Autoimmune hepatitis: Pathogenesis
- Michael A Heneghan, MD, MMedSc, FRCPI
Michael A Heneghan, MD, MMedSc, FRCPI
- Consultant Hepatologist & Reader in Hepatology
- Clinical Director for Liver Services
- Institute of Liver Studies, King's College Hospital
- Section Editor
- Sanjiv Chopra, MD, MACP
Sanjiv Chopra, MD, MACP
- Editor-in-Chief — Gastroenterology/Hepatology
- Section Editor — General Hepatology
- Section Editor — Gallbladder and Biliary Tract Disease
- Professor of Medicine
- Harvard Medical School
- Senior Consultant in Hepatology
- James Tullis Firm Chief
- Beth Israel Deaconess Medical Center
Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration . The current classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder (table 1). Two major forms of AIH have been described: type 1 and type 2. Overlap syndromes also can occur with features of both autoimmune hepatitis and primary biliary cholangitis or primary sclerosing cholangitis. (See "Autoimmune hepatitis: Disease classification".)
●Type 1 autoimmune hepatitis – Type 1 or classic AIH is characterized by circulating antibodies to nuclei (ANA), smooth muscle (ASMA), and IgG F actin (AAA). AAA is not generally measured in most clinical laboratories, but ASMA with titers of 1:320 or greater almost always reflect the presence of AAA. One report found that measuring AAA by an ELISA was more sensitive than ASMA by immunofluorescence and similarly specific . (See "Autoimmune hepatitis: Clinical manifestations and diagnosis".)
A number of other autoantibodies also occur in this disorder, including atypical perinuclear antineutrophil cytoplasmic antibodies (atypical pANCA), antibodies to the liver-specific asialoglycoprotein receptor (see 'Relevant autoantigens' below), anti SLA/LP (soluble liver antigens/liver-pancreas antigens), and double-stranded DNA. The presence of AMA (antimitochondrial antibodies) has occasionally been reported but should raise the likelihood of an underlying diagnosis of primary biliary cholangitis.
●Type 2 autoimmune hepatitis – Type 2 AIH is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1), and, rarely, to ALKM-3.
The pathogenesis of autoimmune hepatitis will be reviewed here. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Autoimmune hepatitis: Clinical manifestations and diagnosis" and "Autoimmune hepatitis: Treatment".)
One theory for the pathogenesis of AIH suggests that the disease is caused by an environmental trigger in a genetically predisposed individual. The exact relationships between the genes and the autoimmune process remain largely undefined, but at the molecular level, they are thought to involve the antigen, the major histocompatibility complex (MHC), and the T cell receptor (TCR). These form a ternary complex in which short segments called complementary determining regions (CDR) identify and contact the antigen-MHC complex. Viruses, drugs, herbs, and immunizations have been suggested as triggering agents but the nature of relevant antigens is still undefined, and in most instances, no specific inducer of autoimmunity can be identified.
- Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006; 354:54.
- Frenzel C, Herkel J, Lüth S, et al. Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis. Am J Gastroenterol 2006; 101:2731.
- Donaldson PT, Albertini, et al. Immunogenetic studies of autoimmune hepatitis and primary sclerosing cholangitis. In: Elsevier Science, Krawitt EL, Wiesner RH, Nishioka M (Eds), Amsterdam 1998.
- Donaldson PT. Genetics of autoimmune and viral liver diseases; understanding the issues. J Hepatol 2004; 41:327.
- Doherty DG, Donaldson PT, Underhill JA, et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 1994; 19:609.
- de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014; 147:443.
- Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30:1205.
- Whittingham S, Mathews JD, Schanfield MS, et al. Interaction of HLA and Gm in autoimmune chronic active hepatitis. Clin Exp Immunol 1981; 43:80.
- Krawitt EL, Kilby AE, Albertini RJ, et al. Immunogenetic studies of autoimmune chronic active hepatitis: HLA, immunoglobulin allotypes and autoantibodies. Hepatology 1987; 7:1305.
- Manabe K, Hibberd ML, Donaldson PT, et al. T-cell receptor constant beta germline gene polymorphisms and susceptibility to autoimmune hepatitis. Gastroenterology 1994; 106:1321.
- Yokosawa S, Yoshizawa K, Ota M, et al. A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology 2007; 45:384.
- Björnsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51:2040.
- García-Buey L, García-Monzón C, Rodriguez S, et al. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995; 108:1770.
- Treichel U, McFarlane BM, Seki T, et al. Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis. Gastroenterology 1994; 107:799.
- Löhr H, Treichel U, Poralla T, et al. Liver-infiltrating T helper cells in autoimmune chronic active hepatitis stimulate the production of autoantibodies against the human asialoglycoprotein receptor in vitro. Clin Exp Immunol 1992; 88:45.
- Wen L, Peakman M, Lobo-Yeo A, et al. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet 1990; 336:1527.
- Löhr HF, Schlaak JF, Lohse AW, et al. Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology 1996; 24:1416.
- Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology 2006; 130:868.
- Hoshino Y, Enomoto N, Izumi N, et al. Limited usage of T-cell receptor beta chains and sequences of the complementarity determining region 3 of lymphocytes infiltrating in the liver of autoimmune hepatitis. Hepatology 1995; 22:142.
- Wies I, Brunner S, Henninger J, et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 2000; 355:1510.
- Herkel J, Heidrich B, Nieraad N, et al. Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas. Hepatology 2002; 35:403.
- Nouri-Aria KT, Hegarty JE, Alexander GJ, et al. Effect of corticosteroids on suppressor-cell activity in "autoimmune" and viral chronic active hepatitis. N Engl J Med 1982; 307:1301.
- Krawitt EL, Kilby AE, Albertini RJ, et al. An immunogenetic study of suppressor cell activity in autoimmune chronic active hepatitis. Clin Immunol Immunopathol 1988; 46:249.
- Lohse AW, Kögel M, Meyer zum Büschenfelde KH. Evidence for spontaneous immunosuppression in autoimmune hepatitis. Hepatology 1995; 22:381.
- Longhi MS, Mitry RR, Samyn M, et al. Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 2009; 50:130.
- Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006; 176:4484.
- Longhi MS, Hussain MJ, Kwok WW, et al. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 2011; 53:536.
- Peiseler M, Sebode M, Franke B, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 2012; 57:125.
- Liberal R, Grant CR, Holder BS, et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology 2015; 62:863.
- IMMUNOGENETIC ASPECTS
- HLA determinants
- Shared epitope hypothesis
- Non-HLA loci
- RELEVANT AUTOANTIGENS
- Asialoglycoprotein receptor
- Soluble liver antigen and liver-pancreas antigen
- IMMUNE REGULATORY MECHANISMS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS