Hepatocellular carcinoma and infections with multiple hepatitis viruses

Hepatitis B virus (HBV) plays a major role in liver carcinogenesis. HBV-DNA integration into cellular DNA provides some molecular basis for understanding the mechanisms of neoplastic transformation of the liver cell. Persistence of HBV-DNA episomic forms, necro-inflammation in the liver, and cirrhosis appear to be additional promoting factors. We studied the possible association between hepatocellular carcinoma (HCC) and the defective hepatitis D virus (HDV), a virus that requires the helper function of HBV. Patients infected with HDV and HBV develop HCC about 10 years earlier than those infected with HBV alone. Persistence of active HDV disease and low levels of "wild-type" HBV (i.e., secreting the hepatitis B surface antigen [HBsAg]) are associated with progressive liver disease and HCC. Therefore, HBV replication, in spite of being inhibited by HDV, appears to play a major role sustaining HDV pathogenicity. Detection of antibody to the hepatitis C virus (HCV) in many HCC patients raises the important question whether HCV has oncogenic potential. Clinico-epidemiological data show that the most severe forms of liver disease in patients with multifactorial liver damage occur in those infected with HCV. The prevalence of HBV markers in patients with cirrhosis, HCC, and HCV infection is higher than in individuals with comparable age and other diseases. HBV-DNA integration occurring early during HBV infection can persist in those with and without detectable HBsAg in their serum. Therefore, one can speculate that in patients with integrated HBV-DNA and concurrent HCV infection, cirrhosis and HCC may develop more easily than in patients without HBV-DNA integration. HCV hampering the immune system also might play a role in the genesis of HCC. The evidence that multiple hepatitis viruses are more frequently associated with HCC than infections of one virus alone has important practical consequences. It warrants the identification of high risk patients so that they can be monitored frequently for early diagnosis and treatment.