Does hepatitis B virus cause hepatocellular carcinoma?

Evaluation of the hypothesis of an association between hepatitis and hepatocellular carcinoma (HCC), first suspected on pathologic grounds, was made easier by the discovery of hepatitis B surface antigen. Population correlation and analytical epidemiologic studies established that there is a strong and specific association between hepatitis B virus (HBV) and HCC. The association is restricted to chronically active forms of HBV infection and is universally present, equally strong in the USA and Europe as in Africa and Asia. The causal nature of the association between HBV and HCC appears indisputable, even though the pathogenesis of HBV-related HCC has not been established. There is no evidence to support any of the non-causal interpretations, i.e., that a third factor causes both persistence of HBV and HCC, or that HCC increases susceptibility to the HBV carrier state. Since about 200 million people are hepatitis B surface antigen carriers, HBV would appear to be second only to cigarette smoking as the most important known human carcinogen. However, a substantial proportion of HCC cases throughout the world show no evidence of active HBV infection; for those cases other causal agents must be invoked. Aflatoxin may be an important etiologic factor in Africa and Asia, whereas in Europe and the USA cigarette smoking and alcohol drinking are serious and numerically important suspects for hepatocellular carcinogenicity. Several other factors, including natural and synthetic chemical carcinogens, infectious agents and steroid hormones are also suspected, but the supporting evidence is weak and the numerical importance of the factors probably limited.