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

Paolo Zamboni, Marcello Izzo, Silvia Tognazzo, Sergio Carandina, Massimiliano De Palma, Linda Catozzi, Alberto Caggiati, Gianluigi Scapoli, D. Gemmati

Research output: Contribution to journalArticlepeer-review


Chronic venous stasis determines red blood cell extravasation and either dermal hemosiderin deposits or iron-laden phagocytes. Several authors have suspected that iron could play a role in the pathogenesis of venous leg ulcers. They hypothesized that local iron overload could generate free radicals or activate a proteolytic hyperactivity on the part of metalloproteinases (MMPs) or else down-regulate tissue inhibitors of MMPs. However, they were unable to explain why iron deposits, visible in the legs of patients with chronic venous disease (CVD), cause lesions in only some individuals, whereas in others they do not. We hypothesized that such individual differences could be genetically determined and investigated the role of the C282Y and H63D mutations of the HFE gene. C282Y mutation significantly increases the risk of ulcer in primary CVD more than six times (OR = 6.69; 1.45-30.8; p = 0.01). Patients carrying the H63D variant have an earlier age of ulcer onset, by almost 10 years (p > 0.004). The increased risk of skin lesion and the early age of onset of the disease in HFE carriers confirm in a clinical setting that intracellular iron deposits of mutated macrophages have less stability than those of the wild type. We hypothesize that the physiologic iron protective mechanisms are affected by the HFE mutations and should be investigated in all diseases characterized by the combination of iron overload and inflammation.

Original languageEnglish
Pages (from-to)1869-1873
Number of pages5
JournalFree Radical Biology and Medicine
Issue number10
Publication statusPublished - May 15 2006


  • Chronic venous disease
  • Free radicals
  • HFE mutation
  • Iron overload
  • Metalloproteinases
  • Venous ulcers

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry


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