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 beta-cell function. METHOD: A total of 83 chronic HCV-infected patients were recruited into this study. We evaluated insulin sensitivity and beta-cell function of all patients in a fasting state (homeostasis model assessment of insulin resistance [HOMA-R] and homeostasis model assessment of beta-cell function [HOMA-beta]) and after an oral load of 75 g glucose (whole-body insulin sensitivity index [WBISI] and Delta-insulin/Delta-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-beta was increased significantly in the subjects with severe fibrosis compared with those with mild fibrosis (P= 0.0169), Delta-insulin/Delta-glucose 30 showed no significant difference in stage of liver fibrosis, suggesting an uncertain association between liver fibrosis and beta-cell function. CONCLUSION: Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients.

Aging of patients with hepatitis C virus-associated hepatocellular carcinoma: long-term trends in Japan.

The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the present study was to analyze epidemiological changes in Japanese HCC patients. A total of 463 patients with HCC diagnosed at our hospital between 1982 and 2001 were recruited for this study. Cohorts of patients with HCC were categorized into intervals of five years. The number of HBV- and HCV-associated HCC cases had decreased and increased in 1987-1991, respectively, and thereafter reached a plateau. The mean age of patients at diagnosis of HCV-associated HCC showed a steady significant increase from 60 to 68 years of age during the period, suggesting that these findings were associated with a shift toward an older-age group that had the highest rate of HCV infection. The mean age of patients with other types of HCC did not significantly change during the period. Since it is known that the prevalence of HCV infection in young Japanese persons is low and that the incidence of HCV infection is very low at present, our findings may indicate that the prevalence of HCC will decline in Japan, an advanced country with regard to HCV-associated HCC, in the near future.

The impact of newer treatment modalities on survival in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, although the therapeutic approaches for HCC have progressed rapidly, it remains unknown whether the current management of patients with HCC has reduced its mortality. We analyzed changes of survival rate in patients with HCC over a 20-year period. METHODS: Between 1982 and 2001, 463 patients were diagnosed with HCC at our hospital. Subjects were enrolled in the current cohort according to the following inclusion criteria: HCC lesion measuring less than 3 cm in diameter, no evidence of extrahepatic metastasis, and no evidence of main portal vein infiltration/thrombosis. A total of 257 patients with HCC were recruited for this study, and categorized into 5-year intervals. RESULTS: The survival rates improved significantly during the study period. When the patients were stratified according to Child-Pugh score, only patients with Child's B showed improved survival rates. Furthermore, patients with surgical resection or transarterial chemoembolization during the latter period had a better prognosis than those during the early period. CONCLUSIONS: Our findings suggest that the development of therapeutic interventions for HCC have led to improvements in the prognosis for HCC patients.

DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells.

Several reports have indicated that nuclear factor-kappaB (NF-kappaB) is constitutively activated in a variety of cancer cells including hepatoma cells and plays a key role in their growth and survival. Dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of an antibiotic epoxyquinomicin C is a novel NF-kappaB inhibitor. In the present study, we evaluated the effect of DHMEQ on the NF-kappaB activity in human hepatoma cells, Huh-7, HepG2 and Hep3B, and the anti-tumor effect of DHMEQ on these cells in vitro and in vivo. DHMEQ inhibited the steady-state transcriptional activity of NF-kappaB in all hepatoma cells. DHMEQ blocked the constitutive DNA-binding activity and TNF-alpha-mediated nuclear translocation of NF-kappaB in Huh-7 cells. DHMEQ (5-20 microg/ml) dose-dependently reduced the viable cell number of all hepatoma cells. DHMEQ (20 microg/ml) induced apoptosis in all hepatoma cells, especially in Hep3B cells, and cell-cycle arrest in Huh-7 and HepG2 cells. These effects were accompanied by downregulation of proteins involved in anti-apoptosis (Bcl-xL, XIAP or c-IAP2) and cell-cycle progression (cyclin D1), and induction of proteins involved in pro-apoptosis (Bax) and cell-cycle retardation (p21Waf1/Cip1), although the degree of changes by DHMEQ was different in each hepatoma cell type. Moreover, intraperitoneal administration of DHMEQ (8 mg/kg) significantly repressed the growth of Huh-7 tumor subcutaneously transplanted into BALB/c nu/nu athymic mice. Our results suggest that DHMEQ could qualify as a candidate for a new chemotherapeutic agent against human hepatoma.

Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study.

Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various tools such as alpha-fetoprotein (AFP) and ultrasonography (USG). The aim of this study was to clarify clinical differences between HCC patients diagnosed by surveillance and those with incidentally detected HCC. Two hundred and seventy-one Japanese patients with HCC diagnosed between January 1991 and December 2001 were recruited. They were categorized into two groups: 178 patients (group 1) had subclinical HCC diagnosed by surveillance and 93 patients (group 2) presented with incidentally detected HCC. The tumor size was significantly smaller in group 1 compared to that of group 2 (2.8 vs. 5.6 cm; P<0.0001). A significantly higher proportion of patients in group 2 had multiple HCC and portal vein infiltration when compared to group 1. Eighty-six (48.3%) group 1 patients and 16 (17.2%) group 2 patients underwent local ablation treatment, which is a curative treatment available for small HCCs (P<0.0001). The cumulative actuarial survival rate was significantly higher in group 1 than in group 2 (P=0.0091). Early detection of HCC by surveillance may contribute to a greater chance of receiving effective treatment and prolonged survival, although a further prospective, randomized study is needed.