The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis

The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis

“…Recent studies demonstrate a pivotal role for tissue iron accumulation in inducing and maintaining inflammation in CVD. [4][5][6][7][8][9] Iron deposits in CVD cause readily visible brownish dermal areas which sometimes precede, but always surround, ulcers. The origin of increased leg iron stores is extravasation of red blood cells (erythrocytes) in conditions of significant venous stasis.…”

“…Over time, with increasing overload of iron, the structure of ferritin changes to haemosiderin. [4][5][6][7][8][9] In 1988, Ackermann found a twenty-fold higher average concentration of iron in lower limbs affected by venous ulcers as compared to the upper arm of the same subjects. 8 The phenomenon of leg haemosiderin deposits seems to be significant for the entire body, since this protein has been demonstrated in the urine of patients affected by CVD.…”

“…C282Y mutation significantly increases the risk of ulcer in primary CVD by more than six-fold, 6 while patients carrying the H63D variant have an earlier age of ulcer onset by almost 10 years. 5 HFE mutations are associated with increased iron efflux from the macrophage. Our findings support the hypothesis that lesions are promoted by enhanced iron release and ROS generation.…”

Genetic risk factors of chronic venous leg ulceration: Can molecular screening aid in the prevention of chronic venous insufficiency complications?

“…The impaired transport of iron by macrophages results in an accumulation of reactive ferric ions in affected tissues, and leads to increased free radical generation. These events increase oxidative stress, augment the inflammatory response and facilitate further tissue destruction (57,(61)(62)(63). Thus, they enhance the risk of primary ulcer formation, and impair wound healing.…”

“…Thus, they enhance the risk of primary ulcer formation, and impair wound healing. It has been demonstrated that, in CVU individuals, the 282Y variant increases the risk of ulcer formation in patients with primary CVI by almost 7-fold, whereas the presence of the 63D allele is responsible for significantly lower age (up to 10 years) of ulcer onset (61,63,64).…”