Shuji Sumie

Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2.

OBJECTIVES:Hepatitis C virus (HCV) infection is linked to greater insulin resistance. Although HCV itself is a candidate for the development of insulin resistance, the effects of antiviral treatment on impaired glucose metabolism remain unclear. The aim of this study is to examine the effects of clearance of HCV on insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate (IRS)1/2, central molecules for insulin signaling.METHODS:We analyzed 89 biopsy-proven patients with chronic HCV infection. Patients received interferon-α or interferon-α plus ribavirin for 6 months and were classified into three groups at 6 months after the conclusion of antiviral therapy according to their response to antiviral therapy: sustained responders (N = 29), relapsers (N = 12), and nonresponders (N = 48). Insulin resistance and beta-cell function were assessed by the homeostasis model assessment method (HOMA-IR and HOMA-%B, respectively). Hepatic expression of IRS1/2 was evaluated by immunoblotting and immunostaining in 14 sustained responders.RESULTS:In nonresponders and relapsers, there were no significant changes in HOMA-IR and HOMA-%B values after antiviral therapy. On the other hand, in sustained responders, HOMA-IR values significantly decreased to 1.7 ± 0.8 from 3.1 ± 1.1 (P < 0.05) after antiviral therapy. Similarly, HOMA-%B values significantly decreased to 90.6 ± 10.0 from 113.7 ± 15.3 (P < 0.05). Immunoblotting showed a threefold increase in IRS1/2 expression after clearance of HCV. Immunostaining revealed that greater IRS1/2 expression was seen in hepatocytes.CONCLUSIONS:We showed that clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression.

Microvascular Invasion in Patients with Hepatocellular Carcinoma and Its Predictable Clinicopathological Factors

BackgroundMacroscopic vascular invasion is known to be a poor prognostic factor in hepatocellular carcinoma (HCC). The aim of this study was to determine the outcomes and predictive factors after hepatic resection for HCC with microvascular invasion (MVI).MethodsOne hundred ten patients who underwent curative resection for HCC without macroscopic vascular invasion were included in this retrospective study. The risk factors of these patients for recurrence-free and disease-specific survival were investigated, and the clinicopathological factors predicting the presence of MVI were also determined.ResultsOf the 110 resected specimens, 49 (45%) had evidence of MVI. By univariate analysis, MVI was found to be statistically significantly associated with greater tumor size, gross classification, histological grade, and intrahepatic micrometastasis. Gross classification proved to be the only independent predictive factor for MVI by multiple logistic regression analysis. By multivariate analysis, cirrhosis and MVI were identified as independent risk factors for recurrence-free survival. The 5-year recurrence-free survival rates for patients with and without MVI were 20.8% and 52.6%, respectively. By multivariate analysis, the number of tumors, presence of MVI, and intrahepatic micrometastasis were identified as independent predictors of disease-specific survival. The 5-year disease-specific survival rates for patients with and without MVI were 59.3% and 92.0%, respectively.ConclusionsThe presence of MVI was the most important risk factor affecting recurrence and survival in HCC patients after curative resection. Furthermore, this study showed that gross classification of HCC can be very helpful in predicting the presence of MVI.

High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications

Abstract: Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-β2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

Insulin resistance and chronic liver disease.

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

Surveillance program for early detection of hepatocellular carcinoma in Japan: results of specialized department of liver disease.

Objective Surveillance of cirrhotic patients enables early detection of hepatocellular carcinoma (HCC) and possibly prolongs survival. The aim of this study was to explore whether early-stage HCC can be detected earlier at a specialized department of liver disease than in other institutions. Methods The study subjects were 574 patients with HCC. Patients were subdivided into 3 groups according to the manner of HCC detection: group A, HCC was detected in 91 patients during periodic examination at Kurume University School of Medicine; group B, HCC was detected in 301 patients during periodic examination at other institutions; group C, HCC was detected incidentally or because of symptoms in 182 patients. Results The HCC detected in group A was significantly of smaller size (20.4 mm) compared with groups B (27.1 mm, P<0.0001) and C (57.8 mm, P<0.0001). The frequency of receiving treatment (surgery or local ablation therapy) was significantly higher in group A (73%) than in groups B (52%, P=0.002) and C (26%, P<0.0001). The 5-year survival rates were 52% for group A, 40% for group B, and 23% for group C, respectively. The survival of group A was significantly better than that of groups B (P=0.0157) and C (P<0.0001). Conclusions Surveillance for HCC at specialized Department of Liver Disease can detect early-stage HCC, resulting in a higher chance of receiving promising treatment.

Altered expression of glucagon‐like peptide‐1 and dipeptidyl peptidase IV in patients with HCV‐related glucose intolerance

Background and Aim:  The pathogenesis of hepatitis C virus (HCV)‐associated glucose intolerance remains unclear. Glucagon‐like peptide‐1 (GLP‐1), a gut hormone, synthesizes hepatic glycogen and is inactivated by dipeptidyl peptidase IV (DPPIV). The aims of this study were to investigate the alterations in the expression of GLP‐1 and DPPIV in HCV‐associated glucose intolerance.

Branched‐chain amino acids improve insulin resistance in patients with hepatitis C virus‐related liver disease: report of two cases

Hepatitis C virus (HCV) infection causes insulin resistance. Because increased insulin resistance is a risk factor for development of hepatocellular carcinoma and reduced long‐term survival, insulin resistance is a therapeutic target in patients with HCV infection. Branched‐chain amino acids (BCAAs) are not only structural constituents of proteins but they are also considered as regulators of insulin signalling. We first describe two cases suggesting that administration of BCAAs improves insulin resistance associated with HCV‐related liver disease. Although there were no changes in body weight, plasma glucose concentration and haemoglobin A1c (HbA1c) value were decreased. Moreover, BCAAs caused a decrease in both fasting insulin concentration and the value of homeostasis model assessment for insulin resistance. Thus, BCAAs are a potential therapeutic agent for improving insulin resistance in patients with HCV‐related liver disease.

Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection.

Background Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection. Methods A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). Results There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC. Conclusions Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Efficacy, Safety, and Survival Factors for Sorafenib Treatment in Japanese Patients with Advanced Hepatocellular Carcinoma

Background: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. Aims: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. Methods: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. Results: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. Conclusions: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.

Intra‐arterial therapy with cisplatin suspension in lipiodol and 5‐fluorouracil for hepatocellular carcinoma with portal vein tumour thrombosis

Aliment Pharmacol Ther 2010; 32: 543–550