Recently, infection with HCV or HBV has been suggested as a risk factor for ICC[3,9–13
]. A case-control (41 cases and 406 controls) study from Korea reported that the prevalence of anti-HCV and HBsAg positivity was 12.5% and 13.8%, respectively, in patients compared with 3.5% and 2.3% in controls. Multivariate analysis found anti-HCV positivity to be associated with ICC (OR, 3.9) but not with HBsAg positivity (OR, 1.3)[3
]. A prospective cohort study from Japan showed that 2.3% of 600 patients with HCV-related cirrhosis developed ICC during a mean follow-up of 7.2 years. The risk of developing ICC among patients with HCV-related cirrhosis was 1000 times higher than that in the general population[9
]. A case-control study from Italy that compared 26 patients with ICC with 824 controls found that seropositivity for anti-HCV and HBsAg was 25 and 13% in ICC cases and 5.8 and 6.7% in controls, respectively. A statistically significant increase in the OR was observed for anti-HCV (OR, 9.7), whereas a weaker, non-significant association was found with HBsAg (OR, 2.7)[10
]. Similarly, according to a case-control study that involved 625 cases and 90 834 controls from the United States, the prevalence of anti-HCV and HBsAg was 5.6 and 0.2% in ICC cases and 1 and 0.2% in controls, respectively. The adjusted OR for ICC was 6.1 for anti-HCV, whereas no association was found with HBsAg (OR, 0.8)[11
]. Another hospital-based case-control study from Japan showed that HCV seropositivity was detected in 36% of ICC patients and 3% of controls, and the adjusted OR for ICC development was 6.02 for anti-HCV[12
]. Overall, these studies suggest that HCV infection may play a role in ICC development, whereas HBV infection does not seem to be a relevant risk factor for the disease. Only sporadic cases of ICC have been reported with HBV infection[13
]. In the current study, seropositivity for HBsAg and anti-HCV were found in 48.4 and 2.9% of ICC cases, and in 9.6 and 1.4% of controls, respectively. This indicates that HBV, but not HCV infection is a strong risk factor for development of ICC. These findings differed markedly from the results of previous studies[3,9–12
]. ICC is characterized by wide variability in incidence and risk factors. HCV seems to be associated with ICC in regions with relatively low prevalence of HBV infection, such as Japan and the United States[9,11
]. China, a highly endemic area for HBV infection, has an HBsAg-positive rate of 9.09% in the general population[14
], but a low incidence of HCV infection (0.42%-2.1%)[15,16
]. Therefore, the difference in etiological factors associated with ICC can be explained by the type of endemic hepatitis virus. Thus, screening and vaccination for hepatitis B may be a useful strategy to decrease the high rate of ICC in China. It is noteworthy that the prevalence of HBV or HCV infection in our controls is compatible with the figure observed in the general population in China, which suggests no relevant selection bias in our controls.
The precise mechanism of HBV infection in the carcinogenesis of ICC is still unknown. Integration of the HBV sequence into the human genome is one of the most important steps in HBV-related carcinogenesis[17
]. HBV sequences are found in human[18
] and duck[19
] bile duct epithelial cells by in situ
hybridization. HBV sequence integration is suggested to have a direct oncogenic effect by modulating the expression of neighboring cellular genes involved in the regulation of cell proliferation and apoptosis. HBV X gene-encoded protein (HBX) acts as a transactivator of various cellular genes and plays a crucial role in the pathogenesis of HCC[17,20
]. Wang et al[21
] has observed frequent, strong HBX immunochemical staining in bile duct cells of cancerous and surrounding hepatic tissues, in some HBV-infected ICC specimens, and has suggested that HBX may contribute to the pathogenesis of ICC. Furthermore, it has been shown that HBX may activate the transcriptional expression of human telomerase reverse transcriptase, which leads to tumorigenesis in cholangiocytes[22
]. Further studies are required to investigate the cellular transformation mechanisms of ICC induced by HBV infection.
Cirrhosis, such as alcoholic cirrhosis and HCV-related cirrhosis, has also been associated with ICC[9,10
]. HBV infection may result in chronic hepatitis, followed by liver cirrhosis. Our data showed that cirrhosis was found in 69 HBsAg-positive ICC cases (45.7%). This finding suggests that HBV-related cirrhosis may be an essential stage in the development of ICC, as it is for HCC in China.
Hepatolithiasis was another independent risk factor for ICC development in our study. This result was compatible with several previous studies[7,8,23,24
]. The carcinogenesis associated with hepatolithiasis may be a multi-step process in which there are changes from hyperplasia to dysplasia, and finally to adenocarcinoma[25
]. Recent studies have demonstrated that several cancer-related genes, including those of p16
, cyclooxygenase-2, prostaglandin E2, c-met, and caudal-related homeobox gene 2, play an important role in the development and progression of ICC arising in hepatolithiasis[26–30
In conclusion, this study showed that HBV, but not HCV infection and hepatolithiasis, are strong risk factors for development of ICC in China.