AIH is a chronic hepatitis of unknown cause that affects children and adults of all ages. It tends to present with a waxing and waning course. As with PBC and PSC, diagnosis is based on an elevation of liver enzymes (transaminase levels tend to be affected the most), histology, and the presence of antibodies in serum. In addi-tion, variant, overlapping, or mixed forms of AIH have been described that share fea-tures with PBC and PSC. It is important to distinguish AIH from PBC and PSC, as a high percentage of patients with AIH respond to anti-inflammatory and immu-nosuppressive therapy.
Although the exact mechanisms under-lying AIH are not known, environmental triggers such as infection with hepatitis, measles, cytomegalovirus, and Epstein-Barr virus are thought to be involved in molecular mimicry. Certain drugs such as oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, IFN, pemoline, minocycline, and atorvastatin can also cause hepatocel-lular injury, which resembles AIH.
Histologically, AIH can be indistin-guishable from a chronic hepatitis. Virol-ogy panels and cholangiography are espe-cially helpful in narrowing the differential diagnosis. AIH is characterized by a mono-nuclear infiltrate that permeates the limit-ing plate (the row of hepatocytes lining the portal triad), in what is referred to as piece-meal necrosis or interface hepatitis, which pro-gresses to hepatocyte inflammation (lobu-lar hepatitis). Plasma cells and eosinophils are frequently present and fibrosis is often present in all but the mildest of cases.
Classification of AIH is based on auto-antibody patterns. Type 1 AIH is character-ized by antinuclear (ANA) and anti-smooth muscle antibodies. Anti-actin is more spe-cific. Atypical pANCA and autoantibodies against soluble liver antigen and liver pan-creas antigen (SLA/LP) may also be pres-ent. Type 1 is also associated with HLA-DR3 and HLA-DR4. Type 2 AIH, which is rare, is characterized by antibodies to liver kidney microsome (LKM-1) and liver cyto-sol (ALC-1).
The autoantigens responsible for AIH are still being explored. One popular contender is the liver-specific membrane protein, asialoglycoprotein receptor. It is expressed in high levels in peripor-tal hepatocytes and shares some com-mon amino acid sequences with SLA/LP antigen. Even more compelling is the discovery that LKM-1 antibodies in type 2 AIH react with epitopes on the 2D6 isoform of cytochrome P450 (CYP2D6). One study found that the sera of 38 percent of chronic hepatitis C patients reacted specifically with CYP2D6, whereas the sera of hepatitis B patients did not show CYP2D5 reactivity. This lends credence to the role of HCV in molecular mimicry.
CD4+ regulatory T cells (Treg) that express the IL-2 receptor α chain (CD25) are known to suppress the proliferation and effector function of autoreactive CD4+ and CD8+ cells. Absence of these T cells has been shown to result in spontaneous autoimmune disease such as autoimmune thyroiditis, gastritis, and insulin-depen-dent diabetes in animal models. A study in humans demonstrated that Treg cells were decreased in patients with AIH as com-pared with normal controls. In addition, the percentage of Treg cells was signifi-cantly decreased at diagnosis rather than remission and was inversely proportional to the titers of anti-LKM and soluble liver antigen antibodies. The suppressor activity of the Treg cells, however, was maintained. This suggests that therapeutic measures in the treatment of AIH may include increas-ing Treg cells.
Several animal models of AIH have been described. The major limitations to most models are that they require complicated induction protocols and the hepatitis observed is generally transient. One of the more recently proposed models is based on CYP2D6 and its involvement in molecular mimicry. In this model, mice express human CYP2D6 under their own promoter in the liver. To break tolerance, these CYP2D6 mice were infected with adenovirus-CYP2D6 vector, which resulted in long-lasting hepatic damage, infiltration with B cells, CD4 and CD8 T cells, and a transient elevation in serum aminotrans-ferases. These CYP2D6 mice also had high titers of anti-CYP2D6 antibodies, which were found to react with the same immu-nodominant epitope in AIH patients.
Early diagnosis is essential as medical treatment is successful at improving long-term outcomes for patients. Prednisolone alone or in combination with azathioprine is the mainstay of treatment. Most patients require lifelong immunosuppression as maintenance therapy. Liver transplantation is required in patients who are refractory to or intolerant of immunosuppressive ther-apy and in whom end-stage liver disease develops. The survival rate among patients and grafts five years after liver transplanta-tion is approximately 80 to 90 percent, the ten-year survival rate is approximately 75 percent, and the recurrence rate has been reported to be as high as 42 percent.