Iron Deficiency Anemia

Pathophysiology

Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport. Iron equilibrium in the body is regulated carefully to ensure that sufficient iron is absorbed in order to compensate for body losses of iron (see the image below). Whereas body loss of iron quantitatively is as important as absorption in terms of maintaining iron equilibrium, it is a more passive process than absorption.

The total body iron in a 70-kg man is about 4 g. This is maintained by a balance between absorption and body losses. Although the body only absorbs 1 mg daily to maintain equilibrium, the internal requirement for iron is greater (20-25 mg). An erythrocyte has a lifespan of 120 days so that 0.8% of red blood cells are destroyed and replaced each day. A man with 5 L of blood volume has 2.5 g of iron incorporated into the hemoglobin, with a daily turnover of 20 mg for hemoglobin synthesis and degradation and another 5 mg for other requirements. Most of this iron passes through the plasma for reutilization. Iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin.

In healthy people, the body concentration of iron (approximately 60 parts per million [ppm]) is regulated carefully by absorptive cells in the proximal small intestine, which alter iron absorption to match body losses of iron (see the image below). Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

Mucosal cells in the proximal small intestine mediate iron absorption. Intestinal cells are born in the crypts of Lieberkuhn and migrate to the tips of the villi. The cells are sloughed into the intestinal lumen at the end of their 2- to 3-day lifespan. Absorptive cells remain attuned to the body requirement for iron by incorporating proportionate quantities of body iron into the absorptive cells. This iron and recently absorbed iron decrease uptake of iron from the gut lumen by satiation of iron-binding proteins with iron, by stimulating an iron regulatory element, or both. The incorporation of iron into these cells in quantities proportional to body stores of iron also provides a limited method of increasing iron excretion in individuals replete in iron.

Either diminished absorbable dietary iron or excessive loss of body iron can cause iron deficiency. Diminished absorption usually is due to an insufficient intake of dietary iron in an absorbable form. Hemorrhage is the most common cause of excessive loss of body iron, but it can occur with hemoglobinuria from intravascular hemolysis. Malabsorption of iron is relatively uncommon in the absence of small bowel disease (sprue, celiac disease, regional enteritis) or previous GI surgery.

Iron uptake in the proximal small bowel occurs by 3 separate pathways (see the image below). These are the heme pathway and 2 distinct pathways for ferric and ferrous iron.

Three pathways exist in enterocytes for uptake of food iron. In the United States and Europe, most absorbed iron is derived from heme. Heme is digested enzymatically free of globin and enters the enterocyte as a metalloporphyrin. Within the cell iron is released from heme by heme oxygenase to pass into the body as inorganic iron. Most dietary inorganic iron is ferric iron. This can enter the absorptive cell via the integrin-mobilferrin pathway (IMP).Some dietary iron is reduced in the gut lumen and enters the absorptive cell via the divalent metal transporter-1 (DMT-1/DCT-1/Nramp-2). The proteins of both pathways interact within the enterocyte with paraferritin, a large protein complex capable of ferrireduction. Excess iron is stored as ferritin to protect the cell from oxidative damage. Iron leaves the cell to enter plasma facilitated by ferroportin and hephaestin, which associate with an apotransferrin receptor. The enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor.

In North America and Europe, one third of dietary iron is heme iron, but two thirds of body iron is derived from dietary myoglobin and hemoglobin. Heme iron is not chelated and precipitated by numerous dietary constituent that render nonheme iron nonabsorbable (see the image below), such as phytates, phosphates, tannates, oxalates, and carbonates. Heme is maintained soluble and available for absorption by globin degradation products produced by pancreatic enzymes. Heme iron and nonheme iron are absorbed into the enterocyte noncompetitively.

Dietary iron contains both heme and nonheme iron. Both chemical forms are absorbed noncompetitively into duodenal and jejunal mucosal cells. Many of the factors that alter the absorption of nonheme iron have little effect upon the absorption of heme iron because of the differences in their chemical structures. Iron is released from heme within the intestinal absorptive cell by heme oxygenase and then transferred into the body as nonheme iron. Factors affecting various stages of iron absorption are shown in this diagram. The simplest model of iron absorption must consider intraluminal, mucosal, and corporeal factors.

Heme enters the cell as an intact metalloporphyrin, presumably by a vesicular mechanism. It is degraded within the enterocyte by heme oxygenase with release of iron so that it traverses the basolateral cell membrane in competition with nonheme iron to bind transferrin in the plasma.

Ferric iron utilizes a different pathway to enter cells than ferrous iron. This was shown by competitive inhibition studies, the use of blocking antibodies against divalent metal transporter-1 (DMT-1) and beta3-integrin, and transfection experiments using DMT-1 DNA. This research indicated that ferric iron utilizes beta3-integrin and mobilferrin, while ferrous iron uses DMT-1 to enter cells.

Which pathway transports most nonheme iron in humans is not known. Most nonheme dietary iron is ferric iron. Iron absorption in mice and rats may involve more ferrous iron because they excrete moderate quantities of ascorbate in intestinal secretions. Humans, however, are a scorbutic species and are unable to synthesize ascorbate to reduce ferric iron.

Other proteins appear to be related to iron absorption. These are stimulators of iron transport (SFT), which are reported to increase the absorption of both ferric and ferrous iron, and hephaestin, which is postulated to be important in the transfer of iron from enterocytes into the plasma. The relationships and interactions among the newly described proteins are not known at this time and are being explored in a number of laboratories.

The iron concentration within enterocytes varies directly with the body’s requirement for iron. Absorptive cells of iron-deficient humans and animals contain little stainable iron, whereas those of subjects who are replete in iron contain significantly higher amounts. Untreated phenotypic hemochromatosis creates little stainable iron in the enterocyte, similar to iron deficiency. Iron within the enterocyte may operate by up-regulation of a receptor, saturation of an iron-binding protein, or both.

In contrast to findings in iron deficiency, enhanced erythropoiesis, or hypoxia, endotoxin rapidly diminishes iron absorption without altering enterocyte iron concentration. This suggests that endotoxin and, perhaps, cytokines alter iron absorption by a different mechanism. This is the effect of hepcidin and the balance of hepcidin versus erythropoietin.

Most iron delivered to nonintestinal cells is bound to transferrin. Transferrin iron is delivered into nonintestinal cells via 2 pathways: the classical transferrin receptor pathway (high affinity, low capacity) and the pathway independent of the transferrin receptor (low affinity, high capacity). Otherwise, the nonsaturability of transferrin binding to cells cannot be explained.

In the classical transferrin pathway, the transferrin iron complex enters the cell within an endosome. Acidification of the endosome releases the iron from transferrin so that it can enter the cell. The apotransferrin is delivered by the endosome to the plasma for reutilization. The method by which the transferrin receptor–independent pathway delivers iron to the cell is not known.

Nonintestinal cells also possess the mobilferrin integrin and DMT-1 pathways. Their function in the absence of an iron-saturated transferrin is uncertain; however, their presence in nonintestinal cells suggests that they may participate in intracellular functions in addition to their capability to facilitate cellular uptake of iron.