Tomoteru Kamimura

Epidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver diseases: A multi-institution analysis

Sixteen medical institutions in Japan collaborated in this study of the epidemiology of hepatitis C virus (HCV) genotypes. A total of 4176 patients with type C chronic liver disease, from the four main islands of Japan, were evaluated. Of those evaluated, 2794 had chronic hepatitis, 727 had liver cirrhosis and 655 had hepatocellular carcinoma. The HCV genotype of the patients was determined by an enzyme‐linked immunosorbent assay based on serological genotype 1‐ and 2‐specific recombinant peptides (SG‐1 and SG‐2, respectively) of the NS4 region. The prevalence of SG‐1 and SG‐2 HCV was similar in the four main islands of Japan. SG‐1 HCV predominated in each disease category (69–76%). The percentage of patients with SG‐1 HCV increased by 7%, while that of patients with SG‐2 HCV decreased by 7%, as liver disease progressed in severity from chronic hepatitis to carcinoma (P < 0.001). Patients with either SG‐1 or SG‐2 had a similar mean age and history of blood transfusion. In conclusion, SG‐1 HCV was found to predominate in Japan, and the HCV genotype was found to be related to the stage of hepatitis C disease.

A multi-center double-blind controlled trial of ursodeoxycholic acid for primary biliary cirrhosis.

SummaryA multi-center double-blind controlled trial of ursodeoxycholic acid (UDCA) for treatment of primary biliary cirrhosis (PBC) was carried out. Twenty two and 23 patients were treated with 600mg/day UDCA and placebo, respectively, for 24 weeks. In UDCA - treated patients, fall of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyltranspeptidase activities started within 4 weeks after start of the trial and continued throughout the trial period. The serum IgM level fell in 7 UDCA-treated patients examined but not in 10 placebo-treated patients examined. Serum bilirubin concentration showed no significant change at the end of the study in either of UDCA- and placebotreated group of patients. There was no significant difference between these two groups with respect to the frequency of improvement of pruritus. In UDCA-treated patients, serum bile acid composition changed markedly, though its concentation showed no significant change. The percentage of total bile acid which ursodeoxycholic acid took up increased, whereas those which cholic acid, chenodeoxycholic acid and deoxycholic acid took up were decreased.

Risk factors and the effect of interferon therapy in the development of hepatocellular carcinoma: A multivariate analysis in 343 patients

The aims of the present study were to clarify the risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection and to investigate the effectiveness of interferon (IFN) therapy. We retrospectively studied 343 patients who had been admitted to our hospital; 161 with chronic hepatitis, 49 with liver cirrhosis, 42 with chronic hepatitis bearing HCC and 91 with liver cirrhosis bearing HCC. The mean (±SD) observation period was 41.6 ± 31.1 months. The mean age of HCC and non‐HCC patients was 63.5 ± 7.6 and 56.9 ±12.5 years, respectively (P< 0.001). The HCV genotype II (1b) was the most prevalent genotype (92.5%) in HCC patients and the mean age was highest among patients with this genotype (63.6 ± 7.7 years). Multivariate analysis identified age (P< 0.001), the male gender (P<0.01), HCV genotype II (1b) (P<0.05) and excessive alcohol intake (P<0.05) as independent factors associated with the development of HCC. There was no relationship between the development of HCC and serum HCV levels as quantified by branched DNA assay or competitive reverse transcription polymerase chain reaction. The incidence of HCC in patients who had not received IFN therapy was 10.4/100 person‐year, while that of patients who had received IFN therapy was 1.2/100 person‐year (P<0.01) by the person‐year method. The low incidence of HCC in patients treated with IFN suggests that IFN may prevent the development of HCC.

Interferon Inhibits Progression of Liver Fibrosis and Reduces the Risk of Hepatocarcinogenesis in Patients with Chronic Hepatitis C: A Retrospective Multicenter Analysis of 652 Patients

A retrospective multicenter analysis of 652 patients with chronic hepatitis C who have been treated with interferon (IFN) was performed to assess the effects of IFN on the clinical course and development of HCC. During a mean follow-up of 54.8 months, hepatocellular carcinoma (HCC) developed in 7.0% of the patients. The rate was significantly higher in the patients who did not respond to IFN treatment than in those with sustained virological response and those who obtained a normalization of alanine aminotransferase levels despite the presence of HCV RNA (incomplete response) (P < 0.01). Using multivariate Coxs proportional hazard model, alcohol abuse (P < 0.05) and a higher level of fibrosis (P < 0.05) before treatment were the significant background factors associated with HCC development in the patients who did not respond to IFN. Interestingly, a significant increase in the rate of HCC development occurred in patients who had a histological finding of progressive fibrosis (F3). In addition, patients with low histological staging scores were likely to have an incomplete response, even if a sustained virological response was not obtained. IFN produced an improvement in histological activity and fibrosis stage in the second biopsy specimens irrespective of the clinical outcome when compared against untreated subjects.

A retrospective study of hepatitis C virus carriers in a local endemic town in Japan. A possible presence of asymptomatic carrier.

Chronic hepatitis, cirrhosis, and hepatocellular carcinoma are the accepted sequelae of chronic hepatitis C virus (HCV) infection. However, the real natural history of HCV infection is not still well understood. To approach this problem, we investigated 91 individuals positive for antibodies against HCV (anti-HCV), who have received annual liver function examination in a local town known to have had high carrier rates of hepatitis B virus (HBV) and HCV. Among the 91 anti-HCV-positive individuals, 63 had undertaken the annual examination more than five times in the past 14 years. We analyzed retrospectively the past liver function test results of these 63 subjects and evaluated their present virological status by determining HCV genotypes and estimating quantity of HCV RNA in the sera. Among the 63 subjects, 50 (79.4%) had HCV RNA in the serum and 40 (80%) of the 50 subjects with HCV RNA had abnormal alanine aminotransferase or aspartate aminotransferase level more than once in their records. However, the other 10 (20%) had no abnormal levels during the period examined. Six of 50 (12%) had ultrasonographic findings suggestive of cirrhosis. Thus, HCV-infected individuals in this area did not seem to have progressive liver diseases. Considering the advanced ages of the individuals examined (mean 64 years old), we may have observed a stage in the natural history of HCV infection in which viremia persists in most individuals and the tendency to progress to serious chronic liver disease is mild.

Hepatic lesions induced by graft-versus-host reaction across MHC class II antigens: An implication for animal model of primary biliary cirrhosis

To induce graft-versus-host reaction (GVHR), C57B1/6 (B6) spleen cells were injected into (B6 x bm1)F1, (B6 x bm12)F1, and (bm1 x bm12)F1 mice. Since the strains bm1 and bm12 are mutant at the H-2Kb and I-Ab regions of major histocompatibility complex (MHC), respectively, we can assess MHC class I- or class II-different GVHR. As reported earlier, immunological perturbations assessed by the number of immunoglobulin-producing cells and immune complex deposition in renal glomeruli were demonstrated in MHC class II-different GVHR. A conspicuous finding in this report is that epithelioid granuloma formation was observed in the portal area and around the central vein of liver of (B6 x bm12)F1 mice injected with B6 spleen cells. The epithelioid granuloma formation was not observed in (B6 x bm1)F1 nor (bm1 x bm12)F1 recipient mice. Degenerative changes resembling chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis were also observed in the bile duct epithelium in (B6 x bm12)F1 and (bm1 x bm12)F1 mice. These lesions were already obvious at the 2 week postinjection of donor cells and were continuously observed up to 10 weeks when immunological perturbations subsided. Thus, class II-disparate GVHR in this experimental system might provide a novel animal model of protracted disease, primary biliary cirrhosis.

Sustained biochemical remission after interferon treatment may closely be related to the end of treatment biochemical response and associated with a lower incidence of hepatocarcinogenesis

Abstract: Clinical background and incidence of hepatocellular carcinoma (HCC) of patients with chronic hepatitis C who obtained biochemical remission without eradication of virus (biochemical response) after interferon (IFN) treatment was retrospectively analyzed for 755 patients. Annual incidence of HCC was significantly lower in the patients with biochemical response and sustained response than that of the patients that did not show these responses. Logistic regression analysis showed that only the normalization of alanine aminotransferase (ALT) value at the end of IFN treatment was a significant factor for biochemical response. Annual incidence of HCC was significantly lower in the patients who obtained normalization of ALT values at the end of treatment than those who did not. Patients who were younger, who had a lower level of activity and fibrosis indices in histology, higher platelet count, and who were given more higher total dose of IFN were more likely to attain normalization of ALT levels at the end of treatment, and this was related to biochemical response. Low incidence of HCC in patients who obtained normalization of ALT values at the end of treatment was likely because they were in the earlier stage of chronic hepatitis. Active treatment of chronic hepatitis C with interferon in the early phase of the disease may bring about a biochemical response in some patients, even if sustained virological response is not obtained.

Combination PEG-IFN a-2b/ribavirin therapy following treatment of hepatitis C virus-associated hepatocellular carcinoma is capable of improving hepatic functional reserve and survival.

BACKGROUND/AIMS Hepatitis C virus (HCV) associated HCC shows a high rate of recurrence even after curative treatment. Outcomes of pegylated interferon PEGIFN a-2b/ribavirin (RBV) therapy for HCV-associated HCC have yet to be elucidated. We investigated therapeutic response and hepatic functional reserve improvement in patients receiving PEG-IFN a-2b/RBV after curative HCC treatment. METHODOLOGY We investigated survival rate, metachronous recurrence and hepatic functional reserve in 54 patients with initial HCV-associated Stage I/II HCC; 29 patients were administered a preparation of PEG-IFN a-2b/RBV after HCC treatment (Secondary IFN group) and 25 were not (Non-secondary IFN group). RESULTS A significant difference was observed in cumulative survival rates among HCV-associated HCC patients with rates of 100% after 1 year and 90.2% after 3 years in the secondary IFN group compared to 96.0% and 61.2%, respectively, in the non-secondary IFN group. Univariate analysis identified secondary IFN treatment, alanine aminotransferase and albumin levels as factors contributing to survival. Serum albumin level decreased temporarily but subsequently increased and improved hepatic functional reserve was observed in PEG-IFN a-2b/RBV therapy. CONCLUSIONS PEG-IFN a-2b/RBV therapy after HCC treatment can improve hepatic functional reserve and may therefore represent a therapeutic option in the event of recurrence. PEG-IFN a-2b/ RBV therapy following HCC treatment shows promise for improving the prognosis of HCC.

Prevention of intrahepatic distant recurrence by transcatheter arterial infusion chemotherapy with platinum agents for stage I/II hepatocellular carcinoma.

The effectiveness of additional chemotherapy in preventing intrahepatic distant tumor recurrence of hepatocellular carcinoma (HCC) has not been fully established. The authors compared the efficacy of 2 platinum‐based chemotherapeutic agents in combination with radical local treatment for preventing intrahepatic distant recurrence (IDR).

Characterization of elevated alanine aminotransferase levels during pegylated-interferon α-2b plus ribavirin treatment for chronic hepatitis C.

Aim:  Elevation of alanine aminotransferase (ALT) levels during pegylated‐interferon (peg‐IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon.