Autoimmune Hepatitis (AIH)

Etiology

The etiology of AIH is multifactorial, involving genetic predisposition, environmental triggers, and dysregulated immune responses.  AIH-1 is commonly associated with HLA-DR3 and HLA-DR4, while AIH-2 has been linked with HLA-DR8. These alleles are involved in antigen presentation and may influence the immune system's ability to recognize and respond to liver antigens. Specific single nucleotide polymorphisms (SNPs) have been associated with an increased risk of AIH. For example, variations in the genes encoding interleukin-10 (IL-10) and tumor necrosis factor receptor (TNFR) have been linked to AIH susceptibility. Environmental factors can act as triggers in genetically predisposed individuals, including viral Infections (Hepatitis A, hepatitis B, and Epstein-Barr virus (EBV) infections have been implicated). Minocycline and isoniazid have been associated with drug-induced autoimmune hepatitis. Estrogen and other sex hormones might influence immune responses and contribute to the higher prevalence of AIH in females.

Diagnosis

AIH is diagnosed based on the presence of hypergammaglobulinemia, serum autoantibodies and histological features of interface hepatitis. Key markers include:

• Liver Biochemistry: Elevated levels of transaminases (AST and ALT) and gamma-glutamyl transferase (GGT) are indicative of liver inflammation and damage.
• Histological Findings: Liver biopsy revealing interface hepatitis, plasma cell infiltration, and a characteristic pattern of necroinflammatory changes supports the diagnosis of AIH.
• Autoantibodies: Specific autoantibodies help differentiate AIH from other liver diseases and autoimmune conditions, and assist in subclassifying AIH into AIH-1 or AIH-2 and can provide insights into disease prognosis. While positivity for anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) identifies type-1 AIH (AIH-1), liver-kidney-microsomal-type-1 (LKM-1) antibodies, which specifically target the cytochrome P4502D6 (CYP2D6) liver enzyme, are the serological hallmarks of type-2 AIH (AIH-2). Additional autoantibodies might aid in AIH diagnosis, especially in patients negative for ANA, SMA and LKM-1 autoantibodies. Antibodies to soluble liver antigen (SLA) have been reported in 58% of AIH patients where they are often associated with severe disease. Anti-liver cytosol type-1 (LC1) antibodies, which target formiminotransferase cyclodeaminase (FTCD), identify AIH-2, and their titer positively correlates with disease activity. Presence of anti-neutrophil cytoplasmic antibody (ANCA), particularly atypical p-ANCA (pANNA), might also help in AIH diagnosis, in the absence of positivity for the above-mentioned autoantibodies.

Table 1: Autoantibodies in different two AIHs