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- HFE Related Hemochromatosis: Uncovering the Inextricable Link between Iron Homeostasis and the Immunological SystemPublication . Porto, Graça; Cruz, Eugénia; Teles, M.; de Sousa, MariaThe HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus accomplished 20 years after the realization of the first link between the then "idiopathic" hemochromatosis and the human leukocyte antigens (HLA). The availability of a good genetic marker in subjects homozygous for the C282Y variant in HFE (hereditary Fe), the reliability in serum markers such as transferrin saturation and serum ferritin, plus the establishment of noninvasive methods for the estimation of hepatic iron overload, all transformed hemochromatosis into a unique age related disease where prevention became the major goal. We were challenged by the finding of iron overload in a 9-year-old boy homozygous for the C282Y HFE variant, with two brothers aged 11 and 5 also homozygous for the mutation. We report a 20 year follow-up during which the three boys were seen yearly with serial determinations of iron parameters and lymphocyte counts. This paper is divided in three sections: Learning, applying, and questioning. The result is the illustration of hemochromatosis as an age related disease in the transition from childhood to adult life and the confirmation of the inextricable link between iron overload and the cells of the immune system.
- Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosisPublication . Simão, M.; Camacho, A.; Ostertag, A.; Cohen-Solal, M.; Pinto, I.; Porto, G.; Hang Korng, E.; Cancela, M.Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron-enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions.