Current understanding of iron homeostasis

Abstract

Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal physiologic range. In the diet, iron is either sequestered within heme or in various nonheme forms. Although the absorption of heme iron is poorly understood, nonheme iron is transported across the apical membrane of the intestinal enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1). Newly absorbed iron binds to plasma transferrin and is distributed around the body to sites of utilization with the erythroid marrow having particularly high iron requirements. Iron-loaded transferrin binds to transferrin receptor 1 on the surface of most body cells, and after endocytosis of the complex, iron enters the cytoplasm via DMT1 in the endosomal membrane. This iron can be used for metabolic functions, stored within cytosolic ferritin, or exported from the cell via FPN1. Cellular iron concentrations are modulated by the iron regulatory proteins (IRPs) IRP1 and IRP2. At the whole-body level, dietary iron absorption and iron export from the tissues into the plasma are regulated by the liver-derived peptide hepcidin. When tissue iron demands are high, hepcidin concentrations are low and vice versa. Too little or too much iron can have important clinical consequences. Most iron deficiency reflects an inadequate supply of iron in the diet, whereas iron excess is usually associated with hereditary disorders. These disorders include various forms of hemochromatosis, which are characterized by inadequate hepcidin production and, thus, increased dietary iron intake, and iron-loading anemias whereby both increased iron absorption and transfusion therapy contribute to the iron overload. Despite major recent advances, much remains to be learned about iron physiology and pathophysiology.

Dietary iron intake, iron status, and gestational diabetes

“…In humans, iron status is primarily regulated by the intestinal iron absorption of consumed external iron (8,9), as discussed elsewhere in these proceedings (10). Dietary iron is present in 2 forms: heme iron (animal flesh products) and nonheme iron (plants, some animal products, and supplements).…”

Integrating themes, evidence gaps, and research needs identified by workshop on iron screening and supplementation in iron-replete pregnant women and young children

“…The extent to which such adaptations might enhance susceptibility to high-level iron supplementation among iron-replete pregnant women and young infants is unknown. However, this possibility needs to be investigated because the primary protective mechanism preventing excess uptake and subsequent excess iron stores may not be fully operating under these adaptations in the hepcidin-dependent homeostatic regulation (12).…”

“…Such consideration becomes more important during pregnancy and young childhood because of the prioritization of iron to erythropoiesis in IDA even in the final and extreme stages of ID. Before the point when screening identifies IDA, the critical development of the brain, heart, and other tissues may already have been permanently impaired by ID in those tissues (12,20). Further, the recent report by Petry et al (24) suggests that only w25% of anemia is attributable to ID.…”

Transferrin receptor 1 overexpression is associated with tumour de‐differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma

“…Iron metabolism is regulated by a complex mechanism in response to the body's iron concentration. 10 Hepcidin is a key factor involved in the control of iron homeostasis in the body. Hepcidin is produced by hepatocytes and suppresses iron absorption in intestinal epithelial cells.…”