Hepatocellular carcinoma: the point of view of the hepatitis B virus

Hepatitis B virus (HBV) infection is the main risk factor for hepatocellular carcinoma (HCC) development, as suggested by many epidemiological and molecular studies (1–13) and as dramatically confirmed by data from Taiwan where the universal childhood vaccination program against HBV determined a striking reduction of new infections in infancy and a parallel decrease of liver cancer incidence in childhood (14). Despite the availability of a very efficacious vaccine, however, HBV infection is still a major health problem worldwide, with an estimate of 400 million chronic carriers of the HBV surface antigen (HBsAg), many of whom suffer from progressive forms of liver disease and show a high propensity to develop HCC. Furthermore, when other risk factors for HCC development—such as hepatitis C virus (HCV) infection, Aflatoxin B1 exposure, alcohol abuse and metabolic factors as obesity and diabetes—coexist with HBV infection, a considerable increase of the relative risk for cancer development occurs, probably due to a synergic pro-oncogenic effect of the different factors (13,15–19). Consequently, the World Health Organization includes HBV in ‘group 1’ human carcinogens classifying it among the most important oncogenic agents after tobacco smoking. HCC development underlies complex and multifactorial pathogenetic mechanisms. Much evidence indicates that HBV exerts its prooncogenic properties playing a role in many of these mechanisms. Moreover, this virus seems to maintain its pro-oncogenic role also in cases with persistence of viral genomes in the liver of individuals who are negative for circulating HBsAg (namely, ‘occult’ HBV infection) (20). Here, we review the different aspects of HBV involvement in heapatocarcinogenesis.