Iron is a transition metal that is the essential core of haemoglobin (the oxygen-carrying protein of red blood cells), myoglobin (the oxygen-carrying protein of muscle), and the cytochromes (the electron transport chain enzymes that generate ATP in the mitochondria). Iron is the most common nutritional deficiency in the world — it affects approximately 2 billion people, primarily women of reproductive age, children, and people in the developing world whose diets are low in bioavailable iron. The clinical manifestations of iron deficiency range from fatigue and reduced exercise tolerance (in mild deficiency) to the iron deficiency anaemia that is characterised by microcytic anaemia, pica, koilonychia, angular cheilitis, and in severe cases, cardiac failure. Iron deficiency is the most common cause of anaemia worldwide, and its prevention and treatment through iron supplementation and through the fortification of staple foods with iron is one of the most cost-effective public health interventions available.
Iron Absorption and the Hepcidin Regulatory System
Iron is absorbed in the duodenum and the proximal jejunum by the enterocytes of the intestinal villi, and the rate of iron absorption is regulated by the hepcidin regulatory system — the hormone that is the primary regulator of iron absorption and of iron distribution in the body. When iron stores are adequate, hepcidin levels are high, the ferroportin exporter on the basolateral membrane of the enterocyte is internalised and degraded, iron absorption is reduced, and the iron that is stored in the macrophages and hepatocytes is retained in these cells. When iron stores are low (as in iron deficiency), hepcidin levels fall, ferroportin is stabilised on the cell membrane, iron absorption from the gut is increased, and the iron that is stored in the macrophages and hepatocytes is released into the blood for delivery to the bone marrow (for erythropoiesis) and to other tissues that require iron. This hepcidin-ferroportin regulatory system is the primary mechanism by which the body maintains iron homeostasis, and its dysregulation (as occurs in the hereditary haemochromatosis, which is caused by hepcidin deficiency and which is characterised by excessive iron absorption and tissue iron overload) demonstrates how critical this regulatory system is for iron metabolism.
The clinical importance of the hepcidin-ferroportin system is also relevant to the understanding of the anaemia of chronic disease (ACD) — the form of anaemia that is associated with chronic infections, chronic inflammatory conditions, and cancer, and that is characterised by a normocytic or microcytic anaemia with low serum iron and low serum ferritin but elevated hepcidin. In ACD, the chronic inflammation produces elevated hepcidin levels, which block the ferroportin-mediated release of iron from the macrophages and from the enterocytes, trapping iron in these cells and producing the functional iron deficiency that characterises ACD. The treatment of ACD is the treatment of the underlying inflammatory condition (with anti-inflammatory drugs, antibiotics, or antineoplastic agents as appropriate), and the iron supplementation that is effective in iron deficiency anaemia is not effective in ACD because the iron is trapped in the storage cells and cannot be released.
Iron and Cognitive Function
Iron deficiency also affects cognitive function — even before the development of anaemia, iron deficiency impairs the cognitive function of children and adults, reducing attention, memory, and executive function in ways that are reversible with iron supplementation. The mechanism of this cognitive impairment is thought to involve the iron-dependent impairment of the synthesis and the function of the neurotransmitters that regulate cognitive function (including dopamine, which requires iron for its synthesis), the iron-dependent impairment of the mitochondrial function in neurons (which requires iron for the cytochromes of the electron transport chain), and the iron-dependent impairment of the myelination of neurons (which requires iron for the synthesis of the myelin basic protein). A meta-analysis of 18 studies in children with iron deficiency anaemia found that iron supplementation significantly improved cognitive function (with an effect size of approximately 0.4), and that the improvement was greatest in the children who had the most severe anaemia at baseline. The cognitive effects of iron deficiency are reversible with iron supplementation, but the reversal may take 6-12 months to become apparent, suggesting that the changes in the brain that are associated with iron deficiency are not fully reversed immediately upon iron repletion.
Practical Application
For general iron supplementation (for the prevention and treatment of iron deficiency anaemia), the evidence-based dose is 30-60mg of elemental iron daily (as ferrous sulfate, ferrous gluconate, or ferrous fumarate, the ferrous forms that are better absorbed than the ferric forms), taken on an empty stomach for optimal absorption (though GI upset may necessitate taking with food). Iron should not be taken at the same time as calcium (which inhibits iron absorption) or as the caffeine-containing beverages (coffee, tea) that inhibit iron absorption — it should be taken with vitamin C (which enhances iron absorption by keeping iron in the ferrous state) and ideally 2 hours apart from calcium supplements. The RDA for iron is 8mg daily for adult men and post-menopausal women, and 18mg daily for premenopausal women and for adolescents, reflecting the menstrual iron losses that occur in women of reproductive age. For comprehensive iron support, iron pairs well with vitamin C (which enhances iron absorption), with folate and vitamin B12 (which are required for the erythropoiesis that is the destination of the iron that is absorbed from the gut and that is stored in the bone marrow), with the probiotics (which support the gut immune system and which may improve iron absorption by reducing the gut inflammation that can impair iron absorption), and with the Mediterranean dietary pattern (which is associated with better iron status and with reduced risk of iron deficiency anaemia).
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