Etiology
The etiology of autoimmune hepatitis (AIH) is unknown. It is probably a consequence of a complex interaction between several factors.
Genetic predisposition
Human leukocyte antigen (HLA) genes of the major histocompatibility complex located on the short arm of chromosome 6 appear to play the dominant role in predisposition to the disease. Type 1 AIH is associated with HLA-DR3 (which is found in linkage disequilibrium with HLA-B8 and HLA-A1) and HLA-DR4, and type 2 with HLA-DQB1 and HLA-DRB. Genotyping has confirmed a high frequency of HLA-DRB1*0301, HLA-DRB3*0101, DQA1*0501, and DQB1*020, and a secondary association with HLA-DRB1*0401.[3][15] There is also evidence for a role of other, non-HLA loci that encode complement factors, immunoglobulins, and T-cell receptors.
Environmental triggering agents
These are still unknown, but may include:[3][15][16][17]
Viruses: measles virus, cytomegalovirus, hepatitis viruses (A, C, D), and Epstein-Barr virus.
Drugs: oxyphenisatin, minocycline, ticrynafen, dihydralazine, methyldopa, nitrofurantoin, diclofenac, atorvastatin, interferon, pemoline, infliximab, and ezetimibe.
Herbal agents: black cohosh and dai-saiko-to.
Autoantigens
The leading candidates are: asialoglycoprotein receptor (ASGP-R) for antibodies against ASGP-R, cytochrome P450 2D6 (CYP2D6) for anti-liver kidney microsomal-1 (anti-LKM-1) autoantibodies, family 1 of UDP-glucuronosyltransferases for anti-LKM-3 autoantibodies, UGA-suppressor tRNA-associated protein and formiminotransferase cyclodeaminase for anti-soluble liver antigen/liver pancreas (anti-SLA/LP), and anti-liver cytosol specific (anti-LC1) autoantibodies.[2][3]
Dysfunction of immunoregulatory mechanisms
AIH may develop as a component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome in 10% to 20% of patients.[2][18] APECED appears to be caused by mutation in the autoimmune regulator gene, representing the only known autoimmune disease with a monogenetic mutation.
Pathophysiology
It is believed that in a genetically predisposed person, an environmental agent can trigger a pathogenic process leading to liver necrosis and fibrosis.
Autoantigens have been implicated in the initiation of the cascade of events in AIH. If environmental agents are involved in triggering the disease, then molecular mimicry may come into play.[3] There appears to be a common susceptibility determinant in the human leukocyte antigen (HLA)-class II binding groove crucial to antigen recognition.[19] It has also been hypothesized that polymorphisms that control cytokine production in favor of the development of AIH may be inherited with the HLA haplotypes. Most of the evidence supports a central role for an alteration in T-cell function, although abnormalities in B-cell function may also be important for the escape from suppressive mechanisms and the development of the necroinflammatory process of AIH.[3]
Classification
Classification of AIH according to autoantibodies[2][3]
According to the pattern of autoantibodies present, classification of AIH into 2 types has been proposed:
Type 1: antinuclear antibody (ANA), smooth muscle antibody (SMA), perinuclear antineutrophil cytoplasmic autoantibody (pANCA), and/or anti-soluble liver antigen/liver pancreas (anti-SLA/LP)-positive
Type 2: anti-liver kidney microsomal-1 (anti-LKM-1) and/or anti-liver cytosol (anti-LC1) specific-positive.
Classification of variants of AIH[3]
Variants of AIH include:
AIH-primary biliary cirrhosis overlap syndrome
Histologic features of AIH, but serologic findings of primary biliary cirrhosis (anti-mitochondrial antibody [AMA]-positive)
Histologic features of primary biliary cirrhosis, but serologic findings of AIH (ANA or SMA-positive, AMA-negative). Sometimes considered autoimmune cholangitis or AMA-negative primary biliary cirrhosis.
AIH-primary sclerosing cholangitis overlap syndrome
Serologic features of AIH, but histologic findings and cholangiographic abnormalities characteristic of primary sclerosing cholangitis.
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