Iwasaki, Yoshiaki

To improve the efficacy of interferon (IFN) treatment for chronic hepatitis C, we have proposed the twice-daily administration of IFN-beta as a promising induction therapy. In this study, we demonstrated differences between the clearance of circulating HCV-RNA and the induction of anti-viral actions during the first 2 weeks of treatment. Nine patients with a high viral load and genotype 1b were randomly assigned to 3 groups: group A received 3MU of IFN-beta twice a day at intervals of 5 and 19 h; group B received 3MU of IFN-beta twice a day at intervals of 10 and 14 h; group C received 6MU of IFN-alpha once a day with ribavirin. The expression of OAS2, PKR, and MxA in peripheral blood mononuclear cells (PBMCs) were quantified by real-time polymerase chain reaction method. The viral clearance showed a bi-phasic pattern, and those in the second phase of groups A and B were significantly steeper than that of group C. The peak level of OAS2 during the first phase was correlated with the first phase decay. The MxA expression tended to be higher in group A and B than in group C. The expression of these 3 proteins tended to decrease at day 6 in group C, but increase in groups A and B. These might make differences in the viral decay during the second phase

It has been documented that the serum complement activities measured by hemolytic assay (CH50) are decreased after storage of sera at a low temperature in some patients with chronic hepatitis C. However, the mechanism of this phenomenon has not been identified yet. Here, we tried to elucidate factors involved in the cold activation of complement (CAC). To clarify what pathway is activated in CAC, we measured complement cleavage products after cold storage of sera. C4d increased significantly after 12 h-storage at cold temperatures in 5 CAC (+) sera compared with 5 CAC (-) (P < 0.01) and 3 control sera (P < 0.05), while Bb did not increase in any of the groups. In order to determine whether IgG or IgG complex is necessary for CAC, 8 CAC (+) sera were incubated with Protein G Sepharose gel beads, and all of them retained hemolytic activities to some extent after cold storage. Column chromatography through Superose 6HR of CAC-positive serum identified the fractions containing molecules that induced CAC in normal serum, which were depleted by treatment with protein G Sepharose. In conclusion, CAC in hepatitis C seems to occur via a classical or lectin pathway, and the IgG complex produced in hepatitis C virus infection may be an important factor in inducing CAC, a common extrahepatic manifestation of hepatitis C.

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P= 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.

The preS2 region of the hepatitis B virus (HBV) has been reported to have human polymerized albumin receptor (PAR) activity, which correlates with viral replication. Here, we studied the genomic sequence of the preS region from rare patients lacking PAR activity, despite active viral replication. PAR and DNA polymerase activity was identified in 178 HBe antigen-positive HBV carriers, and a significant correlation between 2 markers was shown, except in 2 hepatitis patients lacking PAR activity. Nucleotide sequences of the preS region of HBV from both patients were examined by direct sequencing of PCR products. In one patient, a 45-base deletion was found to overlap half of the putative polymerized human albumin binding site in the preS2 region. In the other patient, a point mutation at the first nucleotide of the start codon of the preS2 region of HBV was found. There was no such genomic change in the 3 control HBV sequences. These results indicate that the preS2 region is necessary for binding of polymerized human albumin, and this is the first report of naturally existing mutant virus with no or low PAR activity.

The ultrasonographic characteristics of hepatocellular carcinomas (HCC) were investigated. Four typical features of HCCs, "mosaic internal echo pattern", "halo", "lateral shadow" and "posterior echo enhancement", were not recognized in minute HCCs smaller than 2 cm in diameter. These characteristics developed as the tumors grew. Only hypoechoic space-occupying lesions can be considered as small HCCs. In differentiating small HCCs from hypoechoic non-malignant space-occupying lesions in the cirrhotic liver, the ratios of short to long dimensions of the lesions seemed to be important since the ratios of HCCs were significantly larger than those of non-malignant lesions. The fact that 3 hyperechoic small HCCs could not be diagnosed even by celiac arteriography has suggested to us that ultrasonically guided biopsies should be performed in order to differentiate from small hemangiomas. Serum alpha-fetoprotein (AFP) levels of 1/3 of the patients with HCCs were below 100 ng/ml, indicating that it is impossible to detect small HCCs only by measuring serum AFP.

This study was conducted to develop a simple surrogate index comprised of routinely available laboratory tests to reflect the histological fibrosis stage. Clinical characteristics and laboratory data from 368 and 249 consecutive patients with chronic hepatitis C, a training cohort and a validation cohort, respectively, were retrospectively evaluated. Platelet (Plt) count and albumin (Alb) level contributed to the discrimination of the respective fibrosis stages. We derived the fi brosis index (FI), FI = 8.0-0.01 x Plt (10 multiply 3/microliter) - Alb (g/dl), from a multiple regression model. FI significantly correlated with the histological fibrosis stage in both the initial and validation cohort at p=0.691 and p=0.661, respectively (Spearman's rank correlation coefficient, p<0.0001). The sensitivity and positive predictive value of FI at a cutoff value < 2.10 for predicting fibrosis stage F0-1 were 66.8% and 78.8% in the initial cohort and 68.5% and 63.6% in the validation cohort, respectively. Corresponding values of FI at a cutoff value >- 3.30 for the prediction of F4 were 67.7% and 75.0% in the initial cohort and 70.8% and 81.0% in the validation cohort. The fibrosis index comprised of platelet count and albumin level reflected the histological fibrosis stage in patients with chronic hepatitis C.