December 29, 2013

World J Gastroenterol 2013 December 28; 19(48): 9328-9333

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Arvind Reddy, Elizabeth May, Murray Ehrinpreis, Milton Mutchnick, Division of Gastroenterology, Wayne State University, Detroit, MI 48201, United States

Author contributions: All the authors contributed to this manuscript.

Correspondence to: Arvind Reddy, MD, Division of Gastroenterology, Wayne State University, 6-Hudson c/o Milton Mutchnick, MD 3990 John R, Detroit, MI 48201, United States.

Telephone: +1-313-5772424 Fax: +1-313-5772233

Received August 9, 2013; Revised August 21, 2013; Accepted September 4, 2013;


AIM: To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).

METHODS: This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease. Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-) age, race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC. A subgroup of controls included 118 matched patients with liver cirrhosis. χ2 test and ttest were used for data analysis.

RESULTS: Seventy-seven percent of patients in all 3 groups were African Americans. Patients with HCC had a significantly higher body mass index (P = 0.03), a higher rate of co-infection with human immunodeficiency virus (HIV) (P = 0.05) and a higher prevalence of alcohol abuse (P = 0.03) than the controls. More patients with HCC had LHB than controls (78% vs 39%, P = 0.01). Sixty three percent of patients with HCC were both hepatitis B surface antigen (HBsAb)(-) and HBcAb(+) compared to 23% of controls (P < 0.01). When compared to cirrhotic controls, the frequency of HBcAb(+) remained higher in patients with HCC (78% vs 45%, P = 0.02). Patients with HCC were more likely to be both HBsAb(-) and HBcAb(+) than the cirrhotic controls (63% vs 28%, P = 0.01). Although not statistically significant, 100% of CHC and HIV co-infected patients with HCC (n = 11) were HBcAb(+) when compared to controls (44%; n = 9).

CONCLUSION: These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.

Keywords: Hepatocellular carcinoma, Chronic hepatitis C, Latent hepatitis B, Hepatitis C virus

Core tip: Latent hepatitis B (LHB) has recently received significant attention among researchers and clinicians managing chronic liver disease. It is defined as a combination of hepatitis B surface antigen negative and hepatitis B core antibody positive. The potential association of LHB with hepatocellular carcinoma among patients with chronic hepatitis C infection has been studied and reported in this manuscript.


Emerging data suggest that the mortality rate in cirrhotic patients with hepatocellular carcinoma (HCC) is rising whereas the mortality rate from other complications of cirrhosis is either stable or declining[1]. In the United States, chronic hepatitis C (CHC) accounts for the majority of cases of HCC. Among patients with CHC, factors such as older age, male gender, severity of liver disease, metabolic syndrome and poor response to interferon therapy are established risk factors for hepatocarcinogenesis[1]. “Latent hepatitis B (LHB)”, defined as the presence of detectable hepatitis B core antibody (HBcAb) with undetectable hepatitis B surface antigen (HBsAg)(-) in serum and usually with detectable HBV DNA in hepatocytes, has not been studied as a risk factor for HCC in the United States[2]. Patients with previous exposure to hepatitis B virus but with no evidence of chronic infection are HBsAg(-) and HBcAb(+). This finding alone is now considered as unrecognized LHB[3]. In a large study, the majority of patients with LHB had detectable hepatitis B DNA (HBV DNA) in serum as well as in liver tissue[4]. Various other studies have also confirmed the same findings[5,6]. This led to the identification of a unique group of patients who are HBcAb(+) and at risk for latent hepatitis B.

Early studies from the 1990s suggested that patients with HCC in the absence of chronic hepatitis B and C had detectable covalent closed circular hepatitis B DNA (ccc DNA) in liver parenchyma although they were HBsAg(-) in serum. These patients were considered to have “occult hepatitis B”[7]. A single prospective study by Squadrito et al[8] revealed that among HBsAg(-) patients with CHC, patients with occult hepatitis B with ccc DNA in liver biopsy specimens were at a higher risk for the development of HCC. With the availability of highly sensitive real-time polymerase chain reaction (PCR) assays for the measurement of HBV DNA, tissue analysis for HBV DNA is largely unnecessary to make a diagnosis of latent hepatitis B[2]. Patients with cirrhosis from alcoholic and non-alcoholic fatty liver disease are also at a significantly higher risk for developing HCC when associated with LHB particularly in those who were HBcAb(+) but HBsAg(-)[9]. Injection drug users, patients on hemodialysis, patients with CHC and human immunodeficiency virus (HIV)-infected patients are at increased risk for LHB[10]. In patients with CHC, occult hepatitis B seems to be associated with rapid progression of liver disease[11]. Studies from areas with high prevalence of chronic hepatitis B have associated occult hepatitis B with HCC among patients with CHC[12,13]. This association is much stronger among CHC patients who are non-responders to currently available therapy[14]. Another study reported that although occult hepatitis B may not have a significant impact on response of CHC to interferon, it does increase the risk for HCC among non-responders but not among responders[15].

A large multicenter Japanese study concluded that CHC patients with LHB are at a significantly higher risk for developing HCC[16]. In the same study, interferon was less effective in preventing HCC in patients with LHB when compared to those without evidence of previous HBV exposure. This association was independent of the presence of HBV DNA in serum and therefore, LHB is clinically and prognostically more relevant than serum DNA status.

The above referenced studies establishing LHB as a risk factor for development of HCC are from countries with high endemicity for chronic hepatitis B infection. We studied this potential association among predominantly African American patients with CHC and cirrhosis in an area with low endemicity for chronic hepatitis B.

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