Genetic polymorphisms of transforming growth factor beta-1 promoter and primary biliary cirrhosis in Japanese patients.

As suggested by concordance rates in twins, genetic factors are critical to the susceptibility and progression of primary biliary cirrhosis (PBC). Among cytokines, transforming growth factor beta-1 (TGF-beta1) plays an important role in autoimmunity and liver fibrosis and a TGF-beta1 receptor knockout mouse has been recently proposed as a model for PBC. The promoter region of the TGF-beta1 gene has two single nucleotide polymorphisms (SNPs) at positions -800 and -509, which influence serum concentrations of latent and active TGF-beta1. We studied genomic DNA from 65 Japanese patients with PBC and 71 matched healthy controls for the association of TGF-beta1 SNPs analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with susceptibility and disease progression of PBC. The -800 G to A SNP was not found in the Japanese population and no significant difference in the distribution of TGF-beta1 promoter gene -509 SNP was found between PBC cases and controls. Further, TGF-beta1 genotypes failed to correlate with clinical parameters, including histological stage and prognostic score. In conclusion, the TGF-beta1 promoter gene SNPs are not associated with disease susceptibility or progression in Japanese patients with PBC.

[A case of small cell carcinoma of the esophagus with remarkable response to chemotherapy with CPT-11 and CDDP].

A 63-year-old man visited our hospital with complaints of the chest pain and loss of appetite. A computed tomography of chest showed wall thickening in the lower portion of the esophagus and carinal and para-aorta lymph node swelling. Upper gastrointestinal endoscopy revealed an irregular ulcerated lesion in the middle portion of the esophagus, which was pathologically diagnosed as small cell carcinoma. A computed tomography of the abdomen showed multiple liver metastases and para-aortic, cardiac, and common hepatic arterial lymph node swelling. One course of combined chemotherapy with CPT-11 and CDDP, then 3 courses of chemotherapy with CPT-11 showed clinical complete remission.

Values of Doppler sonography predicts high risk variceal bleeding in patients with viral cirrhosis.

BACKGROUND/AIMS: Gastrointestinal bleeding such as rupture of esophagogastric varices remains one of the leading causes of death in patients with liver cirrhosis. As a critical issue, assessment of the bleeding risk of esophageal varices is extremely important. In the present study, by determining the relationship between several parameters measured by pulsed Doppler sonography and the bleeding risk of esophageal varices assessed by upper endoscopy, we investigated what is the most valuable parameter as a supplement to the bleeding risk. METHODOLOGY: A total of 158 patients with hepatitis virus-infected liver cirrhosis (56 positive for HBs antigen and 102 positive for HCV antibody) were studied. As controls, 171 normal subjects were used. The flow volumes of the portal trunk and the splenic vein, the Congestion Index, and the S/P ratio were measured by pulsed Doppler sonography. Based on upper endoscopic findings, we classified the patients into two groups based on bleeding risk of esophageal varices: high-risk and low-risk. Logistic regression analysis was employed to identify the most valuable parameter as a supplement to the bleeding risk. RESULTS: The flow volume of the splenic vein, the Congestion Index, and the S/P ratio in cirrhotic patients with esophageal varices were significantly higher than those in normal subjects (P = 0.000). The mean flow volumes of the portal trunk and splenic vein and the mean of the S/P ratio in the high-risk group for bleeding of esophageal varices were significantly higher than those in the low-risk group (P = 0.000-0.005). Based on logistic regression analysis, the flow volume of the splenic vein was found to be the most valuable parameter for bleeding risk (P < 0.001). CONCLUSIONS: The flow volume of splenic vein with pulsed Doppler sonography was the most valuable parameter for the bleeding risk of esophageal varices.

Low frequency of anti-SLA/LP autoantibody in Japanese adult patients with autoimmune liver diseases: analysis with recombinant antigen assay.

Anti-soluble liver antigen/liver pancreas (SLA/LP) autoantibody has been proposed to be one of the autoantibodies characterizing autoimmune hepatitis (AIH). Recently, one of the autoantigens to anti-SLA/LP was identified as a UGA suppressor tRNA-associated protein. Although the function of this protein remains unknown, the recombinant protein has been prokaryotically expressed. Using this protein as an antigen, a recombinant immunoassay for anti-SLA/LP autoantibody has been established and the frequency and significance of this autoantibody have been discussed in European countries. So, in the present study, we investigated anti-SLA/LP autoantibodies in Japanese patients with autoimmune liver diseases using the recombinant antigen ELISA and Western blot assay. Seventy-five patients with AIH type 1, 5 with AIH type 2, 46 with primary biliary cirrhosis, 10 with primary sclerosing cholangitis, 47 with chronic hepatitis C, 48 with systemic lupus erythematosus, 3 with cryptogenic hepatitis, and 40 normal controls were the subjects of the present study. Anti-SLA/LP autoantibodies were detected in only 5 of 75 (6.7%) patients with AIH type 1, but in none of the other 159 patients or 40 normal controls. The clinicopathologic features of anti-SLA/LP-positive AIH type 1, including carriers of HLA DR locus variations, were not significantly different from anti-SLA/LP-negative patients except for the mortality rate. Anti-SLA/LP autoantibody was detected at a low frequency in Japanese patients with AIH type 1 and did not significantly influence clinical features. However, since it has high disease-specificity to AIH type 1, further analysis of SLA/LP may contribute to help clarify the pathogenesis of AIH type 1.

Anti-pyruvate dehydrogenase complex-E2 antibody immunoglobulin class switch from IgM to IgG in long-term follow-up patients with primary biliary cirrhosis.

Antibody immunoglobulin class switching from IgM to IgG is usually observed in acute viral infections. However, in autoimmune diseases, the autoantibody immunoglobulin class switch from IgM to IgG has been observed only rarely, and the clinical relevance of this immune phenomenon remains unclear. In this report, anti-pyruvate dehydrogenase complex (PDC)-E2 antibody immunoglobulin class switching was followed in two patients with primary biliary cirrhosis (PBC). IgG and IgM anti-PDC-E2 antibodies were examined by an originally enzyme-linked immunosorbent assay and by immunoblot using human recombinant PDC-E2 protein. In both patients, serum IgG and IgM anti-PDC-E2 antibodies could not be detected at initial admission. However, IgM antibody was subsequently detected, and IgG antibody appeared several years thereafter.

Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients.

Several lines of data suggest that genetic factors play an important role in the onset and/or progression of primary biliary cirrhosis (PBC). Since PBC is an autoimmune disease, it is reasoned to assume that genes encoding cytokines may confer susceptibility to disease. Amongst these factors, interleukin-10 (IL-10) has received significant attention. The promoter region of IL-10 gene has three single nucleotide polymorphisms (SNPs) at positions -1082, -819 and -592. To elucidate the association of the three SNPs of IL-10 promoter region with susceptibility of PBC in two different genetic populations, 159 unrelated patients with PBC (94 Italian and 65 Japanese) and 143 local controls (72 Italian and 71 Japanese) were enrolled. SNPs were determined using allele-specific PCR/RFLP. In Italian PBC patients, the frequency of homozygosity for G/G at position -1082 was significantly higher than that of local controls (p < 0.041, OR = 2.44, 95% C.I.; 1.02-5.86). The frequencies of haplotype GCC in PBC patients, possibly linked to higher IL-10 production, were also significant higher than local controls (p < 0.033). However, in Japanese population, there were no significant differences in the three SNPs and haplotypes between PBC patients and controls. Excessive production of IL-10 may play an important role in some populations in modulating the onset of PBC. Further, immunogenetic studies of PBC should take into account ethnic and geographic variations; this makes such studies in heterogeneous population, like the USA, more difficult.