Fatty Liver Disease Environmental Modifiers of Nonalcoholic Fatty Liver Disease Genetic Modifiers of Nonalcoholic Fatty Liver Disease Clinical Features of Nonalcoholic Fatty Liver Disease Symptoms Signs on Physical Examination Routine Laboratory Abnormalities Histopathologic Features of Nonalcoholic Fatty Liver Disease Steatosis Steatohepatitis Fibrosis Grading and Staging of the Severity of Nonalcoholic Fatty Liver Disease in Clinical Practice Evaluation of Nonalcoholic Fatty Liver Disease Diagnostic Approach to Nonalcoholic Fatty Liver Disease Risk Stratification and Staging of Nonalcoholic Fatty Liver Disease References References 27 Management of Nonalcoholic Fatty Liver Disease and Metabolic Syndrome Abbreviations Introduction Associated Conditions Treatment Lifestyle Modifications Exercise Bariatric Surgery Phlebotomy Pharmacologic Treatment Insulin-Sensitizing Medications Antioxidants Cytoprotective Agents Statins Weight Loss Medications Novel Approaches Conclusion References References 28 Virology and Pathogenesis of Hepatitis C Abbreviations Introduction Overview of the Virion Model Systems Structure and Function of the Viral Proteins Hepatitis C Virus Struct