Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials
Authors: Martin B. Delatycki, Lyle C. Gurrin, Sim Yee Ong, Grant A. Ramm, Greg J. Anderson, John K. Olynyk, Katie J. Allen, Amanda J. Nicoll, Lawrie W. Powell
Journal: Journal of Hepatology (2015)

Decreased 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 Reply to: "Reduced mortality due to phlebotomy in moderately iron-loaded HFE Haemochromatosis? The need for clinical trials"Journal of HepatologyVol. 63Issue 1PreviewAustralian colleagues raise concerns about our study [1], and the accompanying editorial [2]. 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. Full-Text PDF Open Access We read with interest the paper by Bardou-Jacquet and colleagues [[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] examining mortality in HFE-associated hemochromatosis 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]. 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. We are not convinced however, that this conclusion is supported by the data provided for the following reasons:1.If normalization of SF resulted in reduced mortality then it would be expected that HFE p.C282Y homozygotes with normal SF at diagnosis would also have reduced mortality but this was not found to be the case.2.There was no information about the amount of iron removed for 36% of subjects so there was likely to be a significant minority of individuals with SF between the ULN and 1000 μg/L who did not have normalization of SF.3.The cohort had a follow-up mean duration of 8.3 ± 3.9 years. The average age at diagnosis was 45.2 ± 14.2 years. This means that it is likely that many subjects in the group with SF between the ULN and 1000 μg/L had a raised SF for many more years than they had a normalized SF. It is not at all clear how this balance would result in reduced mortality when this was not seen among those with normal SF at diagnosis. Of those who did have information about the amount of iron removed, there is no information about whether they continued venesection therapy in order to maintain a SF level <50 μg/L after a SF of <50 μg/L was achieved initially, or the extent to which follow-up data (number and volume of phlebotomies, clinical and biochemical indicators of tolerance and efficacy of venesection therapy) were available. Moreover, there is no information about a formal, standardized, consistent, cohort-wide protocol around advising participants to start, continue and potentially stop venesection therapy, which makes the claim that the results can be interpreted as "intention-to-treat" difficult to justify. Reasons other than the benefit of normalization of SF that could explain the study findings include:1.Having a mild excess of iron in the body reduces the risk of cardiovascular and extra-hepatic cancer. This is counter intuitive with data suggesting that iron is a pro-oxidant and therefore more likely to result in increased cancer incidence. In addition we found an increase in the incidence of breast and colorectal cancer in a large cohort of HFE p.C282Y homozygotes compared to a matched HFE wild-type control group, we did not, however, have sufficient data to examine the association of cancer occurrence with SF levels [[3]Osborne N.J. Gurrin L.C. Allen K.J. Constantine C.C. Delatycki M.B. McLaren C.E. et al.HFE C282Y homozygotes are at increased risk of breast and colorectal cancer.Hepatology. 2010; 51: 1311-1318Crossref PubMed Scopus (110) Google Scholar]. From the cardiovascular standpoint, there is evidence that low hepcidin levels that are associated with HFE p.C282Y homozygosity, leads to low reticuloendothelial cell iron levels despite high total body iron and that this can lead to reduced levels of atherosclerosis (the so called "hemochromatosis paradox") [[4]Sullivan J.L. Do hemochromatosis mutations protect against iron-mediated atherogenesis?.Circ Cardiovasc Genet. 2009; 2: 652-657Crossref PubMed Scopus (42) Google Scholar].2.As noted by the authors, those with SF between the ULN and 1000 μg/L had increased medical care compared to the average person and this may have resulted in other lifestyle changes that were beneficial. For example lifestyle changes in subjects with fatty liver disease such as diet and exercise, can improve liver function and morbidity. No information is given by the authors on body mass index and any changes in this following appropriate intervention.3.Individuals with SF between ULN and 1000 μg/L are less prone to iron deficiency anemia and this may result in health benefit. The only way to answer the question of the role of venesection therapy in HFE p.C282Y homozygotes with SF between ULN and 1000 μg/L is to do a randomized study with half the cohort having normalization of SF and the other half not being treated. Until such data are available, the question of benefit from treating HFE p.C282Y homozygotes with SF between ULN and 1000 μg/L remains, in our view, unproven. The authors who have taken part in this letter to the editor declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.