Autoimmune hepatitis

Abstract

Autoimmune hepatitis is an uncommon disorder characterized by chronic hepatic inflammation that improves after treatment with corticosteroids and other immunosuppressive drugs. The disorder can occur in children and adults of any age but has a particular predilection for girls and young women. The majority of patients present insidiously with malaise, anorexia and arthralgia but a minority have features that are similar or identical to acute hepatitis. Laboratory abnormalities include abnormal liver function tests, elevated serum levels of IgG and the presence in serum of various autoantibodies including antinuclear antibodies, smooth muscle antibodies (antiactin antibodies), soluble liver antigen antibodies and liver-kidney microsomal antibodies. Autoantibody profiles can be used to categorize patients into autoimmune hepatitis types 1 and 2; a categorization that has implications for responsiveness to treatment and prognosis. The most popular hypothesis for the pathogenesis of autoimmune hepatitis involves an interaction between human leukocyte antigens (HLA), hepatocyte antigens and receptors on T lymphocytes (Fig. 1). HLA antigens are glycopeptides that traverse cell membranes and are involved in the presentation of infectious and other antigens to T lymphocytes. These HLA antigens are highly polymorphic, a characteristic that appears to influence susceptibility to autoimmune disease by effects on discrimination between self and non-self. In autoimmune hepatitis, the candidate self-antigens are the asialoglycoprotein receptor (located on the hepatocyte surface) in type 1 disease and cytochrome P4502D6 or other antigens in the hepatocyte microsomes in type 2 disease. Serotyping for HLA antigens has shown that HLA-DR3 increases the risk of autoimmune hepatitis type 1 by 12–fold in Caucasian populations. An increase in risk has also been associated with HLA-DR4. These findings have been confirmed using HLA genotypes where significant associations have been reported for the HLA haplotype DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201. The first two alleles of the haplotype correspond to the serologic determinants DR3 and DR52 but whether DRB1*0301 or DRB3*0101 is the primary susceptibility allele has not been resolved. The serotype, HLA-DR3, has also been associated with more severe forms of the disease and with onset at a younger age. In Japan, where HLA-DR3 is rare, HLA-DR4 confers a relative risk for autoimmune hepatitis type 1 of approximately 15. Pathogenesis of autoimmune hepatitis. A variety of viruses including hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus and measles virus have been implicated as triggers for autoimmune hepatitis. Additional triggers may include drugs such as minocycline, atorvastatin, methyldopa, nitrofurantoin and pemoline. Whether it is relevant that the proposed target antigen for autoimmune hepatitis type 2 is a drug-metabolizing enzyme remains unclear. In relation to the pathogenesis of autoimmune hepatitis, one possibility is molecular mimicry between the offending virus or drug and hepatocyte antigens. In genetically predisposed individuals, this may result in an inappropriate immune response against the hepatocyte, even after elimination of the virus or cessation of the drug. It is widely believed that the incidence of autoimmune hepatitis has declined, at least in Caucasian populations. This may reflect lower incidence rates for acute viral hepatitis, particularly hepatitis A. The relative importance of other environmental triggers is less clear although case reports have highlighted the potential role of minocycline. The HLA associations described above are not specific for autoimmune hepatitis type 1 as similar associations have been reported for other autoimmune diseases. Furthermore, there is no consensus, as yet, on a role for other polymorphisms that might influence the function of the T-cell receptor or other components of the immune response. Krawitt EL. N. Engl. J. Med. 2006; 354: 54–66. Manns MP, Vogel A. Hepatology 2006; 43: S132–44. Vento S et al. Lancet 1991; 337: 1183–7.