BOOK
Zakim and Boyer's Hepatology
Thomas D. Boyer | Arun J. Sanyal | Norah A Terrault | Keith D Lindor
(2016)
Additional Information
Book Details
Abstract
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.
- 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.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | cover | ||
| Expert Consult page | IFC1 | ||
| Zakim and Boyer's Hepatology | i | ||
| Copyright Page | iv | ||
| Contributors | v | ||
| Preface | xiii | ||
| Table Of Contents | xiv | ||
| I Basics | 1 | ||
| 1 Anatomy and Cellular Functions of the Liver | 2 | ||
| Abbreviations | 2 | ||
| Introduction | 2 | ||
| Gross Anatomy | 2 | ||
| Development of the Liver | 4 | ||
| Microscopic Architecture | 5 | ||
| Portal Tracts and the Biliary System | 5 | ||
| The Biliary Tree | 7 | ||
| Cholangiocytes | 8 | ||
| Peribiliary Glands | 9 | ||
| Portal Tract Mesenchyme | 9 | ||
| Lobular and Acinar Functional Units | 9 | ||
| Hepatocytes | 10 | ||
| Plasma Membrane | 10 | ||
| Nucleus | 11 | ||
| Endoplasmic Reticulum, Ribosomes, and Golgi Apparatus | 11 | ||
| Mitochondria | 12 | ||
| Lysosomes | 12 | ||
| Peroxisomes | 13 | ||
| Cytoplasmic Contents | 13 | ||
| Cytoskeleton and Cytomatrix | 13 | ||
| The Hepatic Sinusoid | 13 | ||
| Sinusoidal Endothelial Cells | 14 | ||
| Kupffer Cells | 16 | ||
| Stellate Cells | 16 | ||
| Liver-Associated Lymphocytes | 18 | ||
| Innervation | 18 | ||
| Heterogeneity | 18 | ||
| Conclusion | 19 | ||
| References | 19 | ||
| References | 19.e1 | ||
| 2 Bile Acids and Bile Flow | 20 | ||
| Abbrevations | 20 | ||
| Introduction | 20 | ||
| Pathways of Bile Acid Synthesis From Cholesterol | 20 | ||
| Bile Acid Conjugation | 24 | ||
| Formation of Secondary Bile Acids | 25 | ||
| Regulation of Bile Acid Synthesis | 25 | ||
| Defects in Bile Acid Synthesis Causing Metabolic Liver Disease and Syndromes of Fat-Soluble Vitamin Malabsorption | 26 | ||
| Defects Involving Reactions to the Steroid Nucleus | 26 | ||
| Cholesterol 7α-Hydroxylase Deficiency | 27 | ||
| Oxysterol 7α-Hydroxylase Deficiency | 27 | ||
| 3β-Hydroxy-Δ5 C27-Steroid Oxidoreductase Deficiency | 28 | ||
| Δ4-3-Oxosteroid 5β-Reductase (AKR1D1) Deficiency | 29 | ||
| Defects Involving Reactions Leading to Side Chain Modification | 31 | ||
| Sterol 27-Hydroxylase Deficiency: Cerebrotendinous Xanthomatosis | 31 | ||
| 2-Methylacyl CoA Racemase Deficiency | 32 | ||
| Side Chain Oxidation Defect in the 25-Hydroxylation Pathway | 32 | ||
| Peroxisomal Disorders | 32 | ||
| Bile Acid-CoA Conjugation Defects | 33 | ||
| Other Disorders Influencing Bile Acid Synthesis and Metabolism | 34 | ||
| Bile Acids as Signaling Integrators of Metabolism | 34 | ||
| Enterocyte Bile Acid Physiology | 34 | ||
| Muscle and Brown Adipose Tissue Metabolism | 35 | ||
| Bile Acid Changes After Bariatric Surgery | 35 | ||
| Bile Acid Signaling as a Treatment for Nonalcoholic Steatohepatitis | 35 | ||
| Conclusion | 36 | ||
| References | 36 | ||
| References | 36.e1 | ||
| 3 Intestinal Microbiome and the Liver | 37 | ||
| Abbreviations | 37 | ||
| Historical Perspective and Technology Development | 37 | ||
| General Principles and the Conceptual Construct: the Gut-Liver Axis in Homeostasis and Implications for Liver Diseases | 39 | ||
| Intestinal Barrier | 39 | ||
| How Does the Host Maintain Homeostasis With Continued Exposure to an Enormous Microbial Load? | 41 | ||
| Interactions of the Liver With the Intestinal Microbiome | 42 | ||
| How Is the Intestinal Microbiome Related to Liver Disease? | 42 | ||
| Mucosal and Liver Tolerance | 42 | ||
| Liver and Pattern Recognition Receptors | 43 | ||
| Microbiota, Hepatic Inflammation, and Fibrosis | 44 | ||
| The Intestinal Microbiota as a Mediator of Hepatic Inflammation | 45 | ||
| The Intestinal Microbiota as a Mediator of Hepatic Fibrosis | 46 | ||
| Germ-Free Models: Implications for the Intestinal Microbiome, the Intestine, and the Liver | 47 | ||
| Role of the Intestinal Microbiome in Specific Liver Diseases | 47 | ||
| Obesity and the Intestinal Microbiome | 47 | ||
| The Intestinal Microbiome and Nonalcoholic Fatty Liver Disease | 47 | ||
| Human Studies | 48 | ||
| Functional and Mechanistic Insights From the Intestinal Microbiome in NAFLD | 50 | ||
| The Intestinal Microbiome and Alcoholic Liver Disease | 53 | ||
| Intestinal Dysbiosis in Alcoholic Liver Disease | 53 | ||
| Corollaries of Intestinal Dysbiosis in Alcoholic Liver Disease | 54 | ||
| The Intestinal Microbiome and Autoimmune Liver Diseases | 55 | ||
| Primary Sclerosing Cholangitis and the Intestinal Microbiome | 56 | ||
| Autoimmune Hepatitis and the Intestinal Microbiome | 56 | ||
| The Intestinal Microbiome in Cirrhosis and Associated Complications | 56 | ||
| Intestinal Dysbiosis in Experimental Fibrosis and Cirrhosis | 56 | ||
| Intestinal Dysbiosis and Cirrhosis in Clinical Practice | 57 | ||
| Clinical and Metabolic Corollaries of Intestinal Dysbiosis in Cirrhosis | 59 | ||
| The Intestinal Microbiome and Hepatocellular Carcinoma | 60 | ||
| The Intestinal Microbiome and Liver Transplant | 61 | ||
| The Intestinal Microbiome and Liver Regeneration | 62 | ||
| Interventions to Modulate the Intestinal Microbiome | 62 | ||
| Conclusion | 65 | ||
| References | 65 | ||
| References | 65.e1 | ||
| 4 The Liver as an Immune Organ | 66 | ||
| Abbreviations | 66 | ||
| Introduction | 66 | ||
| Immune Cell Populations and Their Function in the Liver | 66 | ||
| Neutrophils | 66 | ||
| Monocytes and Macrophages | 66 | ||
| Dendritic Cells | 68 | ||
| Natural Killer Cells and Natural Killer T Cells | 69 | ||
| T-Cell Populations | 69 | ||
| B Cells | 69 | ||
| Functions of the Immune System in the Liver | 69 | ||
| Innate Immunity | 69 | ||
| Pattern Recognition Receptors | 69 | ||
| Chemokines, Cytokines, and Interferons | 71 | ||
| Antigen Presentation and Adaptive Immunity | 71 | ||
| Inflammation and Innate Immunity in Liver Diseases | 72 | ||
| Immune Response in Viral Hepatitis | 72 | ||
| Hepatitis C Virus | 73 | ||
| Hepatitis B Virus | 74 | ||
| Hepatitis D Virus | 74 | ||
| Hepatitis A Virus and Hepatitis E Virus | 74 | ||
| Autoimmunity in Liver Diseases | 75 | ||
| Liver Fibrosis and Immune Response | 75 | ||
| Inflammation and Immunity in Liver Cancer | 75 | ||
| Conclusion | 76 | ||
| References | 76 | ||
| References | 76.e1 | ||
| 5 The Liver’s Response to Injury | 77 | ||
| Abbreviations | 77 | ||
| Introduction | 77 | ||
| Hepatic Inflammation as a Driver of Hepatic Fibrosis | 77 | ||
| Cell Types That Participate in Inflammation and Fibrosis | 78 | ||
| Hepatocytes | 78 | ||
| Hepatic Stellate Cells | 78 | ||
| Macrophages | 80 | ||
| Natural Killer Cells and Natural Killer T Cells | 80 | ||
| T and B Lymphocytes | 81 | ||
| Key Pathways in Hepatic Inflammation and Fibrosis | 81 | ||
| Cell Death–Triggered Inflammation and Fibrosis | 81 | ||
| Toll-like Receptor Pathway | 81 | ||
| Chemokines in Liver Inflammation and Fibrosis | 82 | ||
| MicroRNAs in Hepatic Inflammation and Fibrosis | 82 | ||
| MicroRNAs as Modulators of Liver Inflammation | 82 | ||
| MicroRNAs as Modulators of Liver Fibrosis | 83 | ||
| Conclusion | 83 | ||
| References | 83 | ||
| References | 83.e1 | ||
| 6 Stem Cells and Hepatocyte Transplantation | 84 | ||
| Abbreviations | 84 | ||
| Introduction | 84 | ||
| Preclinical and Background Studies Enabling Clinical Translation | 86 | ||
| Integration of Hepatocytes in the Recipient’s Liver | 86 | ||
| Occlusion of the Portal Veins With Donor Cells | 86 | ||
| Breeching the Endothelial Barrier | 87 | ||
| Integration Into Hepatic Chords | 87 | ||
| Remodeling of Liver | 87 | ||
| Initial Clinical Studies | 87 | ||
| Hepatocyte Transplantation for Acute Liver Failure | 88 | ||
| Hepatocyte Transplantation for Metabolic Liver Disease | 89 | ||
| Patient Selection for Hepatocyte Transplantation | 90 | ||
| Challenges and Solutions Regarding Hepatocyte Transplantation | 91 | ||
| Sources of Hepatocytes and Hepatocyte-Like Cells | 91 | ||
| Identifying the Correct Niche Signals for Hepatocytes | 92 | ||
| Alternative Sources of Hepatocytes | 92 | ||
| Embryonic Stem Cells | 92 | ||
| Induced Pluripotent Stem Cells | 92 | ||
| Directly Reprogrammed Hepatocyte-Like Cells | 93 | ||
| Adult Hepatic Progenitor Cells | 93 | ||
| Organoid Culture of Hepatocyte Cells | 93 | ||
| Assessment of Hepatic Viability and Function Before Transplant | 94 | ||
| Methods for Storage of Cells After Isolation and Before Transplant | 94 | ||
| Tracking Donor Cells and Assessment of Cell Function After Transplant | 94 | ||
| Optimal Immunosuppressive Therapy | 95 | ||
| Engraftment and Long-Term Repopulation of Recipient Liver With Donor Cells | 95 | ||
| Conclusion | 97 | ||
| References | 97 | ||
| References | 97.e1 | ||
| II Management and Assessment of Liver Disease | 98 | ||
| 7 Approach to Jaundice and Abnormal Liver Function Test Results | 99 | ||
| Abbreviations | 99 | ||
| Introduction | 99 | ||
| Historical Perspective: 100 Years of Liver Function Tests | 99 | ||
| Liver Functions Tests: Anatomic, Physiologic, and Pathologic Basis | 100 | ||
| Tests That Assess the Function of Biliary Organic Anion Transport | 100 | ||
| Bilirubin | 100 | ||
| Urinary Bilirubin and Urobilinogen | 101 | ||
| Bile Acids | 101 | ||
| Tests That Assess Hepatobiliary Injury | 102 | ||
| Aminotransferases | 102 | ||
| Alkaline Phosphatase | 103 | ||
| γ-Glutamyl Transpeptidase | 104 | ||
| Other Enzymes | 104 | ||
| Tests That Assess Hepatic Synthetic Function | 104 | ||
| Albumin | 104 | ||
| Prothrombin Time and International Normalized Ratio | 104 | ||
| Clinical Approach to Abnormal Liver Function Test Results | 105 | ||
| Epidemiology and Outcome of Liver Function Tests With Abnormal Results | 105 | ||
| When and Whom to Evaluate Further | 105 | ||
| Normal Reference Range and Definition of Abnormal Liver Enzyme Levels | 105 | ||
| Establishing Abnormal Results | 105 | ||
| Identification of Pattern of Abnormalities: A Clue to the Underlying Cause | 106 | ||
| Cholestatic and Hepatocellular Injury | 106 | ||
| Jaundice | 109 | ||
| Acute-on-Chronic Liver Function Test Abnormalities | 109 | ||
| Liver Function Test Results and Severity of Liver Injury: An Association | 110 | ||
| Estimation of Fibrosis Based on Mathematical Scores | 110 | ||
| Noninvasive Biomarkers of Fibrosis | 111 | ||
| Isolated Biomarkers | 111 | ||
| Fibrosis Biomarker Panels | 111 | ||
| Correlations Between Liver Function Test Results and Clinical Features | 111 | ||
| Patients With Abnormal Liver Function Test Results: What to Ask and Assess | 113 | ||
| Clinical Examination: What to Look for | 114 | ||
| Signs of Chronic Liver Disease | 114 | ||
| Signs of Underlying Cause | 115 | ||
| Clinical Signs of Portal Hypertension | 115 | ||
| Clinical Signs of Hepatic Insufficiency (Liver Failure) | 115 | ||
| Further Testing: Which Tests, as Well as When to Perform Them and What to Look for | 115 | ||
| Laboratory Tests | 115 | ||
| Imaging | 115 | ||
| Liver Biopsy | 116 | ||
| When a Diagnosis Is Not Established: How to Monitor Patients | 116 | ||
| Conclusion | 116 | ||
| References | 116 | ||
| References | 116.e1 | ||
| 8 Noninvasive Assessment of Disease Progression | 117 | ||
| Abbreviations | 117 | ||
| Introduction | 117 | ||
| The Value and Meaning of Fibrosis Staging and the Role of Liver Biopsies | 117 | ||
| Approach to Noninvasive Testing | 118 | ||
| Pathophysiology of Common Serologic Tests for Liver Fibrosis | 118 | ||
| AST/ALT Ratio | 118 | ||
| AST/Platelet Ratio and Fibrosis-4 Indexes | 118 | ||
| Nonalcoholic Fatty Liver Disease Fibrosis Score | 119 | ||
| FibroMeter | 119 | ||
| FibroSure/FibroTest | 120 | ||
| HepaScore | 120 | ||
| FibroSpect | 120 | ||
| Enhanced Liver Fibrosis Score | 120 | ||
| Radiologic Tests for Liver Fibrosis | 120 | ||
| Ultrasound | 120 | ||
| Computed Tomography and Magnetic Resonance Imaging | 121 | ||
| Vibration-Controlled Elastography | 121 | ||
| Magnetic Resonance Elastography | 122 | ||
| Acoustic Radiation Force Impulse Elastography | 122 | ||
| Disease-Specific Considerations | 122 | ||
| Hepatitis C | 122 | ||
| Hepatitis B | 124 | ||
| Nonalcoholic Fatty Liver Disease | 124 | ||
| Cholestatic Diseases | 125 | ||
| Alcoholic Liver Disease | 126 | ||
| Other Liver Diseases | 126 | ||
| Conclusion | 126 | ||
| References | 126 | ||
| References | 126.e1 | ||
| 9 Molecular and Genetics-Based Diagnostics | 127 | ||
| Abbreviations | 127 | ||
| Introduction | 127 | ||
| Monogenic Liver Diseases | 127 | ||
| Hereditary Hemochromatosis | 127 | ||
| Wilson Disease | 127 | ||
| α1-Antitrypsin Deficiency | 128 | ||
| Cystic Fibrosis–Associated Liver Disease | 129 | ||
| Familial Intrahepatic Cholestasis | 129 | ||
| Hereditary Hyperbilirubinemias | 131 | ||
| Polygenic Liver Diseases | 131 | ||
| Intrahepatic Cholestasis of Pregnancy as Example | 131 | ||
| Gallstone Disease | 132 | ||
| Common ABC Transporter Risk Variants | 132 | ||
| Drug-Induced Liver Injury | 132 | ||
| Chronic Viral Hepatitis | 133 | ||
| Fatty Liver Disease | 134 | ||
| Liver Cirrhosis | 134 | ||
| Next-Generation Sequencing | 134 | ||
| References | 135 | ||
| References | 135.e1 | ||
| 10 Imaging in Assessment of Liver Disease and Lesions | 136 | ||
| Abbreviations | 136 | ||
| Introduction | 136 | ||
| Diffuse Liver Disease | 136 | ||
| Active Inflammation | 136 | ||
| Chronic Hepatitis and Cirrhosis | 136 | ||
| Focal Hepatic Lesions | 140 | ||
| Imaging Modalities | 140 | ||
| Ultrasound | 140 | ||
| Computed Tomography | 140 | ||
| Magnetic Resonance Imaging | 142 | ||
| Hepatobiliary-Specific Contrast Agents | 142 | ||
| Benign Lesions | 142 | ||
| Solid | 142 | ||
| Hemangioma | 142 | ||
| Imaging | 142 | ||
| Focal Nodular Hyperplasia | 143 | ||
| Imaging | 143 | ||
| Liver Cell Adenoma | 143 | ||
| Imaging | 145 | ||
| Cystic | 147 | ||
| Cystic Bile Duct Hamartoma | 147 | ||
| III Clinical Consequences of Chronic Liver Disease | 202 | ||
| 14 Neurologic Consequences of Liver Disease | 203 | ||
| Abbreviations | 203 | ||
| Introduction | 203 | ||
| Historical Background | 203 | ||
| Pathogenesis of Hepatic Encephalopathy | 203 | ||
| Ammonia | 203 | ||
| Inflammation | 204 | ||
| Microbiota | 204 | ||
| Neuromodulators | 204 | ||
| Manganese Deposition | 204 | ||
| Spectrum and Nomenclature of Hepatic Encephalopathy | 205 | ||
| Spectrum of Neurocognitive Impairment in Cirrhosis | 205 | ||
| Importance of Hepatic Encephalopathy | 206 | ||
| Overt Hepatic Encephalopathy | 206 | ||
| Covert Hepatic Encephalopathy | 206 | ||
| Diagnosis of Hepatic Encephalopathy | 206 | ||
| Diagnosis of Overt Hepatic Encephalopathy | 207 | ||
| Physical Examination in Patients With Overt Hepatic Encephalopathy | 207 | ||
| Brain Imaging for the Diagnosis of Hepatic Encephalopathy | 207 | ||
| Abdominal Imaging | 207 | ||
| Miscellaneous Imaging | 208 | ||
| Ammonia Levels for the Diagnosis of Overt Hepatic Encephalopathy | 208 | ||
| Clinical Classification of Hepatic Encephalopathy Into Normal and Overt Hepatic Encephalopathy | 208 | ||
| Diagnosis of Covert Hepatic Encephalopathy | 208 | ||
| Neuropsychological Examination and Psychometric Testing for the Diagnosis of Covert Hepatic Encephalopathy | 208 | ||
| Paper and Pencil Tests | 208 | ||
| Neurophysiologic Tests | 209 | ||
| Limitations of Currently Available Psychometric and Neurophysiologic Tests | 210 | ||
| Computerized Tests | 210 | ||
| Management and Treatment of Hepatic Encephalopathy | 210 | ||
| Goals for the Management of Hepatic Encephalopathy | 210 | ||
| Nonabsorbable Disaccharides | 212 | ||
| Antibiotics | 212 | ||
| Neomycin | 212 | ||
| Rifaximin | 212 | ||
| Metronidazole, Vancomycin, and Paromomycin | 212 | ||
| Probiotics | 213 | ||
| Management of Acute Overt Hepatic Encephalopathy | 213 | ||
| Nonabsorbable Disaccharides | 213 | ||
| Antibiotics | 214 | ||
| Neomycin | 214 | ||
| Rifaximin | 214 | ||
| Probiotics | 214 | ||
| Management of Covert Hepatic Encephalopathy | 214 | ||
| Nonabsorbable Disaccharides | 215 | ||
| Antibiotics | 215 | ||
| Probiotics | 215 | ||
| Secondary Prevention of Overt Hepatic Encephalopathy | 216 | ||
| Other Therapies | 216 | ||
| l-Ornithine-l-Aspartate | 216 | ||
| Sodium Benzoate | 216 | ||
| l-Orthinine Phenylacetate and Glycerol Phenylbutyrate | 216 | ||
| Flumazenil | 216 | ||
| Branched-Chain Amino Acid–Enriched Formulations | 216 | ||
| Dopaminergic Agents | 216 | ||
| Zinc Repletion | 217 | ||
| Disaccharidase Inhibitors | 217 | ||
| Albumin | 217 | ||
| Newer Agents | 217 | ||
| Hepatic Encephalopathy Resistant to Therapy or Persistent Hepatic Encephalopathy | 217 | ||
| Liver Support Systems | 218 | ||
| Closure of Portosystemic Shunts | 218 | ||
| Nutrition | 218 | ||
| Liver Transplantation | 218 | ||
| References | 219 | ||
| References | 219.e1 | ||
| 15 Ascites and Hyponatremia | 220 | ||
| Abbreviations | 220 | ||
| Introduction | 220 | ||
| Epidemiology | 220 | ||
| Pathogenesis | 220 | ||
| Sinusoidal Hypertension | 220 | ||
| Plasma Volume Expansion | 220 | ||
| Clinical Features | 221 | ||
| Diagnosis | 221 | ||
| Differential Diagnosis | 222 | ||
| Associated Conditions | 224 | ||
| Disease Complication: Spontaneous Bacterial Peritonitis | 224 | ||
| Epidemiology | 224 | ||
| Clinical Picture | 224 | ||
| Diagnosis | 224 | ||
| Treatment | 225 | ||
| Prophylaxis | 226 | ||
| Treatment of Ascites | 227 | ||
| Sodium Restriction | 227 | ||
| Diuretics | 228 | ||
| Complications | 228 | ||
| Contraindications | 228 | ||
| Large-Volume Paracentesis | 228 | ||
| Complications | 229 | ||
| Contraindications | 229 | ||
| Transjugular Intrahepatic Portosystemic Shunt | 229 | ||
| Complications | 230 | ||
| Contraindications | 230 | ||
| Peritoneovenous Shunt and Other Shunting Devices | 230 | ||
| Treatment of Conditions Associated With Ascites | 230 | ||
| Treatment of Hyponatremia | 230 | ||
| Treatment of Hepatic Hydrothorax | 231 | ||
| Prognosis and Natural History | 231 | ||
| Conclusion | 232 | ||
| References | 232 | ||
| References | 232.e1 | ||
| 16 Portal Hypertension Related to Bleeding | 233 | ||
| Abbreviations | 233 | ||
| Anatomy of the Portal Venous System | 233 | ||
| Physiologic Principles of the Portal Circulation | 233 | ||
| Portal Hypertension | 234 | ||
| Definition | 234 | ||
| Pathogenesis of Portal Hypertension | 234 | ||
| Physiologic Principles of Portal Hypertension | 234 | ||
| Increased Intrahepatic Resistance | 235 | ||
| Increased Splanchnic Blood Flow and the Hyperdynamic Circulatory State | 236 | ||
| Portosystemic Collateral Circulation in Portal Hypertension | 237 | ||
| Clinical Features of Portal Hypertension | 238 | ||
| Portosystemic Collaterals | 238 | ||
| Splenomegaly | 239 | ||
| Assessment of Portal Venous System | 239 | ||
| Upper Gastrointestinal Endoscopy | 239 | ||
| Capsule Endoscopy | 241 | ||
| CT Scan | 241 | ||
| Magnetic Resonance Imaging | 241 | ||
| Ultrasonography | 242 | ||
| Endoscopic Ultrasound | 242 | ||
| Ultrasound Transient Elastography | 242 | ||
| Ultrasound Real-Time Shear Wave Elastography | 242 | ||
| Measurement of Portal Venous Pressure | 243 | ||
| Hepatic Vein Pressure Gradient Measurement | 243 | ||
| Direct Transhepatic Portal Venous Pressure Measurement | 243 | ||
| Measurement of Variceal Pressure and Flow | 244 | ||
| Measurement of Portal Venous and Hepatic Artery Blood Flow | 244 | ||
| Classification of Diseases Causing Portal Hypertension | 244 | ||
| Portal Hypertension Secondary to Increased Portal Venous Blood Flow | 244 | ||
| Splanchnic Arteriovenous Fistula | 244 | ||
| Splenomegaly | 244 | ||
| Portal Hypertension Secondary to Increased Resistance to Portal Blood Flow | 245 | ||
| Extrahepatic Portal Vein Thrombosis | 245 | ||
| Idiopathic Portal Hypertension | 245 | ||
| Schistosomiasis | 246 | ||
| Alcoholic Liver Disease | 246 | ||
| Nonalcoholic Cirrhosis | 247 | ||
| Fibrocystic Liver Disease | 247 | ||
| Nodular Regenerative Hyperplasia of the Liver | 247 | ||
| Partial Nodular Transformation of the Liver | 247 | ||
| Hematologic Disease | 248 | ||
| Hepatocellular Carcinoma | 248 | ||
| Metastatic Carcinoma to the Liver | 248 | ||
| Hereditary Hemorrhagic Telangiectasia | 248 | ||
| Sarcoidosis | 248 | ||
| Cystic Fibrosis | 248 | ||
| Cardiac Disease | 248 | ||
| Portal Hypertension–Related Bleeding | 248 | ||
| Selection of Patients to Screen for Esophageal Varices | 248 | ||
| Risk Factors and Natural History of Portal Hypertension–Related Bleeding | 248 | ||
| Portal Hypertensive Gastropathy and Gastric Vascular Ectasia | 249 | ||
| Bleeding From Other Sites in the Gastrointestinal Tract | 250 | ||
| Diagnosis of Portal Hypertension–Related Bleeding | 250 | ||
| Treatment Options for Portal Hypertension–Related Bleeding | 251 | ||
| Pharmacologic Treatment | 251 | ||
| Vasopressin Analogs | 251 | ||
| Somatostatin Analogs | 251 | ||
| β-Adrenergic Blocking Drugs | 251 | ||
| Combined α- and β-Adrenergic Blockers | 252 | ||
| Nitrates | 252 | ||
| Drugs That Decrease Intrahepatic Vascular Resistance | 252 | ||
| Endoscopic Therapy | 252 | ||
| Sclerotherapy | 252 | ||
| Endoscopic Variceal Ligation | 253 | ||
| Cyanoacrylate Glue Injection | 253 | ||
| Detachable Snares and Clips | 253 | ||
| Radiologic Procedures | 254 | ||
| Transjugular Intrahepatic Portosystemic Shunts (TIPS) | 254 | ||
| Balloon-Occluded Retrograde Transvenous Obliteration of Varices (BRTO) | 254 | ||
| Balloon Tamponade | 254 | ||
| Esophageal Stents | 254 | ||
| Surgical Management of Portal Hypertension | 255 | ||
| Decompressive Shunts | 255 | ||
| Portocaval Shunts | 255 | ||
| Selective Shunts | 255 | ||
| Partial Portosystemic Shunts | 255 | ||
| Mensenterico–Portal Venous Bypass | 255 | ||
| Approach to the Patient With Portal Hypertension–Related Bleeding | 255 | ||
| Esophageal Variceal Bleeding | 255 | ||
| Preprimary Prophylaxis of Variceal Bleeding | 255 | ||
| Primary Prophylaxis: Prevention of First Variceal Bleed | 257 | ||
| Small Esophageal Varices. | 257 | ||
| Large Esophageal Varices. | 257 | ||
| Control of Acute Esophageal Variceal Bleeding | 257 | ||
| General Measures | 257 | ||
| Specific Measures | 258 | ||
| Secondary Prophylaxis: Prevention of Recurrent Esophageal Variceal Bleeding | 259 | ||
| Gastric Varices | 259 | ||
| Portal Hypertensive Gastropathy and Gastric Vascular Ectasia | 260 | ||
| Ectopic Varices | 261 | ||
| Conclusion | 261 | ||
| References | 261 | ||
| References | 261.e1 | ||
| 17 Renal Failure in Cirrhosis | 262 | ||
| Abbreviations | 262 | ||
| Introduction | 262 | ||
| Measurement of Renal Function | 262 | ||
| The Concept of Acute Kidney Injury | 262 | ||
| The RIFLE Diagnostic Criteria for Acute Kidney Injury | 263 | ||
| The Acute Kidney Injury Network (AKIN) Diagnostic Criteria for Acute Kidney Injury | 264 | ||
| The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines | 264 | ||
| The Diagnostic Criteria of the ADQI and the International Ascites Club (IAC) for Acute Kidney Injury in Cirrhosis | 264 | ||
| The Application of the Various AKI Diagnostic Criteria to Cirrhotic Patients | 265 | ||
| The RIFLE Diagnostic Criteria | 265 | ||
| The AKIN Diagnostic Criteria | 266 | ||
| The ADQI-IAC Diagnostic Criteria for Acute Kidney Injury | 266 | ||
| How Well Do These Various Diagnostic Criteria of AKI Serve Cirrhotic Patients? | 267 | ||
| Revised Consensus Recommendations of the IAC on the Diagnosis of Acute Kidney Injury in Cirrhosis | 267 | ||
| The Diagnostic Criteria for Hepatorenal Syndrome | 268 | ||
| Pathophysiology of Acute Kidney Injury and Hepatorenal Syndrome | 269 | ||
| Splanchnic and Systemic Arterial Vasodilatation of Advanced Cirrhosis and Ascites | 269 | ||
| The Consequences of Splanchnic and Systemic Arterial Vasodilatation | 270 | ||
| The Role of Portal Hypertension Independent of Hemodynamic Changes | 271 | ||
| Renal Changes in Advanced Cirrhosis | 271 | ||
| Cardiac Insufficiency | 271 | ||
| The Role of Inflammation | 271 | ||
| Approach to a Patient With Cirrhosis Who Presents With Renal Dysfunction | 272 | ||
| Differential Diagnoses of Acute Kidney Injury | 273 | ||
| Prerenal Azotemia | 273 | ||
| Intrinsic Renal Diseases | 273 | ||
| Non–Volume Responsive Functional Acute Kidney Injury Including Hepatorenal Syndrome | 274 | ||
| Treatment of AKI | 274 | ||
| General Measures | 274 | ||
| Albumin | 275 | ||
| Vasoconstrictors | 275 | ||
| Terlipressin | 275 | ||
| Norepinephrine | 276 | ||
| Midodrine | 277 | ||
| Nonpharmacologic Treatments | 278 | ||
| Liver Transplant | 278 | ||
| Prevention of Hepatorenal Syndrome–Acute Kidney Injury | 278 | ||
| The Use of Albumin in Patients With Bacterial Infection | 278 | ||
| Antibiotic Prophylaxis Against Infection | 279 | ||
| Patients With Alcoholic Hepatitis | 279 | ||
| Prophylaxis Against Circulatory Dysfunction | 279 | ||
| Avoidance of Nephrotoxic Drugs | 279 | ||
| Judicious Use of Diuretics | 279 | ||
| Chronic Kidney Disease in Cirrhosis | 280 | ||
| Conclusion | 280 | ||
| References | 280 | ||
| References | 280.e1 | ||
| 18 Cardiopulmonary Complications of Cirrhosis | 281 | ||
| Abbreviations | 281 | ||
| Introduction | 281 | ||
| Definition and Diagnosis of Cirrhotic Cardiomyopathy | 281 | ||
| Electrocardiography | 281 | ||
| Echocardiography | 281 | ||
| Tissue Doppler Imaging | 282 | ||
| Stress Testing | 282 | ||
| Serologic Markers | 282 | ||
| Natural History and Epidemiology | 282 | ||
| Pathogenesis of Cirrhotic Cardiomyopathy | 282 | ||
| Cardiomyocyte Membrane Alterations | 282 | ||
| Nitric Oxide and Carbon Monoxide Alterations | 282 | ||
| Inflammatory Mediators: Tumor Necrosis Factor α Signaling and Endocannabinoids | 282 | ||
| Clinical Features | 282 | ||
| Management of Cirrhotic Cardiomyopathy | 283 | ||
| Pulmonary Vascular Complications in Liver Disease | 284 | ||
| The Spectrum of Pulmonary Abnormalities in Liver Disease | 284 | ||
| Hepatopulmonary Syndrome | 284 | ||
| Definition | 284 | ||
| Epidemiology | 284 | ||
| Pathogenesis | 284 | ||
| Clinical Features | 286 | ||
| Diagnosis | 286 | ||
| Therapy | 288 | ||
| Prognosis and Natural History | 289 | ||
| Portopulmonary Hypertension | 289 | ||
| Definition | 289 | ||
| Epidemiology | 289 | ||
| Pathogenesis | 290 | ||
| Clinical Features | 290 | ||
| Diagnosis | 290 | ||
| Treatment | 290 | ||
| Liver Transplant | 291 | ||
| Prognosis and Natural History | 292 | ||
| Coexistence of Hepatopulmonary Syndrome and Portopulmonary Hypertension | 292 | ||
| Conclusion | 292 | ||
| References | 292 | ||
| References | 292.e1 | ||
| 19 The Hemostatic and Hematopoietic System in Liver Disease | 293 | ||
| Abbreviations | 293 | ||
| Introduction | 293 | ||
| The Hemostatic System: Normal Physiology and Pathophysiology in Liver Disease | 293 | ||
| Bleeding in Cirrhosis Patients | 295 | ||
| Epidemiology | 295 | ||
| Therapy | 295 | ||
| Thrombosis in Cirrhosis Patients | 297 | ||
| Epidemiology | 297 | ||
| Therapy | 297 | ||
| Other Abnormalities in the Hematopoietic System in Liver Disease | 298 | ||
| Erythrocytes | 298 | ||
| Platelets | 299 | ||
| Leukocytes | 299 | ||
| Conclusion | 299 | ||
| References | 300 | ||
| References | 300.e1 | ||
| 20 Acute Liver Failure | 301 | ||
| Abbreviations | 301 | ||
| Introduction | 301 | ||
| Causes and Epidemiology | 301 | ||
| Hepatotropic Viruses | 303 | ||
| Hepatitis A | 303 | ||
| Hepatitis B | 304 | ||
| Hepatitis D | 304 | ||
| Hepatitis C | 304 | ||
| Hepatitis E | 304 | ||
| Non–Hepatitis A-E Viruses | 304 | ||
| Systemic Viral Infections | 304 | ||
| Drug-Induced Acute Liver Failure | 305 | ||
| Acetaminophen | 305 | ||
| Biologic Toxins | 307 | ||
| Metabolic Causes of Acute Liver Failure | 308 | ||
| Autoimmune Acute Liver Failure | 308 | ||
| Ischemic Causes of Acute Liver Failure | 308 | ||
| Diffuse Malignant Infiltration of the Liver | 308 | ||
| Pathogenesis of the Syndrome of Acute Liver Failure | 308 | ||
| Early Presentation of the Acute Injury | 308 | ||
| Failure of Liver Function | 309 | ||
| Failure of Hepatobiliary Excretion | 309 | ||
| Failure to Metabolize Toxic Substances | 309 | ||
| Failure of Intermediary Metabolism | 309 | ||
| Failure of Biosynthetic Function of the Liver | 309 | ||
| Effects of Acute Liver Failure on Extrahepatic Systems | 309 | ||
| Microcirculatory Dysfunction | 310 | ||
| Cardiovascular Consequences | 310 | ||
| Pulmonary Consequences | 310 | ||
| Renal and Electrolyte Disturbances | 311 | ||
| Hematologic Disturbances | 311 | ||
| Breakdown of Host Immune Defenses | 311 | ||
| Gastrointestinal Consequences | 312 | ||
| Neurologic Consequences | 312 | ||
| Hepatic Encephalopathy | 313 | ||
| Intracranial Hypertension and Cerebral Edema | 313 | ||
| Management of Acute Liver Failure | 314 | ||
| General Management | 314 | ||
| Initial Evaluation and Triage | 314 | ||
| Therapies for Liver Injury | 314 | ||
| N-Acetylcysteine for Acetaminophen Overdose | 314 | ||
| N-Acetylcysteine for Nonacetaminophen Acute Liver Failure | 316 | ||
| Other Cause-Specific Therapies | 316 | ||
| Management of Fluids, Electrolytes, and Acid-Base Abnormalities | 316 | ||
| Management of Nutrition | 317 | ||
| Prevention and Management of Specific Complications of Acute Liver Failure | 317 | ||
| Bleeding | 317 | ||
| Cardiovascular Derangements | 317 | ||
| Pulmonary Complications and Ventilatory Support | 317 | ||
| Prevention and Management of Infection | 318 | ||
| Management of Acute Kidney Injury | 318 | ||
| Multiorgan System Failure | 319 | ||
| Hepatic Encephalopathy, Cerebral Edema, and Intracranial Hypertension | 319 | ||
| Methods to Protect the Liver From Injury and Promote Liver Regeneration | 321 | ||
| Orthotopic Liver Transplantation | 321 | ||
| Assessment of Prognosis: When to Initiate Orthotopic Liver Transplantation Evaluation | 322 | ||
| References | 323 | ||
| References | 323.e1 | ||
| 21 Acute-on-Chronic Liver Failure | 324 | ||
| Abbreviations | 324 | ||
| Introduction | 324 | ||
| Definition | 324 | ||
| Precipitating Events | 325 | ||
| Prevalence | 326 | ||
| Natural History | 326 | ||
| Economic Burden | 326 | ||
| Pathophysiology | 326 | ||
| Extrahepatic Organ Failure | 327 | ||
| Renal Failure | 329 | ||
| Hepatic Encephalopathy | 329 | ||
| Cardiovascular Dysfunction | 329 | ||
| Respiratory Failure | 329 | ||
| Coagulation Dysfunction | 329 | ||
| Prognostic Models | 330 | ||
| Potential Prognostic Biomarkers | 330 | ||
| Management of ACLF | 330 | ||
| General Measures | 330 | ||
| Liver Support Devices | 331 | ||
| Potential Hepatic Regenerative Therapy | 331 | ||
| Liver Transplantation | 331 | ||
| Conclusion | 332 | ||
| References | 332 | ||
| References | 332.e1 | ||
| IV Specific Diseases | 333 | ||
| 22 Epidemiology and Pathogenesis of Alcoholic Liver Disease | 334 | ||
| Abbreviations | 334 | ||
| Introduction | 334 | ||
| Epidemiology of Alcoholic Liver Disease | 335 | ||
| Ethanol Metabolism | 335 | ||
| Alcoholic Fatty Liver | 337 | ||
| Alcoholic Steatohepatitis | 338 | ||
| Infiltration of Neutrophils | 338 | ||
| Activation of Kupffer Cells and Infiltrating Macrophages | 339 | ||
| Activation of Natural Killer T Cells | 339 | ||
| Activation of Adaptive Immunity | 339 | ||
| Inflammatory Mediators (Cytokines and Chemokines) | 339 | ||
| Alcoholic Hepatitis | 339 | ||
| Alcoholic Fibrosis and Cirrhosis | 340 | ||
| Alcoholic Liver Cancer | 341 | ||
| Risk Factors for Alcoholic Liver Disease | 341 | ||
| Animal Models of Alcoholic Liver Disease | 341 | ||
| Chronic Ethanol Feeding | 341 | ||
| “Second-Hit” Model | 341 | ||
| Chronic-Plus-Binge Ethanol Feeding | 342 | ||
| High-Fat Diet (HFD) and Ethanol Feeding | 342 | ||
| Comorbid Conditions | 343 | ||
| Therapeutic Targets | 343 | ||
| Conclusion | 344 | ||
| References | 344 | ||
| References | 344.e1 | ||
| 23 Natural History and Cofactors of Alcoholic Liver Disease | 345 | ||
| Abbreviations | 345 | ||
| Introduction | 345 | ||
| Pattern, Dosage, and Types of Alcohol Consumption and Risk of Alcoholic Liver Disease | 345 | ||
| Sex | 346 | ||
| Dietary Factors and Risk of Alcoholic Liver Disease | 346 | ||
| Genetic Risk Factors for Alcoholic Liver Disease | 346 | ||
| Genes Influencing Alcohol Metabolism | 346 | ||
| Cytokine-Related Genes and Endotoxin Receptor | 347 | ||
| PNPLA3 and Alcoholic Liver Disease | 347 | ||
| Oxidative Stress–Related Genes | 347 | ||
| Natural History of Alcoholic Liver Disease | 347 | ||
| Alcoholic Fatty Liver | 347 | ||
| Alcoholic Hepatitis | 348 | ||
| Alcoholic Cirrhosis | 348 | ||
| Special Considerations for Factors Influencing the Natural History of Alcoholic Liver Disease | 348 | ||
| Hepatitis C | 348 | ||
| Hepatitis B | 349 | ||
| Obesity and Nonalcoholic Fatty Liver Disease | 349 | ||
| Toxicity of Acetaminophen and Other Drugs | 349 | ||
| Obstructive Sleep Apnea | 349 | ||
| Conclusion | 350 | ||
| References | 350 | ||
| References | 350.e1 | ||
| 24 Prevention and Management of Alcoholic Liver Disease | 351 | ||
| Abbreviations | 351 | ||
| Prevention of Alcoholic Liver Disease | 351 | ||
| Primary Prevention | 351 | ||
| Secondary Prevention | 351 | ||
| Screening for Alcohol Consumption | 351 | ||
| Tertiary Prevention | 352 | ||
| Treatment of Alcoholic Liver Disease | 352 | ||
| Diagnosis of Alcoholic Hepatitis | 352 | ||
| Assessment of Disease Severity | 353 | ||
| Modified Discriminant Function Score | 353 | ||
| Model for End-Stage Liver Disease Score | 354 | ||
| Child-Turcotte-Pugh Score | 354 | ||
| Glasgow Alcoholic Hepatitis Score | 354 | ||
| Age, Bilirubin Concentration, International Normalized Ratio, Creatinine Concentration | 354 | ||
| Lille Score | 354 | ||
| Comparison of Scoring Systems | 355 | ||
| Liver Histology | 355 | ||
| Emerging Scoring Systems | 355 | ||
| Treatment of Severe Episodes of Alcoholic Hepatitis | 355 | ||
| Corticosteroids | 355 | ||
| Efficacy of Corticosteroids in Alcoholic Hepatitis Treatment | 355 | ||
| Current Status of Corticosteroid Therapy in the Management of Alcoholic Hepatitis | 356 | ||
| Mechanism of Action | 356 | ||
| Use of Corticosteroids in Practice | 357 | ||
| Contraindications for Corticosteroid Therapy | 357 | ||
| Infections in Patients Receiving Corticosteroid Therapy | 357 | ||
| Pentoxifylline | 358 | ||
| Current Status of Pentoxifylline in the Treatment of Alcoholic Hepatitis | 358 | ||
| Tumor Necrosis Factor α Inhibitors | 359 | ||
| Antioxidants | 359 | ||
| Hepatic Mitogens and Growth Factors | 359 | ||
| Propylthiouracil | 359 | ||
| Albumin Dialysis and Miscellaneous Therapies | 359 | ||
| General Management Measures | 359 | ||
| Management of Alcohol Withdrawal | 359 | ||
| Management of Complications of Cirrhosis | 359 | ||
| Management of Malnutrition | 359 | ||
| Enteral Supplementation | 360 | ||
| Parenteral Supplementation | 360 | ||
| Alcohol Abstinence | 360 | ||
| Behavioral Therapies | 361 | ||
| Pharmacologic Therapies | 361 | ||
| Emerging Pharmacologic Treatments | 361 | ||
| Gut-Liver Axis | 361 | ||
| Inflammatory Cascade | 362 | ||
| Oxidative Stress | 362 | ||
| Apoptosis and Liver Regeneration | 362 | ||
| Liver Transplant in Alcoholic Hepatitis | 362 | ||
| Controversy Surrounding Liver Transplant in Alcoholic Hepatitis | 362 | ||
| Six Months’ Abstinence Rule | 363 | ||
| Beneficial Efficacy of Early Liver Transplant in Alcoholic Hepatitis | 363 | ||
| Selection Criteria and Impact on the Donor Pool | 363 | ||
| Barriers to Liver Transplant in Alcoholic Hepatitis | 364 | ||
| Treatment of Mild Episodes of Alcoholic Hepatitis | 364 | ||
| Treatment of Alcoholic Cirrhosis | 364 | ||
| Alcohol Abstinence and Monitoring | 364 | ||
| Management of Cirrhosis and Its Complications | 364 | ||
| Pharmacologic Treatments | 364 | ||
| Antioxidants | 364 | ||
| Propylthiouracil | 365 | ||
| Colchicine | 365 | ||
| Management of Malnutrition | 365 | ||
| Enteral Supplementation | 365 | ||
| Liver Transplant for Alcoholic Cirrhosis | 365 | ||
| Alcohol Consumption and Dependence | 365 | ||
| Evaluation for Comorbidities | 365 | ||
| Psychosocial Evaluation | 366 | ||
| Posttransplant Recidivism | 366 | ||
| Graft and Patient Outcomes | 366 | ||
| Conclusion | 368 | ||
| References | 368 | ||
| References | 368.e1 | ||
| 25 Pathogenesis of Nonalcoholic Fatty Liver Disease | 369 | ||
| Abbreviations | 369 | ||
| Introduction | 370 | ||
| Making Foie Gras | 371 | ||
| Nonalcoholic Fatty Liver Disease: An Adiposopathy | 374 | ||
| Nonalcoholic Fatty Liver Disease and Insulin Resistance: The Chicken and Egg Paradox | 375 | ||
| Oxidative Stress: Overburning Fat | 378 | ||
| Lipotoxicity: The Ugly and the Beast | 380 | ||
| Endoplasmic Reticulum Stress: A Tree Born Crooked Cannot Straighten Its Trunk | 381 | ||
| Autophagy: The Ouroboros Housekeeper | 383 | ||
| Sterile Inflammation: When the Aggressor Is Fat | 383 | ||
| Dysbiota: The Unwanted Guests | 385 | ||
| Cell Death: A Cry for Help | 387 | ||
| Fibrogenesis: To Heal or to Scar | 387 | ||
| Conclusion | 390 | ||
| References | 390 | ||
| References | 390.e1 | ||
| 26 Epidemiology, Natural History, and Evaluation of Nonalcoholic Fatty Liver Disease | 391 | ||
| Abbreviations | 391 | ||
| Introduction | 391 | ||
| Epidemiology | 392 | ||
| Prevalence | 392 | ||
| Causes of and Conditions Associated With Nonalcoholic Fatty Liver Disease | 393 | ||
| Natural History of Nonalcoholic Fatty Liver Disease | 394 | ||
| Progression to Advanced Liver Fibrosis and Cirrhosis in Nonalcoholic Fatty Liver Disease | 394 | ||
| Nonalcoholic Fatty Liver Disease and the Risk of Hepatocellular Carcinoma | 395 | ||
| Modifiers of Progression of Nonalcoholic Fatty Liver Disease | 395 | ||
| Environmental Modifiers of Nonalcoholic Fatty Liver Disease | 396 | ||
| Genetic Modifiers of Nonalcoholic Fatty Liver Disease | 396 | ||
| Clinical Features of Nonalcoholic Fatty Liver Disease | 398 | ||
| Symptoms | 398 | ||
| Signs on Physical Examination | 398 | ||
| Routine Laboratory Abnormalities | 399 | ||
| Histopathologic Features of Nonalcoholic Fatty Liver Disease | 399 | ||
| Steatosis | 399 | ||
| Steatohepatitis | 399 | ||
| Fibrosis | 399 | ||
| Grading and Staging of the Severity of Nonalcoholic Fatty Liver Disease in Clinical Practice | 399 | ||
| Evaluation of Nonalcoholic Fatty Liver Disease | 401 | ||
| Diagnostic Approach to Nonalcoholic Fatty Liver Disease | 401 | ||
| Risk Stratification and Staging of Nonalcoholic Fatty Liver Disease | 402 | ||
| References | 405 | ||
| References | 405.e1 | ||
| 27 Management of Nonalcoholic Fatty Liver Disease and Metabolic Syndrome | 406 | ||
| Abbreviations | 406 | ||
| Introduction | 406 | ||
| Associated Conditions | 406 | ||
| Treatment | 406 | ||
| Lifestyle Modifications | 407 | ||
| Exercise | 407 | ||
| Bariatric Surgery | 408 | ||
| Phlebotomy | 408 | ||
| Pharmacologic Treatment | 408 | ||
| Insulin-Sensitizing Medications | 408 | ||
| Antioxidants | 409 | ||
| Cytoprotective Agents | 409 | ||
| Statins | 409 | ||
| Weight Loss Medications | 409 | ||
| Novel Approaches | 409 | ||
| Conclusion | 409 | ||
| References | 411 | ||
| References | 411.e1 | ||
| 28 Virology and Pathogenesis of Hepatitis C | 412 | ||
| Abbreviations | 412 | ||
| Introduction | 412 | ||
| Overview of the Virion | 412 | ||
| Model Systems | 412 | ||
| Structure and Function of the Viral Proteins | 413 | ||
| Hepatitis C Virus Structural Proteins | 413 | ||
| Core | 413 | ||
| Envelope Glycoproteins | 413 | ||
| p7 | 415 | ||
| Hepatitis C Virus Nonstructural Proteins | 415 | ||
| NS2-3 Protease | 415 | ||
| NS3-4A Protease Complex | 415 | ||
| NS4B | 415 | ||
| NS5A | 415 | ||
| NS5B | 415 | ||
| The Virus and Its Life Cycle | 415 | ||
| Pathogenesis of Hepatitis C Virus Infection | 419 | ||
| Role of Innate and Adaptive Immunity | 419 | ||
| Acute Hepatitis C Virus Infection | 419 | ||
| Overview | 419 | ||
| Humoral Immunity | 420 | ||
| Cellular Immunity | 420 | ||
| Chronic Hepatitis C Virus Infection | 422 | ||
| Immunological Basis for Viral Persistence | 422 | ||
| Cellular Response to Chronic Hepatitis C Virus Infection | 422 | ||
| Immunoregulation | 422 | ||
| Cytotoxic T Cells | 423 | ||
| Viral Immune Escape Mutation | 424 | ||
| Vaccine Development in Hepatitis C Virus Infection | 424 | ||
| Mechanisms of Liver Injury in Hepatitis C Virus Infection | 424 | ||
| Overview | 424 | ||
| Virus-Mediated Injury | 424 | ||
| Immune-Mediated Liver Injury | 424 | ||
| T Cell–Mediated Injury | 424 | ||
| Chemokines in Recruitment of Immune Cells Into the Liver | 425 | ||
| Natural Killer Cells and Liver Injury | 426 | ||
| Fibrosis Progression | 426 | ||
| Conclusion | 426 | ||
| References | 427 | ||
| References | 427.e1 | ||
| 29 Epidemiology, Natural History, and Diagnosis of Hepatitis C | 428 | ||
| Abbreviations | 428 | ||
| Discovery of Hepatitis C Virus | 428 | ||
| Hepatitis C Virus Transmission | 429 | ||
| Receipt of Infected Blood or Blood Products | 429 | ||
| Occupational Transmission Among Healthcare Workers | 430 | ||
| Healthcare Settings | 430 | ||
| Injection Drug Use | 430 | ||
| Sexual Transmission | 430 | ||
| Vertical Transmission | 431 | ||
| Other Exposures | 431 | ||
| Other Populations | 431 | ||
| Natural History of Acute Hepatitis C Infection | 431 | ||
| Incidence of Hepatitis C Virus Infection | 432 | ||
| Global | 432 | ||
| United States | 432 | ||
| Natural History of Chronic Hepatitis C | 433 | ||
| Hepatitis C Virus in Children | 436 | ||
| Prevalence of Hepatitis C Virus | 436 | ||
| United States | 439 | ||
| Hepatitis C Virus Genotypes | 439 | ||
| Diagnosis | 441 | ||
| Anti–Hepatitis C Virus Screening Assays | 441 | ||
| Confirmatory Testing | 441 | ||
| Detection of Current Hepatitis C Virus Infection | 442 | ||
| Screening to Prevent Hepatitis C Virus–Related Transmission and Disease | 442 | ||
| Primary Prevention | 443 | ||
| Conclusion | 444 | ||
| References | 445 | ||
| References | 445.e1 | ||
| 30 Treatment of Hepatitis C | 446 | ||
| Abbreviations | 446 | ||
| Introduction | 446 | ||
| The Evolution of Hepatitis C Virus Therapies | 446 | ||
| Interferon-α | 447 | ||
| Ribavirin | 447 | ||
| Protease Inhibitors | 450 | ||
| Polymerase Inhibitors | 450 | ||
| NS5A Inhibitors | 450 | ||
| Goals of Hepatitis C Virus Treatment | 450 | ||
| Candidacy for Antiviral Therapy and Pretreatment Assessments | 451 | ||
| Hepatitis C Virus Treatment Regimens | 452 | ||
| Genotype-1 Regimens | 453 | ||
| Ledipasvir and Sofosbuvir | 453 | ||
| Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir | 454 | ||
| Simeprevir and Sofosbuvir | 455 | ||
| Grazoprevir and Elbasvir | 456 | ||
| Genotype-2 Regimens | 456 | ||
| Sofosbuvir and Ribavirin | 456 | ||
| Genotype-3 Regimens | 456 | ||
| Sofosbuvir and Ribavirin | 457 | ||
| Daclatasvir and Sofosbuvir | 458 | ||
| Genotype-4 Regimens | 458 | ||
| Sofosbuvir Plus Peginterferon-α and Ribavirin | 458 | ||
| Sofosbuvir and Ribavirin | 458 | ||
| Sofosbuvir and Ledipasvir | 458 | ||
| Paritaprevir/Ritonavir and Ombitasvir | 458 | ||
| Genotype-5 and Genotype-6 Regimens | 458 | ||
| Monitoring During and After Hepatitis C Virus Therapy | 458 | ||
| Direct-Acting Antiviral Resistance | 459 | ||
| Special Populations | 461 | ||
| Decompensated Cirrhosis | 461 | ||
| Post–Liver Transplantation | 461 | ||
| HIV-HCV Coinfection | 461 | ||
| Renal Disease | 462 | ||
| African Americans | 462 | ||
| Acute Hepatitis C Virus | 462 | ||
| Conclusion | 463 | ||
| References | 463 | ||
| References | 463.e1 | ||
| 31 Virology and Pathogenesis of Hepatitis B | 464 | ||
| Abbreviations | 464 | ||
| Introduction | 464 | ||
| Hepatitis B Virus: Host and Model Systems | 464 | ||
| Hepatitis B Virus Biology | 465 | ||
| Hepatitis B Virus Structure, Genome, and Proteins | 465 | ||
| The Hepatitis B Virus Life Cycle | 466 | ||
| Hepatitis B Virus Entry | 467 | ||
| Hepatitis B Virus Capsid Transport Toward the Nucleus and Genome Release | 467 | ||
| Covalently Closed Circular DNA Formation | 467 | ||
| Capsid Formation, Maturation, and Secretion | 467 | ||
| Hepatitis B Virus Genome Variability | 468 | ||
| Immunopathogenesis of Hepatitis B Virus Infection | 468 | ||
| The Immunologic Profile of Hepatitis B Virus Control | 468 | ||
| Immune-Mediated Inhibition of Hepatitis B Virus Replication | 470 | ||
| The Impact of Age in the Pathogenesis of Hepatitis B Virus–Mediated Hepatitis | 470 | ||
| Liver Damage Pathogenesis During Hepatitis B Virus Infection | 471 | ||
| Conclusion | 473 | ||
| References | 473 | ||
| References | 473.e1 | ||
| 32 Epidemiology, Diagnosis, and Natural History of Hepatitis B | 474 | ||
| Abbreviations | 474 | ||
| Introduction | 474 | ||
| Epidemiology | 474 | ||
| Burden of Disease | 474 | ||
| Changing Epidemiology | 474 | ||
| Mode of Transmission | 475 | ||
| Sexual | 475 | ||
| Percutaneous | 475 | ||
| Perinatal | 476 | ||
| Healthcare Associated | 476 | ||
| Diagnosis | 476 | ||
| Screening Recommendations | 476 | ||
| Hepatitis B Surface Antigen and Hepatitis B Surface Antibody | 476 | ||
| Hepatitis B Core Antigen and Hepatitis B Core Antibody | 477 | ||
| Hepatitis B e Antigen and Hepatitis B e Antibody | 478 | ||
| Hepatitis B Virus DNA | 479 | ||
| Hepatitis B Virus Genotyping | 479 | ||
| Liver Biopsy and Noninvasive Assessment of Liver Fibrosis | 479 | ||
| Natural History | 479 | ||
| Acute Infection | 479 | ||
| Clinical Manifestations | 479 | ||
| Laboratory Findings | 479 | ||
| Outcomes and Predictors | 480 | ||
| Chronic Infection | 480 | ||
| Clinical Manifestations | 480 | ||
| Extrahepatic Manifestations | 481 | ||
| Laboratory Findings | 481 | ||
| Phases of Chronic Infection | 481 | ||
| Immune-Tolerant Phase | 481 | ||
| Immune Clearance Phase (HBeAg-Positive Chronic Hepatitis) | 482 | ||
| Inactive Carrier Phase | 482 | ||
| Reactivation Phase (HBeAg-Negative Chronic Hepatitis) | 482 | ||
| Spontaneous HBsAg Clearance | 483 | ||
| Latent/Occult HBV Infection | 483 | ||
| Clinical Outcomes and Mediating Factors | 483 | ||
| Liver Cirrhosis and Decompensated Cirrhosis | 483 | ||
| Hepatocellular Carcinoma | 483 | ||
| Special Groups With Altered Natural History | 484 | ||
| Coinfection With Other Viruses | 484 | ||
| Immunosuppressed Patients | 484 | ||
| Conclusion | 484 | ||
| References | 484 | ||
| References | 484.e1 | ||
| 33 Treatment of Hepatitis B | 485 | ||
| Abbreviations | 485 | ||
| Introduction | 485 | ||
| Indications for Treatment | 485 | ||
| Natural History | 485 | ||
| Phases of Chronic Hepatitis B Virus Infection | 485 | ||
| Progression to Cirrhosis and Hepatocellular Carcinoma | 486 | ||
| Treatment Indication | 486 | ||
| Initial Evaluation | 487 | ||
| Treatment End Points | 487 | ||
| Nucleoside/Nucleotide Analogs | 488 | ||
| Introduction | 488 | ||
| Tenofovir | 488 | ||
| Clinical Response | 488 | ||
| Resistance | 488 | ||
| Safety | 490 | ||
| Entecavir | 491 | ||
| Clinical Response | 491 | ||
| Resistance | 491 | ||
| Safety | 491 | ||
| Lamivudine | 491 | ||
| Adefovir | 492 | ||
| Telbivudine | 492 | ||
| Clinical End Points | 492 | ||
| General Management Issues in Treatment With Nucleoside/Nucleotide Analogs | 492 | ||
| Is a Finite Duration of Nucleoside/Nucleotide Analog Therapy Possible? | 492 | ||
| Prevention of Antiviral Drug Resistance | 493 | ||
| Pegylated Interferon | 494 | ||
| Efficacy in Hepatitis B e Antigen–Positive Patients | 494 | ||
| Efficacy in Hepatitis B e Antigen–Negative Patients | 494 | ||
| Selection of Patients for Pegylated Interferon Therapy | 494 | ||
| Hepatitis B e Antigen–Positive Patients | 494 | ||
| V Liver and Other Infections | 535 | ||
| 37 HIV and the Liver | 536 | ||
| Abbreviations | 536 | ||
| Introduction | 536 | ||
| Epidemiology of Liver Disease in Those With HIV Infection | 536 | ||
| Mechanisms of Liver Disease Unique to HIV | 537 | ||
| Liver Biopsy and Noninvasive Markers of Liver Disease Severity | 538 | ||
| Noninvasive Fibrosis Assessment Using Biochemical Markers | 539 | ||
| AST to Platelet Ratio Index | 539 | ||
| Forns Index | 539 | ||
| Fibrosis 4 Score | 539 | ||
| Hospital Gregorio Maranon Indices | 540 | ||
| Models Utilizing Assays Available in Specialized Labs | 540 | ||
| Noninvasive Fibrosis Assessment Using Elastography or Imaging Modalities | 540 | ||
| Transient Elastography | 540 | ||
| Panels and Radiologic Modalities | 540 | ||
| Practical Application of Noninvasive Measures of Fibrosis | 541 | ||
| Noninvasive Markers in HIV-Infected Patients and Long-Term Outcomes | 541 | ||
| Viral Hepatitis in Those With HIV Infection | 542 | ||
| Hepatitis A | 542 | ||
| Hepatitis B | 542 | ||
| Hepatitis C | 545 | ||
| Hepatitis D | 545 | ||
| Hepatitis E | 546 | ||
| Epstein Barr Virus (EBV) | 546 | ||
| Cytomegalovirus (CMV) | 547 | ||
| Fungal Infections | 547 | ||
| Parasitic Infections | 547 | ||
| Bacterial Infections | 548 | ||
| Granulomatous Processes | 548 | ||
| Nonalcoholic Fatty Liver Disease | 549 | ||
| Hepatotoxic Drugs and Drug-Drug Interactions | 550 | ||
| Hepatic Malignancies Associated With HIV | 553 | ||
| AIDS Cholangiopathy | 554 | ||
| Liver Transplantation in HIV | 555 | ||
| Conclusion | 555 | ||
| Acknowledgments | 555 | ||
| References | 555 | ||
| References | 555.e1 | ||
| 38 Liver Disease Associated With Systemic Viral Infection | 556 | ||
| Abbreviations | 556 | ||
| Introduction | 556 | ||
| Opportunistic Viral Infections (Table 38-1) | 556 | ||
| Epstein-Barr Virus | 556 | ||
| Cytomegalovirus | 557 | ||
| Herpes Simplex Virus | 558 | ||
| Varicella-Zoster Virus | 560 | ||
| Human Herpesviruses | 560 | ||
| Adenoviruses | 561 | ||
| Systemic Viral Infections (Table 38-2) | 562 | ||
| Human Immunodeficiency Virus | 562 | ||
| Influenza | 562 | ||
| Severe Acute Respiratory Syndrome Coronavirus | 563 | ||
| Parvovirus B19 | 563 | ||
| Measles (Rubeola) Virus | 563 | ||
| Rubella | 563 | ||
| Enteroviruses | 564 | ||
| Viral Hemorrhagic Fevers (Table 38-3) | 564 | ||
| Dengue Fever | 564 | ||
| Yellow Fever | 565 | ||
| Lassa Fever | 565 | ||
| Ebola Virus Disease | 566 | ||
| Conclusion | 567 | ||
| References | 567 | ||
| References | 567.e1 | ||
| 39 Parasitic Liver Disease | 568 | ||
| Abbreviations | 568 | ||
| Introduction | 568 | ||
| Schistosomiasis | 569 | ||
| Clinical Manifestations | 570 | ||
| Diagnosis | 570 | ||
| Treatment | 571 | ||
| Praziquantel | 571 | ||
| New Drugs | 572 | ||
| Control | 572 | ||
| Echinococcosis (Echinococcus granulosus and Echinococcus multilocularis) | 572 | ||
| Introduction | 572 | ||
| Immune Response | 572 | ||
| Clinical Manifestations | 572 | ||
| Diagnosis | 573 | ||
| Treatment | 573 | ||
| Amebiasis | 573 | ||
| Introduction | 573 | ||
| Clinical Manifestations | 574 | ||
| Asymptomatic Patients | 574 | ||
| Symptomatic Patients | 574 | ||
| Amebic Colitis | 574 | ||
| Amebic Liver Abscess | 574 | ||
| Diagnosis | 574 | ||
| Treatment | 575 | ||
| Hepatobiliary Parasites | 575 | ||
| Fascioliasis | 575 | ||
| Clinical Manifestations | 575 | ||
| Diagnosis | 576 | ||
| Treatment | 576 | ||
| Clonorchiasis and Opisthorchiasis | 576 | ||
| Clinical Manifestations | 577 | ||
| Diagnosis | 577 | ||
| Treatment | 577 | ||
| Capillaria hepatica | 577 | ||
| Ascaris lumbricoides | 577 | ||
| Human Immunodeficiency Virus and Parasitic Infections | 578 | ||
| Conclusion | 578 | ||
| References | 578 | ||
| References | 578.e1 | ||
| 40 Bacterial and Miscellaneous Infections of the Liver | 579 | ||
| Abbreviations | 579 | ||
| Introduction | 580 | ||
| Bacterial Infections in Cirrhosis | 580 | ||
| Pyogenic Liver Abscess | 580 | ||
| Epidemiology | 580 | ||
| Etiology, Pathogenesis, and Pathophysiology | 581 | ||
| Microbiology | 582 | ||
| Clinical Manifestations, Diagnosis, and Management | 582 | ||
| Peliosis Hepatis | 584 | ||
| Disseminated Bacterial Infections With Involvement of the Liver | 584 | ||
| Miscellaneous Bacterial Infections | 585 | ||
| Conclusions | 585 | ||
| Bacterial Infections in Liver Transplant Recipients | 585 | ||
| Risk Factors for Bacterial Infections | 585 | ||
| Genetic Polymorphism as Risk Factors for Bacterial Infections in LT Recipients | 586 | ||
| Immune Tolerance in Liver Disease | 586 | ||
| Surgical Site Infections | 587 | ||
| Post–Liver Transplant SSIs | 587 | ||
| Biliary Tract Infections and Post–Liver Transplant Biliary Complications | 587 | ||
| Biliary Reconstruction | 587 | ||
| Biliary Strictures | 587 | ||
| Infected Biloma | 588 | ||
| Bile Leak | 588 | ||
| Multidrug Resistant Bacterial Infections in LT Population | 588 | ||
| Fungal Infection Prophylaxis in Liver Transplant Recipients | 589 | ||
| Candida Species | 589 | ||
| Aspergillus Species | 589 | ||
| Cryptococcus Species | 589 | ||
| Coccidioidomycosis | 590 | ||
| Pneumocystis (jiroveci) Pneumonia | 590 | ||
| Commonly Encountered Fungal Infections of the Liver | 590 | ||
| Pathogenesis of Liver Disease: the Bloodborne Route | 590 | ||
| Candida Species | 591 | ||
| Endemic Mycoses | 591 | ||
| Pathogenesis of Fungal Liver Disease | 591 | ||
| Diagnosis of Fungal Liver Disease | 591 | ||
| Treatment of Fungal Liver Disease | 591 | ||
| Conclusion | 592 | ||
| References | 592 | ||
| References | 592.e1 | ||
| VI Immune Diseases and the Liver | 593 | ||
| 41 Autoimmune Hepatitis | 594 | ||
| Abbreviations | 594 | ||
| Introduction | 594 | ||
| History and Epidemiology | 594 | ||
| Genetic Factors in Disease Pathogenesis | 594 | ||
| Other Factors in Disease Pathogenesis | 596 | ||
| Association With Other Autoimmune Diseases | 596 | ||
| Animal Models of Autoimmune Hepatitis | 596 | ||
| Clinical Presentation | 596 | ||
| Laboratory Features | 597 | ||
| Autoantibodies | 597 | ||
| Antinuclear Autoantibodies | 598 | ||
| Smooth Muscle Autoantibodies | 598 | ||
| Soluble Liver Antigen/Liver Pancreas Antibodies | 600 | ||
| Liver Kidney Microsomal Autoantibodies | 600 | ||
| Other Autoantibodies | 601 | ||
| Histology | 601 | ||
| Diagnosis | 601 | ||
| Treatment and Management | 603 | ||
| General Principles | 603 | ||
| Remission Induction | 603 | ||
| Maintenance Therapy | 604 | ||
| Trial of Treatment Withdrawal | 605 | ||
| Experimental and Novel Treatment Approaches | 605 | ||
| Quality of Life | 605 | ||
| Special Patient Groups | 606 | ||
| Autoimmune Hepatitis in Children and Transition Into Adulthood | 606 | ||
| Autoimmune Hepatitis and Pregnancy | 606 | ||
| Autoimmune Hepatitis in Old Age | 607 | ||
| Comorbidity | 607 | ||
| Fulminant Autoimmune Hepatitis | 607 | ||
| Autoimmune Hepatitis and Cholestatic Liver Diseases (Overlap Syndromes) | 607 | ||
| Autoimmune Hepatitis and Primary Sclerosing Cholangitis | 608 | ||
| Autoimmune Hepatitis Features in Primary Biliary Cholangitis | 608 | ||
| Cancer Risk and Surveillance | 608 | ||
| Liver Transplantation | 609 | ||
| Delivery of Quality Care and Management Issues | 609 | ||
| Conclusion | 609 | ||
| References | 609 | ||
| References | 609.e1 | ||
| 42 Primary Biliary Cholangitis | 610 | ||
| Abbreviations | 610 | ||
| Introduction | 610 | ||
| Epidemiology | 610 | ||
| Incidence and Prevalence | 610 | ||
| Age, Gender, and Race Variation | 611 | ||
| Geographic Clustering | 611 | ||
| Predisposing Factors | 611 | ||
| Etiopathogenesis | 612 | ||
| Immunogenicity | 613 | ||
| Role of Infectious Agents and Xenobiotics | 613 | ||
| Genetics | 613 | ||
| Clinical Manifestations | 614 | ||
| Asymptomatic Disease | 614 | ||
| Symptomatic Disease | 614 | ||
| Fatigue | 614 | ||
| Pruritus | 615 | ||
| Portal Hypertension | 616 | ||
| Extrahepatic Complications | 616 | ||
| Bone Disease | 616 | ||
| Fat-Soluble Vitamin Deficiency | 616 | ||
| Hyperlipidemia | 616 | ||
| Associated Autoimmune Diseases | 616 | ||
| Malignancies | 616 | ||
| Diagnosis | 616 | ||
| Laboratory Findings | 617 | ||
| Antimitochondrial Antibodies | 617 | ||
| Other Autoantibodies | 617 | ||
| Imaging Studies | 617 | ||
| Histology | 618 | ||
| Natural History of Untreated Patients | 618 | ||
| Treatment | 619 | ||
| Treatment of Primary Biliary Cholangitis | 619 | ||
| Ursodeoxycholic Acid | 619 | ||
| Other Older Drugs for Primary Biliary Cholangitis | 621 | ||
| New Agents | 621 | ||
| Obeticholic Acid | 621 | ||
| Fibrates | 622 | ||
| Immunomodulators | 622 | ||
| Stem Cell Transplantation | 622 | ||
| Treatment of Associated Symptoms and Conditions | 622 | ||
| Pruritus | 622 | ||
| Fatigue | 622 | ||
| Fat-Soluble Vitamin Deficiency | 623 | ||
| Hyperlipidemia | 623 | ||
| Metabolic Bone Disease | 623 | ||
| Liver Transplantation | 623 | ||
| Recurrent Primary Biliary Cholangitis | 623 | ||
| Prognosis | 624 | ||
| Laboratory Tests | 624 | ||
| Histology | 624 | ||
| Elastography | 624 | ||
| Mathematic Models | 624 | ||
| Special Populations | 624 | ||
| Antimitochondrial Antibody–Negative Primary Biliary Cholangitis | 624 | ||
| Overlap of Primary Biliary Cholangitis and Autoimmune Hepatitis | 625 | ||
| Conclusion | 625 | ||
| References | 625 | ||
| References | 625.e1 | ||
| 43 Primary and Secondary Sclerosing Cholangitis | 626 | ||
| Abbreviations | 626 | ||
| Introduction | 626 | ||
| Variants of Sclerosing Cholangitis | 626 | ||
| Primary Sclerosing Cholangitis Variants | 627 | ||
| Large Duct Primary Sclerosing Cholangitis | 627 | ||
| Non-IBD Primary Sclerosing Cholangitis | 627 | ||
| Small Duct Primary Sclerosing Cholangitis | 627 | ||
| PSC–Autoimmune Hepatitis Overlap | 627 | ||
| Pediatric Primary Sclerosing Cholangitis | 628 | ||
| PSC in Non-Caucasian Populations | 628 | ||
| Immunoglobulin G4–Related Sclerosing Cholangitis | 628 | ||
| Secondary Sclerosing Cholangitis | 628 | ||
| Epidemiology | 629 | ||
| Pathogenesis | 629 | ||
| Genetic and Environmental Risks | 629 | ||
| Immune Responses in Primary Sclerosing Cholangitis | 632 | ||
| Leaky Gut Hypothesis | 633 | ||
| Primary Sclerosing Cholangitis Dysbiosis | 633 | ||
| Lymphocyte Trafficking | 633 | ||
| Toxic Bile Theory | 634 | ||
| Clinical Features | 634 | ||
| Diagnostic Criteria | 634 | ||
| Presenting Signs and Symptoms | 635 | ||
| Laboratory Tests | 635 | ||
| Imaging | 636 | ||
| Histology | 637 | ||
| Inflammatory Bowel Disease in PSC | 637 | ||
| Natural History | 638 | ||
| Risk Prediction in PSC | 639 | ||
| Malignancy Risks in Patients With PSC | 640 | ||
| Pretransplant Management | 640 | ||
| Pharmacotherapy | 642 | ||
| Endoscopic Management | 644 | ||
| Cancer Screening for Cholangiocarcinoma, Gallbladder Cancer, and Colorectal Cancer | 644 | ||
| Pruritus, Mineral Bone Disease, and Quality of Life | 645 | ||
| Transplant for Primary Sclerosing Cholangitis | 645 | ||
| Posttransplant Management of PSC | 646 | ||
| Conclusion | 647 | ||
| References | 647 | ||
| References | 647.e1 | ||
| VII Vascular Diseases of the Liver | 648 | ||
| 44 Budd-Chiari Syndrome and Sinusoidal Obstruction Syndrome | 649 | ||
| Abbreviations | 649 | ||
| Introduction | 649 | ||
| Budd-Chiari Syndrome | 649 | ||
| Etiology | 649 | ||
| Clinical Manifestations | 650 | ||
| Diagnosis of BCS | 650 | ||
| Diagnosis of Underlying Cause of Thrombosis | 651 | ||
| Management | 652 | ||
| Anticoagulation | 652 | ||
| Management of Causes Leading to Thrombosis | 652 | ||
| Management of Portal Hypertension | 652 | ||
| Thrombolysis | 652 | ||
| Angioplasty and Stenting | 652 | ||
| Portosystemic Shunting | 652 | ||
| Liver Transplantation | 653 | ||
| Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease) | 653 | ||
| Risk Factors and Epidemiology | 653 | ||
| Pathogenesis | 654 | ||
| Clinical Presentation | 655 | ||
| Diagnosis | 655 | ||
| Prevention | 656 | ||
| Treatment | 656 | ||
| Conclusion | 657 | ||
| References | 657 | ||
| References | 657.e1 | ||
| 45 Portal and Splenic Vein Thrombosis | 658 | ||
| Abbreviations | 658 | ||
| Introduction | 658 | ||
| Portal Vein Thrombosis in the Absence of Underlying Liver Disease | 658 | ||
| Epidemiology | 658 | ||
| Etiology | 658 | ||
| General Risk Factors | 658 | ||
| Myeloproliferative Neoplasms | 658 | ||
| Inherited Thrombophilia | 658 | ||
| Acquired Prothrombotic Disorders | 659 | ||
| Local Factors | 659 | ||
| Manifestations | 660 | ||
| Clinical and Laboratory Features | 660 | ||
| VIII Tumors of the Liver | 667 | ||
| 46 Hepatocellular Carcinoma | 668 | ||
| Abbreviations | 668 | ||
| Introduction | 668 | ||
| Epidemiology | 668 | ||
| Risk Factors | 669 | ||
| Hepatitis B | 670 | ||
| Hepatitis C | 671 | ||
| Cirrhosis | 671 | ||
| Obesity | 671 | ||
| Diabetes | 671 | ||
| Nonalcoholic Fatty Liver Disease | 672 | ||
| Alcohol | 672 | ||
| Smoking | 672 | ||
| Aflatoxin | 672 | ||
| Prevention | 673 | ||
| Chemoprevention | 673 | ||
| Coffee | 673 | ||
| Statins | 673 | ||
| Pathogenesis | 673 | ||
| Mitogen-Activated Protein Kinase Pathway | 673 | ||
| Phosphoinositide 3-Kinase–AKT–Mammalian Target of Rapamycin Pathway | 673 | ||
| Wnt-β-Catenin Pathway | 674 | ||
| Proangiogenic Pathways | 674 | ||
| Epidermal Growth Factor Receptor Pathway | 674 | ||
| Hepatocellular Carcinoma Surveillance | 675 | ||
| Viral Hepatitis | 675 | ||
| Staging | 678 | ||
| Pathology | 679 | ||
| Histologic Variants | 680 | ||
| Fibrolamellar Hepatocellular Carcinoma | 680 | ||
| Scirrhous Hepatocellular Carcinoma | 681 | ||
| Radiology | 681 | ||
| Treatment | 682 | ||
| Hepatic Resection | 682 | ||
| Liver Transplantation | 685 | ||
| Living Donor Liver Transplantation | 686 | ||
| Liver-Directed Therapy | 686 | ||
| Ablative Therapy | 687 | ||
| Transcatheter Arterial Chemoembolization | 688 | ||
| Selective Internal Radiation Therapy | 689 | ||
| Systemic Therapy | 690 | ||
| Sorafenib | 691 | ||
| Combination of Sorafenib With Liver-Directed Therapy or Resection | 691 | ||
| Tyrosine Kinase Inhibitors | 691 | ||
| Mammalian Target of Rapamycin Inhibitors | 692 | ||
| Immunotherapy | 692 | ||
| Conclusion | 692 | ||
| References | 692 | ||
| References | 692.e1 | ||
| 47 Cholangiocarcinoma | 693 | ||
| Abbreviations | 693 | ||
| Introduction | 693 | ||
| Epidemiology and Risk Factors | 693 | ||
| Epidemiology | 693 | ||
| Risk Factors | 694 | ||
| Molecular Pathogenesis | 695 | ||
| Pathology and Classification | 698 | ||
| Clinical Presentation and Diagnosis | 698 | ||
| Perihilar and Distal CCA | 698 | ||
| Intrahepatic CCA | 700 | ||
| Staging | 700 | ||
| Therapy | 702 | ||
| Surgical Therapy | 703 | ||
| Perihilar and Distal CCA | 703 | ||
| Intrahepatic CCA | 703 | ||
| Palliative Therapeutic Approaches | 703 | ||
| Biliary Stents | 703 | ||
| Systemic Therapy | 704 | ||
| Locoregional Therapies | 705 | ||
| Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma | 706 | ||
| Conclusion | 707 | ||
| References | 707 | ||
| References | 707.e1 | ||
| 48 Other Malignant Hepatic Tumors | 708 | ||
| Abbreviations | 708 | ||
| Introduction | 708 | ||
| Fibrolamellar Hepatocellular Carcinoma | 708 | ||
| Epidemiology | 708 | ||
| Pathogenesis | 708 | ||
| Pathology | 709 | ||
| Clinical Features | 709 | ||
| Diagnosis | 709 | ||
| Treatment and Prognosis | 709 | ||
| Hepatoblastoma | 711 | ||
| Epidemiology | 711 | ||
| Pathogenesis | 711 | ||
| Pathology | 711 | ||
| IX Liver Transplantation | 736 | ||
| 50 Pretransplant Evaluation and Care | 737 | ||
| Abbreviations | 737 | ||
| Introduction | 737 | ||
| Pretransplant Evaluation | 737 | ||
| Timing of Referral for Evaluation | 738 | ||
| Exploring Alternatives to Liver Transplantation | 742 | ||
| Indications for Liver Transplantation | 743 | ||
| Acute Liver Failure | 743 | ||
| Hepatitis C Virus Infection | 744 | ||
| Alcoholic Cirrhosis | 744 | ||
| Nonalcoholic Steatohepatitis | 744 | ||
| Hepatitis B Virus Infection | 745 | ||
| Cholestatic Liver Diseases | 745 | ||
| Hepatocellular Carcinoma | 745 | ||
| Other Primary Hepatic Malignancies | 746 | ||
| Repeated Transplant: Recurrent Disease and Graft Failure | 746 | ||
| Contraindications for Liver Transplantation: Absolute and Relative | 747 | ||
| Medical Issues | 747 | ||
| Cardiovascular Disease | 747 | ||
| Pulmonary Disease | 748 | ||
| Renal Failure | 748 | ||
| Infection | 748 | ||
| Extrahepatic Malignancy | 749 | ||
| Advanced Age | 749 | ||
| Obesity | 749 | ||
| Cachexia, Sarcopenia, and Frailty | 749 | ||
| Psychosocial Issues | 749 | ||
| Active Alcohol or Substance Abuse | 750 | ||
| Psychiatric Comorbidities | 750 | ||
| Social Support | 750 | ||
| Technical Issues | 750 | ||
| Monitoring and Management | 750 | ||
| Allocation and Distribution Systems | 750 | ||
| Donor Liver Choices | 751 | ||
| Conclusion | 751 | ||
| References | 752 | ||
| References | 752.e1 | ||
| 51 Transplantation of the Liver | 753 | ||
| Abbreviations | 753 | ||
| Introduction | 753 | ||
| Brief History of Liver Transplantation | 753 | ||
| Indications and Contraindications to Liver Transplantation | 754 | ||
| Indications | 754 | ||
| Contraindications | 754 | ||
| Candidate Evaluation and Listing | 756 | ||
| Evaluation | 756 | ||
| Assessment of Disease Severity and Waitlist Stratification | 756 | ||
| Candidates With Hepatocellular Carcinoma | 757 | ||
| Liver Transplantation: Deceased and Living Donors | 758 | ||
| Historical Perspectives | 758 | ||
| Deceased Donors: Brain Death Versus Cardiac Death | 758 | ||
| Expanded Criteria Donors | 758 | ||
| Organ Procurement Operation | 758 | ||
| Reduced-Sized and Split Livers | 759 | ||
| Living Donor: Historic Perspectives | 760 | ||
| Living Donor: Preoperative Evaluation and Planning | 760 | ||
| Living Donor: Hepatectomy | 761 | ||
| Living Donor: Impact on the Waitlist | 762 | ||
| Liver Transplantation: The Recipient Operation | 762 | ||
| Recipient Hepatectomy | 762 | ||
| Venous, Arterial, and Biliary Anastomoses | 764 | ||
| Postreperfusion Syndrome | 765 | ||
| Early Postoperative Complications of Liver Transplantation | 765 | ||
| Assessment of Early Allograft Function | 765 | ||
| Postoperative Bleeding | 765 | ||
| Technical Complications: Vascular | 766 | ||
| Technical Complications: Biliary | 766 | ||
| Current Outcomes of Liver Transplantation | 767 | ||
| Conclusion | 768 | ||
| References | 768 | ||
| References | 768.e1 | ||
| 52 Post–Liver Transplant Management | 769 | ||
| Abbreviations | 769 | ||
| Introduction | 769 | ||
| Morbidity and Mortality After Liver Transplantation | 769 | ||
| Approach to the Care of the Liver Transplant Recipient | 769 | ||
| The First 90 Days | 769 | ||
| Beyond the First 90 Days | 770 | ||
| Allograft Immune Response | 771 | ||
| Acute Allograft Rejection | 774 | ||
| Chronic Ductopenic Rejection | 775 | ||
| Antibody-Mediated Rejection | 775 | ||
| Immunosuppression | 776 | ||
| Corticosteroids | 776 | ||
| Nucleotide Synthesis Inhibitors | 776 | ||
| Calcineurin Inhibitors | 776 | ||
| Mammalian Target of Rapamycin Inhibitors | 776 | ||
| Interleukin-2 Receptor Blockers | 776 | ||
| T Cell–Depleting Agents | 776 | ||
| Use of Immunosuppressive Medications | 776 | ||
| Complications Occurring After Liver Transplantation | 778 | ||
| Persistent Portal Hypertension After Liver Transplant | 778 | ||
| Biliary Complications | 778 | ||
| Vascular Complications | 779 | ||
| Arterial | 779 | ||
| Venous | 779 | ||
| Metabolic Complications | 779 | ||
| Hypertension | 779 | ||
| Diabetes Mellitus | 779 | ||
| Dyslipidemia | 779 | ||
| Obesity | 779 | ||
| Cardiovascular Disease | 780 | ||
| Renal Disease | 780 | ||
| Metabolic Bone Disease | 781 | ||
| Posttransplant Malignancies | 781 | ||
| Skin Cancers | 781 | ||
| Posttransplant Lymphoproliferative Disorder | 781 | ||
| Solid Organ Malignancy | 781 | ||
| Infectious Disease Complications | 781 | ||
| Reproductive Health | 782 | ||
| Repeated Transplantation | 783 | ||
| Conclusion | 783 | ||
| References | 783 | ||
| References | 783.e1 | ||
| 53 Recurrent Primary Disease After Liver Transplantation | 784 | ||
| Abbreviations | 784 | ||
| Introduction | 784 | ||
| Hepatitis B and Liver Transplantation | 784 | ||
| Natural History After Liver Transplantation | 785 | ||
| Pathology of Hepatitis B After Liver Transplantation | 786 | ||
| Prevention of Recurrent Hepatitis B Virus Disease | 788 | ||
| Pretransplant Antiviral Treatment | 788 | ||
| Prophylactic Therapy | 789 | ||
| Historical Perspective | 789 | ||
| Overview of Prophylactic Strategies | 790 | ||
| Prophylaxis Using Hepatitis B Immunoglobulin Plus Nucleoside/Nucleotide Analog Therapy | 790 | ||
| Prophylaxis Using Long-Term Nucleoside/Nucleotide Analog Therapy With and Without Short Duration Hepatitis B Immunoglobulin Therapy | 791 | ||
| Treatment of Recurrent Hepatitis B Virus Disease | 791 | ||
| Management of Hepatitis B in Special Populations | 792 | ||
| Human Immunodeficiency Virus–Coinfected Patients | 792 | ||
| Hepatitis D Virus–Coinfected Patients | 793 | ||
| Recipients of Hepatitis B Core Antibody–Positive Donors | 794 | ||
| Repeated Transplantation | 794 | ||
| Hepatitis C and Liver Transplantation | 794 | ||
| Natural History After Liver Transplantation | 794 | ||
| Assessment of Hepatic Fibrosis in Liver Transplant Recipients | 795 | ||
| Pathology of Hepatitis C After Liver Transplant | 796 | ||
| Acute Rejection in Patients With Hepatitis C | 797 | ||
| Factors Associated With Disease Progression and Graft Loss | 797 | ||
| Recipient-Related Factors | 798 | ||
| Donor- and Peritransplant-Related Factors | 798 | ||
| Viral Factors | 799 | ||
| Transplantation-Related Factors | 799 | ||
| Immunosuppression and Acute Rejection | 800 | ||
| Induction Antibody Therapy | 800 | ||
| Corticosteroids | 801 | ||
| Calcineurin Inhibitors | 801 | ||
| Antiproliferative Drugs | 801 | ||
| Mammalian Target of Rapamycin Inhibitors | 801 | ||
| Treatment of Acute Rejection | 801 | ||
| Prevention and Treatment of Recurrent Disease | 801 | ||
| Pretransplant Antiviral Therapy | 802 | ||
| To Achieve Cure | 802 | ||
| To Prevent Recurrence | 803 | ||
| Posttransplant Therapy | 803 | ||
| Preemptive Therapy to Achieve Cure | 804 | ||
| Significant Fibrosis/Compensated Cirrhosis | 804 | ||
| Severe Early Recurrent Hepatitis C Virus Infection and Decompensated Cirrhosis | 805 | ||
| Retransplantation | 806 | ||
| Primary Biliary Cholangitis and Liver Transplantation | 806 | ||
| Natural History After Liver Transplantation | 806 | ||
| Risk Factors for Recurrent Primary Biliary Cholangitis | 807 | ||
| Diagnosis of Recurrent Primary Biliary Cholangitis | 808 | ||
| Management of Recurrent Primary Biliary Cholangitis | 808 | ||
| Primary Sclerosing Cholangitis and Liver Transplantation | 808 | ||
| Natural History After Liver Transplantation | 808 | ||
| Risk Factors for Recurrent Primary Sclerosing Cholangitis | 809 | ||
| Diagnosis of Recurrent Primary Sclerosing Cholangitis | 809 | ||
| Management of Recurrent Primary Sclerosing Cholangitis | 809 | ||
| Autoimmune Hepatitis and Liver Transplantation | 810 | ||
| Natural History After Liver Transplantation | 810 | ||
| Risk Factors for Recurrent Autoimmune Hepatitis | 810 | ||
| Diagnosis of Recurrent Autoimmune Hepatitis | 811 | ||
| Management of Recurrent Autoimmune Hepatitis | 811 | ||
| Nonalcoholic Fatty Liver and Liver Transplantation | 811 | ||
| Natural History After Liver Transplantation | 811 | ||
| Risk Factors for Recurrent Nonalcoholic Fatty Liver Disease | 812 | ||
| Diagnosis of Recurrent Nonalcoholic Fatty Liver Disease | 812 | ||
| Management of Recurrent Nonalcoholic Fatty Liver Disease | 813 | ||
| Alcoholic Liver Disease and Liver Transplantation | 813 | ||
| Natural History After Liver Transplantation | 813 | ||
| Risk Factors for Recurrent Alcoholic Liver Disease | 814 | ||
| Management of Recurrent Alcoholic Liver Disease | 814 | ||
| Metabolic Liver Diseases and Liver Transplantation | 814 | ||
| Wilson Disease | 814 | ||
| Hemochromatosis | 814 | ||
| Conclusion | 815 | ||
| References | 815 | ||
| References | 815.e1 | ||
| X Liver Affected by Other Conditions or Diseases | 816 | ||
| 54 The Liver in Pregnancy | 817 | ||
| Abbreviations | 817 | ||
| Introduction | 817 | ||
| Changes in Liver Anatomy and Function During Normal Pregnancy | 817 | ||
| Liver Anatomy and Histology | 817 | ||
| Hemodynamics and Hepatic Blood Flow | 818 | ||
| Changes in Liver Function | 818 | ||
| Drug Metabolism | 818 | ||
| Serum Proteins and Lipids | 819 | ||
| Bilirubin | 819 | ||
| Bile Acids | 820 | ||
| Changes in Liver Function Test Values | 820 | ||
| Liver-Related Symptoms and Physical Examination in Pregnancy | 821 | ||
| Hepatobiliary Ultrasonography in Pregnancy | 821 | ||
| Liver Diseases Not Specific to Pregnancy | 821 | ||
| Viral Hepatitis | 821 | ||
| Hepatitis A | 821 | ||
| Hepatitis B | 822 | ||
| Hepatitis C | 823 | ||
| Hepatitis E | 823 | ||
| Autoimmune Hepatitis | 824 | ||
| Wilson Disease | 824 | ||
| Pregnancy and Vascular Liver Diseases | 824 | ||
| Hemodynamic Changes Associated With Pregnancy | 825 | ||
| Portal Vein Thrombosis in Pregnancy | 825 | ||
| Budd-Chiari Syndrome and Pregnancy | 825 | ||
| Hereditary Hemorrhagic Telangiectasia | 826 | ||
| Cirrhosis and Portal Hypertension | 826 | ||
| Management of Variceal Bleeding | 826 | ||
| Management of Labor and Delivery | 826 | ||
| Hepatobiliary Disease During Pregnancy | 827 | ||
| Pregnancy and Liver Transplant | 828 | ||
| The Evaluation of a Liver Mass During Pregnancy | 828 | ||
| Liver Diseases Unique to Pregnancy | 829 | ||
| Hyperemesis Gravidarum | 829 | ||
| Etiology | 829 | ||
| Pathophysiology | 829 | ||
| Diagnosis | 829 | ||
| Management | 829 | ||
| Outcomes | 830 | ||
| Intrahepatic Cholestasis of Pregnancy | 830 | ||
| Pathogenesis | 830 | ||
| Clinical Presentation | 830 | ||
| Diagnosis | 830 | ||
| Management | 831 | ||
| Prognosis | 831 | ||
| HELLP Syndrome | 831 | ||
| Pathogenesis | 831 | ||
| Clinical Presentation | 831 | ||
| Diagnosis | 831 | ||
| Management | 832 | ||
| Outcomes | 832 | ||
| Acute Fatty Liver of Pregnancy | 832 | ||
| Pathogenesis | 833 | ||
| Clinical Manifestations | 833 | ||
| Diagnosis | 833 | ||
| Differential Diagnosis | 834 | ||
| Management | 835 | ||
| Prognosis | 835 | ||
| Future Pregnancies | 835 | ||
| Consultation of Liver Patient Regarding Pregnancy | 836 | ||
| Reference | 836 | ||
| References | 836.e1 | ||
| 55 Nutrition and the Liver | 837 | ||
| Abbreviations | 837 | ||
| Introduction | 837 | ||
| What Is Sarcopenia in Cirrhosis? | 837 | ||
| How Is Sarcopenia Diagnosed in Cirrhosis? | 838 | ||
| Clinical Significance of Sarcopenia in Cirrhosis | 838 | ||
| Contributors to Sarcopenia in Cirrhosis | 839 | ||
| Mechanisms of Sarcopenia in Cirrhosis | 839 | ||
| Therapeutic Options for Sarcopenia | 840 | ||
| Nutritional Supplementation | 841 | ||
| Exercise and Physical Activity | 841 | ||
| Anabolic Hormones | 842 | ||
| Ammonia-Lowering Measures | 842 | ||
| Molecular Targeted Therapies | 842 | ||
| Post–Liver Transplant Sarcopenia | 842 | ||
| Nonalcoholic Fatty Liver Disease and Nutrition | 842 | ||
| Conclusion | 842 | ||
| Reference | 843 | ||
| References | 843.e1 | ||
| 56 Drug-Induced Liver Injury | 844 | ||
| Abbreviations | 844 | ||
| Introduction | 844 | ||
| Epidemiology, Common Causes, and Clinical Risk Factors | 846 | ||
| Causality Assessment | 847 | ||
| Mechanisms of Hepatic Injury Due to Drugs and Chemicals | 847 | ||
| Apoptosis and Necrosis | 847 | ||
| Bioactivation of Xenobiotic Agents | 848 | ||
| Role of Glutathione in Chemical Detoxification of Reactive Electrophiles | 849 | ||
| Oxidative Stress and Free-Radical Reactions in Hepatotoxicity | 850 | ||
| Immunologic Mechanisms of Drug-Induced Liver Injury | 852 | ||
| Mechanisms: Haptens and p-i Concept | 853 | ||
| Clinicopathologic Patterns of Drug-Induced Liver Injury | 853 | ||
| Hepatocellular (Hepatitic) Pattern of Injury | 853 | ||
| Cholestatic Pattern of Injury | 857 | ||
| Mixed Pattern of Injury | 857 | ||
| Steatotic (Fatty Liver) Pattern of Injury | 858 | ||
| Macrovesicular or Mixed Microvesicular and Macrovesicular Steatosis | 858 | ||
| Predictable Versus Unpredictable Drug-Induced Liver Injury | 859 | ||
| Drug-Induced Liver Injury Due To Specific Agents | 859 | ||
| Anesthetics | 859 | ||
| Anticonvulsants | 860 | ||
| Newer Anticonvulsants | 864 | ||
| Psychotropic Drugs | 864 | ||
| Attention Deficit–Hyperactivity Disorder | 864 | ||
| Antipsychotics: First Generation | 864 | ||
| Antipsychotics: Second Generation | 864 | ||
| Antidepressants | 865 | ||
| Anxiolytic and Soporific Agents | 865 | ||
| Agents Used in the Treatment of Parkinson Disease, Migraines, and Alzheimer Disease | 865 | ||
| Antidiabetic Agents | 866 | ||
| Sulfonylureas | 866 | ||
| Biguanides | 867 | ||
| Mitiglinide Analogs | 867 | ||
| α-Glucosidase Inhibitors | 867 | ||
| Antimicrobial Agents: Antifungals, Antiparasitics, Antimalarials, and Antituberculars | 868 | ||
| Antifungals | 868 | ||
| Amphotericin B | 868 | ||
| Ketoconazole and Other Azoles | 869 | ||
| Terbinafine | 869 | ||
| Griseofulvin | 869 | ||
| Caspofungin | 869 | ||
| Flucytosine | 869 | ||
| Antimalarials | 869 | ||
| Benzimidazole Antiparasitics | 870 | ||
| Antituberculars | 870 | ||
| Isoniazid, Rifampicin, and Pyrazinamide | 870 | ||
| Ethambutol | 870 | ||
| Dapsone | 871 | ||
| Rifapentine | 871 | ||
| Ethionamide | 871 | ||
| Antimicrobials: Antivirals | 871 | ||
| Anti-HIV Agents | 871 | ||
| Nucleoside Analog Reverse Transcriptase Inhibitors | 871 | ||
| Protease Inhibitors | 872 | ||
| Nonnucleoside Reverse Transcriptase Inhibitors | 873 | ||
| Nucleotide Reverse Transcriptase Inhibitors | 873 | ||
| Fusion Inhibitors and Integrase Inhibitor | 873 | ||
| Antimicrobials: Antibacterials | 873 | ||
| Penicillins and Cephalosporins | 873 | ||
| Amoxicillin–Clavulanic Acid | 873 | ||
| Macrolides | 874 | ||
| Quinolones | 875 | ||
| Sulfonamides | 875 | ||
| Tetracyclines | 875 | ||
| Other Antibiotics | 875 | ||
| Cardiovascular Agents | 876 | ||
| Antiplatelet/Anticoagulant/Thrombolytic Agents | 876 | ||
| Angiotensin-Converting Enzyme Inhibitors | 876 | ||
| Angiotensin II Receptor Blockers | 876 | ||
| Antiarrhythmic Drugs | 876 | ||
| β-Blockers | 878 | ||
| Ca2+ Channel Blockers | 878 | ||
| Diuretics | 878 | ||
| Other Antihypertensive Agents, Including Prescription Drugs for Pulmonary Hypertension | 878 | ||
| Cholesterol-Lowering Agents | 878 | ||
| Hydroxymethylglutaryl-Coenzyme a Reductase Inhibitors (Statins) | 878 | ||
| Nonsteroidal Antiinflammatory Drugs and Acetaminophen | 880 | ||
| Antineoplastic and Immunosuppressive Agents | 883 | ||
| Antimetabolites | 883 | ||
| Alkylating Agents | 886 | ||
| Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin) | 886 | ||
| Immunosuppressants for Solid Organ Transplant | 887 | ||
| Tyrosine Kinase Inhibitors | 887 | ||
| Biologic Response Modulators | 887 | ||
| Liver Injury Due to Immune Checkpoint Inhibitors | 888 | ||
| Botanicals, Herbal Products, and Dietary Supplements | 888 | ||
| Some Botanicals, Herbal Products, and Dietary Supplements Associated With Liver Injury | 888 | ||
| Summary | 889 | ||
| Conclusion | 889 | ||
| Acknowledgments | 889 | ||
| References | 890 | ||
| References | 890.e1 | ||
| 57 Preoperative and Postoperative Hepatic Dysfunctions | 891 | ||
| Abbreviations | 891 | ||
| Introduction | 891 | ||
| Preoperative Liver Dysfunction | 891 | ||
| Postoperative Liver Dysfunction | 893 | ||
| Anesthetic-Induced Liver Injury | 894 | ||
| Ischemic Hepatitis | 894 | ||
| Acute Viral Hepatitis | 894 | ||
| Drug-Induced Hepatitis | 894 | ||
| Benign Postoperative Cholestasis | 895 | ||
| Bile Duct Obstruction | 895 | ||
| Evaluation of Patients With Postoperative Liver Dysfunction | 896 | ||
| References | 896 | ||
| References | 896.e1 | ||
| XI Inherited and Pediatric Liver Diseases | 897 | ||
| 58 Bilirubin Metabolism and Its Disorders | 898 | ||
| Abbreviations | 898 | ||
| Introduction | 898 | ||
| Jaundice as an Indicator of Hepatic Dysfunction | 898 | ||
| Formation of Bilirubin | 898 | ||
| Opening of the Heme Ring by Heme Oxygenase | 899 | ||
| Conversion of Biliverdin to Bilirubin | 900 | ||
| Potential Beneficial Effects of Products of Heme Breakdown | 900 | ||
| Measurement of Bilirubin Production | 900 | ||
| Chemistry of Bilirubin | 901 | ||
| Physical Conformation and Solubility of Bilirubin IXα | 901 | ||
| Absorption Spectra and Circular Dichroism of Bilirubin IXα | 901 | ||
| Photochemistry of Bilirubin | 902 | ||
| Conformational Isomerization and Cyclization | 902 | ||
| Fluorescence | 902 | ||
| Photooxidation and Degradation | 902 | ||
| Dismutation | 902 | ||
| Bilirubin Toxicity | 902 | ||
| Bilirubin Encephalopathy in Gunn Rats | 902 | ||
| Clinical Features of Bilirubin Encephalopathy | 904 | ||
| The Blood-Brain Barrier and Cerebral Bilirubin Clearance | 904 | ||
| Biochemical Basis of Bilirubin Toxicity | 904 | ||
| Bilirubin Nephrotoxicity | 905 | ||
| Disposition of Bilirubin | 905 | ||
| The Role of Albumin | 906 | ||
| Bilirubin-Binding Sites and Completion With Other Ligands | 907 | ||
| Determination of Reserve Bilirubin-Binding Capacity of Albumin | 907 | ||
| Irreversible Binding of Bilirubin to Albumin | 907 | ||
| Bilirubin Metabolism in Inherited Analbuminemia | 907 | ||
| Hepatic Bilirubin Uptake | 907 | ||
| Transporters | 907 | ||
| Acquired and Inherited Abnormalities of Hepatic Bilirubin Uptake | 908 | ||
| Storage of Bilirubin Within the Hepatocyte | 909 | ||
| Conjugation of Bilirubin | 909 | ||
| Enzyme-Catalyzed Glucuronidation of Bilirubin | 909 | ||
| Latency of Uridine Diphosphoglucuronate Glucuronosyltransferases | 909 | ||
| Multiple Forms of Uridine Diphosphoglucuronate Glucuronosyltransferases | 909 | ||
| Organization of the UGT1A Gene Family | 910 | ||
| Bile Canalicular Secretion of Bilirubin Conjugates and Related Organic Anions | 911 | ||
| ATP-Dependent Organic Anion Transport | 911 | ||
| Transport of Bile Acids and Non–Bile Acid Organic Anions | 911 | ||
| Role of Nuclear Receptors in the Orchestration of Various Steps Involved in Bilirubin Throughput | 912 | ||
| Fate of Bilirubin in the Gastrointestinal Tract | 912 | ||
| Extrahepatic Handling of Bilirubin | 913 | ||
| Renal Handling of Bilirubin | 913 | ||
| Intestinal Bilirubin Metabolism | 913 | ||
| Alternative Pathways of Bilirubin Elimination | 913 | ||
| Photoisomerization | 913 | ||
| Enzyme-Catalyzed Oxidation | 913 | ||
| Quantification of Bilirubin | 913 | ||
| Conversion of Bilirubin to Azo Derivatives | 913 | ||
| Chromatographic Analysis of Bilirubin Species as Intact Tetrapyrroles: Thin-Layer and High-Pressure Liquid Chromatography | 913 | ||
| Slide Tests | 914 | ||
| Transcutaneous Bilirubinometry | 914 | ||
| The Nature and Significance of Bilirubin in Body Fluids and Tissues | 914 | ||
| Bilirubin in Plasma | 914 | ||
| Bilirubin in Urine | 914 | ||
| Bilirubin Species in Bile | 914 | ||
| Bilirubin in Tissue Fluids | 914 | ||
| Bilirubin in Cerebrospinal Fluid | 914 | ||
| Bilirubin in Skin and Sclera | 915 | ||
| Disorders of Bilirubin Metabolism | 915 | ||
| Disorders Associated With Unconjugated Hyperbilirubinemia | 915 | ||
| Neonatal Hyperbilirubinemia | 915 | ||
| Increased Bilirubin Load | 915 | ||
| Immaturity of Hepatic Bilirubin Uptake | 915 | ||
| Bilirubin Conjugation | 915 | ||
| Maternal Milk Jaundice. | 915 | ||
| Maternal Serum Jaundice (Lucey-Driscoll Syndrome). | 915 | ||
| Bile Canalicular Bilirubin Excretion | 916 | ||
| Increased Intestinal Reabsorption | 916 | ||
| Management of Neonatal Hyperbilirubinemia | 916 | ||
| Hyperbilirubinemia Caused by Bilirubin Overproduction | 916 | ||
| Inherited Disorders of Bilirubin Glucuronidation | 916 | ||
| Crigler-Najjar Syndrome Type 1 | 916 | ||
| Laboratory Tests. | 916 | ||
| Abnormalities of Hepatic Uridine Diphosphoglucuronate Glucuronosyltransferases and Their Molecular Mechanisms. | 917 | ||
| Animal Models of Crigler-Najjar Syndrome Type 1: The Gunn Rat. | 917 | ||
| Ugt1a1-Deficient Transgenic Mice. | 918 | ||
| Treatment of Crigler-Najjar Syndrome Type 1. | 918 | ||
| Phototherapy. | 918 | ||
| Plasmapheresis. | 918 | ||
| Orthotopic Liver Transplant. | 918 | ||
| Experimental Methods Aimed at Reducing Serum Bilirubin Levels | 918 | ||
| Inhibition of Heme Oxygenase. | 918 | ||
| Induction of Cytochrome P-450c. | 918 | ||
| Methods Aimed at Replacing Hepatic Uridine Diphosphoglucuronate Glucuronosyltransferase Family 1 Member A1 Activity. | 918 | ||
| Hepatocyte Transplant. | 918 | ||
| Gene Therapy. | 919 | ||
| Crigler-Najjar Syndrome Type 2 (Arias Syndrome) | 919 | ||
| Clinical Features. | 919 | ||
| Laboratory Tests. | 919 | ||
| Molecular Mechanism and Inheritance. | 919 | ||
| Gilbert Syndrome | 920 | ||
| Clinical Features. | 920 | ||
| The Genetic Basis of Gilbert Syndrome. | 920 | ||
| Organic Anion Transport. | 920 | ||
| Effect of Fasting. | 921 | ||
| Effect of Nicotinic Acid Administration. | 921 | ||
| Bilirubin Conjugates in Bile. | 921 | ||
| Diagnosis. | 921 | ||
| Animal Model. | 921 | ||
| Disorders Resulting in Predominantly Conjugated Hyperbilirubinemia | 921 | ||
| Acquired Defects of Hepatobiliary Transport | 921 | ||
| Inherited Disorders of Excretion of Conjugated Bilirubin | 922 | ||
| Dubin-Johnson Syndrome. | 922 | ||
| Clinical Findings. | 922 | ||
| Laboratory Tests. | 922 | ||
| Organic Anion Transport. | 922 | ||
| The Genetic Basis of Dubin-Johnson Syndrome. | 923 | ||
| Inheritance. | 923 | ||
| Urinary Coproporphyrin Excretion. | 923 | ||
| Animal Models | 923 | ||
| Mutant Corriedale Sheep. | 923 | ||
| TR− Rats and Eisai Hyperbilirubinemic Rats. | 923 | ||
| Rotor Syndrome | 924 | ||
| Clinical Findings. | 924 | ||
| Organic Anion Excretion. | 924 | ||
| Urinary Coproporphyrin Excretion. | 924 | ||
| The Genetic and Mechanistic Basis of Rotor Syndrome. | 924 | ||
| Acknowledgments | 925 | ||
| References | 925 | ||
| References | 925.e1 | ||
| 59 Wilson Disease | 926 | ||
| Abbreviations | 926 | ||
| Introduction | 926 | ||
| Wilson Disease: History | 926 | ||
| Copper Pathway | 926 | ||
| Epidemiology: Incidence and Geographic Distribution | 927 | ||
| Pathogenesis | 927 | ||
| Basic Defect | 927 | ||
| Copper Transport and Homeostasis in Hepatocytes | 928 | ||
| Consequences of Copper Storage | 929 | ||
| Clinical Manifestations | 929 | ||
| Clinical Diagnostic Features | 929 | ||
| Hepatic Involvement | 929 | ||
| Neurologic Involvement | 930 | ||
| Psychiatric Aspects | 931 | ||
| Ocular Features | 931 | ||
| Involvement of Other Systems | 931 | ||
| Biochemical Diagnostic Features | 932 | ||
| Imaging Studies | 933 | ||
| Histopathology | 933 | ||
| Diagnosis by Mutation Analysis | 933 | ||
| Specific Mutations and Clinical Features | 934 | ||
| Diagnosis of Presymptomatic First-Degree Relatives | 935 | ||
| Diagnosis by Population Screening | 935 | ||
| Genetic Differential Diagnosis | 935 | ||
| Treatment | 936 | ||
| Chelation | 936 | ||
| Induction of Metallothioneins and Interference With Copper Absorption | 937 | ||
| Antioxidants | 938 | ||
| Dietary Management | 938 | ||
| Liver Transplantation | 938 | ||
| Gene Therapy | 939 | ||
| Special Situations | 939 | ||
| Pregnancy | 939 | ||
| Wilsonian Fulminant Hepatic Failure | 939 | ||
| Disease Complications | 940 | ||
| Consideration of Risk of Copper Deficiency | 940 | ||
| Prognosis and Natural History | 940 | ||
| Conclusion | 940 | ||
| References | 940 | ||
| References | 940.e1 | ||
| 60 Hemochromatosis | 941 | ||
| Abbreviations | 941 | ||
| Introduction | 941 | ||
| Historical Aspects | 941 | ||
| Hepcidin, the Hemochromatosis Hormone | 943 | ||
| The Genetic and Pathogenic Basis for Hemochromatosis | 943 | ||
| The Iron-Sensing Machinery | 943 | ||
| The Common Pathogenic Basis of All Forms of Hemochromatosis | 946 | ||
| Genetics and Epidemiology | 949 | ||
| The Clinical Spectrum of Hemochromatosis | 951 | ||
| Fully Expressed Hemochromatosis | 951 | ||
| The Low Penetrance of HFE C282Y Homozygotes | 951 | ||
| Non–HFE-Associated Hemochromatosis | 953 | ||
| TFR2-Associated Hemochromatosis | 953 | ||
| SLC40A1-Associated Hemochromatosis | 953 | ||
| HAMP- and HFE2-Associated Hemochromatosis (Juvenile Hemochromatosis) | 953 | ||
| Acquired Hemochromatosis | 953 | ||
| Suspecting and Diagnosing Hemochromatosis | 954 | ||
| Management | 956 | ||
| Nonhemochromatotic Genetic Iron Overload | 957 | ||
| Ferroportin Disease | 957 | ||
| Aceruloplasminemia | 957 | ||
| Atransferrinemia/Hypotransferrinemia | 957 | ||
| Divalent-Metal Transporter 1 Deficiency | 958 | ||
| Hereditary Iron-Loading Anemias With Inefficient Erythropoiesis or Altered Intracellular Iron Traffic | 958 | ||
| Porphyria Cutanea Tarda | 958 | ||
| Miscellaneous | 959 | ||
| Bantu Siderosis | 959 | ||
| Alloimmune (Neonatal) Hemochromatosis | 959 | ||
| Conclusion | 959 | ||
| Acknowledgments | 959 | ||
| References | 959 | ||
| References | 959.e1 | ||
| 61 α1-Antitrypsin Deficiency | 960 | ||
| Abbreviations | 960 | ||
| Introduction | 960 | ||
| Epidemiology | 960 | ||
| Pathogenesis | 960 | ||
| Clinical Features | 964 | ||
| Diagnosis | 966 | ||
| Treatment | 967 | ||
| Conclusion | 970 | ||
| References | 970 | ||
| References | 970.e1 | ||
| 62 Approach to and Evaluation of Metabolic Liver Diseases | 971 | ||
| Introduction | 971 | ||
| General Approach and Clinical Evaluations | 971 | ||
| Diagnostics for Metabolic Liver Diseases | 972 | ||
| Use of Age as a Determining Factor for Diagnostic Approach and Urgency | 972 | ||
| Infancy | 972 | ||
| Childhood | 973 | ||
| Adulthood | 974 | ||
| Benefits of Making a Diagnosis of Metabolic Liver Disease | 975 | ||
| Application of Genetic Testing to Diagnose Metabolic Liver Disease and the Modern Hepatologist | 975 | ||
| References | 975 | ||
| References | 975.e1 | ||
| 63 Pediatric Cholestatic Syndromes | 976 | ||
| Abbreviations | 976 | ||
| Introduction | 976 | ||
| Intrahepatic Disease | 976 | ||
| Cholestasis Associated With Infection | 976 | ||
| Bacterial Infection | 976 | ||
| Generalized Bacterial Infection | 976 | ||
| Congenital Syphilis | 976 | ||
| Other Infections | 977 | ||
| Toxoplasmosis | 977 | ||
| Rubella | 977 | ||
| Cytomegalovirus | 978 | ||
| Herpes Simplex Virus | 978 | ||
| Enteroviruses | 978 | ||
| Parvovirus B19 | 978 | ||
| Varicella-Zoster Virus | 978 | ||
| Hepatotropic Viruses | 979 | ||
| Cholestasis Associated With Endocrine Disorders | 979 | ||
| Hypopituitarism | 979 | ||
| Adrenal and Thyroid Disorders | 979 | ||
| Cholestasis Associated With Genetic Mutations | 979 | ||
| α1-Antitrypsin Deficiency (OMIM 613490) | 979 | ||
| Biochemistry and Genetics | 979 | ||
| Clinical Manifestations and Outcomes of α1-Antitrypsin Deficiency–Associated Liver Disease | 979 | ||
| Hepatic Pathology | 980 | ||
| Diagnosis | 980 | ||
| Treatment | 981 | ||
| Cystic Fibrosis (OMIM 219700) | 982 | ||
| Clinical Manifestations and Hepatic Pathology | 982 | ||
| Diagnosis | 983 | ||
| Treatment | 983 | ||
| Inborn Errors of Bile Acid Synthesis and Metabolism | 983 | ||
| Biosynthesis and Enterohepatic Circulation | 983 | ||
| Defects of Bile Acid Biosynthesis | 983 | ||
| Clinical Manifestations | 983 | ||
| Diagnosis | 984 | ||
| Treatment | 984 | ||
| Inherited Syndromes of Progressive Cholestasis | 984 | ||
| Familial Intrahepatic Cholestasis 1 Deficiency, or Progressive Familial Intrahepatic Cholestasis Type 1 (OMIM 211600) | 984 | ||
| Bile Salt Export Pump Deficiency, or Progressive Familial Intrahepatic Cholestasis Type 2 (OMIM 601847) | 985 | ||
| Multidrug Resistance Protein 3 Deficiency, or Progressive Familial Intrahepatic Cholestasis Type 3 (OMIM 602347) | 985 | ||
| Tight Junction Protein Type 2 Deficiency, or Progressive Familial Intrahepatic Cholestasis Type 4 (OMIM 607709) | 985 | ||
| Treatment | 985 | ||
| Alagille Syndrome | 986 | ||
| Clinical Features | 986 | ||
| Laboratory Evaluation | 986 | ||
| Histology | 986 | ||
| Genetics | 986 | ||
| Management and Prognosis | 986 | ||
| Neonatal Ichthyosis and Sclerosing Cholangitis (OMIM 607626) | 987 | ||
| Lymphedema Cholestasis Syndrome Type 1, or Aagenaes Syndrome (OMIM 214900) | 987 | ||
| Cholestasis in Less Characterized Disorders | 987 | ||
| Nonsyndromic Paucity of Bile Ducts | 987 | ||
| Neonatal Hepatitis | 987 | ||
| Giant Cell Hepatitis With Autoimmune Hemolytic Anemia (Bernard Syndrome) | 987 | ||
| Liver Disease Associated With Intestinal Failure and Total Parenteral Nutrition | 987 | ||
| Clinical Features | 987 | ||
| Liver Histology | 988 | ||
| Lipid Emulsions in Intestinal Failure–Associated Liver Disease | 988 | ||
| Treatment | 988 | ||
| Extrahepatic Disorders | 988 | ||
| Choledochal Cyst | 988 | ||
| Clinical Features | 988 | ||
| Diagnosis | 989 | ||
| Index | 1029 | ||
| A | 1029 | ||
| B | 1031 | ||
| C | 1032 | ||
| D | 1034 | ||
| E | 1036 | ||
| F | 1036 | ||
| G | 1037 | ||
| H | 1037 | ||
| I | 1041 | ||
| J | 1042 | ||
| K | 1042 | ||
| L | 1042 | ||
| M | 1044 | ||
| N | 1045 | ||
| O | 1046 | ||
| P | 1046 | ||
| Q | 1048 | ||
| R | 1048 | ||
| S | 1049 | ||
| T | 1050 | ||
| U | 1051 | ||
| V | 1051 | ||
| W | 1052 | ||
| X | 1052 | ||
| Y | 1052 | ||
| Z | 1052 | ||
| Clinical Key ad | IBC1 |