Basic Iron Metabolism
Reproduced with permission from Andrews NC, New Engl J Med. 341:1986-1995, Copyright © 1999 Massachusetts Medical Society. All rights reserved.

Most of the iron within the body is found in hemoglobin within erythrocytes (about 1800 mg of iron). Iron is stored in macrophages (and to a lesser extent in hepatocytes), which represents the storage pool of iron (about 1600 mg of iron). Small amounts of iron are found in myoglobin and in plasma (bound to transferrin) (see image to the right and below). Iron is conserved within the body. The typical adult human body contains about 3000-4000 mg of iron. Only about 1 mg of iron is lost from the body per day (through blood loss or sloughed mucosal epithelial cells) and must be replaced through the diet. The majority of iron required by the body is acquired by recycling iron from senescent red cells.

Iron absorption in gastrointestinal tract

Dietary iron is obtained either from inorganic sources or animal sources (in heme from breakdown of hemoglobin or myoglobin). Dietary iron enters intestinal cells via specific transporters.The iron is then used by the cell (incorporated into enzymes), stored as ferritin (excreted in the feces when the intestinal epithelial cell sloughs) or is transferred to the plasma (see figure below). Plasma transfer of iron from enterocytes to the transport protein, apotransferrin, occurs through specific iron channels, called ferroportins, and is facilitated by a protein (with ferroxidase activity) called hephaestin. When apotransferrin binds iron, it is called transferrin. Hephaestin contains copper, so copper deficiency will decrease iron absorption (as the iron absorbed from the diet cannot be transferred to plasma). Hepcidin, a main iron regulating protein, decreases ferroportin and thus decreases iron absorption.

 

Iron absorbed from the intestine is stored as ferritin in intestinal epithelium or transported in plasma as transferrin. Erythroid progenitors obtain iron for hemoglobin synthesis from plasma transferrin or from recycling of senescent erythrocytes by macrophages in bone marrow, spleen and liver. Iron that is in excess for that required for hemoglobin production is stored in macrophages as ferritin, which is oxidized to hemosiderin. These stores can be released from macrophages in times of need (increased erythropoiesis).

Iron transfer/recycling

Iron is not free in the circulation but exists as transferrin (bound to apotransferrin). Most of the iron used for red blood cell hemoglobin production is obtained from hemoglobin breakdown of senescent RBCs (called recycling). When red blood cells reach the end of their lifespan (senescent), they are phagocytized by macrophages (in the spleen, liver, bone marrow). Hydrolytic enzymes in macrophages degrade the ingested RBCs and release hemoglobin. Proteolytic digestion of hemoglobin liberates heme and globins. Globins are broken down to amino acids which can be used for protein production. The iron is released from heme, leaving a porphyrin ring which is converted to bilirubin. For more information on this, refer to the page on extravascular hemolysis). Once iron is released from the heme, it is utilized by the cell (iron is an essential component of many enzymes), exported (via ferroportin), or stored as ferritin (like enterocytes - see above figure). In macrophages, ceruloplasmin (which like hephaestin in intestinal cells also requires copper) is a ferroxidase and facilitates the transfer of macrophage iron to transferrin. So copper deficiency decreases iron release from macrophages and affects iron absorption. Like enterocytes, hepcidin downregulates ferroportin causing iron sequestration in macrophages.

Erythroid progenitors clustering around a central macrophage (black arrow) in an aspirate from a canine spleen. This is called an "erythroblastic island".

Iron uptake by eythroid progenitors

Transferrin-bound iron (from absorption of dietary iron in the intestine or released by macrophages) binds to transferrin receptors, which are highly expressed on the surface of red cell precursors, and is taken up into the cells where it is used to form hemoglobin. Erythroid progenitors cluster around macrophages in the bone marrow and spleen (see image to the right), because they are obtaining their iron (required for hemoglobin synthesis) from these iron-storing cells, as well as from circulating transferrin (see above figure).

Excess iron is dangerous, because it promotes free radical production. Whole body iron levels are regulated primarily at the level of absorption by enterocytes, there is no regulated pathway for active excretion of iron (can only occur by bleeding or sloughing of iron-laden enterocytes). Regulation of iron uptake by enterocytes and release of iron stores from macrophages and hepatocytes is mediated by the hormone hepcidin, and its effect on ferroportin (see above). Hepcidin decreases serum iron by decreasing iron absorption and preventing macrophages from releasing iron (causing iron sequestration). Hepcidin is regulated by iron levels and erythropoiesis. Increased iron will upregulate hepcidin which then decreases iron and vice versa. Active erythropoiesis inhibits hepcidin (allowing iron to be absorbed/released for hemoglobin synthesis). Hepcidin is increased by inflammatory cytokines, particularly IL-6, and reduces available iron during inflammatory processes (see below). Inflammation thus causes a "functional" iron deficiency because iron is not released from macrophages (results in increased iron stores). This contributes to the anemia of inflammatory disease.

 
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