Chronic Liver Failure (eBook)

Preface 5
Acknowledgements 8
Contents 9
Contributors 12
I The Organ 16
1 Cells in the LiverFunctions in Health and Disease 17
1 Introductory Remarks 17
2 Hepatocytes 18
2.1 Hepatocytes in Physiological Conditions 19
2.2 Hepatocyte Apoptosis: A Driving Force for Acute and Chronic Liver Injury 20
2.3 Hepatocytes as a Putative Source of Myofibroblasts via Epithelial-to-Mesenchymal Transition 22
3 Kupffer Cells 23
3.1 Kupffer Cells in Acute and Chronic Liver Injury 24
4 Hepatic Stellate Cells 28
4.1 HSC in Hepatic Physiology and Pathophysiology 29
5 Sinusoidal Endothelial Cells 33
5.1 Fenestration, Ultrafiltration, and the Scavenger Role of LSECs 34
5.2 LSECs as a Source of Biologically Active Mediators 35
5.3 LSECs and Oxygen Tension (Ischemia--Reperfusion Injury, Angiogenesis) 36
5.4 Interactions of LSECs with Leucocytes and Cancer Cells 36
5.5 The Putative Role of LSECs in Immune Response 37
6 Conclusions 37
References 37
2 Liver Physiology 47
1 Bile Acids and Bile 47
2 The Liver as a Factory 49
3 The Liver as a Detoxifier 54
3.1 Specific Detoxification Pathways 54
4 The Liver as a Filter 56
References 58
3 Assessment of Liver Function in Clinical Practice 60
1 Commonly Used Liver Biochemical Tests 61
1.1 Aminotransferases 61
1.2 Alkaline Phosphatase 62
1.3 Gamma Glutamyl Transpeptidase 63
1.4 5 Nucleotidase 63
1.5 Bilirubin 64
2 Patterns of Abnormal Liver Biochemical Tests 64
2.1 Hepatocellular Pattern 65
2.2 Cholestatic Pattern 69
2.3 Hyperbilirubinemia 74
3 Evaluation for Drug-Induced Liver Injury 76
4 Tests of Hepatic Synthetic Function 77
4.1 Prothrombin Time 77
4.2 Albumin 79
5 Liver Biopsy and Noninvasive Markers of Liver Fibrosis 79
6 Quantitative Liver Biochemical Tests 83
7 ChildTurcottePugh Score and Model for End-Stage Liver Disease Score 84
References 85
4 Physiology of the Splanchnic and Hepatic Circulations 90
1 Introduction 91
2 Anatomy of the Splanchnic Circulation 91
3 Regulation of Splanchnic Blood Flow 93
4 Postprandial Hyperemia 93
5 Local Regulation of Splanchnic Blood Flow 94
6 Autoregulation of Splanchnic Blood Flow 94
7 Extrinsic Regulation of Splanchnic Blood Flow 95
8 The Hepatic Arterial Buffer System 96
9 Regulation of Sinusoidal Blood Flow 98
10 Summary 100
References 101
5 Fibrosis as a Major Mechanism of Chronic Liver Disease 104
1 Introduction 104
2 Biochemical and Structural Features of Hepatic Fibrogenesis 105
3 Biology of Fibrogenic Cells in Liver 105
4 Resolution of Fibrosis 108
5 Disease-Specific Patterns of Fibrosis 109
6 Clinical Aspects of Fibrosis - Staging and Quantification 110
7 Treatment of Fibrosis 112
References 115
6 Stem Cells and Chronic Liver Failure: Potential New Therapeutics 121
1 Introduction 121
2 Stem Cell Populations for Cell-Based Therapy 123
3 Hepatic Stem Cells in Adult Liver 124
4 Hepatic Stem Cell Activation 125
5 Identification and Isolation of Hepatic Stem Cells 128
6 Hepatic Stem Cells and Cancer 128
7 Cell-Based Therapy for Chronic Liver Disease 131
8 Conclusion 134
References 134
7 The Role of Inflammatory Mediators in Liver Failure 142
1 Introduction 142
2 Cytokines 143
2.1 TNF-a 
143 
2.2 IL-6 Cytokine Family 145
3 Reactive Oxygen Species 145
4 Arachidonic Acid-Derived Lipid Mediators 146
4.1 COX Pathway 146
4.2 Cyclopentenone PGs 150
4.3 Isoprostanes 150
4.4 5-LO Pathway 152
5 Summary 155
References 159
8 Genomics of the Liver in Health and Disease 165
1 Introduction 166
2 Single-Gene vs. Complex Diseases 166
3 Structure and Variation of the Human Genome 168
4 Relation of Genetic Variation to Disease Phenotypes 170
4.1 A. The Common Disease--Common Variant Hypothesis 170
4.2 B. The Common Disease--Rare Allele Hypothesis 171
5 Study Designs to Dissect Disease-Causing Genetic Variants 171
5.1 Candidate--Gene Approaches 171
5.2 Genome-Wide Association Studies 172
6 The Human Haplotype Map 172
7 Ethical, Legal, and Social Implications of Human Genomics 173
8 Summary 174
References 177
II Effects of Liver Failure on Organ Systems 178
9 Hepatic Encephalopathy and Alterations of Cerebral Function 179
1 Introduction 179
2 Effects of Liver Failure on Brain Function 180
2.1 Disturbances of Neurotransmission 180
2.2 Injury to Astrocytes 180
2.3 Energy Impairment 181
2.4 Brain Edema 181
2.5 Brain Atrophy 183
3 Mechanisms by which Liver Failure Induces HE 183
3.1 Ammonia Toxicity 183
3.2 Inflammation 185
3.3 Circulatory Dysfunction 185
4 Principles of Treatment 186
4.1 Nutritional Measures 186
4.2 Decreasing the Production of Toxins: Prebiotics, Probiotics, and Antibiotics 188
4.3 New Therapies 189
References 190
10 Bacterial Translocation and Alterations of the Digestive System 196
1 Pathological Bacterial Translocation in Chronic Liver Failure: Definition and Diagnosis of Bacterial Translocation 197
2 Pathophysiology of Pathological Bacterial Translocation 198
3 Pathological BT and its Potential Consequences 204
3.1 Macro- and Microscopic Changes in the Digestive System in Chronic Liver Failure 208
3.2 Functional Changes in the Digestive System and Nutrition in Chronic Liver Failure 210
References 213
11 SIRS, Bacterial Infections, and Alterations of the Immune System 226
1 Introduction 226
2 Role of Sirs in Chronic Liver Disease 227
3 Bacterial Infections in Liver Cirrhosis 228
4 Pathophysiology of Immune Dysfunction 229
4.1 Innate Immunity 229
4.2 Gut--Liver Axis 231
4.3 Adaptive Immune Response 231
4.4 Toll-like Receptors 232
4.5 Role of Albumin 233
4.6 Models of Immunopathology in ACLF 233
5 Potential Therapeutic Strategies 234
6 Summary 237
References 238
12 Regulation of the Extracellular Fluid Volume and Renal Function 246
1 Introduction 247
2 Extracellular Fluid Volume Regulation 248
2.1 Plasma and Interstitial Space Dynamics 248
3 Distribution and Regulation of Plasma Volume 254
3.1 Splanchnic and Peripheral Vasodilatation 254
3.2 Dynamic Coupling Between the Heart and Central Arterial Tree 256
4 Neurohumoral Regulation 257
4.1 Kidney Function 259
4.2 Renal Blood Flow (RBF) 260
4.3 Glomerular Filtration Rate (GFR) 261
4.4 Proximal Tubules 261
4.5 Thick Ascending Limb of Henle's Loop and Distal Tubules 262
4.6 Collecting Ducts 262
5 Hepatic Nephropathy and the Hepatorenal Syndromes 263
6 Conclusion 265
References 265
13 The Heart in Chronic Liver Failure 275
1 Clinical Features 276
1.1 Blunted Contractile Response to Stimuli 276
1.2 Electrophysiological Abnormalities 277
1.3 Abnormal Structure and Histology 278
2 Consequences of Cirrhotic Cardiomyopathy (Table 1) 279
2.1 Abnormal Renal Function 279
2.2 Responses and Survival After TIPS Insertion 282
2.3 Liver Transplantation 283
3 Possible Pathogenic Mechanisms 284
3.1 
284 
3.2 Membrane Physicochemical Changes 284
3.3 Cellular Calcium Kinetics 285
3.4 Nitric Oxide 286
3.5 Carbon Monoxide 287
3.6 Endocannabinoids 287
3.7 NF- 
288 
3.8 Myofilament Proteins 288
4 Treatment 289
References 290
14 Haemostasis Abnormalities in Chronic Liver Failure 295
1 Introduction 295
2 Primary Haemostasis 296
3 Coagulation 298
3.1 Pathophysiology of Coagulation 298
3.2 Hypocoagulability 299
3.3 Hypercoagulability 302
4 Fibrinolysis 304
5 Conclusive Remarks 306
References 307
15 The Systemic and Splanchnic Circulations 310
1 Introduction 310
1.1 Vasodilatation in the Intestinal, Splanchnic, and Systemic Circulations 312
1.1.1 Intestinal and Splanchnic Circulations 312
1.1.2 The Systemic Circulation 313
1.2 Molecular Mechanisms of Vasodilatation 314
1.2.1 Role of Nitric Oxide (NO) 314
1.2.2 Role of Carbon Monoxide (CO) 316
1.2.3 Role of Prostacyclin (PGI 
317 
1.2.4 Role of Endocannabinoids 317
1.2.5 Other Important Vasodilator Molecules 317
1.2.6 Factors That Induce and Sustain Vasodilatation 318
2 Conclusion 319

320 
References 320
16 Hepatic Microcirculation 327
1 Introduction 327
2 Physiology of Regulation of Hepatic Microcirculation 328
3 Pathophysiology of Hepatic Microcirculation 330
3.1 Microcirculation in Cirrhosis 331
3.2 Pathophysiology of Hepatic Microcirculation Due to Ischemia 332
3.3 Microcirculatory Failure in Hepatic Steatosis 333
3.4 Pathophysiology of Hepatic Microcirculation in Sepsis 333
3.5 Role of Toll-Like Receptor-4 (TLR4) Signaling 335
3.6 Role of TGF-ß 
335 
3.7 Role of MAPK Signaling Pathway 336
3.8 Role of Cyclooxygenase Pathway (TXA2) 337
3.9 Role of Endothelin-1 and Nitric Oxide 338
3.10 Role of Rheological Behavior of Red Blood Cells 340
3.11 Role of Normal Coagulation Cascade 340
3.12 Role of Arteriovenous Shunts in Sepsis 340
4 Effect of Treatment on Hepatic Perfusion in Sepsis and Shock 341
5 Conclusion 342
References 342
17 Angiogenesis and Vascular Growth in Liver Diseases 346
1 Introduction 346
2 Long-Term Structural Changes of the Hepatic Angioarchitecture in Chronic Liver Diseases 347
3 Long-Term Structural Changes of Splanchnic and Systemic Angioarchitecture in Chronic Liver Diseases 355
3.1 Long-Term Structural Changes of Splanchnic Angioarchitecture in Chronic Liver Diseases 355
3.2 Vascular Remodeling in Conductance Vessels 356
4 Conclusions 358
References 358
18 Pulmonary Alterations in Chronic Liver Failure 363
1 Introduction 363
2 Effects of Ascites, Encephalopathy, and Sleep-Disordered Breathing 364
3 Arterial Oxygenation and Pulmonary Function Testing 367
4 Hepatic Hydrothorax 368
5 Pulmonary Vasculopathies the Dilemma 370
5.1 Hepatopulmonary Syndrome (HPS) 370
5.2 Portopulmonary Hypertension (POPH) 374
References 376
19 Adrenal Function in Chronic Liver Failure 379
1 Hypothalamic-Pituitary-Adrenal Axis in Critical Illness 380
2 Effects of Cortisol During Critical Illness 382
3 A Challenging and Controversial Issue: Clinical Diagnosis of Relative Adrenal Insufficiency 383
4 Adrenal Insufficiency in Critical Illness in the General Population 384
5 Adrenal Insufficiency in Severe Sepsis or Septic Shock in Cirrhosis 385
6 Adrenal Function in other Populations of Patients with Cirrhosis 389
7 Possible Mechanisms of Relative Adrenal Insufficiency in Cirrhosis 389
8 Other Unsolved Questions 390
References 391
III Management of Chronic Liver Failure 394
20 Antibiotic Prophylaxis and Management of Bacterial Infections 395
1 Epidemiology of Bacterial Infections in Cirrhosis 395
2 Consequences of Bacterial Infection 396
3 Spontaneous Bacterial Infections 397
4 SBP Treatment 398
4.1 Basic Principles 398
4.2 Accepted Antibiotic Therapies 399
4.3 Role of Albumin 400
5 SBP Prophylaxis 400
5.1 Prophylaxis in Hospitalized Patients with Gastrointestinal Hemorrhage 401
5.2 Prophylaxis in Patients with Prior Episodes of SBP 403
5.3 Prophylaxis in Patients Without a Prior Episode of SBP 404
6 Nonspontaneous Bacterial Infections 404
6.1 Summary 405
References 406
21 Management of Ascites and Hyponatremia 411
1 Management of Ascites 412
1.1 Pharmacological Therapy 412
1.2 Choice of Diuretics and Efficacy of Treatment 412
1.3 Side Effects of Diuretics 414
1.4 Therapeutic Paracentesis 415
1.5 Transjugular Intrahepatic Portosystemic Shunt (TIPS) 416
2 Management of Hyponatremia 418
2.1 Fluid Restriction 420
2.2 Sodium Chloride Administration 420
2.3 Albumin Administration 420
2.4 AVP Antagonists -- the Vaptans 421
References 424
22 Management of Renal Failure 428
1 Introduction 428
2 Diagnosis of Renal Failure and HRS in Cirrhosis 429
3 Pathogenesis of HRS in Cirrhosis 432
4 Treatments of Type 1 HRS 440
4.1 Liver Transplantation 440
4.2 Vasoconstrictors and Albumin 440
4.3 Transjugular Intrahepatic Portosystemic Shunt (TIPS) 441
4.4 Extracorporeal Albumin Dialysis (MARS) 442
5 Treatments for Type 2 HRS 442
5.1 Transjugular Intrahepatic Portosystemic Shunt 442
5.2 Vasoconstrictors and Albumin 443
5.3 Prevention of HRS 443
References 444
23 Correction of Abnormalities of Haemostasis in Chronic Liver Disease 451
1 Introduction 451
2 Assessment of the Risk of Bleeding 453
3 Invasive procedures 454
4 Coagulation During Infection and Sepsis 456
5 Therapy of Haemostatic Abnormalities in Liver Disease 458
5.1 Vitamin K 458
5.2 Fresh Frozen Plasma and Transfusion Requirements 459
5.3 Prothrombin Complex 460
5.4 Cryoprecipitate 460
5.5 Recombinant Activated Factor VII 461
5.6 Platelet Transfusions and Treatment for Thrombocytopaenia 462
5.7 Desmopressin 464
5.8 Antifibrinolytics 464
5.9 Antithrombin III Infusion 465
6 Assessment of the Risk of Thrombosis and Clinical Use of Anticoagulation 465
References 467
24 The Treatment and Prevention of Variceal Bleeding 475
1 Introduction 476
2 Natural History of Varices in Cirrhosis 476
3 Screening for Varices 477
4 Selection of Patients for Prophylaxis 477
4.1 Patients Without Varices 477
4.2 Patients with High-Risk Varices 477
5 Treatments for the Prevention of First Bleeding: Beta-Adrenergic Blockers vs. Endoscopic Band Ligation 478
6 Prevention of Recurrent Bleeding from Esophageal Varices 481
6.1 Drug Therapy 481
6.2 Endoscopic Therapy 482
6.3 Drug vs. Endoscopic Therapy 482
6.4 TIPS in the Prevention of Rebleeding 482
7 The Acute Bleeding Episode 483
8 Treatment of Acute Variceal Bleeding 483
8.1 General Management 483
8.2 Specific Therapy for Control of Bleeding 484
8.3 Pharmacological Therapy 485
8.4 Endoscopic Therapy 486
8.5 Current Recommendations for Initial Treatment 486
8.6 Rescue Therapies: Tamponade, Surgery, and TIPS 486
9 Bleeding from Gastric Varices 488
10 Bleeding from Portal Hypertensive Gastropathy (PHG) 489
References 490
25 Extracorporeal Artificial Liver Support Systems 499
1 Introduction: Reasons for Artificial Liver Support 499
2 Pathophysiological Approach to Artificial Liver Support and Types of Liver Support Systems 500
3 Pathophysiological Effects of Liver Support Systems 506
3.1 Pathophysiological Effects of Albumin Dialysis in ACLF 506
4 Clinical Efficacy of Liver Support Systems 509
4.1 Nonbiological Artificial Devices in Acute-on-Chronic Liver Failure 509
4.2 Difficulties in the Evaluation of Clinical Efficacy of Artificial Liver Support 513
4.3 Requirements of a Future Ideal Liver Support System 513
References 514
26 Issues in Transplantation of Patients with Chronic Liver Failure 518
1 Introduction 518
2 Liver Transplant Referral and Evaluation 519
2.1 Indications 519
2.2 Pretransplant Evaluation 520
2.3 Contraindications to Transplantation 520
3 Allocation Overview 523
4 Prediction Models 524
4.1 Mayo Primary Biliary Cirrhosis Natural History Model 524
4.2 Child--Turcotte--Pugh 525
4.3 Model for End-Stage Liver Disease (MELD) and MELD Variants 526
4.3.1 MELDN a 527
4.3.2 Delta-MELD 528
4.3.3 D-MELD 528
4.4 Survival Benefit Models 529
5 The Critically Ill Liver Patient 530
5.1 Prediction Models in the Critically Ill Cirrhotic Patient 531
References 532
27 Chronic Liver Disease in the Intensive Care 537
1 Introduction 537
2 Airway 540
3 Breathing 541
4 Respiratory Mechanics, Ascites and Intra-Abdominal Pressure 541
5 Hepatopulmonary Syndrome 543
6 Portopulmonary Hypertension 544
7 Cardiovascular 544
8 Specific Liver-Related Pathologies 545
8.1 Acute Kidney Injury (AKI) 545
8.2 Hepatorenal Syndrome 546
8.3 Renal Replacement Therapy 547
8.4 Variceal Haemorrhage 548
8.5 Hepatic Encephalopathy 550
9 Summary 552
References 552
Subject Index 556