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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (2) : 187-219     DOI: 10.1007/s11684-015-0386-y
REVIEW |
Autoimmune hepatitis
Farhad Sahebjam,John M. Vierling()
Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St. Luke’s Medical Center, Houston, TX 77030, USA
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Abstract  

Autoimmune hepatitis is a chronic liver disease putatively caused by loss of tolerance to hepatocyte-specific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. It is currently divided into types 1 and 2, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2. Although autoimmune hepatitis occurs in childhood, this review focuses on disease in adults. In the absence of pathognomonic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features also occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. New practice guidelines have redefined criteria for remission to include complete biochemical and histological normalization on immunosuppressive therapy. Immunosuppression is most often successful using prednisone or prednisolone and azathioprine; however, the combination of budesonide and azathioprine for non-cirrhotic patients offers distinct advantages. Patients failing standard immunosuppression are candidates for alternative immunosuppressive regimens, yet none of the options has been studied in a randomized, controlled trial. Overlap syndromes with either primary sclerosing cholangitis or primary biliary cirrhosis occur in a minority. Liver transplantation represents a life-saving option for patients presenting with acute liver failure, severely decompensated cirrhosis or hepatocellular carcinoma. Transplant recipients are at risk for recurrent autoimmune hepatitis in the allograft, and de novo disease may occur in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo inflammatory bowel disease. Progress in our understanding of the immunopathogenesis should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies.

Keywords autoimmune hepatitis      autoantibodies      diagnosis      immunological diseases      drug-induced liver injury      therapy      immunosuppression      outcomes      hepatocellular carcinoma      liver transplantation     
Corresponding Authors: John M. Vierling   
Online First Date: 05 March 2015    Issue Date: 22 May 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0386-y     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I2/187
2002 practice guideline 2010 practice guideline
Goal Reduce mortality and symptoms Prevent progression of disease and need for OLT
Biochemistry Reduce AST/ALT to 1.5-2 × ULN Normalize ALT
Histology Eliminate interface hepatitisConfine inflammation to portal tracts Eliminate interface hepatitisEliminate lymphoplasmacytic inflammatory infiltrates in portal ?tracts
Clinical outcome Reduce rate of progression to cirrhosis Prevent development of cirrhosisPrevent progression of established cirrhosis
Immunosuppressive therapy Minimize immunosuppression to decrease serious adverse ?events Combine immunosuppressive drugs to minimize adverse events
Tab.1  Comparison of AASLD 2002 and 2010 autoimmune hepatitis practice guidelines
AIH type 1 AIH type 2
Signature autoantibodies ANA, ASM, Anti-f-actin* Anti-LKM1, Anti-LC1, Anti-LKM3
Overlapping autoantibodies Anti-SLA/LP Anti-SLA/LP
Geographic distribution Global Global but with geographic differences in adult ?prevalence: Europe>USA
Female to male ratio 4 to 1 10 to 1
Age distribution Infancy to elderly adulthood Childhood to young adulthood
Clinical presentation and course Indolent>>Severe Severe
Histology at presentation Spectrum ranging from mild disease to cirrhosis to ?ALF with massive hepatocellular necrosis High grade inflammation cirrhosis common
Treatment failure Uncommon Common
Requirement for long-term immunosuppression Majority Universal
Tab.2  Comparison of autoimmune hepatitis type 1 and type 2
Fig.1  Hypothetical sequence of events in the immunopathogenesis of autoimmune hepatitis.
Susceptibility alleles Geographic area
DRB1*0301 North America and Europe
DRB1*0401 North America and Europe
DRB1*0404 Japan, China and Mexico (Mestizo)
DRB1*0405 Japan, China and Argentina (adults)
Resistance alleles
DRB1*1501 North and South America, Europe, ?Japan
DRB1*1302 South America
DQB1*0301 South America
Tab.3  HLA DRB1 alleles associated with autoimmune hepatitis susceptibility and resistance in different geographic areas
Revised original scoring system1 Simplified scoring system2 Proposed diagnostic criteria for ?ALF3
Female sex +2 Autoantibodies Autoantibodies
Alk Phos/AST or (ALT) ratio >3 –2 ANA or SMA ≥1:40 +1 ?ANA, SMA, LKM1, Anti-SLA,
<1.5 +2 ≥1:80 +2 anti-f-actin
LKM-1 ≥1:40 +2 Histopathological features
g-globulin or IgG × ULN >2 +3 Anti-SLA Positive +2 ???massive hepatic necrosis
1.5–2.0 +2 ???lymphoid follicles
1.0–1.5 +1 Immunoglobulin level? ???plasma cell-enriched
<1.0 0 IgG or >ULN +1 inflammatory infiltrates
g-globulin >1.1 × ULN +2 ???central zonal
ANA, SMA, LKM-1 titers >1:80+3 +3 necrosis/perivenulitis
1:80 +2 Histological features
1:40 +1 Compatible with ?AIH +1
<1:40 0 Typical of AIH* +2
AMA positive –4 Absence of viral hepatitis
Viral markers Positive –3 Yes +2
Negative +3 No 0
Drugs Yes –4 Pretreatment aggregate score
No +1 Definite diagnosis ≥7
Probable diagnosis ≥6
Alcohol <25 g/d +2
>60 g/d –2
HLA DR3 or DR4 +1
Concurrent immunological disease
Thyroiditis, colitis, etc. +2
Other markers
Anti-SLA, f-actin, pANCA +2
Histological features
Interface hepatitis +3
Plasma cells +1
Rosettes +1
None of above –5
Biliary changes –3
Other features –3
Treatment response
Complete +2
Relapse +3
Pre-treatment aggregate score
Definite diagnosis >15
Probable diagnosis 10–15
Post-treatment aggregate score
Definite diagnosis >17
Probable diagnosis 12–17
Tab.4  Diagnostic criteria for scoring systems in autoimmune hepatitis
Autoantibody Target antigen(s) Liver diseases Diagnostic value
Type 1
ANA Multiple antigens: chromatin,?ribonucleoproteins, ribonucleoprotein ?complexes AIH, PBC, PSC, DILI, chronic ?HBV, HCV infections, NAFLD Compatible with type 1 AIH, but not diagnostic
SMA Microfilaments: filamentous actin (f-actin) Intermediate filaments: vimentin, desmin AIH, PBC, PSC, DILI, HBV, ?HCV, NAFLD Compatible with type 1 AIH, but not diagnostic
pANCA β-tubulin isotype 5, cross reacts with ?bacterial precursor protein FtsZ AIH, PSC, IBD Compatible with diagnosis of type 1 AIH but ?not diagnostic
Type 2
LKM-1 Cytochrome P450 2D6 (CYP2D6) AIH, chronic HCV infection, ?halothane-induced hepatitis Diagnostic of type 2 AIH in absence of HCV ?infection
LC-1 Formiminotransferase cyclodeaminase ?(FTCD) AIH type 2 Liver specificDiagnostic of type 2 AIH
LKM-3 Family 1 UDP-glucuronosyltransferases ?(UGT1A) AIH, chronic HDV Diagnostic of type 2 AIH in absence of chronic ?HDV infection
Type 1 or 2
SLA tRNA-selenocysteinyl-tRNA synthase ?(SepSecS protein) AIH type 1 or 2HCV infection? Liver specificDiagnostic of AIH in absence of HCV infectionPrognostic for severe disease, relapse after ?withdrawal of immunosuppression
ASGPR Asialoglycoprotein receptor AIH, PBC, DILI, chronic HBV, ?HCV, HDV infections Liver specificCompatible with type 1 or 2 AIHPrognostic for severe disease, histopathological ?activity and relapse after withdrawal of ?immunosuppression
Tab.5  Autoantibodies and the differential diagnosis of AIH
Fig.2  Diagnosis and treatment of autoimmune hepatitis. Abbreviations: RDC, revised diagnostic criteria [50]; SDC, simplified diagnostic criteria [51]. *Clinical trials in USA proved that azathioprine at a fixed dose of 50 mg/d was safe and effective when combined with prednisone to induce remission in AIH. Clinical trials in the European Union proved that azathioprine dosages of 1–2 mg/(kg·d) also were safe and effective when combined with prednisone to induce remission in AIH. Thus, both are evidence-based induction regimens [1]. ** Budesonide is appropriate only for patients without cirrhosis.
Fig.3  Histopathology of acute and chronic autoimmune hepatitis. (A) Photomicrograph showing lymphoplasmacytic portal inflammation and interface hepatitis in chronic autoimmune hepatitis. (B) Photomicrograph showing central zonal necrosis and perivenulitis of the terminal hepatic venule in acute autoimmune hepatitis.
Prescription drug Multiple reports?
Minocycline Yes
Nitrofurantoin Yes
Propylthiouracil Yes
Diclofenac Yes
Tienilic acid Yes
Alpha-methyldopa Yes
Stains Yes
Pemoline Yes
Ornidazole Yes
Clometazine No
Infliximab Yes
Adalimumab Yes
Natalizumab No
Ramelton Yes
Tab.6  Prescription drugs reported to cause autoimmune hepatitis
Therapeutic approaches Comments
New immunosuppressive agents Belatacept is a protein created by fusion of the Fc fragment of a human IgG1 immunoglobulin linked and the extracellular domain of CTLA-4, a homolog of CD28 on T cells. It binds to B7.1/7.2 (CD80/CD86), blocking CD80/CD86 costimulation of T cells required for T cell proliferation and development of effector cell functions. It is a promising agent for pilot studies in refractory AIH.Leflunomide inhibits pyrimidine synthesis required for lymphocytes proliferation. In addition, it interferes with T cell transendothelial migration and modulates cytokine production, effector cell functions and production of metalloproteinases.Fingolimod causes sequestration of lymphocytes in lymphoid tissue and the thymus, preventing the lymphocyte circulation and transendothelial migration into tissue. Cumulative consequences include modulation of monocytic dendritic cell functions, lymphocyte apoptosis, inhibition of transendothelial migration of activated T cells, prevention of activation of tissue-infiltrating lymphocytes, and inhibition of germinal centers with suppression of humoral immunity. Clonal T cell activation, proliferation and differentiation of effector functions remain unaltered. It has been used to prevent experimental AIH.Chemokine receptor inhibitors have potential to treat AIH. Chemokines promote transendothelial migration of activated leukocytes bearing specific chemokine receptors. Chemokine gradients within tissue chemoattract leukocytes and induce effector functions. Thus, chemokines produced by activated leukocytes and epithelial cells within tissue and organs control the composition, quantity and functions of inflammatory cells migrating to a site of inflammation. Multiple inhibitors of chemokine receptors have been identified, including antagonists of CCR1, CCR3, CCR5, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR6. Preliminary studies indicate the potential therapeutic value of chemokine receptor inhibition in hepatic inflammatory diseases. CD4 T helper 1 cells mediating immunopathology predominantly express the chemokine receptor CXCR3. CXCR3 ligands CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (ITAC) are generated by leukocytes and epithelial cells in sites of inflammation. CXCR3 antagonists are candidates for pilot studies in AIH.
Antifibrotic agents Antifibrotic strategies are appealing to prevent progression of chronic AIH to cirrhosis. Antifibrotics appear most applicable as a concomitant therapy with immunosuppression to reduce inflammation and the associated cytokines responsible for fibrogenesis and proliferation of activated myofibroblasts. Simtuzamab, a humanized monoclonal antibody against lysl-oxidase like-2 that prevents cross-linkage of collagen, is being studied as an antifibrotic agent in clinical trials for NASH and PSC.
Autoantigen-specific immunoregulation Antigen-specific T regulatory cells appear to be the most promising candidates to inhibit antigen-specific effector functions of CD4 T cells. See text for further discussion.
Restoration of tolerance to autoantigens Re-establishing self-tolerance to autoantigens in autoimmune diseases is a primary goal of research in immunology. To date, no strategies applicable to AIH have been proposed.
Prevention with tolerogenic immunization Ingestion of an antigen leads to induction of antigen-specific tolerance in the liver and prevents systemic responses when the antigen is subsequently administered. Oral administration of autoantigens responsible for the autoimmune diseases type 1 diabetes mellitus and multiple sclerosis has been proposed to prevent these diseases. Autoantigens responsible for type 2 AIH are also potential candidates for oral tolerance.
Tab.7  Conceptual approaches to future therapies for autoimmune hepatitis
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