Normal iron metabolism, erythropoiesis, and pathogenesis of functional iron deficiency. In the normal (noninflamed) state, dietary iron (or an oral iron supplement) is ingested. Iron is absorbed by enterocytes in the proximal small intestine via the divalent metal transporter 1 and transported to blood vessels via ferroportin, then to the bone marrow via transferrin. In the bone marrow, iron is taken up by macrophages where it is stored as ferritin until needed for erythropoiesis. At that time, stored iron is transferred via ferroportin to red blood cell (RBC) precursors for hemoglobin synthesis. Erythropoietin (EPO) is the physiologic regulator of RBC production. EPO is produced by fibroblasts in the kidney in response to hypoxia. In the “inflamed state” (lower portion of Fig. 1), interleukin (IL)-6 is produced, inducing hepatic release of hepcidin. Hepcidin binds both enterocyte and macrophage ferroportin; the hepcidin-ferroportin complexes are internalized and degraded in lysosomes, resulting in an “iron block” – inability of enterocyte- and macrophage-stored iron to be exported. (For figure simplicity, only hepcidin inhibition of macrophage ferroportin is shown.) This leads to reduced serum iron levels, increased storage of iron in bone marrow macrophages (i.e., ferritin), and the condition of functional iron deficiency. Erythroferrone (ERFE) is a negative regulator of hepcidin production. ERFE is produced by erythroblasts in response to EPO. REPC, renal EPO-producing cells.