The reasons for why HBsAg seroclearance was not associated with reduced HCC rate are unknown but likely multifactorial. It is possible that factors early in the course of HBV infection, such as the HBV DNA level or degree of hepatic necroinflammation, might have had a greater influence on HCC risk.[10, 12, 27] We compared the distribution of HBV DNA level for the time periods before and after HBsAg seroclearance among case-patients and for the corresponding time periods among control-patients. The lack of difference in HCC rate between case- and control-patients corresponds with the similarity in HBV DNA levels among case-patients compared with control-patients before HBsAg clearance. These results support previous reports that the HBV DNA level before HBsAg seroclearance is an important predictor for developing HCC.[10, 12] It is likely for the reason that treatment with nucleos(t)ide analogues decreases both the risk for developing HCC and the risk of HCC recurrence after surgical resection.[28-31] One mechanism by which HBV infection causes HCC could be through the integration of HBV DNA into the host hepatocyte genome and as covalently closed circular (ccc) DNA in hepatocyte nuclei.[27, 32] The integrated viral DNA and cccDNA that result from HBV viremia persist after HBsAg seroclearance and might promote the development of HCC. Furthermore, a substantial proportion of case-patients in our study had a detectable HBV DNA level after HBsAg seroclearance. Thus, it is possible that ongoing low-level HBV DNA replication with continued integration into the host hepatocyte also contributes to the persistent HCC risk after HBsAg seroclearance.
Issue
The Journal of Pathology
The Journal of Pathology
Special Issue: Viruses and Disease
Volume 235, Issue 2, pages 355–367, January 2015
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1
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
2
Second Medical Department, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
3
German Centre for Infection research (DZIF), Munich Partner Site, Germany
*Correspondence to: Marc Ringelhan or Mathias Heikenwalder, Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Schneckenburgerstrasse 8, D-81675 München, Germany. E-mail: [email protected] or [email protected]
No conflicts of interest were declared.
Keywords:
HBV;chronic hepatitis B;HBs antigen;HBx;X-protein;liver cancer;HCC;direct role of viral proteins;hepatocarcinogenesis