Hepatitis viruses and hepatocellular carcinoma

Of the hepatitis viruses that have been identified and their pathological consequences characterised, three - hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) - have been implicated as risk factors for hepatocellular carcinoma (HCC) in humans. Sufficient evidence is now available to justify the conclusions that chronic infection with HBV and HCV, but not HDV, are causes of HCC. Hepatocellular carcinogenesis is a complex step-wise process that evolves over many years, and the precise way(s) in which these two viruses induce malignant transformation remain uncertain. The observation that HBV DNA is integrated into cellular DNA in the great majority of, and perhaps all, HBV-related HCCs, whereas replicative intermediates of HCV do not insert into host DNA in HCVrelated HCC, makes it very likely that different pathogenic mechanisms operate in HBV- and HCV-induced HCC. Indeed, evidence is mounting that both direct and indirect mechanisms, and often the two together, are involved in the genesis of HBV-related HCC, but that HCV appears only to induce HCC indirectly by causing chronic necroinflammatory hepatic disease which in turn is responsible for tumour formation. There is some evidence that the two viruses may interact in the development of HCC, but this remains to be proven. Animal models - other members of the hepadnavirus family (to which HBV belongs) that also cause HCC in their respective animal hosts, and transgenic mice into which sequences of HBV DNA have been inserted - are proving useful in elucidating putative mechanisms of HBV-related hepatocellular carcinogenesis, but no models for studying HCV-induced HCC are yet available. Whatever the pathogenesis of HBV-induced and HCV-induced HCC, the viruses do not act alone but in conjunction with other environmental carcinogens and a number of host factors