Reply to: Hepatocyte iron accumulation: A new string to ribavirin’s antiviral bow?
Authors: Carine Fillebeen, Kostas Pantopoulos
Journal: Journal of Hepatology (2011)

Hepatocyte iron accumulation: A new string to ribavirin's antiviral bow?Journal of HepatologyVol. 55Issue 1PreviewBuilding on previous work, the recent article by Fillebeen and Pantopoulos elegantly demonstrates a role for iron as an inhibitor of hepatitis C virus (HCV) replication [1]. Using HCV-infected Huh7.5.1 hepatoma cells, the authors show a dose-dependent reduction in the expression of HCV viral proteins and RNA upon exogenous administration of iron. Moreover, the anti-viral effect of iron was attributed to the direct inhibition of the HCV RNA polymerase NS5B by iron [2]. Full-Text PDF Open Access We thank Drs. J.D. Ryan and J. Crowe for their comments to our recent article [[1]Fillebeen C. Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.J Hepatol. 2010; 53: 995-999Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. In their letter, they discuss earlier reports showing that prolonged treatment of HCV-infected patients with ribavirin associates with hepatic iron deposition, mainly in hepatocytes [2Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar, 3Di Bisceglie A.M. Bacon B.R. Kleiner D.E. Hoofnagle J.H. Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C.J Hepatol. 1994; 21: 1109-1112Abstract Full Text PDF PubMed Scopus (59) Google Scholar]. This is largely attributed to extravascular hemolysis, a known side effect of ribavirin ([[2]Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar] and references therein) even though one would expect a predominant distribution of excess iron within Kupffer cells. The authors further hypothesize that accumulation of iron within hepatocytes may potentiate the antiviral efficacy of this therapeutic regimen, considering that iron inhibits the replication of HCV in permissive Huh7.5.1 cells [[1]Fillebeen C. Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.J Hepatol. 2010; 53: 995-999Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. We completely agree that this hypothesis merits further exploration. It will be interesting to examine the effects of ribavirin in the infectious HCV replicon model, with or without exogenous iron administration. Nevertheless, given the complexity of the pharmacological responses to ribavirin in vivo, which impinges on systemic iron traffic, we should be cautious in extrapolating data from this cell culture model. Moreover, the iron deposition in hepatocytes of patients did not appear to affect the "biochemical or histologic response to ribavirin therapy" over a period of 9 months, even though sustained virological response (SVR) was not assessed [[2]Fiel M.I. Schiano T.D. Guido M. Thung S.N. Lindsay K.L. Davis G.L. et al.Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.Am J Clin Pathol. 2000; 113: 35-39Crossref PubMed Google Scholar]. A more recent prospective study evaluated how iron perturbations affect combination therapy with pegylated interferon and ribavirin [[4]Ferrara F. Ventura P. Vegetti A. Guido M. Abbati G. Corradini E. et al.Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C.Am J Gastroenterol. 2009; 104: 605-616Crossref PubMed Scopus (33) Google Scholar]. The data revealed a negative correlation between iron load in Kupffer cells and the prospect of achieving SVR, and did not provide any evidence for potential benefits of hepatocyte iron accumulation. Further clinical studies with HCV-infected patients and, possibly, also experiments with humanized mouse models for HCV infection [[5]Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, et al. A Humanized Mouse Model to Study Hepatitis C Virus Infection, Immune Response, and Liver Disease. Gastroenterology, in press, doi:10.1053/j.gastro.2011.01.001.Google Scholar], may provide a more clear view on how hepatocyte iron accumulation interferes with antiviral therapy. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.