One third of the world’s population is infected with hepatitis B virus (HBV), with the vast majority achieving hepatitis B surface antigen (HBsAg) seroconversion and not progressing to chronic infection or carrier state.1 Nevertheless, even after HBsAg loss, there is evidence that low-level HBV replication may occur with detectable HBV DNA in the liver and serum. Should these patients worry about complications down the road?
Regardless whether defined as resolved hepatitis B (American Association for the Study of Liver Disease,2) or occult hepatitis B (European Association for the Study of the Liver,1), there are conflicting data about the consequences of this clinical entity characterized by positive hepatitis B core antibody (anti-HBc) with or without hepatitis B surface antibody (anti-HBs) in the setting of negative HBsAg, normal ALT levels, and low or undetectable serum HBV DNA. Of note, there is also seronegative occult hepatitis B,3 when HBV DNA is detected in the liver and/or serum, with all other markers (anti-HBc, anti-HBs) being absent, both in immunosuppressed patients (HIV or on hemodialysis), as well as healthy individuals (blood donors, general population).
A growing body of literature, summarized in several review articles,3,4 suggests that patients with resolved or occult hepatitis B have an increased risk not only for transmission and reactivation of hepatitis B, but also progression of liver fibrosis to established cirrhosis and development of hepatocellular carcinoma (HCC), particularly in those with coexisting chronic liver disease. In this issue of Journal of Clinical Gastroenterology, Tang et al5 explore if exposure to HBV is a risk factor for HCC and pancreatic cancer.
In the present study, Tang and colleagues used administrative data from an integrated health care delivery system and identified patients who underwent testing for hepatitis B over 13 years (1995 to 2008), dividing them in 3 cohorts: negative infection (n=28,719), previous exposure (n=5141), or active infection (n=404). Previous exposure was defined as anti-HBs and anti-HBc positive or anti-HBc positive alone, and active infection was defined as HBsAg and anti-HBc positive, HBeAg positive, or HBV DNA positive. For all patients, pathology reports were reviewed for presence of pancreatic cancer or HCC. Univariable and multivariable Cox regression analyses were used to assess the impact of HBV status on development of pancreatic cancer and HCC. The multivariable analyses were adjusted for race (African American vs. non-African American—for pancreatic cancer; Asian vs. non-Asian for HCC), sex, age, presence of diabetes, HIV status—for pancreatic cancer and HCC; HCV status, and presence of cirrhosis—for HCC. As expected, age and diabetes increased the risk for pancreatic cancer [odds ratio (OR)=1.08] and HCC (OR=1.88); however, there was no significant association with HBV exposure or active HBV infection. With regard to HCC, only active HBV infection, not HBV exposure, was associated with a higher risk for cancer development (OR=4.64 vs. 1.03). In addition, predictably, male sex, age, HCV positivity, and cirrhosis were risk factors for HCC (OR=2.05, 1.08, 5.4, and 27.84). There were no data in regard to alcohol use in either pancreatic cancer or HCC analyses.
How can we reconcile these results with other studies that demonstrate the opposite finding? Theoretically, HBV could be involved in pancreatic carcinogenesis, as there are data proving HBV replication in pancreatic cells, but clinical results are contradictory in proving an association between pancreatic cancer and HBV. The largest positive study (Hassan et al6) looked at 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 matched healthy controls, finding an increased risk of cancer with HBV exposure: 72 of 476 patients with pancreatic cancer had HBV exposure versus 53 of 879 healthy patients (OR=2.3 to 3.9); interestingly, there was only 1 patient in the control group with active HBV infection (none among patients with cancer), in discordance with the expected association if HBV were to be involved in pancreatic carcinogenesis. A large prospective study (Berrington de Gonzalez et al7) following >200,000 patients for a median time of 12 years did not demonstrate a relationship with HBsAg positivity in 664 patients who developed pancreatic cancer. Results of Tang and colleagues also contradict a HBV-pancreatic cancer association, but the authors recognize the limitations of their study to identify this relationship, and cite the need for studying HBV DNA in pancreatic tissue.
When evaluating the association between hepatitis B exposure and HCC, the strength of the findings by Tang and colleagues is conferred by their large database of a diverse US population; in contrast, most prior studies have predominantly included Asian patients. The retrospective nature of analysis and incomplete clinical information captured in the database represent significant limiting factors. In many patients, the diagnosis of HCC could have been established on imaging alone—Tang and colleagues captured only biopsy-proven HCC. Missed patients with HCC could explain why on multivariate analysis the OR for HCV-related risk was higher than for active HBV-related risk (5.4 vs. 4.64). Alcohol use is an important confounder especially in regard to cirrhosis and HCC as no information was available. In addition, HBV exposure could have had an additional impact in increasing the risk of HCC in specific populations—patients coinfection with HCV or with HIV, perspective not captured even if the multivariate analyses were adjusted for HCV and HIV.
The literature is equally limited, with studies showing both increased risk of HCC in the setting of HBV exposure or no significant association, even in the setting of hepatitis C coinfection. For example, Reddy et al8 analyzed 185 patients (United States) with HCC and HCV and compared them with 356 patients with HCV and no HCC (118 patients with cirrhosis)—across the board, there was a significant difference in the prevalence of HBV exposure: 78% versus 39% in all controls versus 42% in cirrhotics controls. On the contrary, Lok et al9 analyzed 91 patients with HCC and 182 matched controls who participated in the HALT-C Trial, without finding any significant difference in terms of prevalence of anti-HBc, serum or liver HBV DNA. Shiratori et al10 studied 368 consecutive HCC patients at the University of Tokyo and found seropositivity in 83% for HCV antibody (C-viral), HBsAg in 10% (B-viral), dual infection in 2%, and negativity for both in 5% of patients. The incidence of dual infection in HCC patients was similar to that in 549 patients with chronic hepatitis (1%) and 119 patients with cirrhosis (1%). Interestingly, mutually exclusive viral replication occurred in patients with persistent coinfection. In “C-viral” HCC, HBV core antibody (HBcAb) was tested in 192 patients and was found to be positive in 111 and negative in 81; patients had similar characteristics irrespective of the presence or absence of HBcAb. Overall, they concluded that coinfection plays little if any role in the development of HCC.
What are the implications of this study for a busy practitioner who gets back a viral hepatitis panel result negative except for anti-HBc? Although that patient has an excellent prognosis because of HBsAg negativity, HBV DNA is worth checking to exclude chronic occult HBV infection, and discuss the potential low risk of progression to cirrhosis and liver cancer. This may be applicable especially for older patients who might have achieved HBs seroconversion after significant fibrosis had already occurred, or patients coinfected with HCV, HIV, or other chronic liver diseases such as alcoholic or nonalcoholic fatty liver disease.
Despite negative findings from Tang and colleagues with regard to the role of HBV exposure and HCC/pancreatic cancer, the jury is still out. We need prospective studies linking clinical information with HBV replication data in the liver and other organs, as well as better understanding of HBV-triggered carcinogenesis pathways in different sites of HBV activity and across various ethnic groups.
1. EASL Clinical Practice Guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–185.
2. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:2–36.
3. Raimondo G, Pollicino T, Cacciola I, et al.. Occult hepatitis B virus infection. J Hepatol. 2007;46:160–170.
4. Schmeltzer P, Sherman KE. Occult hepatitis B—clinical implications and treatment decisions. Dig Dis Sci. 2010;55:3328–3335.
5. Tang J, Sharma R, Lamerato L, et al.. Is previous exposure to hepatitis B a risk factor for pancreatic cancer or hepatocellular carcinoma?J Clin Gastroenterol. 2014;48:729–733.
6. Hassan MM, Li D, El-Deeb AS, et al.. Association between hepatitis B virus and pancreatic cancer. J Clin Oncol. 2008;26:4557–4562.
7. Berrington de Gonzalez A, Yun JE, Lee SY, et al.. Pancreatic cancer and factors associated with the insulin resistance syndrome in the Korean cancer prevention study. Cancer Epidemiol Biomarkers Prev. 2008;17:359–364.
8. Reddy A, May E, Ehrinpreis M, et al.. Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C. World J Gastroenterol. 2013;19:9328–9333.
9. Lok AS, Everhart JE, Di Bisceglie AM, et al.. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in US patients with chronic hepatitis C. Hepatology. 2011;54:434–442.
10. Shiratori Y, Shiina S, Zhang PY, et al.. Does dual infection by hepatitis B and C viruses play an important role in the pathogenesis of hepatocellular carcinoma in Japan?Cancer. 1997;80:2060–2067.