Diabetes in HFE Hemochromatosis

Abstract

Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.

Figure 1

Diabetes in nonscreening hemochromatosis. Percentages of patients diagnosed to have hemochromatosis phenotypes in nonscreening settings who also had diabetes [, , –, , , –169]. HFE mutation genotyping was a diagnostic adjunct in three studies [1, 2, 10].

Figure 2

Diabetes in screening hemochromatosis. Percentages of participants in population-based screening studies discovered to have HFE p.C282Y homozygosity who reported that they had previous diagnoses of diabetes [, –172]. There were two such reports from 2002 and two others from 2008. Hemochromatosis was also evaluated with iron phenotyping. In the respective populations, the prevalence of diabetes in p.C282Y homozygotes and control subjects did not differ significantly.

Figure 3

Cirrhosis in nonscreening hemochromatosis. Percentages of patients diagnosed to have hemochromatosis phenotypes who also had cirrhosis [, , , –177]. There were two such reports from 1997. HFE mutation genotyping was a diagnostic adjunct in the more recent study [3]. Modified from [25, 178]. Greater proportions of men than women had cirrhosis. See cirrhosis prevalence in screening hemochromatosis cases in Figure 4.

Figure 4

Cirrhosis in screening hemochromatosis. Percentages of participants in population-based studies [3, 172, 179, 180] and in an archived liver biopsy collection (second 2000 publication) [181] discovered to have HFE p.C282Y homozygosity who were previously diagnosed or were subsequently demonstrated to have advanced hepatic fibrosis or cirrhosis by biopsy [3, 170, 172, 180, 181]. Greater proportions of men than women had cirrhosis. See cirrhosis prevalence in nonscreening hemochromatosis cases in Figure 3.