Version May 2024
INTRODUCTION — 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 [1]. 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.
●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 [2]. (See "Overview of autoimmune hepatitis".)
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 [3,4].
The pathogenesis of autoimmune hepatitis will be reviewed here. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Overview of autoimmune hepatitis" and "Management of autoimmune hepatitis".)
OVERVIEW — 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, and the T cell receptor. These form a ternary complex in which short segments called complementary determining regions 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 [5].
Most of the evidence supports a central role for an alteration in T cell function in the pathogenesis of AIH, although abnormalities in B cell function also may be important. Implicit in this loss of tolerance is an escape from normal suppression of self-reactive T cells, which results in ongoing inflammation and necrosis.
IMMUNOGENETIC ASPECTS — The search for genetic predisposing factors has, in large part, been directed at genes of the immunoglobulin superfamily which includes those encoding human leukocyte antigens (HLA) located in the major histocompatibility complex, immunoglobulins (Ig), and TCR molecules [6-8].
HLA determinants — In White individuals, classical (type 1) autoimmune hepatitis (AIH) is strongly associated with the HLA-DR3 serotype (which is found in linkage disequilibrium with HLA-B8 and HLA-A1) and with HLA-DR4. DRB1*0301 and DRB3*0101 are common genotypes in North America. In South America, DRB1*1301 is common. These findings have been confirmed in a genome-wide association study (GWAS) from the Netherlands [9]. In Northern European children, association with HLA-DRB1*03 represented the strongest risk factor for disease. However, DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in children with AIH-1 [10].
●HLA-DR3-associated disease is more commonly found in the early-onset, severe form of disease (often occurring in girls and young women). In comparison, HLA-DR4 is more common in patients with late-onset disease and appears to be associated with a higher incidence of extrahepatic manifestations and a better response to corticosteroids.
●Type 2 disease is associated with HLA-DRB1*07, HLA-DRB1*03 and DQB1*0201 alleles.
●In Japan, where HLA-DR3 is rare, there is a primary association with the HLA-DR4 serotype (genotype DRB1*0405 and genotype DQB1*0401).
There may be weaker associations with HLA-class I MICA genes, the promoter region of tumor necrosis factor alpha and complement genes (class III). The GWAS study from the Netherlands also identified variants of SH2B3 on chromosome 12, and CARD10 on chromosome 22 with AIH [9].
Shared epitope hypothesis — There appears to be a common susceptibility determinant in the HLA-class II binding groove crucial to antigen recognition that is carried by the DRB1*0301, DRB3*0101, and the DRB1*0401 alleles. A detailed analysis of the amino acid sequences encoded by these susceptibility alleles revealed a particular motif Leu-Leu-Glu-Gln-Lys-Arg at positions 67-72 of the DR polypeptide, which is encoded by DRB1*0301, DRB3*0101, and DRB1*0401 [8]. The critical amino acid in this motif may be the Lys residue at position 71. Although the alleles determining susceptibility are different, a similar shared epitope in the DRB molecule (amino acids 67-74) appears to control the susceptibility to rheumatoid arthritis [11]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
The determinants are different in Japanese patients in which the predominant DR4 allele in AIH is DRB1*0405. Arg or His at position 13 may be critical in these patients. The DRB1*0405 allele encodes Leu-Leu-Glu-Gln at position 67-70 and Arg at position 72, but Arg is at the presumed critical position 71.
Non-HLA loci — There is also evidence that loci that code for immunoglobulins and TCR play a role in the genetic predisposition to autoimmune hepatitis [6]. One of two studies seeking an association between AIH and genes encoding constant regions of Ig heavy chains on chromosome 14 found a weak association with the Ig allotype Gm(a,x) [12]. The effect of the Ig genes appeared to be interactive with those of the HLA-genes in that Gm(a,x) in the presence of HLA-B8 resulted in a relative risk of 39 compared to a relative risk of 12 for individuals with B8 or DR3 in the absence of Gm(a,x). Subsequent family studies did not support linkage between a disease-susceptibility locus and an Ig locus [13].
A study of TCR constant germline restriction fragment length polymorphisms uncovered an increase of homozygosity for a 10 kb/Bgl II fragment in AIH patients, which was more pronounced in those without DR3 or DR4 [14]. A study using a genome-wide DNA microsatellite approach in 81 Japanese patients looking for weaker associations than those that occur at HLA loci found 26 candidate susceptibility regions in DR4-positive patients [15]. Understanding the weaker associations in AIH will probably require genome-wide association analysis or other advanced modalities in large numbers of patients to ensure statistical validity.
TRIGGERING — The presumed environmental triggering agent(s) important in autoimmune hepatitis are unknown, but may involve viruses, drugs, herbs, and immunizations. There is some evidence implicating measles virus, hepatitis viruses, herpes simplex virus, varicella zoster virus, cytomegalovirus, and Epstein-Barr virus as initiators of disease, perhaps involving a long latency period after infection, perhaps because of molecular mimicry of viral sequences to host proteins.
A few drugs induce hepatocellular injury that mimics autoimmune hepatitis. These include oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, minocycline, and possibly statins [16]. The administration of interferon may unmask or induce autoimmunity, and treatment of chronic viral hepatitis with interferon alfa may induce or unmask autoimmune hepatitis [17]. Although autoantibodies and hyperglobulinemia occur in so-called drug-induced AIH, there is scant evidence that a self-perpetuating injury can occur after discontinuation of the drug. There has there been no evidence of any drug definitely altering a self-antigen or the production of a neo-antigen, although these are reasonable hypotheses. Lupus-like syndromes can be caused by drugs and have occurred in patients taking minocycline and atorvastatin. (See "Drug-induced lupus".)
RELEVANT AUTOANTIGENS — The autoantigens responsible for initiating the cascade of events in autoimmune hepatitis (AIH) have yet to be definitely identified.
Asialoglycoprotein receptor — Over the years, a leading autoantigen candidate has been the asialoglycoprotein receptor (ASGPR), a liver-specific membrane protein expressed in high density in the periportal hepatocytes, to which circulating antibodies appear in many patients with AIH. In one study of North American, European, and Japanese patients with AIH, 53 of 62 (85 percent) with active disease had antibodies against this protein [18].
ASGPR-reactive peripheral and liver-infiltrating lymphocytes have been described. In one report, for example, liver-infiltrating T cells obtained from liver biopsy showed a proliferative response to ASGPR and could induce anti-ASGPR antibodies from peripheral blood monocytes, which had been depleted of T cells [19]. This antigen could serve alone or be altered by an environmental agent to produce a neoantigen to function as a relevant self-antigen. The levels of circulating ASGPR antibodies correlate with disease activity, but their presence in other diseases suggests that they may reflect autoimmune processes not specific to AIH.
There are a number of experimental observations supporting the hypothesis that ASGPR plays a central role in the pathogenesis of AIH. These include the demonstration that this antigen can initiate an antibody-dependent cellular cytotoxic process directed against hepatocytes [20].
Anti-CYP2D6 — In type 2 AIH, anti-LKM-1 antibodies, which are directed at an epitope of CYP2D6 (cytochrome P450IID6), may be intimately involved in pathogenesis. In one report, for example, peripheral blood mononuclear cells from all eight patients with type 2 AIH and from 6 of 12 LKM-1 antibody-negative type 1 disease patients proliferated after exposure to a 23-amino acid LKM peptide and a shorter 18-amino acid LKM peptide; the activated T cells secreted large amounts of interferon gamma [21]. The response rate was much lower (13 percent) with mononuclear cells from control patients with hepatitis C virus infection. Follow-up showed that these LKM-specific T-cell responses decreased after immunosuppressive therapy was initiated. Polyclonal T cell responses to CYP2D6 appear to be involved in type 2 AIH [22]. Clonal analysis of the TCR chain variable region repertoires in liver-infiltrating lymphocytes has demonstrated oligoclonality for CDR region 3 (V3) [23].
Soluble liver antigen and liver-pancreas antigen — Antibodies against SLA/LP have proven rather specific for AIH and have been described in both type 1 and type 2 AIH. Their presence in both the type 1 and 2 disease argues against these antibodies defining a unique type of AIH, although it is possible that the pathogenesis of different forms of AIH may differ according to the autoantibody profile.
Cloning and characterization of the SLA antigen revealed that it was a unique enzyme (possibly a UGA-suppressor or tRNA-associated protein) and a member of the superfamily of pyridoxal phosphate-dependent transferases [24,25]. Furthermore, the antigen is identical to the liver-pancreas antigen; thus, the designation SLA/LP was adopted. The role of this enzyme in the pathogenesis of autoimmune hepatitis remains to be elucidated. The antibodies themselves are of the IgG1 subtypes, suggesting that they may arise from a specific immune stimulus such as a viral protein. However, no homologous virus-derived peptides could be identified in one report. Nevertheless, anti SLA/LP antibodies are important diagnostic markers for AIH, particularly in those who lack other serologic markers. Positive results appear to be confined to patients with either AIH or an AIH/PBC overlap syndrome.
IMMUNE REGULATORY MECHANISMS — Early studies of immune regulation, based primarily upon in vitro observations, supported the hypothesis of a defect in downregulation of the immune response; suppressor cell dysfunction mediated by CD8 positive lymphocytes was reversed in AIH patients with corticosteroid treatment [26,27]. Based upon observations in a murine model of experimental AIH and in patients, it has been postulated that spontaneous remission and long-lasting remission after discontinuance of immunosuppressive therapy may result from spontaneous immunosuppression. In one study, for example, T cells obtained during remission markedly suppressed the liver-specific T cell responses by T cells obtained during the active phase of the disease [28].
Over the past decade, focus has shifted to pathways involving regulatory T cells (Treg). This subpopulation of T cells down regulates immune responses and maintains tolerance to self-antigens. These cells express high levels of CD25, low levels of CD127, and express CTLA-4 and the forkhead transcription factor forkhead box P3 (FOXP3). FOXP3 regulates their development. Several studies have described defective Treg function in autoimmune hepatitis, although defective T cell activation may also be relevant [29-32]. Data suggest that Tregs are numerically impaired in autoimmune liver disease and that the impairment is more prominent during active disease [33]. Additionally, defective IL-10 production, resulting from low Treg responsiveness to IL-2, contributes to Treg functional impairment. In type 2 AIH, both effector T cells and Treg recognize the same autoantigen, thus making Treg therapy an attractive potential therapeutic option [31]. In contrast, for type 1 AIH, the potential use of Treg therapy assumes that a polyclonal Treg cell population can be developed.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Autoimmune hepatitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Autoimmune hepatitis (AIH) is a chronic hepatitis characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. (See 'Introduction' above.)
●The cause is unknown, but believed to be autoimmunity. One theory 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, and the T cell receptor. (See 'Overview' above.)
Most of the evidence also supports a central role for an alteration in T cell function in the pathogenesis of AIH, although abnormalities in B cell function also may be important. Implicit in this loss of tolerance is an escape from normal suppression of self-reactive T cells, which results in ongoing inflammation and necrosis.
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