Analysis of the mechanism of liver injury and carcinogenesis in HCV infection

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Since the genome of hepatitis C virus (HCV) was been cloned from experimentally infected chimpanzee plasma, testing for antibody to hepatitis C virus has shown that HCV is the etiological agent for most cases of non-A, non-B (NANB) hepatitis. We evaluated the prevalence of antibody to the core protein of HCV and found that HCV is related with more than 95% of NANB chronic liver disease and that there is a close correlation between the presence of anti-HCV core and HCV carriers. We quantified HCV RNA in serum by the competitive RT-PCR assay to correlate the replicative level of HCV with (1)various stages of the carrier states or (2)a sustained response to interferon (IFN) therapy. The amounts of HCV RNA in serum ranged from 10^4 to 10^<9.5> copies/mL serum. The titer of HCV RNA were lower in asymptomatic blood donors and in patients with chronic persistent hepatitis compared with those having chronic active hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The initial titer … More of HCV RNA before IFN therapy of long-term responders were significantly lower than those of short-term responders and non-responders. Multivariate analysis showed that the HCV RNA titer before therapy was the strongest independent predictor of a sustained response to IFN therapy. We determined the localization of the HCV-infected hepatocytes by immunohistochemical studies and "in situ"hybridization technique. Positive staining or signal was found in less than 50% of studied specimens. Hepatocytes with positive results were scattered in the lobules. Intralobular inflammation and fibrosis had higher scores for samples with positive rather than negative results. In liver tissue of patients with HCC, detection of strand-specific HCV RNA by PCR showed that not only positive-strand but also negative-strand could be amplified in both cancerous and non- cancerous liver tissue. These results showed that the replicative level of HCV is higher in advanced liver disease, and that elevation of viral replication might play an important role in liver injury, progression of liver disease and carcinogenesis. Less