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Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice

Nature Reviews Endocrinology volume 6, pages 26–33 (2010)Cite this article

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Abstract

Hereditary hemochromatosis (HH) is a genetic condition that can lead to unregulated absorption of iron from the gut with resultant iron overload. The most common form of HH is caused by mutations in the HFE gene, with most cases of HH presenting in patients who are homozygous for the Cys282Tyr mutation. The prevalence of HFE gene mutations in persons of Northern European ancestry is fairly high (0.3–0.7% homozygous and 9–14% heterozygous for the Cys282Tyr mutation), but the penetrance of the disease is considered fairly low and is quite variable. While routine screening of the general population is not recommended, a targeted approach to screening in symptomatic patients and in those with a family member with iron overload is warranted. Untreated, iron overload can lead to considerable morbidity including liver cirrhosis, arthritis and diabetes mellitus, and increased mortality. The pathophysiology of diabetes mellitus in HH is thought to be due primarily to defects in the early insulin response to glucose. An Hfe−/− mouse model of HH has demonstrated defects in β-cell function and β-cell apoptosis that may be mediated by increased oxidative stress. Fortunately, these defects seem to be reversible if phlebotomy treatment is initiated before the development of cirrhosis or diabetes mellitus in patients. Further research into the long-term effects of treatment on prevention of diabetes mellitus in HH is needed.

Key Points

  • Most cases of hereditary hemochromatosis (HH) result from mutations in the HFE gene, consequential low hepcidin levels and continued iron absorption from the gut despite high iron levels

  • Homozygosity for the Cys282Tyr HFE gene mutation occurs in 0.3–0.7% of people with North European ancestry, but clinical disease occurs in only a small percentage of these

  • Pathophysiology of diabetes mellitus in iron overload is thought to be a result of β-cell dysfunction that leads to inadequate insulin secretion for the prevailing degree of insulin sensitivity

  • Increased oxidative stress may be one mechanism whereby iron overload causes β-cell dysfunction and β-cell apoptosis

  • Early identification and treatment with phlebotomy before the onset of diabetes mellitus and cirrhosis can prevent the increased morbidity and mortality associated with HH

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Figure 1: Regulation of iron metabolism: a simplified overview of the upstream pathways involved in hepcidin regulation.
Figure 2: Algorithm for the diagnosis of hereditary hemochromatosis in patients with a | signs or symptoms or b | in those with a family history of iron overload.

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Acknowledgements

This work is supported in part by the VA Puget Sound Health Care System, Seattle, WA and the Department of Veterans Affairs (to K. M. U.) and NIH Grant DK02957 (to K. V. K.).

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Authors and Affiliations

  1. Division of Metabolism, Department of Medicine, Endocrinology and Nutrition, VA Puget Sound Health Care System, 1600 S. Columbian Way (151), Seattle, 98108, WA, USA

    Kristina M. Utzschneider

  2. Center for Liver Disease, Virginia Mason Medical Center and Benaroya Research Institute, 1201 9th Avenue, Seattle, 98101, WA, USA

    Kris V. Kowdley

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Correspondence to Kristina M. Utzschneider.

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Utzschneider, K., Kowdley, K. Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. Nat Rev Endocrinol 6, 26–33 (2010). https://doi.org/10.1038/nrendo.2009.241

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