Iron is stored within cells in the cavities of ferritin protein multimers. There are two types of ferritin subunit (L and H), both approximately 20 kDa in size. These subunits assemble in varying proportions into 24-subunit cage-like structures. Up to several thousand iron atoms can be stored in each ferritin multimer. Like transferrin, ferritin serves the purpose of preventing iron from reacting with other cellular constituents, and allows controlled iron release in response to increased cellular needs. The molecular details of iron incorporation into and release from ferritin are not well understood. Under some circumstances, ferritin and other cellular components are partially degraded and conglomerated to form hemosiderin, a heterogeneous iron-containing substance that probably serves little purpose but to keep iron from causing harm. Both ferritin and hemosiderin accumulate in iron-overloaded tissues.
The liver serves as the primary depot for iron in excess of immediate needs. It has a very large capacity for storing iron, though this capacity is ultimately exceeded in iron overload disorders. While other tissues (myocardium, pancreas) also fill up with iron in iron overload, the liver is frequently the first site where damage from iron overload becomes apparent. Hepatocytes avidly take up non-transferrin-bound iron from the plasma.
Reticuloendothelial macrophages are also important for iron storage, but their iron comes from degraded erythrocytes. Patients treated with frequent transfusions typically accumulate excess iron in macrophages first, and only later in other tissues. This pattern of iron accumulation has been referred to as 'siderosis' to distinguish it from hemochromatosis, which is primary iron loading of parenchymal cells.
Iron homeostasis requires the coordinated regulation of iron transport and iron storage so that tissues will have adequate amounts to meet their needs but will not become overloaded with iron. Regulation must involve the control of cellular iron import, export and partitioning. Recently, several clues have emerged that should help lead to a comprehensive understanding of regulation at each of these steps.
There are at least four known regulators of intestinal iron absorption: iron stores, erythropoietic demand, hypoxia and inflammation. The stores regulator modulates absorption several-fold, increasing absorption in iron deficiency and decreasing absorption in iron overload. The erythroid regulator is more potent: it can increase iron absorption many-fold when erythropoiesis becomes iron-restricted. The hypoxia regulator is not well characterized, but its effects appear to be distinct from those of the erythroid regulator. This regulator increases iron absorption in response to hypoxia. Finally, emerging evidence suggests that an inflammation regulator also exists, decreasing iron absorption in response to inflammation from a variety of causes.
Recently, a peptide hormone has been discovered that is likely to be a common effector of the stores, erythroid, hypoxia and inflammation regulators. Hepcidin (also called LEAP,
HAMP) is a 20- to 25-amino acid protein, produced by the liver, which is cleaved from a larger precursor molecule. Animal experiments have shown that hepcidin acts as a negative regulator of both intestinal iron absorption and macrophage iron recycling. The production of hepcidin is increased in animals given carbonyl iron to produce iron overload, presumably as part of a compensatory mechanism to decrease iron absorption and decrease plasma iron (primarily derived from recycling macrophages). This suggests that it mediates the effects of the stores regulator. The production of hepcidin is decreased by iron-restricted erythropoiesis, allowing more iron to enter the body through the intestine and more iron to enter the plasma from recycling macrophages. In this way, it also mediates the effects of the erythroid regulator. The production of hepcidin is also decreased in hypoxia, suggesting that it is an effector of the hypoxia regulator. Finally, hepcidin expression is induced by inflammation, probably through a direct action of the cytokine interleukin-6 on hepatocytes. In this case, induced hepcidin expression leads to decreased intestinal iron absorption and decreased macrophage iron release, acting as an inflammation regulator. There is growing evidence that, in response to the inflammatory regulator, increased hepcidin expression contributes to the abnormal iron homeostasis observed in the 'anemia of chronic disease' (also known as the anemia of chronic disorders). It is likely that a useful clinical assay for hepcidin levels in serum and/or urine will be available within the next few years. The actions of the various regulators are summarized in Figure 13.3.
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