No abstract

Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.

Background/AimsRecent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study.Methodology/Principal FindingsGenomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23–2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13–1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies).Conclusions/SignificanceThis is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.

Using an autoimmune hepatitis model of A/J mice which was prepared with immunization by syngeneic crude liver proteins, various influences of neonatal thymectomy were studied by observations of histological liver changes, autoantibody to liver-specific membrane lipoprotein (LSP), delayed-type hypersensitivity (DTH) to LSP, and purified protein derivative (PPD), and suppressor activity to LSP. The liver changes in the thymectomized mice were more intense than those in the non-thymectomized controls. Production of the anti-LSP autoantibodies and positive DTH to syngeneic LSP could be recognized in both groups of the thymectomized mice and the non-thymectomized controls, but the levels of those were higher in the former. In the level of DTH to PPD the thymectomized mice were lower than the non-thymectomized controls. Adoptive transfer experiments showed that suppressor activity to LSP was reduced in the spleen cells of neonatally thymectomized mice. This experiment suggests that neonatal thymectomy is apt to abolish tolerance to LSP on account of depressed suppressor activity to autoantigen, and accordingly liver damage is increased Keywords experimental hepatitis liver-specific membrane lipoprotein neonatal thymectomy suppressor cells

Autoimmune hepatitis (AIH) is a chronic and progressive liver disease characterized by histological interface hepatitis and circulating autoantibodies. Our aims were to evaluate risk factors that contribute to the outcome and, particularly, the development of liver cirrhosis in a prospective multicenter cohort study of AIH. One hundred and seventy-four patients were enrolled. Histologically 21 (12.1%) had cirrhosis at the initial observation and the remaining 153 showed chronic or acute hepatitis at presentation. Among the latter 153 patients, 14 developed cirrhosis during the follow-up period (mean 8.0 years). Demographic, clinical, and laboratory indices associated with the development of cirrhosis were identified. Patients who developed cirrhosis differed in mean levels of alanine aminotransferase (ALT; 158 ± 182 vs. 441 ± 423 IU/ml) and platelet counts (14.7 ± 5.5 vs. 19.4 ± 6.9 × 10(4)/μl) at presentation and received lower doses of corticosteroid (13.9 ± 15.8 vs. 31.8 ± 85.5 mg/day). In a multivariate analysis, an independent predictor for progression to cirrhosis was an older age of onset (≥ 60 years). AIH patients with cirrhosis, or those who developed cirrhosis, had a worse survival. AIH patients with an older age of onset were likely to develop cirrhosis, and careful observation and aggressive treatments are necessary for such patients.