HBV + HCV = HCC?

Gut 1999;45:168-169 ( August )

Commentary

Most people infected with Hepatitis C virus (HCV) develop a chronic infection with persistent viraemia and are at risk of progressive liver damage. However, the outcome of chronic HCV infection is extremely variable and is influenced by many factors, including HCV genotype, HCV viral load, route of infection, age at infection, sex, and alcohol consumption. Ultimately, it is the progression to cirrhosis that is the key determinant of both morbidity and mortality¹ and a better understanding of additional influences likely to promote this development is needed.

Both Hepatitis B virus (HBV) and HCV are transmitted parenterally and coinfection is not uncommon, particularly in intravenous drug users and in countries with a high prevalence of HBV infection.² Coinfection with evidence of chronic HBV and HCV seems to result in more severe liver disease than either infection alone,³ with an increased risk of liver cancer² and probably an increased risk of fulminant hepatitis when superinfection with HCV occurs on the background of chronic HBV.⁴

The presence of Hepatitis B surface and/or Hepatitis B core antibodies (anti-HBs and anti-HBc) in the absence of Hepatitis B surface antigen (HBsAg) is generally taken to indicate resolution of infection and provides evidence of previous HBV infection. However, it is becoming increasingly recognised that low levels of HBV DNA can still be found in serum, circulating lymphocytes and in the liver of many patients with apparently self-limited HBV infection years after clinical recovery from acute HBV infection.⁵ In keeping with this, transmission of HBV infection has been reported following transfusion of blood⁶ or transplantation of livers from HBsAg negative, anti-HBc positive donors.⁷

It is not clear whether evidence of previous, rather than chronic, infection with HBV has any impact on disease progression or the development of hepatocellular carcinoma (HCC) in patients with chronic HCV infection. The paper by Marusawa et al (see page 284) has set out to tackle this possibility. They have looked for the presence of anti-HBs and/or anti-HBc in a large cohort of HBsAg negative Japanese patients with HCV infection. The 2014  patients studied were subdivided into three groupsthose with chronic hepatitis, those with cirrhosis and those with HCC. In all groups there was a significant increase in the proportion of cases with evidence of previous HBV infection compared with age matched, non-HCV infected controls. Overall, 49.9% of patients had evidence of previous HBV infection (compared with 12.2% of controls) with the most striking increase seen in the 611 cases with HCC, of whom over 59% were anti-HBc positive. Patients with HCC were significantly more likely to have evidence of previous HBV infection than patients with either cirrhosis or chronic hepatitis, and patients with cirrhosis were more likely than those with chronic hepatitis to be anti-HBs and/or anti-HBc positive.

Although the numbers in this study are impressive, the authors have not looked in detail at virological or histological parameters to try and elucidate possible mechanisms for the associations found. It would be interesting to see whether there were any differences in HCV RNA levels or histological activity between patients with and without anti-HBs/anti-HBc, or whether immunostaining or HBV DNA detection from liver biopsy samples revealed evidence of continuing HBV infection. Furthermore, it is not clear how or when the majority of cases studied acquired either infection, so that the role of superinfection (i.e. sequential infection) as opposed to co-infection (simultaneous infection) cannot be answered.

How can a link between previous HBV infection and development of HCC be explained? The association between both chronic HBV and HCV infections and development of HCC is well known. Furthermore, there is an increased risk of developing HCC, even in HBsAg negative, anti-HBs positive cases, most probably related to persistence of low levels of hepatic HBV DNA which can also be isolated from tumour tissue.^{8  9} The HBV encoded X protein is known to regulate both cell proliferation and apoptosis, and the combination of chronic HCV infection with its attendant increase in hepatocyte turnover together with continuing production of HBV encoded proteins may be synergistic with regard to HCC development.

Is there a link between serological markers of previous HBV infection and disease severity in patients with chronic HCV? The findings reported by Marusawa et al suggest that there is, and this is supported by previous reports.¹⁰ A possible explanation for this is that the onset of HCV infection occurs after HBV has been acquiredHBV infection is more prevalent in Japan than in the UK and many of the patients reported on in this series may have acquired HBV infection vertically and acquired HCV infection subsequently. HCV superinfection can reduce HBsAg expression and may promote HBsAg clearance,⁴ so that anti-HBs/anti-HBc positive patients with HCV infection may already have had pre-existing chronic liver disease before the onset of their HCV infection.

Do these findings from Japan apply in other countries? The link between previous HBV infection and HCC complicating HCV infection seems clear and has been reported in other populations.⁹ The association between previous HBV infection and severity of HCV infection is less clear. In the UK, HBV infection is uncommon and evidence of previous HBV infection in patients with chronic HCV is most likely to have resulted from intravenous drug usage, with vertically acquired HBV being rare. HBV infection in adults behaves very differently to that in children and further studies are needed to clarify whether apparently resolved HBV infection in adults is truly a factor contributing to the progression of HCV related liver damage.

M E CRAMP
Institute of Liver Studies, Kings College Hospital, London SE5 9RS, UK

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