The mechanism by which HBV infection causes HCC is not completely known (reviewed in (9
), ). Evolution to HCC may be the direct effect of the virus itself, or it may be an indirect effect, through the process of the inflammation, regeneration and fibrosis associated with cirrhosis due to the HBV infection. HBV DNA has been shown to become integrated within the chromosomes of infected hepatocytes, the integration of viral genetic material occuring in a critical location within the cellular genome. For example, integration of HBV DNA has been observed within the retinoic acid receptor alpha gene and within the human cyclin A gene, both playing crucial roles in cellular growth. However, in many if not most cases, the HBV DNA integration site does not appear to be in a critical location and the process appears to be random. Furthermore, the length and the components in the HBV DNA integrant varies considerably and the viral DNA may be rearranged, deleted or present in repeats (10
). These findings suggest that it is not the process of integration itself that leads to HCC.
Table 1 Possible mechanisms of HBV-Induced HCC (9)
The hepatitis B x gene (HBx) product has been implicated in causing HCC because it is a transcriptional activator of various cellular genes associated with growth control (11
). The HBx gene expression is also associated with activation of the Ras-Raf-MAP kinase pathway, an important cellular pathway that has been implicated in hepatocarcinogenesis. In addition, HBx has been found to interact with p53, interfering with its function as a tumor suppressor. Another viral gene product that has been implicated in causing HCC is the truncated HBsAg gene product, although the mechanism by which this might result in HCC is not clear.
In keeping with the suggestion that HCC may be directly related to HBV infection, is the observation from several studies that elevated serum levels of HBV DNA (a marker of higher levels of HBV replication) are associated with a higher risk of HCC (12
). A recent longitudinal study of 3,653 HBsAg-positive subjects in Taiwan found that an elevated serum level of HBV DNA (>10,000 copies/mL; ~ 2000 IU/mL) at baseline was a strong predictor of subsequent development of HCC, independent of serum hepatitis B e antigen (HBeAg) status, serum aminotransferases levels or the presence of cirrhosis (15
). Although these data were compelling, serial measurements of serum HBV DNA levels were not available from the cohort. Thus, data are lacking on the impact of persistently high versus changing or fluctuating serum HBV DNA levels.
Another line of evidence suggesting a direct hepatocarcinogenic role of HBV is the association of certain genotypes with higher rates of HCC (16
). Thus, in Asian cohorts, HBV genotype C is generally thought to increase the risk of HCC above that of genotype B. It has been speculated that this may be because patients infected with genotype C are likely to remain seropositive for HBeAg for longer periods and thus have higher serum levels of HBV DNA for a greater period of time. However, studies in other populations have found genotype B or even F to be more strongly associated with HCC (17
). Thus the exact role of HBV genotype in hepatocarcinogenesis remains to be clarified.
Consistent with the hypothesis that HBV-related HCC may occur indirectly, via cirrhosis, is the observation that approximately 70% of cases of HBV-related HCC occur in association with cirrhosis, although the rate of cirrhosis appears to be lower in younger patients with HCC (18
). Cirrhosis independent of its cause (alcohol, hepatitis C, metabolic errors) is associated with a high rate of HCC. Thus, the high rate of HCC in persons with chronic HBV infection may merely reflect the fact that hepatitis C is a common cause of cirrhosis.