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Editor,—Dr Marusawa and colleagues (OpenUrlAbstract/FREE Full Text) , commenting on their findings of a high prevalence of antibodies to hepatitis B virus (HBV) core antigen (anti-HBc) in Japanese patients with hepatitis C virus (HCV) chronic liver disease, suggest that HBV infection has a role in the development of hepatocellular carcinoma (HCC) in patients with chronic HCV infection. I would like to raise a methodological point that may influence the interpretation of their findings.
HBV and HCV infections share common mechanisms of transmission and are highly correlated. Therefore, it is not surprising that the prevalence of anti-HBc was much higher in individuals with chronic HCV infection than in the anti-HCV negative controls. But why would patients with HCV associated HCC have a higher prevalence of anti-HBc than individuals with HCV chronic hepatitis and liver cirrhosis? Stratified analyses suggested this finding is not related to age or history of past transfusion, or to other risk factors that might have confounded this association. An alternative explanation to that provided by Marusawaet al is that the differences in prevalence are due to timing of transfusion, an important fact that was not analysed in the study. Before screening of blood donors for HBsAg, transfusions were much more likely to transmit hepatitis B. Patients with HCC were, on average, more than five years older than other individuals with chronic HCV infection, and were therefore more likely to have received HBV positive blood transfusions.
Dr Marusawa and colleagues' hypothesis may well be correct, and it has support from findings of other studies, quoted in their article, that have shown evidence of persistent HBV infection in HBsAg negative, anti-HBc positive individuals. Nevertheless, one should be cautious in accepting this hypothesis until all alternative explanations are ruled out.
Reply
Editor,—As pointed out by Dr Nishioka, hepatitis B virus (HBV) can be transmitted via blood transfusion from infected donors or by injection using contaminated instruments, as is the case with hepatitis C virus (HCV) infection. Thus it may appear reasonable to consider that a high prevalence of HBV related serological markers in patients with HCV positive liver disease is due to simultaneous transmission of HCV and HBV. On the contrary, in patients with HCV related chronic liver disease, we could not find any correlation between anti-HBc positivity and various risk factors for blood borne infection, including previous history of blood transfusion and intravenous drug abuse.1-1 Furthermore, although the prevalence of anti-HBc increases as liver disease progresses, among patients with chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC), the percentage with a history of blood transfusion was not markedly different. Therefore, we concluded that the high prevalence of HBV serological markers in patients with HCV related chronic liver disease was not correlated with their history of blood transfusion. We certainly appreciate the comments of Dr Nishioka suggesting that the differences in HBV seroprevalence among patients with CH, LC, and HCC may be due to the different timing of transfusion.
In fact, the mean age of patients with HCC was five years older than that of patients with CH or LC in our study population.1-1In Japan, screening of blood donors for hepatitis B surface antigen (HBsAg) was initiated 20 years ago, and since then occurrence of post-transfusion hepatitis B has dramatically decreased.1-2Thus those patients with HCC might actually have experienced a higher risk of receiving HBV positive blood transfusion than those with CH or LC. To address this possibility, we further investigated the seroprevalence of antibody against hepatitis B core antigen (anti-HBc) among our patients who had received blood transfusion before the start of HBsAg screening of blood donors. Even among the HCV positive patients who had received blood transfusion before screening began, the percentages of anti-HBc-positive cases were markedly different between patients with CH (85/192, 44.2%), LC (50/101, 49.5%), and HCC (68/119, 57.1%). Moreover, these percentages reflected those of the total population of patients with CH, LC, and HCC, irrespective of their blood transfusion history (43.8%, 49.8%, and 59.4%, respectively).1-1
That said, we believe that the high prevalence of HBV related serological markers in HCV positive patients is not attributed to timing of blood transfusion. Unfortunately, when and how these anti-HBc positive patients were infected with HBV are not yet known. To this end, although the HBV genome is almost invariably present in the liver tissue of healthy subjects,1-3 whether or not this is also the case in patients with anti-HBc positive HCV related liver disease deserves clarification in future studies.