[58] This reduction in iron export capacity most significantly

affects cells of the reticuloendothelial system, namely macrophages, which are responsible for the recycling of iron from quiescent red blood cells. This reduces the recycling of iron, resulting in macrophage iron loading within the liver and spleen. This reduced capacity for iron recycling also results in transferrin saturation usually toward the lower end of the normal range. As a result of the reduced capacity of cells to export iron and thus mobilize iron stores, aggressive venesection can lead to anemia Vismodegib in these patients even in the presence of persisting iron overload.[59] Mutations that lead to non-classical ferroportin disease result in ferroportin protein that is resistant to hepcidin-induced internalization.[60]

The interaction of hepcidin with ferroportin is the key event in controlling iron homeostasis. When a mutation prevents this interaction or internalization after hepcidin binding, the ferroportin protein remains at the cell surface, constitutively exporting iron. This persistent ferroportin activity in enterocytes of the duodenum and in reticuloendothelial macrophages results in increased dietary iron absorption and recycling, eventually resulting in parenchymal iron accumulation. This is essentially the same situation that occurs in the autosomal recessive forms of HH that result from hepcidin deficiency. Because of this commonality in the iron loading mechanism, the phenotypic presentation Tanespimycin supplier of non-classical ferroportin disease is indistinguishable from HFE and TFR2-HH. Over 30 mutations associated with iron overload have been reported in the ferroportin gene. Ferroportin disease has a worldwide distribution. The first description of a non-HLA

linked form of iron overload with possible autosomal dominant inheritance was in a Melanesian pedigree from the Solomon Islands,[61] and since then, many check details of the reported cases have been in the Asia-Pacific region (Fig. 2). It now seems likely that the iron overload disease present in the Solomon Islands is the non-classical form of ferroportin disease caused by the N144T mutation.[62] Some mutations have been reported in Australian and New Zealand individuals with European backgrounds. Such mutations include A77D[63] and V162del,[64] which are associated with classical disease, and N144D[65] and S338R[66] associated with non-classical disease. The V162del mutation is the most common mutation reported in ferroportin. It has been detected in several geographically distinct populations including in a female Sri Lankan.[67] The A77D mutation has also been reported in Indian patients with thalassemia major; unusually, one patient was reported to be homozygous for this mutation, although no further explanation was given.

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