Autoimmune Hepatitis (eBook)

Autoimmune Hepatitis 3
Preface 5
Contents 7
Contributors 9
Chapter 1: Introduction 11
Chapter 2: The Pathogenesis of Autoimmune Hepatitis 13
Introduction 14
The Liver as an Organ of Immunity 16
Pathogenesis of Autoimmune Hepatitis: Interplay of Susceptibility, Immune Responses, and Immunoregulation 18
Genetic Factors in Pathogenesis 18
HLA Class I, II, and III Molecules 18
Class I HLA 18
Class II HLA 20
Type I Autoimmune Hepatitis 21
Type 2 Autoimmune Hepatitis 23
Class III HLA 24
Non-HLA Genes 24
CTLA-4 24
Cytokines 25
Fas 25
Vitamin D Receptor 25
Autoimmune Regulator 1 25
Gender 26
Environmental Factors in Pathogenesis 26
Viral Infections 27
Drugs and Xenobiotics as Triggers 28
Immune Reactions and Regulation in Pathogenesis 28
Histopathology 28
Cellular Immunity 29
Oligoclonal T Cells and Liver-Specific Autoantigens 29
Role of .(Gamma)/ d(Delta)T Cells 
31 
Role of Macrophages 31
Pivotal Role of Immunoregulation 31
Treg Deficiencies 32
Restoration of Treg Function 33
Humoral Immunity 33
Role of B Cells and Antibodies 33
Autoantibodies and Type I AIH 34
Autoantibodies in Type 2 AIH 35
Role of Cytokines in Hepatic Fibrosis and Progression to Cirrhosis 35
A Working Model of AIH Pathogenesis 36
Genetic Susceptibility 36
Evolution of a Permissive Immune Repertoire 36
Environmental Triggers and Permissive Hepatic Microenvironment 37
Presentation of Hepatocyte Autoantigens or Molecular Mimics 37
Activation of Autoreactive T Cells and B Cells 38
Production of Autoantibodies 38
Failure of Immunoregulation 38
Intensification of Immunopathology: Bias Toward CD4 Th1, CD8 CTL, and Activated Effector Mechanisms 39
Regulation of Hepatocyte Cytolysis 39
Evolution of Effector Cells and Cytokines 39
Positive Feedback for Fibrogenesis Resulting in Accelerated Bridging Fibrosis and Progression to Cirrhosis 40
Appendix 41
Immune Responses: A Primer 41
Innate Immunity 41
Pattern Recognition Receptors (PRRs) and Pathogen-Associated Molecular Patterns (PAMPs) 42
Damage-Associated Molecular Patterns 42
Proinflammatory and Immunosuppressive Cytokines 42
NK Cells 43
NKT Cells 43
Adaptive Immunity 43
T Cell Receptors and HLA Class I, II, and III Molecules 44
Selection of the Immune Repertoire and Natural T Regulatory Cells 44
Costimulation 45
Dynamic Family of CD4 T Cells 45
CD8 T Cells 46
.(Gamma)/d(Delta) T Cells 
47 
B Cell Activation and Functions 47
Generation of T and B Effector Cell Responses 48
Immunoregulation of Immune Responses 48
T Regulatory Cells 49
Regulatory Dendritic Cells 49
Th17 Cells and Immunoregulation 49
Liver as an Organ of Adaptive Immunity 50
Alternatives to an Autoimmune Pathogenesis 51
References 52
Chapter 3: Clinical Presentation 60
Introduction 60
The Many Faces of Autoimmune Hepatitis 61
Acute AIH 61
Confirmation of Diagnosis of AIH 62
Chronic Autoimmune Hepatitis 63
Fulminant AIH 64
Recurrence of AIH Postliver Transplantation 65
Overlapping Autoimmune Hepatitis and Sclerosing Cholangitis 66
Overlapping Autoimmune Hepatitis and Primary Biliary Cirrhosis 67
Clinical Presentation AIH According to Ethnicity 67
African Americans/Blacks 67
South America 68
North American Indigenous Peoples 69
South Asia 69
South East Asians 70
Age at Clinical Presentation of AIH 70
Gender 72
Chapter Summary 72
Useful Tips for Practitioners 73
Common Pitfalls in Practice 73
References 73
Chapter 4: Confirmation of the Diagnosis: Interpreting the Serology 76
Introduction 77
Autoimmune Serological Types of AIH 79
Autoantibody Testing 80
Diagnostic Relevance of Autoantibodies in AIH 82
Antinuclear Antibody Testing 82
Clinical Interpretation of ANA Testing 84
Antismooth Muscle Antibody Testing 86
Clinical Interpretation of SMA Testing 86
Antiliver Kidney Microsomal Antibody Testing 88
Clinical Interpretation of Anti-LKM Antibody Testing 88
Antiliver Cytosol-1 Antibody Testing 90
Clinical Interpretation of Anti-LC1 Antibody Testing 90
Antineutrophil Cytoplasmic Antibody Testing 91
Clinical Interpretation of ANCA Antibody Testing 91
Antisoluble Liver Antigen Antibody Testing 91
Clinical Interpretation of Anti-SLA Antibody Testing 92
Antiasialoglycoprotein Receptor Antibodies 93
Conclusion 93
Chapter Summary 94
Useful Tips for Practitioners 94
Common Pitfalls in Practice 94
References 95
Chapter 5: Mimics of Autoimmune Hepatitis: Drug Induced and Immune Mediated Liver Disease 101
Introduction 101
Cytochrome P450 Family and Immune-Mediated Liver Injury 102
CYPs in Autoimmune Hepatitis 103
CYPs in the Autoimmune Polyendocrine Syndrome Type 1 (APECED) 105
CYPs in Hepatitis C Virus Infection 106
CYPs in Drug-Induced Hepatitis 107
CYPs in Alcohol-Induced Liver Disease 109
Role of Molecular Mimicry for Induction of Autoantibodies to CYP Enzymes 110
Role of Cellular Autoimmunity to CYP Enzymes 112
Uridine Diphosphate 5' -Glucuronosyltransferases and Immune-Mediated Liver Injury 
112 
UGTs in Hepatitis D Virus Infection 113
UGTs in Autoimmune Hepatitis 114
Drug-Induced Liver Without Antibodies Directed Against CYP or UGT Enzymes 114
Conclusion 114
Chapter Summary 115
Useful Tips for Practitioners 115
Common Pitfalls in Practice 115
References 116
Chapter 6: When and How to Treat the Adult Patient 122
Introduction 122
Indications for Treatment 122
Absolute Indications 123
Relative or Uncertain Indications 123
No Indication for Treatment 124
Presence of Symptoms and Decision of Treatment 124
Fulminant Autoimmune Hepatitis 124
Conventional Treatment Schedules 125
Treatment End Points 126
Treatment Outcomes 128
Treatment of Suboptimal Responses 128
Relapse After Drug Withdrawal 130
Different Treatment Schedules 131
Screening of Patients Receiving Treatment 131
Liver Transplantation for Autoimmune Hepatitis 132
New Drug Therapies for Autoimmune Hepatitis 132
Conclusion 136
Chapter Summary 137
Useful Tips for Practitioners 137
Common Pitfalls in Practice 137
References 137
Chapter 7: When and How to Treat the Pediatric Patient 142
Introduction 142
Treatment 143
Definition of Remission and Relapse 144
When to Treat 144
How to Treat 144
Standard Treatment 145
Alternative Treatments 145
Treatment of Autoimmune Sclerosing Cholangitis 146
Duration of Treatment and Prognosis 147
Liver Transplantation 147
Future Treatment Options 148
Chapter Summary 149
Useful Tips for Practitioners 149
Common Pitfalls in Practice 149
References 150
Chapter 8: Strategies for Treatment Nonresponders: Second-Line Therapies and Novel Approaches 153
Introduction 153
Antimetabolites 156
Mycophenolate Mofetil 156
6-Mercaptopurine 157
Cyclophosphamide 157
Steroid Alternatives 157
Budesonide 157
Deflazacort 158
Calcineurin Inhibitors 158
Tacrolimus 158
Cyclosporine 159
Other Medications 160
Ursodeoxycholic Acid 160
Infliximab 161
Conclusion 162
Chapter Summary 162
Useful Tips for Practitioners 163
Common Pitfalls in Practice 163
References 163
Chapter 9: Liver Transplantation for Autoimmune Hepatitis 165
Introduction 166
Indications for Liver Transplantation 166
Chronic Liver Disease 166
Hepatocellular Carcinoma 168
Fulminant AIH 169
Contraindications to Liver Transplantation 170
Outcome of Patients Following Liver Transplantation for AIH 171
Recurrent AIH (rAIH) 171
Diagnosis 174
Factors Associated with Recurrence 174
Management of Recurrent Disease and Outcomes 176
De Novo AIH 177
Conclusion 178
Chapter Summary 179
Useful Tips for Practitioners 179
Common Pitfalls in Practice 179
References 180
Chapter 10: Autoimmune Hepatitis and Pregnancy 183
Introduction 183
Background 183
Impact of Pregnancy on Disease Activity 184
Exacerbation of AIH in Pregnancy 186
Index Presentation of AIH in Pregnancy 187
Cirrhosis and Pregnancy in Patients AIH 189
Fetal Outcomes 191
Fetal Loss 191
Affect of Maternal Antibody Profile on Fetal Loss 191
Prematurity, Birth Weight and Outcomes After Delivery 191
Drug Safety 192
Azathioprine 192
Corticosteroids 193
Tacrolimus 194
Mycophenolate Mofetil 194
ß(Beta) Blockers 
195 
Breast Feeding 195
Fertility 195
Contraception 196
In Vitro Fertilisation 197
Conclusion 197
Chapter Summary 198
Useful Tips for Practitioners 198
Common Pitfalls in Practice 198
References 198
Chapter 11: Treatment Side Effects and Associated Autoimmune Diseases 202
Introduction 203
Treatment Side Effects 203
Prednisone/Prednisolone 203
Azathioprine/6-Mercaptopurine 205
Cyclosporine A 206
Tacrolimus 207
Mycophenolate Mofetil 207
Budesonide 207
Tioguanine Nucleotides 208
Others 208
Associated Autoimmune Diseases 208
Frequency 208
Risk Factors 208
Types 209
Endocrine Diseases 210
Autoimmune Thyroiditis 210
Diabetes Mellitus 210
Autoimmune Polyglandular Syndromes 210
Rheumatic Diseases 211
Arthritis/Synovitis 211
Sjogren’s Syndrome 211
Rheumatoid Arthritis 212
Systemic Sclerosis 212
Systemic Lupus Erythematosus 212
Polymyositis 213
Gastrointestinal Diseases 213
Inflammatory Bowel Disease 213
Celiac Disease 213
Hematologic Diseases 214
Idiopathic Thrombocytopenic Purpura 214
Autoimmune Hemolytic Anemia 214
Pernicious Anemia 214
Neurologic 215
Cutaneous 215
Renal 215
Conclusion 215
Chapter Summary 216
Useful Tips for Practitioners 216
Common Pitfalls in Practice 216
References 217
Chapter 12: Managing the Patient with Features of Overlapping Autoimmune Liver Disease 222
Introduction 222
Characteristics of PBC 223
Characteristics of PSC 224
Overlapping Autoimmune Disorders 224
Patients with Overlapping Features Between PBC and AIH 225
Patients with Overlapping Features Between PSC and AIH 226
Treatment of Patients with Overlap PBC–AIH 227
Studies Indicating a Positive Response of PBC–AIH Overlap Conditions to a Combination of UDCA and Immunosuppressants 227
Studies Indicating that UDCA Alone is Sufficient Therapy in PBC–AIH Overlap Conditions 230
Impact of PBC–AIH Overlap on Prognosis 230
Recommendations for Therapy in Patients with PBC–AIH Overlap Conditions 231
Treatment of Patients with Overlap PSC–AIH 231
Studies of Immunosuppression±UDCA in Patients with PSC–AIH Overlap Conditions 
232 
Impact of PSC–AIH on Prognosis 232
Conclusion: Recommendations for Therapy in Patients with PSC–AIH Overlap Conditions 233
Chapter Summary 234
Useful Tips for Practitioners 234
Common Pitfalls 235
References 235
Chapter 13: Autoimmune Hepatitis: A Look Toward the Future 240
Index 242