Search

AbstractBackground: By analyzing a tumor growth of hepatocellular carcinoma (HCC) detected in sustained responders (SR) to interferon (IFN) therapy for chronic hepatitis C, we sought to determine the duration of follow up in SR that would be sufficient to detect HCC. In addition, we sought to elucidate the presence of HCC, which truly developed after the eradication of hepatitis C virus (de novo HCC development). Methods: Tumor volume doubling time (DT) was calculated in a total of 46 cases of HCC detected in SR after IFN therapy. Based on DT, the annual growth rate was estimated for each tumor. Survival was compared between patients with HCC ≤ 30 mm and patients with HCC > 30 mm in diameter. Results: Doubling time in SR was similar to the previously reported DT of HCC irrespective of IFN therapy. However, extensive DT was observed in three HCCs despite relatively poor differentiation, which may represent de novo HCC development. In the analysis of tumor growth, all HCCs grew to exceed 20 mm in estimated diameter between 6 months and 7 years after the end of IFN therapy. Better survival was observed in patients with HCC ≤ 30 mm in diameter compared with patients with HCC > 30 mm (P = 0.0107). In surviving patients, recurrences of HCC were very infrequent. Conclusions: We may be able to detect most HCC in SR between 6 months and 7 years after IFN therapy. However, we cannot neglect the presence of de novo HCC development after the eradication of HCV, which makes it difficult to determine completely sufficient follow-up duration after IFN therapy in this population. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-alpha-2b in chronic hepatitis C virus (HCV) patients aged 65 years and older., Methods: Five hundred and ninety-one consecutive HCV patients were treated with combination therapy. These patients were divided into elder patients (> or = 65 years) (n=115) and younger patients (< 65 years) (n=476). The clinical characteristics, sustained virological response (SVR) rates and discontinuation rates were compared between the two groups., Results: Compared with younger patients, baseline haemoglobin levels and baseline platelet counts were significantly lower (P<0.0001, P=0.013 respectively) and fibrosis was more advanced in elderly patients (P=0.0310). Moreover, the SVR rate was significantly lower (37.4 vs. 51.5%; P=0.0067) while the combination therapy discontinuation rate was significantly higher (32.2 vs. 17.0%; P=0.0003) in elderly patients. A multivariate analysis revealed that HCV load and genotype were significantly associated with an SVR in elderly patients. An SVR was achieved in over 50% of elderly male patients with genotype 1 and HCV RNA concentrations under 2,000,000 IU/ml. In contrast, the SVR rate was under 30% in elderly male patients with genotype 1 and with HCV RNA concentrations over 2,000,000 IU/ml and in all elderly female patients with genotype 1., Conclusions: The SVR rate was lower in elderly patients than in younger patients. However, in elderly patients combination therapy was most beneficial for genotype 1 patients, male patients with HCV RNA concentrations < 2,000,000 IU/ml and patients with genotype 2.

Branched-chain alpha-keto acid dehydrogenase (BCKDH) kinase (BDK) is responsible for the regulation of BCKDH complex, which is the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAAs). In the present study, we investigated the expression and activity of hepatic BDK in spontaneous type 2 diabetes using hyperinsulinemic Zucker diabetic fatty rats aged 9weeks and hyperglycemic, but not hyperinsulinemic rats aged 18weeks. The abundance of hepatic BDK mRNA and total BDK protein did not correlate with changes in serum insulin concentrations. On the other hand, the amount of BDK bound to the complex and its kinase activity were correlated with alterations in serum insulin levels, suggesting that hyperinsulinemia upregulates hepatic BDK. The activity of BDK inversely corresponded with the BCKDH complex activity, which was suppressed in hyperinsulinemic rats. These results suggest that insulin regulates BCAA catabolism in type 2 diabetic rats by modulating the hepatic BDK activity., (2010 Elsevier Inc. All rights reserved.)

Background/aims: Although the efficacy and safety of pegylated-interferon (PEG-IFN) alpha-2a and PEG-IFN alpha-2b have been comparatively studied, there are few study results available in which the two PEG-IFN products were strictly compared. To compare the effects of two PEG-IFN products on blood cell profile., Methodology: The time-course change in blood cell counts was compared between chronic hepatitis C patients with genotype 1b receiving PEG-IFN alpha-2a/ribavirin and PEG-IFN alpha-2b/ribavirin combination therapy. The comparison was made after matching patients from the two groups based on ribavirin apparent clearance (CL/F), a surrogate marker of the steady state blood ribavirin level, in order to eliminate the effect of ribavirin. Fifteen pairs of matched patients were selected., Results: The time-course change in hemoglobin did not differ significantly between the two groups. However, significantly greater reductions in both neutrophil and platelet counts were observed with PEG-IFN alpha-2a compared to PEG-IFN alpha-2b. A slightly longer period was required with PEG-IFN alpha-2a than with PEG-IFN alpha-2b for a reduction in neutrophil or platelet count large enough to necessitate dose reduction., Conclusions: Two types of PEG-IFN products affected the blood cell profile in different manners. Long-term monitoring of laboratory test values is necessary with PEG-IFN alpha-2a.

Background: In Japan, patients with hepatitis C virus (HCV)-associated liver disease are getting older, and thus the number of deaths due to such disease is increasing. The efficacy of combination therapy with ribavirin and interferon for chronic HCV infection in elderly patients has not been fully clarified. The aim of the present study was to evaluate the efficacy and tolerability of combination therapy in such patients., Methods: Two hundred and twenty consecutive patients with chronic hepatitis C were treated with combination therapy. These patients were divided into two groups according to age: patients >or= 60 years (n = 66) and patients < 60 years (n = 154). Clinical characteristics, the sustained virologic response (SVR) rate obtained by intention-to-treat analysis, and the rate of reduction or discontinuation of ribavirin were compared between the two groups., Results: The ribavirin discontinuation rate was significantly higher in the patients aged >or=60 years than in the patients aged <60 years. However, the SVR rates did not differ significantly between patients aged >or=60 years and those aged <60 years (31.8% vs 38.3% by intention-to-treat analysis). According to multivariate analysis, genotype and HCV viral load were significantly associated with SVR while patient age did not affect SVR., Conclusions: Treatment of chronic hepatitis C with combination therapy was comparably effective between patients aged >or=60 years and those aged <60 years, although the ribavirin discontinuation rate was higher among the older patients than the younger patients.

Background/aims: The 5'-untranslated region (5'UTR) of hepatitis C virus (HCV) is a useful region for determinations of genotype and viral load. 5'UTR can be used for simultaneous analysis of HCV genotype and viral load, therefore several assays have been described. A method which used direct sequencing of the 5'UTR can also be used to identify mutations in this region. The objective of the present study was to evaluate possible associations of 5'UTR mutations with responsiveness to interferon (IFN) therapy in chronic hepatitis C patients., Methodology: Seventy patients with chronic hepatitis C were included in this study. The relations between responsiveness to IFN therapy and HCV genotype, viral load, and 5'UTR mutations before IFN treatment were evaluated., Results: We detected HCV genotype 1a (n = 5), 1b (n = 32), 2a (n = 15), 2b (n = 12), and 3a (n = 6). Forty-eight patients were non-sustained responders (NR). Seven of 37 (18.9%) patients with the 1a or 1b genotype were sustained responders (SR), and 14 of 27 (51.9%) patients with genotype 2a or 2b were SR. Responses of patients with genotype 1 were poorer than those of patients with genotype 2. HCV viral loads of all SR patients infected with genotype la or 1b were less than 100 KIU/mL, but more than 50% of SR patients infected with genotype 2a or 2b had viral loads over 100 KIU/mL. Thus, viral load in patients with genotype 1 is strongly associated with IFN sensitivity. 5'UTR were well conserved, and there were no differences in the distribution of genotypes between SR and NR., Conclusions: The 5'UTR is a suitable region for determining HCV genotype and viral load, which are predictors of responsiveness to IFN therapy, but specific mutations of the 5'UTR do not appear to be associated with responsiveness to IFN.

The interferon sensitivity-determining region (ISDR) is useful as a predictive marker of the response to interferon (IFN) therapy for chronic hepatitis patients with a Japan-specific subtype (J-type) of hepatitis C virus (HCV) genotype 1b. This marker is not useful for predicting responsiveness of a worldwide subtype (W-type) of HCV 1b, which could explain the restricted usefulness of this system only to Japan. In the present study, we examined the predictive value of the ISDR for ribavirin combination therapy. A total of 79 patients with HCV 1b comprising 35 patients with J-type and 44 patients with W-type were treated with IFN in combination with ribavirin for more than 48 weeks. Mutations in the ISDR were detected more frequently often seen in J-type HCV 1b than in W-type; however, the sustained virological response (SVR) rate for the combination therapy was similar between the two subtypes. Multivariate analysis revealed that factors associated with SVR were IFN dose and the number of amino acid substitutions in ISDR but not with subtypes J and W. The correlation between the number of substitutions in ISDR and responses to IFN-ribavirin combination therapy was restricted to patients with J-type HCV 1b. The ISDR is a useful predictive marker for response to IFN-ribavirin combination therapy in J-type HCV.

Leucine stimulates protein synthesis by modulating the mammalian target of rapamycin (mTOR) signaling pathway. We hypothesized that promotion of the branched-chain amino acid (BCAA) catabolism might influence the leucine-induced protein synthesis. Clofibric acid (an active metabolite of clofibrate) is known to promote the BCAA catabolism by activation of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), the rate-limiting enzyme of the BCAA catabolism. In the present study, we examined the phosphorylation state of mTOR, eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and ribosomal protein S6 kinase 1 (S6K1) in liver of rats with or without activation of the BCKDC by clofibrate treatment. Clofibrate-treated rats were prepared by oral administration of clofibrate 5 h before sacrifice. In order to stimulate phosphorylation of components in the mTOR signaling pathway, rats were orally administered with leucine 1 h before sacrifice. Clofibrate treatment almost fully activated hepatic BCKDC and significantly decreased the plasma leucine concentration in rats without leucine administration, resulting in decreased mTOR and 4E-BP1 phosphorylation. Similarly, in rats administered with leucine, clofibrate treatment attenuated the predicted increase in plasma leucine concentration as well as the phosphorylation of mTOR, 4E-BP1, and S6K1. These results suggest that BCAA catabolism enhanced by clofibrate treatment has significant influences on the leucine-induced activation of translation initiation processes.

We treated 665 patients with chronic hepatitis C with interferon (IFN) monotherapy and 288 with combined IFN and ribavirin. At the baseline, age (53.8 +/- 11.1 vs. 49.7 +/- 10.5 years, p < 0.0001) and activity (p = 0.0207) as well as fibrosis (p = 0.0270) were higher in patients who received combination therapy than in those receiving monotherapy. Compliance to treatment (64.2 vs. 62.1%, p < 0.0001) and discontinuation were more frequent (18.1 vs. 14.5%, p < 0.0001) in patients with combination therapy than in those with monotherapy. Patients with combination therapy with genotype 2 infection achieved sustained viral response (SVR) at a rate of 77.0%, regardless of viral loads, in contrast to those with genotype 1 infection, of whom only 24.4% gained SVR. Of patients with combination therapy, reduction (42.6 vs. 29.0%, p = 0.0453) and discontinuation (34.0 vs. 21.6%, p = 0.0414) of ribavirin were more frequently required in the 47 patients > or =65 years than in the 241 patients <65 years. Although a trend for higher SVR to combination therapy was observed in patients aged < 65 than in those aged > or =65 years (39.4 vs. 25.2%), the difference was not significant (p = 0.0819). In patients with genotype 1 infection, IFN monotherapy in addition to the 24-week combination therapy increased the SVR rate (18.3 vs. 42.6%, p = 0.0003). A decrease in SVR was observed with an increased body mass index in patients who received combination therapy., (Copyright (c) 2006 S. Karger AG, Basel.)

Background/aims: Hepatitis C virus induces various clinical features in a host depending on duration of the viral infection., Methodology: We investigated peripheral lymphocyte subsets in patients with three different stages of hepatitis C virus infection: 5 patients with acute hepatitis, 10 with chronic hepatitis unassociated with cirrhosis, and 10 with cirrhosis. Peripheral lymphocytes were double-stained with multiple fluorescent antibody combinations: anti-CD3 plus anti-gammasigmaT cell receptor; anti-CD19 plus anti-CD5; anti-CD4 plus anti-CD45RA; or anti-CD8 plus anti-CD11b. Triple staining was performed with fluorescent antibodies against CD4, interferon gamma, and interleukin-4. Both staining protocols were followed by flow cytometric analysis., Results: Acute hepatitis patients had a high proportion of CD3+ T cells with increased CD4+CD45RA-T helper and CD8+CD11b- cytotoxic T cells. Compared to this group, chronic hepatitis patients showed a decrease in CD4+ cells and an increase in CD19+ B cells and interleukin-4-producing Th2 cells. Cirrhotic patients showed decreased circulating lymphocytes and a low proportion of CD8+ cells accompanied by a decrease in cytotoxic T cells. Furthermore, their lymphocyte profiles showed decreases in primordial lymphocyte subpopulations (T cells with gammasigmaT cell receptors and B cells with CD5)., Conclusions: Although the same pathogenic agent was involved, immune dynamics differed greatly according to duration of viral infection.

A 65-year-old man diagnosed with hepatitis C virus-positive hepatitis and severe valvular heart disease was scheduled to undergo cardiac valve replacement. We then found hepatocellular carcinoma in the liver. Because of his severe cardiac dysfunction, we treated him surgically with radiofrequency ablation for the hepatocellular carcinoma only. We continued medical treatment of the heart disease. He hoped to undergo with cardiac surgery one year later for the cardiac dysfunction. There was no evidence of tumor recurrence. We informed him that cardiac surgery requiring extracorporeal circulation might lead to tumor recurrence. He agreed to cardiac valve replacement, and the surgery was successful. Recurrent hepatocellular carcinoma was found in the liver 1 month after the surgery. Over the next month, the tumor progressed rapidly, showing portal vein thrombi. We believe the use of extracorporeal circulation in particular triggered the rapid growth of the recurrent hepatocellular carcinoma. This is the first report of a recurrent hepatocellular carcinoma associated with hepatitis C virus that progressed extensively after cardiac surgery.

Background/aims: Serum aminotransferase, a sensitive marker of hepatocellular damage, often poorly correlates with the severity of damage. Serum nuclear matrix protein (NMP), a structural protein released from dead cell nuclei, is investigated as a candidate marker of organ damage in liver disease., Methodology: Serum NMP and aminotransferase levels of 134 patients with various liver diseases and 26 healthy individuals were examined., Results: Patients with chronic viral hepatitis showed slightly higher NMP levels (17.8 U/mL; 95% CI 15.0-20.5 U/mL) than those of healthy individuals (6.05 U/mL; 95% CI 4.82-7.27 U/mL). Their NMP values had no correlation with aminotransferase levels. NMP levels were similar irrespective of liver disease progression, whereas aminotransferase values decreased in parallel with progression. Patients with autoimmune hepatitis or primary biliary cirrhosis who were under an appropriate treatment as well as individuals with fatty liver showed no elevation of serum NMP levels. Patients with acute viral hepatitis showed very high NMP levels (38.8 U/mL; 95%CI 27.6-50.0 U/mL) that correlated with serum aminotransferase levels in their sera., Conclusions: In chronic liver diseases, the serum NMP level elevates to various degrees independent from the degree of aminotransferase elevation. Serum NMP, putatively representing the number of dead cells, is a candidate as an indicator of organ damage severity in liver disease.

Background/aims: Branched-chain alpha-keto acid dehydrogenase (BCKDH) complex catalyses the committed step in the branched-chain amino acid (BCAA) catabolic pathway. In many cases of liver failure, the serum BCAAs/aromatic amino acids ratio (Fisher's ratio) decreases, and BCAAs have been administered to patients with liver failure to correct this ratio. We conducted an animal study to examine whether the effects on hepatic BCKDH complex differ between acute liver failure (ALF) and chronic liver failure (CLF)., Methods: ALF and CLF was induced in rats by a single high-dose injection and 21 weeks of repeated low-dose injections of carbon tetrachloride, respectively. Plasma BCAA and branched-chain alpha-keto acid (BCKA) levels, and activities and protein amounts of hepatic BCKDH complex and kinase were measured., Results: ALF was characterized by elevated plasma BCAA and BCKA levels and decreased hepatic BCKDH activity. CLF was characterized by decreased plasma BCAA and BCKA levels and increased hepatic BCKDH activity. This increase in BCKDH activity in CLF was associated with the decreased BCKDH kinase, which is responsible for the BCKDH inactivation., Conclusions: The results obtained in the present study suggest that BCAA catabolism is suppressed in ALF and increased in CLF.

To investigate influence of HIV co-infection on HCV, we examined 58 Japanese hemophiliacs with chronic hepatitis C(CHC) including 25 patients co-infected with HIV. HCV RNA levels and liver function were not affected statistically by the presence of HIV. Further studies are necessary to evaluate the impact of HIV on the prognosis of CHC in hemophiliacs. We were the first to report a beneficial effect of GBV-C/HGV infection on the course of HIV disease and many studies were confirmed our results. Discussions of these important issues such as impact of HIV on GBV-C/HGV and HBV have been performed in this paper.