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Abstract: The natural course of hepatitis C virus (HCV) carriers is not well understood. We examined the clinical characteristics of individuals exhibiting spontaneous elimination of HCV as part of a cohort study of residents of a HCV hyperendemic area in Japan. In individuals who were judged to have persistent HCV infection in 1995, 302 had at least 4 annual ALT measurements between 1993 and 2000, and had not been treated with IFN. They were tested for the presence of HCV RNA in 2001 and/or 2002 and HCV RNA could not be detected in 20 of the 302 individuals. In these 20 individuals, 7 were confirmed to have detectable HCV RNA and 13 were not until 2000. Thus, 2.4% (7/289) were judged to have spontaneously eliminated the HCV infection during that 6-year period. Although there were no differences in age, sex, ALT levels, or serologically defined HCV genotype between individuals with and without exhibiting spontaneous elimination, there was a significant relationship between the elimination of HCV RNA and a low level of HCVcAg (<20pg/mL) (P < 0.001) upon testing in 1995. These results suggest that spontaneous elimination of HCV RNA following persistent infection is rare and appears to be related to viral load. [Copyright &y& Elsevier]

Abstract: Measurement of serum human hepatocyte growth factor (HGF) by enzyme-linked immunosorbent assay (ELISA) is useful for the early diagnosis and prediction of prognosis of patients with acute liver failure (ALF). This ELISA methodology, however, is neither rapid nor convenient for use at the bedside. In this study, we have developed a rapid semi-quantitative immunochromatographic (IC) assay and evaluated its usefulness in assessing patients with acute hepatic injury. Only 100μl of serum is required; the assay can be easily completed in 20min. The values obtained using this novel assay correlated well with the values obtained using the standard ELISA protocol. In addition, the values obtained in the IC assay correlated with clinical course; increased serum HGF levels were associated with an increased frequency of ALF and death. These results indicate that this rapid semi-quantitative IC assay for HGF is useful for the early diagnosis of ALF and prediction of clinical outcome in acute hepatic injury. [Copyright &y& Elsevier]

Abstract: Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-γ expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-α. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, α-smooth muscle actin, and transforming growth factor-β1 in comparison to rats without PGZ. These results suggest that PPAR-γ agonist is a potential therapeutic modality to treat NASH. [Copyright &y& Elsevier]

Abstract: α-Fetoprotein (AFP) is produced abundantly in fetal liver but is hardly detectable in adults. In this study, we investigated two unrelated Japanese families with hereditary persistence of AFP. A g→a substitution at nucleotide −119 (−119g→a) in the hepatocyte nuclear factor (HNF)-1 binding site of the AFP promoter was identified in both families. The activity of the wild- or variant-type human AFP promoter was evaluated by in vitro and in vivo transfection experiments. This substitution in the AFP promoter significantly stimulated its transcriptional activity in human hepatoma cells, regardless of their prior AFP production. The variant-type AFP promoter was also active in adult mouse livers in vivo. Additionally, overexpression of HNF-1α stimulated the activity of both the wild- and variant-type AFP promoters in hepatoma cells. HNF-1α expression also activated both AFP promoters even in nonhepatoma cells, and this activation was suppressed by nuclear factor (NF)-I overexpression. These results indicate that an HNF-1 binding site mutation leads to induction of the AFP gene expression in adult liver, and suggest that competition between HNF-1 and NF-I in this region is involved in transcriptional regulation of the AFP gene during hepatic development. [Copyright &y& Elsevier]

The cell strain M, which was established from normal rat liver cells, is characterized by the active formation of a collagen fiber network. In this study, we investigated the characterization of M cells and evaluated the anti-fibrogenic effects of taurine using this culture system. M cells expressed cytokeratin (CK)8, CK18, vimentin, and α-smooth muscle actin, whereas expression of CK-19 or desmin was not detected. Also, M cells expressed transforming growth factor (TGF)-β1, -β2, and TGF-β type I and II receptors, and treatment with TGF-β1 (1 ng/ml) for 6 days markedly stimulated the formation of a collagen fiber network and expression of procollagen α1(I) mRNA. When M cells were treated with various concentrations of taurine (10–50 mM), network formation and procollagen α1(I) expression were significantly suppressed in a dose dependent manner. Additionally, even in the presence of TGF-β1, taurine treatment effectively reduced the formation of a collagen fiber network. These results suggest that M cells exhibit features of not only hepatocytes but also myofibroblasts, and TGF-β1 plays an important role in the formation of collagen fiber networks in this culture system. Additionally, this M cell culture system is appropriate for use as an in vitro model of hepatic fibrosis in the evaluation of the anti-fibrogenic effects of various agents. [Copyright &y& Elsevier]

In a rat model of hepatocarcinogenesis induced by a choline-deficient, l-amino acid-defined (CDAA) diet, hepatocellular carcinoma (HCC) occurs in conjunction with fatty liver, hepatocyte injury and regeneration, fibrosis and cirrhosis. This is similar to human HCC development with cirrhosis. The aim of this study is to clarify sequential changes in the expression of growth and growth inhibitory factors, and hepatocyte proliferation and apoptosis during development of preneoplastic nodules in rats fed a CDAA diet. The expression of hepatocyte growth factor was stimulated at about the same time as CDAA diet-induced liver injury within 1 week. Hepatocyte growth factor reached a maximum level of expression from 4 to 8 weeks. Transforming growth factor (TGF)-α expression increased from 4 to 40 weeks. Although TGF-β, a growth inhibitory factor for hepatocytes, was also expressed with a peak from 4 to 8 weeks followed by a gradual decrease until 48 weeks, expression of cyclin D1 and hepatocyte proliferation continued to be stimulated throughout the experimental period. Additionally, the number of apoptotic hepatocytes was markedly reduced after peaking at 8 weeks. These results suggest that some hepatocytes in the livers of rats fed a CDAA diet may escape from TGF-β-induced growth inhibition and apoptosis, leading to development of preneoplastic nodules. [Copyright &y& Elsevier]