Birth order, as a proxy for age at infection, in the etiology of hepatocellular carcinoma.

First-born and second-born children are exposed to common infections after enrollment at school, whereas later-born children are exposed to these infections earlier through their older siblings. We have evaluated whether birth order is a risk factor for hepatitis B virus (HBV)-related, hepatitis C virus (HCV)-related, and apparently virus-unrelated hepatocellular carcinoma (HCC) in a large case-control study that included 333 HCC cases and 632 controls. In comparison with controls who were carriers of hepatitis B surface antigen (HBsAg), HBsAg-positive HCC cases were more likely to have been later-born children (odds ratio per increase in birth order = 2.0; 95% confidence interval = 1.2-3.6). There was no such evidence for anti-HCV-positive cases compared with anti-HCV-positive controls or for virus-negative HCC cases compared with virus-negative controls. We conclude that early infection with HBV increases the risk of HBV carriers to develop HCC, over and beyond its role in facilitating the establishment of a carrier state.