Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis

Objectives We studied associations between iron status and early functional and structural vascular abnormalities in patients with hereditary hemochromatosis (HH). Background Iron may be involved in atherogenesis, and patients bearing a genetic mutation associated with HH are possibly at risk of developing coronary heart disease. Methods We studied the vascular properties of 41 HH patients who had homozygosity for the C282Y mutation, along with 51 age-matched control subjects, by determination of endothelium-dependent dilation (EDD) of the brachial artery and intima-media thickness (IMT) of the carotid artery. Results Male HH patients who were not receiving phlebotomy therapy showed a reduced EDD and increased IMT compared with controls and HH patients receiving therapy. In female HH patients, irrespective of treatment status, vascular parameters were not different from those of controls, and none of these patients had severe iron overload. In HH patients, increased iron load was significantly associated with reduced EDD and increased IMT. Moreover, we found a positive correlation between body iron stores and indicators of oxidative stress. When previously untreated male HH patients were re-investigated after intensive phlebotomy therapy, a significant improvement in EDD was observed (2.6 ± 1.3% before vs. 5.5 ± 2.1% after treatment, p = 0.0015). Conclusions Impaired endothelial function and increased IMT are associated with iron overload, with subsequent induction of oxidative stress, and are not linked to a genetic disability in HH patients. Consequent iron-depletion therapy normalizes endothelial function and may thus reduce the increased risk of cardiovascular events. Female patients may be at a reduced risk, presumably due to continuous iron loss by menstruation.