An update on iron physiology

Abstract

Iron is an essential micronutrient, as it is required for adequate erythropoietic function, oxidative metabolism and cellular immune responses. Although the absorption of dietary iron (1-2 mg/d) is regulated tightly, it is just balanced with losses. Therefore, internal turnover of iron is essential to meet the requirements for erythropoiesis (20-30 mg/d). Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron-deficiency anemia. Hepcidin, which is made primarily in hepatocytes in response to liver iron levels, inflammation, hypoxia and anemia, is the main iron regulatory hormone. Once secreted into the circulation, hepcidin binds ferroportin on enterocytes and macrophages, which triggers its internalization and lysosomal degradation. Thus, in chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, which results in hypoferremia and iron-restricted erythropoiesis, despite normal iron stores (functional ID), and anemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD + ID). In contrast, low hepcidin expression may lead to iron overload, and vice versa. Laboratory tests provide evidence of iron depletion in the body, or reflect iron-deficient red cell production. The appropriate combination of these laboratory tests help to establish a correct diagnosis of ID status and anemia.

Figures

Figure 1

Major stages of human erythropoiesis showing the point of commitment, the period of EPO dependence and the requirements for essential nutrients. BFU-E: Burst-forming unit-erythroid; CFU-E: Colony-forming unit-erythroid; EPO: Erythropoietin.

Figure 2

Main pathways of iron absorption by enterocytes in mammals. 1: Ferrireductase; 2: Divalent metal transporter 1 (DMT-1); 3: Heme protein carrier 1 (HPC1); 4: Heme oxygenase; 5: Heme exporter; 6: Ferroportin (Ireg-1); 7: Hephaestin; 8: Transferrin receptor-1 (TfR1) (for details see Table 1).

Figure 3

Main pathways of iron utilization by erythroblasts in mammals. 1: TfR1; 2: Diferric-transferrin-TfR1 complex; 3: Natural resistance macrophage protein (NRAMP-1); 4: Mitoferrin; 5: Mitochondrial heme exporter (Abcb6); 6: Heme exporter (FLVCR, Bcrp/Abcg2) (for details see Table 1).

Figure 4

Main pathways of iron storage and exportation by macrophages in mammals. 1: NRAMP-1; 2: TfR1; 3: DMT-1; 4: Others: others: bacteria, lactoferrin, hemoglobin-haptoglobin, heme-hemopexin; 5: Ferroportin (Ireg-1); 6: Hephaestin (for details see Table 1).

Figure 5

Main pathways of iron storage and exportation by hepatocytes in mammals. 1: TfR1; 2: TfR2; 3: DMT-1; 4: Others: hemoglobin, heme, ferritin; 5: Ferroportin (Ireg-1); 6: Ceruloplasmin (for details see Table 1).

Figure 6

Effects of inflammation on erythropoiesis and iron homeostasis in mammals. (-): Negative effect; (+): Positive effect.

Figure 7

A simplified algorithm for the diagnosis of IDA (modified from Weiss et al[19]).