**2. Normal iron metabolism**

Iron stores in healthy humans average 3 to 4 g in men and 2.2 to 3.5 g in women [13, 14]. About 60% of iron is located within the hemoglobin protein of circulating erythrocytes and, to a lesser degree, in medullary erythrocytes; 20% of iron stores are located in the liver (hepatocytes and Kupffer cells) and in the reticulo-endothelial system (mainly in spleen macrophages), in the form of the iron-storage protein ferritin (marginally in haemosiderin) whereas muscle myoglobin accounts for about 10% of body iron [8, 13, 14]. Iron-containing enzymes represent only 1% of iron stores, while plasma transferrin-bound iron represents only a small fraction (0.2%=3 mg) of total body iron [13, 14]. Each day, macrophages of the reticulo-endothelial system recycle about 30 mg of iron from senescent erythrocytes, thus providing the 20-30 mg of iron required for normal erythropoïesis [8, 13, 14]. Physiological iron losses are estimated at about 1 mg/day (urinary loss: 0.1 mg/day; gut loss secondary to enterocyte desquamation: 0.6 mg/day; skin loss: 0.3 mg/day) but are increased in women by menstruation (the main cause of iron-deficiency anemia worldwide), pregnancy and breast-feeding [14]. Therefore, recom‐ mended daily dietary iron intake to compensate for iron losses is 10 mg/day generally (because of an absorption rate of only 10%) and 30 mg/day in pregnant women and nursing mothers [14]. Hepcidin-25, a hormone synthesized in the liver, is the master regulator of iron metabo‐ lism, acting negatively on both intestinal iron absorption and iron release from reticuloendothelial macrophages and liver cells by decreasing the expression of ferroportin, a protein that regulates iron export from these cells [8]. Hepcidin-25 synthesis is increased by iron itself and by inflammation (via IL6), and decreased by anemia, hypoxia, iron deficiency, haemor‐ rhage, erythropoïetin, and increased medullary erythropoïesis [8]. The mechanism by which this latter situation down-regulates hepcidin synthesis was recently linked to a new peptide hormone, erythroferrone, secreted by erythroblasts and acting directly on the liver [15]. Defective hepcidin-25 synthesis plays a paramount pathophysiological role in genetic hemo‐ chromatoses, whereas excessive, unregulated hepcidin synthesis is the mainstay of a newly discovered genetic (autosomal recessive) form of iron-deficiency anemia called IRIDA (iron refractory iron deficiency anemia) related to mutation of the *TMPRSS6* gene (encoding matriptase-2); IRIDA is refractory to oral iron but partially responsive to IV iron products [16].
