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INTRODUCTION

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Iron is the most abundant metal on earth, and despite that, iron deficiency is the most prevalent single nutrient deficiency worldwide. Term newborns possess about 75 mg of elemental iron/kg (0.25–0.5 g of total body iron), largely acquired during transfer of maternal iron stores during the third trimester of pregnancy. They must then gain 4.5 g of iron over the course of their childhood (1 mg/day) to achieve the nearly 5.0 g of body iron in the average adult. An additional 0.2 to 0.5 mg/day of absorbed iron is required to balance normal physiologic iron losses.

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PATHOGENESIS

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Iron Homeostasis

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Body iron is predominantly incorporated into the hemoglobin of circulating erythrocytes and their marrow precursors. Phagocytosis of senescent erythrocytes by reticuloendothelial (RE) macrophages and degradation of hemoglobin allow for recovery and recycling of heme iron that provides the majority of the daily iron requirement to the bone marrow. Only a small fraction of the average daily iron requirement is obtained from dietary iron.

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In iron-sufficient states, an estimated 10% of dietary iron is absorbed. Therefore, children’s diets must contain 10 to 15 mg of iron to maintain a positive iron balance. During periods of maximal growth—infancy and adolescence—iron requirements for the expanding blood volume and muscle mass may exceed dietary iron accrual, placing those individuals at risk for iron deficiency. In infancy, particularly when exclusively breastfed, an adequate level of iron intake is difficult to achieve if iron supplementation, iron-fortified formula, or iron-rich foods are not provided.

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Iron Absorption
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Non-heme dietary iron found in plants is primarily in the ferric (Fe3+) state and is reduced to the ferrous (Fe2+) state in the acidic environment of the proximal duodenum by a brush border ferrireductase. The use of histamine H2 blockers or proton pump inhibitors to treat peptic gastroesophageal reflux reduces acidity and may result in impaired iron absorption. Absorption of non-heme iron is limited both by low solubility and dietary chelators such as phytates that bind ambient iron. Heme or organic iron present in animal food products is the most readily absorbed form of iron. Its absorption, which is incompletely understood, occurs by a different mechanism that is independent of gastric pH. After reduction to the ferrous form, iron is cotransported with protons through the apical membrane of the enterocyte by divalent metal transporter 1 (DMT1), the expression of which is significantly increased in iron deficiency. Some imported iron remains stored within the enterocyte cytoplasm as ferritin; the remainder is exported through the basolateral membrane by another transporter protein, ferroportin. Ferroportin-mediated transport is facilitated by hephaestin or ceruloplasmin, which return iron to its ferric (Fe3+) state, allowing iron to bind to the circulating glycoprotein transferrin (Tf), the predominant iron-binding protein in plasma. Note that only a fraction of dietary iron is imported by the enterocyte, and ...

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