Aetiology
The aetiology 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.
Auto-antigens
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) auto-antibodies, family 1 of UDP-glucuronosyltransferases for anti-LKM-3 auto-antibodies, 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) auto-antibodies.[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 pre-disposed person, an environmental agent can trigger a pathogenic process leading to liver necrosis and fibrosis.
Auto-antigens 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 hypothesised that polymorphisms that control cytokine production in favour 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 necro-inflammatory process of AIH.[3]
Classification
Classification of AIH according to autoantibodies[2][3]
According to the pattern of auto-antibodies present, classification of AIH into 2 types has been proposed:
Type 1: antinuclear antibody (ANA), smooth muscle antibody (SMA), perinuclear anti-neutrophil cytoplasmic auto-antibody (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
Histological features of AIH, but serological findings of primary biliary cirrhosis (anti-mitochondrial antibody [AMA]-positive)
Histological features of primary biliary cirrhosis, but serological 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
Serological features of AIH, but histological findings and cholangiographic abnormalities characteristic of primary sclerosing cholangitis.
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