Should C282Y homozygotes with mild iron overload be treated?
Authors: Heinz Zoller, Armin Finkenstedt
Journal: Journal of Hepatology (2014)

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 Gold is for the mistress – silver for the maid – copper for the craftsmen cunning in his trade, “Good!” said the Baron sitting in his hall, “But Iron – Cold Iron – is the master of them all!” Beyond the metaphorical meaning of iron in Rudyard Kipling’s famous poem, iron literally is here also described as the most important transition metal in human biology [[1]Guengerich F.P. Thematic minireview series: metals in biology 2014.J Biol Chem. 2014; 289: 28094Crossref PubMed Scopus (8) Google Scholar]. Iron’s unique abilities to carry oxygen and to transfer electrons render this element essential for oxidative phosphorylation and life. Iron therefore is not just an essential nutrient but also a symbol of power and strength in different cultural contexts. However, as hepatologists we are all too familiar with the dark side of iron’s power. In hemochromatosis excess iron is stored in the liver, heart, endocrine glands and integument, where it can cause cirrhosis, cardiomyopathy, diabetes and darkening of the skin [[2]Sheldon J.H. Haemochromatosis. Oxford University Press, Oxford1935Google Scholar]. Although this clinical description of ‘bronzed diabetes’ is included in every comprehensive medical textbook, full-blown hemochromatosis with liver, heart, and endocrine manifestations is or has become a rare condition [[3]Beutler E. Felitti V.J. Koziol J.A. Ho N.J. Gelbart T. Penetrance of 845G --> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.Lancet. 2002; 359: 211-218Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar]. Since phlebotomy, genetic testing and especially insulin have been introduced, hemochromatosis has turned from a condition with a dismal prognosis into a curable and even preventable health problem. Accordingly, several studies have shown that survival in timely (‘pre-cirrhotic’) and adequately treated hemochromatosis patients does not differ from that expected of a matched healthy control population [[4]Niederau C. Fischer R. Purschel A. Stremmel W. Haussinger D. Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.Gastroenterology. 1996; 110: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar]. So everything appears to be solved in hemochromatosis, where the quest for progress may appear just as ridiculous as one would ask for sustained viral response rates in excess of 100% in the treatment of chronic hepatitis C virus infection. The findings reported by Edouard Bardou-Jacquet and coworkers from Rennes in this issue of the Journal of Hepatology show that in a subgroup of hemochromatosis patients, survival is actually better than that of a matched control group [[5]Bardou-Jacquet E. Morcet J. Manet G. Laine F. Perrin A. Jouanolle A. 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 (34) Google Scholar]. The findings raise immediate questions as to why this had not been observed in previous reports and if this is a result of earlier diagnosis or phlebotomy? If this was due to the treatment, could phlebotomies have beneficial health effects in other patient groups as well? To answer these questions we need to take a closer look at the data and view the results in the context of previous studies. The group from Rennes analyzed a large cohort of 1085 consecutively diagnosed C282Y homozygous hemochromatosis patients recruited between 1996 and 2009. Included patients were treated according to current recommendations and prospectively followed in the LOGIFER cohort. By comparison, one of the last reports on hemochromatosis outcomes before the HFE gene had been identified reported on 251 patients diagnosed between 1947 and 1991 [[4]Niederau C. Fischer R. Purschel A. Stremmel W. Haussinger D. Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.Gastroenterology. 1996; 110: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar]. Although the prevalence of hemochromatosis certainly differs between Brittany in France and Nordrhein-Westfahlen in Germany and although both centers may not necessarily serve an equally sized population, the difference in calculated annual incidences is remarkable and amounts to a factor of 14. The main reason for this difference in our view is the introduction of genetic testing. Since genetic tests have been introduced, hemochromatosis has gradually and subtly changed its face [[6]Beutler E. The HFE, Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis.Blood. 2003; 101: 3347-3350Crossref PubMed Scopus (108) Google Scholar]. This is also reflected by the almost equal distribution between males and females in the LOGIFER cohort, which is in stark contrast to the previously reported 9:1 distribution between males and females in the German cohort. Originally, hemochromatosis was diagnosed as ‘bronzed diabetes’ in patients with clinical disease manifestations. Liver biopsy, serum iron parameters, HLA typing and ultimately HFE genotyping have increased the sensitivity to diagnose hemochromatosis [[7]Kanwar P. Kowdley K.V. Diagnosis and treatment of hereditary hemochromatosis: an update.Expert Rev Gastroenterol Hepatol. 2013; 7: 517-530Crossref PubMed Scopus (37) Google Scholar]. Accordingly disease severity at presentation has decreased and the LOGIFER cohort certainly includes individuals, who would have never developed any clinical manifestation of the disease even without venesection. The concept that C282Y homozygosity has a low penetrance and even untreated C282Y homozygotes have an excellent prognosis unless ferritin is >1000 μg/L or increases over time, has emerged from population-based studies [[8]Gurrin L.C. Osborne N.J. Constantine C.C. McLaren C.E. English D.R. Gertig D.M. et al.The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis.Gastroenterology. 2008; 135: 1945-1952Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. For instance, when 48 untreated C282Y homozygotes and a large control population were followed over 15-years, it was found that both groups had comparable survival rates [[9]Pankow J.S. Boerwinkle E. Adams P.C. Guallar E. Leiendecker-Foster C. Rogowski J. et al.HFE C282Y homozygotes have reduced low-density lipoprotein cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study.Transl Res. 2008; 152: 3-10Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. In light of the new findings from the Rennes group, one can no longer regard equal survival in hemochromatosis and control population as acceptable. In the LOGIFER cohort, standardized mortality rates were significantly reduced in the subgroups of patients with hyperferritinemia below 1000 μg/L and in patients with 2 to 10 g iron removed. This reduced mortality was mainly due to reduced cardiovascular events and reduced extrahepatic cancer. Furthermore, the data clearly show that phlebotomy does certainly no harm to this group of patients with mild iron overload. In accordance with previous reports, the most important factors associated with death were alcohol consumption >30 g/day, presence of liver cirrhosis, and diabetes at the time of diagnosis. Notably, the standardized mortality rate for liver cancer associated death in C282Y homozygous hemochromatosis patients with diabetes was 92, which supports a functional link between iron, energy metabolism and hepatocellular carcinogenesis [10Dongiovanni P. Fracanzani A.L. Fargion S. Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target.J Hepatol. 2011; 55: 920-932Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 11Vecchi C. Montosi G. Garuti C. Corradini E. Sabelli M. Canali S. et al.Gluconeogenic signals regulate iron homeostasis via hepcidin in mice.Gastroenterology. 2014; 146: 1060-1069Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Finally, can phlebotomy possibly reduce mortality also in patients with mild to moderate iron overload in the absence of C282Y homozygozity? Unfortunately, this question cannot be answered from this study, although some conclusions can be inferred. First, phlebotomy was also associated with reduced overall mortality if less than 2 g of iron were removed, although this observation did no reach statistical significance. Furthermore in patients without fibrosis overall mortality was also reduced, which was mainly due to lower cardiovascular events and extrahepatic cancer. These findings and encouraging results from smaller pilot trials in patients with dysmetabolic iron overload syndrome and metabolic hyperferritinemia provide a strong rational base for conducting larger controlled multicentric trials with well-defined endpoints on the effect of phlebotomy in patients with hyperferritinemia in the context of non-alcoholic fatty liver disease [12Valenti L. Fracanzani A.L. Dongiovanni P. Bugianesi E. Marchesini G. Manzini P. et al.Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study.Am J Gastroenterol. 2007; 102: 1251-1258Crossref PubMed Scopus (241) Google Scholar, 13Beaton M.D. Chakrabarti S. Levstik M. Speechley M. Marotta P. Adams P. Phase II clinical trial of phlebotomy for non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2013; 37: 720-729Crossref PubMed Scopus (66) Google Scholar, 14Houschyar K.S. Ludtke R. Dobos G.J. Kalus U. Broecker-Preuss M. Rampp T. et al.Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial.BMC Med. 2012; 10: 54Crossref PubMed Scopus (117) Google Scholar, 15Piperno A. Vergani A. Salvioni A. Trombini P. Vigano M. Riva A. et al.Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.Liver Int. 2004; 24: 471-476Crossref PubMed Scopus (46) Google Scholar]. Until we have the results from such trials, our best advice ‘Hang on! To phlebotomy’ has to be restricted to hemochromatosis patients, and the answer to the question raised in the title is an unambiguous ‘Yes!’. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.