Correspondence

Excess Iron Storage in Patients with Type 2 Diabetes Unrelated to Primary Hemochromatosis

N Engl J Med 2000; 343:891September 21, 2000

Article

To the Editor:

The discovery of mutations in the HFE gene in patients with hemochromatosis has made possible earlier or more complete ascertainment of cases of this disease.1 Diabetes mellitus is one manifestation of hemochromatosis, but in several studies, the frequency of HFE mutations was similar in normal subjects and in patients with type 2 diabetes.2

We analyzed exons 2 and 4 of the HFE gene by sequencing in 19 patients with primary hemochromatosis and in the 5 patients, of a total of 551 with type 2 diabetes, who had a positive biochemical screening test for hemochromatosis (serum transferrin saturation, ≥50 percent; serum ferritin concentration, ≥1000 μg per liter). Liver biopsy was performed in four of the five patients; in Patient 3, the diagnosis was established on the basis of total iron removed (>4 g). Studies included measurements of glucose, estradiol, testosterone, and gonadotropins; calculation of hepatic iron storage per gram of dry tissue; and echocardiography (Table 1Table 1Clinical, Biochemical, and Genetic Characteristics of 19 Patients with Primary Hemochromatosis and 5 Patients with Type 2 Diabetes.). Of the 19 patients with primary hemochromatosis, 13 (68 percent) had type 2 diabetes mellitus, and 18 (95 percent) were homozygous for the Cys282Tyr mutation in the HFE gene. In contrast, only one of the five patients with diabetes had this mutation, and she was a heterozygous carrier.

There was no correlation between the genotype and the clinical manifestations in any of the patients. The only difference between the two groups was the age at the time of diagnosis of iron overload: the five patients with diabetes were significantly older (P=0.03). Thus, iron accumulation in patients with diabetes is not caused by hemochromatosis related to mutations in the HFE gene, and although not biochemically different from hemochromatosis, it develops later in life.

Homozygosity for Cys282Tyr may result in a greater accumulation of iron in the pancreas in a shorter time than that which occurs in other forms of hemochromatosis and may therefore result in earlier insulin dependence. To date, none of the five patients with diabetes has been treated with insulin, whereas four of the patients with hemochromatosis are receiving insulin therapy. In these four patients, diabetes is secondary to hemochromatosis, whereas in the patients with diabetes, the diabetes preceded the hemochromatosis. High body iron stores are associated with abnormally altered glucose homeostasis in patients with type 2 diabetes,3 and serum ferritin concentrations are higher in patients with diabetes than in the general population.4 The development of hemochromatosis in some patients with type 2 diabetes may be the consequence of an anomalous trend toward iron accumulation mediated by mechanisms other than mutations in the HFE gene.

Guiomar Pérez de Nanclares, B.Sc.
Luis Castaño, M.D., Ph.D.
Sonia Gaztambide, M.D., Ph.D.
Jose Ramón Bilbao, Ph.D.
Hospital de Cruces, Barakaldo–Basque Country E48903, Spain

Javier Pi, M.D.
Maria Luisa González, M.D., Ph.D.
Hospital General Yagüe, Burgos E09006, Spain

Jose Antonio Vázquez, M.D., Ph.D.
Hospital de Cruces, Barakaldo–Basque Country E48903, Spain

4 References

1. 1

   Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998;114:319-323
   CrossRef | Web of Science | Medline

2. 2

   Frayling T, Ellard S, Grove J, Walker M, Hattersley AT. C282Y mutations in HFE (haemochromatosis) gene and type 2 diabetes. Lancet 1998;351:1933-1934
   CrossRef | Web of Science | Medline

3. 3

   Tuomainen T-P, Nyyssonen K, Salonen R, et al. Body iron stores are associated with serum insulin and blood glucose concentrations: population study in 1,013 eastern Finnish men. Diabetes Care 1997;20:426-428
   CrossRef | Web of Science | Medline

4. 4

   Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care 1999;22:1978-1983
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

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