Naota Taura

Association Between Liver Fibrosis and Insulin Sensitivity in Chronic Hepatitis C Patients

BACKGROUND:Several clinical studies have suggested a possible link between chronic hepatitis caused by hepatitis C virus (HCV) and the development of diabetes mellitus. We investigated the association between liver fibrosis and glucose intolerance in HCV-infected patients by measuring insulin sensitivity and β-cell function.METHOD:A total of 83 chronic HCV-infected patients were recruited into this study. We evaluated insulin sensitivity and β-cell function of all patients in a fasting state (homeostasis model assessment of insulin resistance [HOMA-R] and homeostasis model assessment of β-cell function [HOMA-β]) and after an oral load of 75 g glucose (whole-body insulin sensitivity index [WBISI] and Δ-insulin/Δ-glucose 30).RESULTS:In a multivariate analysis, severe fibrosis was the only independent factor associated with insulin resistance. There were significant differences in both HOMA-R (P = 0.0063) and WBISI (P = 0.0159) between patients with mild fibrosis (N = 34) and those with severe fibrosis (N = 49). Although HOMA-β was increased significantly in the subjects with severe fibrosis compared with those with mild fibrosis (P = 0.0169), Δ-insulin/Δ-glucose 30 showed no significant difference in stage of liver fibrosis, suggesting an uncertain association between liver fibrosis and β-cell function.CONCLUSION:Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients.

Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease.

Non‐alcoholic fatty liver disease (NAFLD) is believed to be a type of metabolic syndrome. MicroRNA‐122 (miR‐122) is the most abundant microRNA in the liver and is an important factor for the metabolism of glucose and lipids. In the present study, we examined the correlation between the hepatic and serum miR‐122 expression levels and the clinicopathological factors of patients with NAFLD.

Baseline Serum Cholesterol Is Associated with a Response to Pegylated Interferon Alfa-2b and Ribavirin Therapy for Chronic Hepatitis C Genotype 2

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P = 0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

Significance of hepatitis B virus core‐related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re‐infection after liver transplantation

Currently, hepatitis B virus (HBV) re‐infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV‐DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core‐related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re‐infection.

Endoplasmic Reticulum Stress Contributes to Helicobacter Pylori VacA-Induced Apoptosis

Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ER-localized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa.

Usefulness of intraoperative diagnosis of hepatic tumors located at the liver surface and hepatic segmental visualization using indocyanine green- photodynamic eye imaging

BACKGROUND To improve the diagnostic accuracy for hepatic tumors on the liver surface, we investigated the usefulness of an indocyanine green-photodynamic eye (ICG-PDE) system by comparison with Sonazoid intraoperative ultrasonography (IOUS) in 117 patients. Hepatic segmentation by ICG-PDE was also evaluated. METHODS ICG was administered preoperatively for functional testing and images of the tumor were observed during hepatectomy using a PDE camera. ICG was injected into portal veins to determine hepatic segmentation. RESULTS Accurate diagnosis of liver tumors was achieved with ICG-PDE in 75% of patients, lower than with IOUS (94%). False-positive and false-negative diagnosis rates for ICG-PDE were 24% and 9%, respectively. New small HCCs were detected in 3 patients. The ICG fluorescent pattern in tumors was strong staining in 41%, weak staining in 13%, rim staining in 20% and no staining in 26%. Hepatocellular carcinoma predominantly showed strong staining (61%), while rim staining predominated in cholangiocellular carcinoma (60%) and liver metastasis (55%). Hepatic segmental staining was performed in 28 patients, proving successful in 89%. CONCLUSION ICG-PDE is a useful tool for detecting the precise tumor location at the liver surface, identifying new small tumors, and determining liver segmentation for liver resection.

Usefulness of sonazoid–ultrasonography during hepatectomy in patients with liver tumors: A preliminary study

To improve diagnostic accuracy of intraoperative ultrasonography (IOUS), we investigated the usefulness of new contrast medium of microbubble agent, Sonazoid as a preliminary study.

Detection of HBV core promoter and precore mutations helps distinguish flares of chronic hepatitis from acute hepatitis B.

Background and Aim:  Acute exacerbation of chronic hepatitis B has to be distinguished from acute hepatitis, because treatment strategies differ between them.

Relationship between Regulatory T Cells and the Combination of Pegylated Interferon and Ribavirin for the Treatment of Chronic Hepatitis Type C

Background/Aim: The frequency of regulatory T cells (Tregs) may be related to persistent hepatitis C virus (HCV) infection. We studied the alteration of the Treg ratio in peripheral blood mononuclear cells (PBMCs) from chronic hepatitis C patients during combination therapy compared with the Treg ratio in liver-infiltrating lymphocytes (LILs) before therapy. Method: The study group consisted of 20 patients who were treatment-naive and had high virus titers of HCV genotype 1. Blood samples were collected prior to treatment and at several time points during treatment. All patients received a liver biopsy prior to treatment. Forkhead box P3 (Foxp3)+, CD3+, CD4+ and CD8+ cells in PBMCs and LILs were stained by specific antibodies. Results: Ten patients had a sustained virological response (SVR), and 10 patients were non-responders. The SVR group had a significant increase in the Foxp3+/CD4+ ratio in PBMCs at 8 and 12 weeks as well as a significant decrease in the Foxp3+/CD4+ ratio and increase in the CD8+/Foxp3+ ratio in LILs. Conclusion: The evaluation of Tregs, a potentially significant factor for persistent HCV infection, in LILs prior to treatment and in PBMCs during treatment could predict the result of combination therapy.

The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased in Kyushu area

Summary Background The incidence of hepatocellular carcinoma (HCC) in Japan has still been increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the western area of Japan, Kyushu. Material/Methods A total of 10,010 patients with HCC diagnosed between 1996 and 2008 in the Liver Cancer study group of Kyushu (LCSK), were recruited for this study. Cohorts of patients with HCC were categorized into five year intervals. The etiology of HCC was categorized to four groups as follows; B: HBsAg positive, HCV-RNA negative, C: HCV-RNA positive, HBsAg negative, B+C: both of HBsAg and HCV-RNA positive, nonBC: both of HBsAg and HCV-RNA negative. Results B was 14.8% (1,485 of 10,010), whereas 68.1% (6,819 of 10,010) had C, and 1.4% (140 of 10,010) had HCC associated with both viruses. The remaining 1,566 patients (15.6%) did not associate with both viruses. Cohorts of patients with HCC were divided into six-year intervals (1996–2001 and 2002–2007). The ratio of C cases decreased from 73.1% in 1996–2001 to 64.9% in 2002–2007. On the other hand, B and -nonBC cases increased significantly from 13.9% and 11.3% in 1996–2001 to 16.2% and 17.6% in 2002–2007, respectively. Conclusions The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased after 2001 in Kyushu area. This change was due to the increase in the number and proportion of the HCC not only nonBC patients but also B patients.