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Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations

Response to Equitani et al.

From the Department of Internal Medicine, University of Milano, Fondazione Policlinico Mangiagalli e Regina Elena Hospital, Milano, Italy

Address correspondence to Prof. Silvia Fargion, Internal Medicine, UO Medicina Interna IB, University of Milano Fondazione Policlinico Mangiagalli e Regina Elena IRCCS, Via F Sforza 35, 20122 Milano, Italy. E-mail: silvia.fargion{at}unimi.it

Equitani et al. (1) reported on the effect of iron depletion by phlebotomy on insulin resistance and release in 17 carriers of mutations of hereditary hemochromatosis HFE gene with nonalcoholic fatty liver disease (NAFLD). They found that iron depletion ameliorated insulin sensitivity and secretion and reduced hepatic iron stores and nonalcoholic steatohepatitis activity score, and they concluded that results justify glucose tolerance testing and preventive iron depletion in asymptomatic carriers of HFE mutations. The study adds new valuable information to the field, but we suggest that the conclusions be tempered for a number of reasons.

First, the large majority of subjects included in the study by Equitani et al. carried HFE genotypes conferring predisposition to develop iron overload (C282Y/C282Y, C282Y/H63D, H63D/H63D, C282Y/wt: 16 of 17 [94%]) (2). The large majority of HFE mutations carriers in the general population are heterozygous for the H63D mutation (prevalence 23 vs. 6% of the aforementioned genotypes in Italy), which, in the absence of cofactors, has never been associated with increased iron stores (2).

Second, all of the subjects included in the study had histologically confirmed NAFLD, which per se is associated with hepatic insulin resistance, increased risk of diabetes, and mild iron overload (3).

Last, the study was not controlled; therefore, the effect of lifestyle modifications and weight loss (which appeared to be significant after 2 years) on insulin release and resistance could not be fully ascertained.

Nevertheless, iron depletion has recently been reported to improve insulin resistance (as evaluated by the homeostasis model assessment of insulin resistance index) more than lifestyle modifications alone in a case-control study including 128 patients with NAFLD without diabetes and hereditary hemochromatosis followed for 1 year (4). However, serum lipids and alanine aminotransferase levels did not further improve compared with those in standard treatment. The effect of iron depletion on insulin sensitivity was more marked in patients positive for HFE mutations, whereas an increase in insulin release was not observed. A controlled trial evaluating liver damage and glucose tolerance as end points is required to support iron depletion in HFE mutation carriers with NAFLD.

References

1. Equitani F, Fernandez-Real JM, Menichella G, Koch M, Calvani M, Nobili V, Mingrone G, Manco M: Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations. Diabetes Care 31:3–8, 2008[Abstract/Free Full Text]
   
2. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P: Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769–1778, 2005[Abstract/Free Full Text]
   
3. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N: Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107:450–455, 1999[Medline]
   
4. Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, Vanni E, Fargion S: 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 102:1–8, 2007
   

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				M. Manco, G. Mingrone, V. Nobili, and F. Equitani Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations: Response to Valenti et al. Diabetes Care, March 1, 2008; 31(3): e19 - e19. [Full Text] [PDF]

This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Valenti, L. Articles by Fargion, S. Search for Related Content PubMed PubMed Citation Articles by Valenti, L. Articles by Fargion, S. Social Bookmarking                What's this?