Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives.

OBJECTIVE: Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families. METHODS: To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS). RESULTS: Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive. CONCLUSIONS: Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

Effects of serum aspartate aminotransferase levels in patients with autoimmune hepatitis influence disease course and outcome.

BACKGROUND & AIMS: Untreated patients with autoimmune hepatitis (AIH) who present with aspartate aminotransferase (AST) levels that are more than 5-fold greater than the upper limit of normal (UPLN) have a mortality rate of up to 80%. This study evaluated whether serum AST levels of patients, determined at presentation, are associated with disease course or outcome. METHODS: The records of 235 patients (median age, 46 y; range, 5-80 y) who presented with AIH, based on International AIH Group score (median, 22; range, 16-28), between 1970 and 2005, were examined. AST levels at presentation were available for 213 patients, who were assigned to 3 groups: group 1, AST less than 2x the UPLN, n = 26 (median, 62 IU; range, 23-97 IU); group 2, AST 2 to 10x the UPLN, n = 71 (median, 241 IU; range, 107-500 IU); and group 3, AST greater than 10x the UPLN, n = 116 (median, 1073 IU; range, 563-4603 IU). RESULTS: Patients in groups 1 and 2 had a significantly worse outcome (risk of liver transplantation or death) compared with those in group 3 (60% survival vs 82%; P = .01; odds ratio, 2.1). These patients were more likely to present with ascites (P < .001), hematemesis (P = .009), and cirrhosis or advanced fibrosis based on an index biopsy (P < .001). Patients in groups 1 and 2 also had lower bilirubin levels at presentation (P < .001) and were less likely to be symptomatic (P < .001). CONCLUSIONS: In patients with AIH, AST levels greater than 10x the UPLN at presentation were associated with a lower risk of cirrhosis and a better long-term outcome than those with AST levels that were less than 10x the UPLN.

Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease.

Prevalence and clinical relevance of antibodies to soluble liver antigen (tRNP((Ser)Sec)/SLA) in autoimmune hepatitis (AIH) have been investigated using partially purified or prokaryotically expressed antigen. The aim of this study was to improve the detection of anti-tRNP((Ser)Sec)/SLA by establishing an immunoassay that was able to identify antibodies directed to conformational epitopes and to investigate the clinical implication of this autoantibody in autoimmune liver disease. By using eukaryotically expressed tRNP((Ser)Sec)/SLA as target in a radioligand assay (RLA), 81 patients with autoimmune liver disease (AILD) (33 type 1 AIH, 31 type 2 AIH, and 17 autoimmune sclerosing cholantitis [ASC]), 147 pathologic, and 56 healthy controls were investigated. RLA results were compared with those obtained using a commercial enzyme-linked immunosorbent assay (ELISA) and immunoblot. Reactivity to tRNP((Ser)Sec)/SLA was present in 58% of patients with type 1 and type 2 AIH, 41% with ASC, but in only 3 pathologic controls. RLA was similarly disease-specific but remarkably more sensitive than ELISA and immunoblot. A prospective study showed that anti-tRNP((Ser)Sec)/SLA-positive patients run a severe clinical course, having worse histology, needing longer to achieve remission, relapsing and requiring liver transplantation or dying more frequently than anti-tRNP((Ser)Sec)/SLA negative patients. Anti-tRNP((Ser)Sec)/SLA production was favored by the possession of DR3 and A1-B8-DR3 in AIH type 1 and ASC, and prevented by the possession of A2 in all 3 types of AILD, particularly in type 2 AIH. In conclusion, anticonformational tRNP((Ser)Sec)/SLA reactivity is frequent in type 1 and type 2 AIH and ASC, defining patients with a worse prognosis.