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Hepatic steatosis and insulin resistance are factors that aggravate the progression of liver disease caused by hepatitis C virus (HCV) infection. In the pathogenesis of liver disease and metabolic disorders in HCV infection, oxidative stress due to mitochondrial respiratory chain dysfunction plays a pivotal role. Tacrolimus (FK506) is supposed to protect mitochondrial respiratory function. We studied whether tacrolimus affects the development of HCV-associated liver disease using HCV core gene transgenic mice, which develop hepatic steatosis, insulin resistance, and hepatocellular carcinoma. Administration of tacrolimus to HCV core gene transgenic mice three times per week for 3 months led to a significant reduction in the amounts of lipid in the liver as well as in serum insulin. Tacrolimus treatment also ameliorated oxidative stress and DNA damage in the liver of the core gene transgenic mice. Tacrolimus administration reproduced these effects in a dose-dependent manner in HepG2 cells expressing the core protein. The intrahepatic level of tumor necrosis factor-α, which may be a key molecule for the pathogenesis in HCV infection, was significantly decreased in tacrolimus-treated core gene transgenic mice. Tacrolimus thus reversed the effect of the core protein in the pathogenesis of HCV-associated liver disease. These results may provide new therapeutic tools for chronic hepatitis C, in which oxidative stress and abnormalities in lipid and glucose metabolism contribute to liver pathogenesis.

Background & Aims: Epidemiological studies have suggested a linkage between type 2 diabetes and chronic hepatitis C virus (HCV) infection. However, the presence of additional factors such as obesity, aging, or cirrhosis prevents the establishment of a definite relationship between these 2 conditions. Methods: A mouse model transgenic for the HCV core gene was used. Results: In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis factor-α, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-α antibody restored insulin sensitivity. Conclusions: The ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.

Hepatitis G virus (HGV) has recently been discovered as a potential causative agent for non-ABCDE hepatitis. However, it is not clear whether this virus is associated with chronic hepatitis that eventually leads to the development of hepatocellular carcinoma (HCC). To elucidate the role of HGV in the development of HCC, we examined the presence of HGV genome in nine HCC patients who had neither HBs antigen (Ag) or antibody to hepatitis C virus (anti-HCV) in serum and 21 HCC patients who had HBsAg and/or anti-HCV in serum. Detection of HGV-RNA in the liver and serum was performed by the reverse transcription-polymerase chain reaction assay followed by Southern blotting. HGV-RNA was not detectable in the serum or liver of any of the 9 HCC patients who had neither HBsAg or anti-HCV. In contrast, HGV-RNA was detected in the serum of 2 out of 6 HCC patients who had HBsAg alone, and in the serum of 4 out of 15 HCC patients who had anti-HCV alone. HGV-RNA was detected in the livers of 4 out of 6 patients whose sera contained HGV-RNA, but not detected in the livers of 24 patients who did not show HGV-RNA in serum. Our results suggest that the contribution of HGV to the development of HCC may be small although a co-carcinogenic role of HGV in hepatocarcinogenesis must be further investigated.

1012 HEPATOCELLULAR CARCINOMA IN JAPANESE PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE, ALCOHOLIC LIVER DISEASE AND CHRONIC LIVER DISEASE OF UNKNOWN ETIOLOGY: REPORT OF THE NATIONWIDE SURVEY M. Taniai, E. Hashimoto, K. Tokushige, K. Kodama, T. Kogiso, N. Torii, K. Shiratori. Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan E-mail: taniai@ige.twmu.ac.jp

BACKGROUND/AIMS For the evaluation of response to cytostatic agents, determination of changes in tumor growth speed seems to be essential. RECIST, which lacks the dimension of time, may not be particularly suitable for these agents. The aim of this study is to elucidate the usefulness of tumor marker doubling time (DT) in the evaluation of response to a molecular target agent. PATIENTS AND METHODS A total of 25 patients with advanced HCC participated in the phase I/II clinical trial of TSU-68, a novel tyrosine kinase inhibitor of VEGF. We enrolled 15 patients whose alpha-fetoprotein (AFP) or des-gamma-carboxyprothrombin (DCP) showed exponential increase during wash-out phase before TSU administration. We analyzed the relationship between tumor marker DT and tumor volume DT measured on two CT examinations before the commencement of TSU-68 administration. Next, tumormarker DT in the first 8 weeks of TSU-68 administration was similarly calculated, and compared with DT before TSU-68 administration. DT should be elongated, or turn negative, if TSU-68 was effective. The evaluation based on tumor marker DT was compared with RECIST. Lastly, tumor marker DT after the cessation of TSU-68 was calculated and compared with DT in 4 weeks immediately before the cessation. RESULTS DT of tumor marker level and that of tumor volume before TSU-68 administration were almost identical (R2=0.94, P