macrophages. The average American diet contains 10–15 mg of iron per day. About 10% of this amount is absorbed in the stomach, duodenum, and upper jejunum under acidic conditions.
Dietary iron present as heme is efficiently absorbed (10–20%) but non heme iron less so (1–5%), largely because of interference by phosphates, tannins, and other food constituents. The major iron transporter from the diet across the intestinal lumen is ferroportin, which also facilitates the transport
of iron to apotransferrin in macrophages for delivery to erythroid cells prepared to synthesize hemoglobin. Hepcidin, produced during inflammation, negatively regulates iron transport by
promoting the degradation of ferroportin. Small amounts of iron—approximately 1 mg/day—are
normally lost through exfoliation of skin and mucosal cells. With hemorrhage, there is decreased oxygen delivery to the kidneys resulting in stabilization of a hypoxia-inducible factor in the kidneys and increased erythropoietin generation in the kidneys and liver. The erythropoietin stimulates erythropoiesis, leading to an increased synthesis of erythroferrone. In turn, erythroferrone suppresses hepcidin synthesis leading to ferroportin stability and enhanced iron transport across the gastrointestinal lumen.
Menstrual blood loss plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL but may be five times greater in some individuals.
To maintain adequate iron stores, women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day. This strains the upper limit of what may reasonably be absorbed, and women
with menorrhagia of this degree will almost always become iron deficient without iron supplementation.
In general, iron metabolism is balanced between absorption of 1 mg/day and loss of 1 mg/day. Pregnancy and lactation upset the iron balance, since requirements increase to 2–5 mg of iron per day. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Decreased iron absorption can also cause iron deficiency, such as in people
affected by celiac disease, and it commonly occurs after gastric resection or jejunal bypass surgery.
The most important cause of iron deficiency anemia in adults is chronic blood loss, especially menstrual and gastrointestinal blood loss. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and
repeated blood donations) are excluded. Prolonged aspirin or nonsteroidal anti-inflammatory drug use may cause it even without a documented structural lesion. Celiac disease (gluten enteropathy), even
when asymptomatic, is an occult cause of iron deficiency through poor absorption in the gastrointestinal tract. Zinc deficiency is another cause of poor iron absorption. Chronic hemoglobinuria may lead to iron deficiency, but this is uncommon; traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. The cause of iron deficiency is not found in up to 5% of
cases.
Pure iron deficiency might prove refractory to oral iron replacement. Refractoriness is defined as a hemoglobin increment of less than 1 g/dL (10 g/L) after 4–6 weeks of 100 mg/day of elemental oral iron. The differential diagnosis in these cases includes malabsorption from autoimmune gastritis, Helicobacter pylori gastric infection, celiac disease, and hereditary iron-refractory iron deficiency
anemia. Iron-refractory iron deficiency anemia is a rare autosomal recessive disorder due to mutations in the transmembrane serine protease 6 (TMPRSS6) gene, which normally down-regulates hepcidin. In iron-refractory iron deficiency anemia, hepcidin levels are normal to high and ferritin
levels are high despite the iron deficiency
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