Reply to: “Reduced mortality due to phlebotomy in moderately iron-loaded HFE Haemochromatosis? The need for clinical trials”
Authors: Edouard Bardou-Jacquet, Fabrice Lainé, Yves Deugnier
Journal: Journal of Hepatology (2015)

Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trialsJournal of HepatologyVol. 63Issue 1PreviewWe read with interest the paper by Bardou-Jacquet and colleagues [1] examining mortality in HFE-associated hemochromatosis and the accompanying editorial [2]. Both the authors of the study and the writers of the editorial concluded that the observation that HFE p.C282Y homozygotes with a serum ferritin (SF) at diagnosis between the upper limit of normal (ULN) and 1000 μg/L have reduced mortality compared to the population at large is predominantly due to venesection therapy. Full-Text PDF Open AccessDecreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosisJournal of HepatologyVol. 62Issue 3PreviewMortality studies in patients with hemochromatosis give conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of patients homozygous for the C282Y mutation in the HFE gene, diagnosed since the availability of HFE testing. Full-Text PDF Australian colleagues raise concerns about our study [[1]Bardou-Jacquet E. Morcet J. Manet G. Laine F. Perrin M. Jouanolle A.M. et al.Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis.J Hepatol. 2015; 62: 682-689Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar], and the accompanying editorial [[2]Zoller H. Finkenstedt A. Should C282Y homozygotes with mild iron overload be treated?.J Hepatol. 2015; 62: 510-511Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. We showed that HFE C282Y homozygotes with initial serum ferritin (SF) between the upper limit of normal and 1000 μg/L had significantly lower overall mortality than that of the general French population. Delatycki et al. disagree with our conclusion that this could be due to early management of patients, and putatively to the maintenance of low body iron stores through iron removal. With respect to their comments about methodological aspects, we would like to stress the following points:-We were able to provide the amount of iron removed in 64% of our patients. This high proportion demonstrates the efficacy of our recommendations. However, we agree that, for a significant number of patients, we had no reliable information about long-term maintenance therapy. Therefore, we have been cautious when discussing the putative role of venesection therapy in lowering mortality rate.-Since the early 1990s, we deliver written guidelines and a personal follow-up notebook to every C282Y homozygote. With time, our recommendations did not vary with respect to the indications and management of initial and maintenance of venesection therapy [[3]Bircher J, Benhamou J, McIntyre N, Rizzetto M Rodés J. Oxford textbook of clinical hepatology. 2nd ed. Oxford University Press: New York, USA; 1999.Google Scholar]. They were taken back by the French Haute Autorité de Santé [[4]Haute Autorité de Santé. Management of patients with HFE-related haemochromatosis; 2005 [cited 16/03/2015]; Available from: <http://www.has-sante.fr/portail/jcms/c_432802/en/management-of-patients-with-hfe-related-haemochromatosis-type-1-haemochromatosis>.Google Scholar]. Then, all our patients received the same information about both initial and maintenance therapy for several decades.-Delatycki et al. discuss about morbidity aspects. However we studied mortality and not morbidity. Fortunately a large proportion of patients with breast or colon cancer do not die from their malignancy. Thus it is not correct to compare mortality and morbidity data. This is likely also true for cardiovascular disease. More importantly, iron stores in the body of patients who were not venesected because of normal SF at diagnosis were and remained higher than in those with moderately increased SF who were early enrolled in a phlebotomy program. Indeed, maintenance of SF below 50 μg/L results in lower than normal body iron stores. Therefore, assimilating two sub-groups that were absolutely not identical with respect to iron burden raises serious concerns. For all these reasons we persist to hypothesize that the discrepancy in mortality data between patients with normal SF and those with moderately increased SF strongly supports a beneficial role of early management of hemochromatosis. However we agree that, as already stressed in our manuscript, we did not demonstrate that iron removal per se was responsible for decreasing mortality. Other factors must be discussed (lifestyle modifications, medical follow-up etc.). Nevertheless, the fact that patients had lower mortality when treated for mild hemochromatosis was well shown in this study, regardless of its precise cause. Finally, in our view, a randomized study of venesection therapy in mild hemochromatosis is neither realistic nor ethical. Moreover, the AASLD guidelines endorsed by Powell et al. do not suggest to perform such a study and recommend that «… C282Y homozygotes who have an elevated ferritin (but <1000 μg/L) should proceed to phlebotomy …» [[5]Bacon B.R. Adams P.C. Kowdley K.V. Powell L.W. Tavill A.S. American Association for the Study of Liver DiseasesDiagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.Hepatology. 2011; 2011: 328-343Crossref Scopus (465) Google Scholar]. The authors who have taken part in this letter to this editor declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.