[905][906][907][908][909][910]

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Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42% of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR beta polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.

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Previous studies based on serological HLA phenotyping have implicated genes in the HLA class II region in susceptibility to and protection from primary sclerosing cholangitis. In a recent report, the HLA DRw52a antigen was present in all 29 patients who had been referred for liver transplantation. In this study, HLA DRB, DQA and DQB genotypes were studied using gene amplification and sequence-specific oligonucleotide probing in 71 patients with primary sclerosing cholangitis and 68 healthy controls to determine the frequency among the patients of the DRB3*0101 allele that encodes DRw52a and whether other class II alleles are involved in susceptibility or protection. DRB3*0101 was the most strongly associated allele, being present in 55% of the patients and 22% of the controls. Survival among the DRB3*0101-positive patients was reduced compared with the DRB3*0101-negative patients. Both DRB3*0101 and DRB5*0101, a possible second DRB susceptibility allele, encode a leucine residue at position 38 of the DR beta molecule. The DRB4*0101 allele, which encodes DRw53 and may be protective, encodes an alanine residue at this position. Susceptibility to and protection from primary sclerosing cholangitis may result from amino acid substitutions at position 38 of the DR beta molecule because maximum relative risk was conferred by two leucine-38-containing DR beta molecules, whereas minimum relative risk was conferred by two alanine-38-containing molecules.

A 20‐year experience with 112 patients with cholangiocarcinoma was reviewed with reference to the demographic, etiologic, and clinical features and prognosis in the following two types: peripheral (originating from the intrahepatic small duct radicles) and hilar (originating from the major hepatic ducts at or near the junction of the right and left hepatic ducts). Seventy of the 112 patients were in the hilar group, and 42 were in the peripheral group. Prolonged high alcohol consumption was a prominent feature in both categories (45% and 37%, respectively). Among the women, 35% of those with the peripheral tumor had used oral contraceptive preparations. The major identifiable etiologic factor among the hilar tumors was ulcerative colitis, with or without sclerosing cholangitis, which was documented in 20 of 70 cases (28.6%), with an additional 4 patients having Crohn's disease. The hilar group mainly had obstructive jaundice initially, whereas abdominal pain and weight loss were the predominant symptoms in the peripheral type. Tumor recurrence was frequent in those undergoing resection or transplantation, and none of those undergoing chemotherapy or radiation therapy showed any objective evidence of response. Overall median survival time was poor in both groups at 12 months.

Human leukocyte antigen typing was performed in 81 patients with primary sclerosing cholangitis to investigate reported associations between human leukocyte antigen type and this disease. The results showed a significant increase in the frequency of the antigens B8 and DR3 compared with controls (53% vs. 23%, p less than 0.0005, and 56% vs. 21%, p less than 0.0005). This was caused by a significant rise in the frequency of the human leukocyte antigen A1 B8 DR3 haplotype (32 of 81 patients, 40% vs. 12 of 100 patients, 12%, p less than 0.0005). By contrast, a significant reduction was seen in the frequency of the antigens B44 and DR4 (12% vs. 31%, p less than 0.005, and 12% vs. 34%, p less than 0.001, pc less than 0.011) because of the complete absence of the B44 DR4 haplotype in the patient group (p = 0.027, Fisher's exact test). When all the DR3-positive individuals (including the DR2/DR3 heterozygotes) were eliminated, a significant secondary association with DR2 was noted, 25 (69%) of 36 remaining patients being DR2-positive compared with 27 (34%) of 79 DR3 negative controls (p less than 0.0005, pc less than 0.006). Only 9% of the patients were DR2-positive and DR3-positive. Kaplan-Meier analysis demonstrated that survival was not influenced by the presence of either haplotype nor by the individual antigens. Patients who were DR3-positive were first seen at a significantly younger age than those who were DR2-positive (mean ages = 33 yr and 44 yr, respectively, p less than 0.002, Student's t test).(ABSTRACT TRUNCATED AT 250 WORDS)