AIM: To investigate if there is an association between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and the risk of pancreatic cancer.

METHODS: All relevant studies published before 11 October, 2012 were identified by a systematic search of MEDLINE, EMBASE, BIOSIS Previews and the Cochrane Library databases and with cross-referencing. The observational studies that reported RR or OR estimates with 95%CIs for the association between HBV or HCV and pancreatic cancer were included. A random-effects model was used to summarize meta-analytic estimates. The Newcastle-Ottawa quality assessment scale was applied to assess the quality of the methodology in the included studies.

RESULTS: A total of 8 eligible studies were selected for meta-analysis. Overall, chronic hepatitis B and inactive hepatitis B surface antigen (HBsAg) carrier state (HBsAg positive) had a significantly increased risk of pancreatic cancer with OR of 1.20 (95%CI: 1.01-1.39), especially in the Chinese population (OR = 1.30, 95%CI: 1.05-1.56). Past exposure to HBV (possible occult HBV infection) had an increased OR of pancreatic cancer risk (OR = 1.24, 95%CI: 1.05-1.42), especially among those patients without natural immunity [anti hepatitis B core (HBc) positive/hepatitis B surface antibody (anti HBs) negative], with OR of 1.67 (95%CI: 1.13-2.22). However, past exposure to HBV with natural immunity (anti-HBc positive/anti-HBs positive) had no association with pancreatic cancer development, with OR 0.98 (95%CI: 0.80-1.16), nor did the HBV active replication (hepatitis B e antigen positive status), with OR 0.98 (95%CI: 0.27-1.68). The risk of pancreatic cancer among anti-HBs positive patients was significantly lower than among anti-HBs negative patients (OR = 0.54, 95%CI: 0.46-0.62). Past exposure to HCV also resulted in an increased risk of pancreatic cancer (OR = 1.26, 95%CI: 1.03-1.50). Significant between-study heterogeneity was observed. Evidence of publication bias for HBV/HCV infection-pancreatic cancer association was not found.

CONCLUSION: Chronic HBV and HCV infection increases pancreatic cancer risk. Our findings underscore the need for more studies to confirm this potential relationship.

Pancreatic cancer is one of the most lethal and devastating human malignancies and the fourth leading cause of cancer-related fatality worldwide. Because of absence of early symptoms, lack of sensitive and specific tests to screen the cancer in the initial phases, limited therapeutic options and rapid progression, nearly all patients die of the disease within one year of diagnosis with the overall 5-year survival rate being less than 5%[1]. Therefore, it is crucial to identify the intrinsic genes as well as other risk factors, that may influence the progression of the cancer, and to develop more accurate screening programs for early monitoring and intervention strategies. Although several risk factors associated with pancreatic cancer have been explored, the causative factors for pancreatic cancer are far from being understood, one of which is chronic hepatitis infection[2,3].

The prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection varies worldwide, ranging from less than 0.5% in Western countries to 7% and 25% in East Asian and African countries[4,5]. Infection with HBV is a huge global public health concern, especially in China. According to the World Health Organization, there are 2 billion people infected with HBV globally, with China accounting for 65% of the HBV infective public health burden of the world[6]. HBV/HCV have been detected not only in hepatotropic tissue but also in extrahepatic sites such as the pancreas[7,8]. Several studies reported conflicting results regarding the association between HBV infection and the risk of subsequent pancreatic cancer. Studies by Berrington de Gonzalez et al[9] and Hong et al[10] found no relationship between chronic infection with HBV and the development of pancreatic cancer, while several published studies found an association between presence of HBV infection and incidence of pancreatic cancer, not only in countries with a lower prevalence of HBV infection such as the United States but also in countries with a higher number of HBV infections such as China[11,12]. Meanwhile, little is known about the association between the presence of HCV infection and the risk of pancreatic cancer[3].

The purpose of the present study is to summarize all available evidence of observational studies in order to better define the impact of HBV and HCV infection on the risk of pancreatic cancer in patients following the meta-analysis of observational studies in epidemiological guidelines.

This is the first comprehensive meta-analysis of observational studies on the association between chronic hepatitis viral infection and pancreatic cancer risk. We found that HBV and HCV infection is associated with 20% and 23% higher risk of pancreatic cancer, respectively. Our results reveal that prior infection with hepatitis B, especially in those without natural immunity would significantly increase the risk of pancreatic cancer. However, active hepatitis B viral replication does not increase the pancreatic cancer incidence. These observations provide evidence supporting the importance role of chronic HBV and HCV infection in the development of pancreatic cancer. In light of the fact that pancreatic cancer is a highly fatal tumor with a 5-year survival rate of less than 5% and that the number of people with HBV is 2 billion[6,26], our findings have substantial clinical and public significance on a global scale. It points to the need for further investigation on the etiological causes involved in human pancreatic carcinogenesis, the recognition of pancreatic damage mechanisms caused by chronic hepatic viral infection, and for long-term, large scale clinical studies to confirm this clinical association.

If the positive association between the chronic or inactive HBV or HCV carriers and the development of pancreatic cancer is a true, what mechanism could explain such a link From the anatomical point of view, the proximity of the liver to the pancreas, as well as the sharing of the two organs blood vessels and ducts may make the pancreas a potential reservoir of hepatitis viruses. HBV or HCV may travel through the blood stream and be deposited in non-liver tissue[27,28]. In fact, by means of situ hybridization and immunohistochemical techniques, the serological markers of present or past HBV infection, HBsAg was detected in chronic inflammatory pancreatic acinar cells and in the pancreatic duct epithelia with pancreatic adenocarcinoma[29]. The same was true with HCV antigen, which was also found in pancreatic acinar cells[30]. These findings demonstrated the possibility of HBV infection and evidence of a chronic inflammatory reaction in non-hepatic tissues.

HBV and HCV replication intermediates in pancreatic cells support the assumption that the permissiveness of these extrahepatic cells for viral replication might also induce the chronic inflammatory response, thus eventually promoting tumor development. Anti-HBc-positive status, the sero biological marker of past exposure to HBV had an increased risk of developing pancreatic cancer. The observation provides some biological plausibility to the idea that long-lasting persistence of viral infection could indeed replicate in the pancreas. In fact, HBV and HCV are oncogenic viruses, and both are able to integrate the viral RNA or DNA into the genome of the infected cells[31,32]. DNA integration may play a key role in the regulation of the cell cycle, inducing carcinogenesis associated with HBV infection[33].

The third reason why our finding of a relationship between HBV infection and pancreatic cancer incidence may not be surprising is that the presence of HBV infection protection marker, seroconversion from HBsAg to anti-HBs, which is considered a sign of disease protection, leads to a significantly decreased risk of pancreatic cancer showing an OR of 0.54 in the pooled studies.

As with all meta-analyses of observational studies, our findings might have some limitations. First, because five of eight studies used a case-control design[10-12,17,18], the findings provided by this meta-analysis should be viewed with caution since more recall and selection bias might be seen in case-control studies. In addition, all the case-control studies were hospital-based and therefore may not fully represent the general population of pancreatic cancer patients, thereby introducing potential for selection bias into our meta-analysis.

Second, when investigating the association between hepatic virus infection and the risk of pancreatic cancer, the potential residual confounding and the allocation bias, with hepatic virus infection being at different stage and baseline risk of pancreatic cancer would affect the results. For example, it is difficult to understand the biological explanation for finding the cancer risk in subjects with chronic infection and not in those with current and active replication of the virus as shown by a positive HBeAg. The progression from active hepatitis virus infection to chronic inflammatory response targeted to pancreatic carcinogenesis is still unknown, for there is a lack of such data[34]. This incomplete information on HBV/HCV in the pathogenesis of progressive stages limits our knowledge on the true relationship of these oncogenic viruses with pancreatic cancer development. Although an increased risk of pancreatic cancer was observed for anti-HBs-seronegative/anti-HBc-seropositive carriers who were previously exposed to HBV without natural immunity, it is very difficult to interpret a pooled analysis of only 2 studies. Another issue is that none of the studies directly tested for the presence of markers of hepatitis virus infection in the pancreatic tissue. Therefore, a correlation between the level of the markers of HBV/HCV infection in peripheral blood and that in pancreatic tissue could not be established, which would throw some doubt into the reliability of the summary of RRs. More research is necessary to assess a dose-response association to examine the influence of viral load on the progression of pancreatic cancer to support biological plausibility.

Third, possible confounding factors and biases that may not have been fully adjusted for in this study exist. In fact, risk factors such as cigarette smoking, alcohol intake and diabetes, all of which could increase risk of pancreatic cancer associated with a history of chronic hepatitis virus infection. Only 4[2,10-12], 3[2,11], and 4[10-12,17] studies provided risk estimated adjusting for smoking, alcohol intake, and diabetes, respectively. The positive association between chronic HBV infection and pancreatic cancer risk was found after adjustment by smoking and alcohol drinking, but no positive correlation was maintained after adjustment by diabetes, suggesting that residual confounding by diabetes modified the association between chronic HBV infection and pancreatic cancer risk.

Finally, it is also important to realize that there is still a significant heterogeneity observed across studies, mostly due to the diversity of the study designs and the varying incidence of pancreatic cancer and HBV/HCV infection rates may vary from continent to continent.

Even with these limitations, our meta-analysis supports the hypothesis that chronic HBV and HCV infection may significantly increase pancreatic cancer risk. The findings of this study raise the question of whether the early detection and provision of aggressive antiviral treatment for chronic hepatitis virus infection could prevent the development of pancreatic cancer, and whether patients with past exposure to HBV/HCV should be screened for malignancies other than HCC particularly in patients at high risk of HBV/HCV infection.

In conclusion, our meta-analysis favors the association between HBV/HCV infection and pancreatic cancer risk. However, observational studies were moderately heterogeneous and biased. Additional long-term prospective evidence for HBV/HCV infection among higher risk of pancreatic disease patients should be monitored and new evaluations on the effects of early intervention including HBV/HCV treatment, especially in occult HBV infection (anti-HBc-seropositive status), on the molecular carcinogenesis of pancreatic cancer are warranted.