The body requires iron for the synthesis of hemoglobin and myoglobin and for the formation of heme and other enzymes involved in electron transfer. Iron is also a cofactor for enzymes in the brain [8,9]. Approximately 60% of the body's iron is found in hemoglobin in circulating erythrocytes; 25% is contained in a mobilizable iron store; and the remaining 15% is bound to myoglobin in muscle tissue [10,11,12].

Iron also plays a role in dopamine signaling. Iron deficiency is associated with a disturbance in dopamine metabolism, reduced activity of the dopamine transporter, and abnormal activity of dopamine D1 and D2 receptors in the basal ganglia of the brain [12,13]. Dopamine regulates cognition and emotion and the reward and pleasure centers in the brain, and it controls the release of hormones. Dopamine is active in the prefrontal cortex to promote cognitive control of executive functions, such as planning, working, memory, and sustained attention [14].

Hepcidin, a hormone secreted by the liver, functions as master regulator of systemic iron homeostasis by coordinating iron use and storage with acquisition [18]. Ferroportin is an iron transporter expressed in macrophages, duodenal enterocytes, and hepatocytes [19]. Hepcidin acts by binding to ferroportin, causing its internalization and degradation [20,21]. Loss of ferroportin from the cell surface prevents iron entry into plasma, resulting in low transferrin saturation and less iron delivered to developing erythroblasts. Conversely, decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption [18,20]. Disturbances in this process are the basis for many iron-associated disorders, including anemia and iron-overload-related disorders [22,23].

Iron in the diet is either heme or nonheme iron [15,16,24]. Heme iron, derived from hemoglobin and myoglobin of animal food sources (i.e., meat, fish, poultry), is the most easily absorbable form and contributes 10% or more of total absorbed iron. Nonheme iron is derived from plants and iron-fortified foods and is less well absorbed [24].

Approximately 2 mg of iron is absorbed daily in the duodenum and jejunum. This is balanced by losses resulting from desquamation of skin, sloughing of intestinal epithelial cells, and blood loss [16]. Losses also occur due to hemorrhage, problems absorbing iron, and other medical conditions (e.g., end-stage renal disease) [25].

Signs of iron-deficiency anemia include koilonychia, cheilosis, pale/sallow skin, and atrophic glossitis [25]. With koilonychia, the nails (usually fingernails) are abnormally thin and may be spoon-shaped or concave [33]. Cheilosis is an abnormal condition of the lips characterized by surface scaling and fissures in the corners of the mouth [34,35]. Pale, sallow skin may be a result of low levels of hemoglobin. With atrophic glossitis, the tongue appears to be smooth and glossy with a red or pink background [36]. Each of these conditions is reversible with correction of the iron deficiency.

Symptoms of iron-deficiency anemia include [5,14,25,32,37,38,39]:

Iron deficiency develops in stages. Stage 1 is characterized by decreased iron stores in bone marrow and serum ferritin levels <20 ng/mL. Iron absorption increases, causing an increase in transferrin level. Erythropoiesis is impaired in stage 2. Although transferrin level is increased, the serum iron level decreases and the transferrin saturation decreases. Anemia develops during stage 3 (with indices that appear normal). Microcytosis and then hypochromia develop in stage 4. In stage 5, iron deficiency affects tissues, with resulting signs and symptoms [51].

A hemoglobin level <11 g/dL in the first or third trimester or a hemoglobin level <10.5 g/dL in the second trimester indicates iron-deficiency anemia in the pregnant woman [61]. A maternal hemoglobin level <6 g/dL has been associated with abnormal fetal oxygenation resulting in non-reassuring heart tracings, low amniotic fluid volumes, fetal cerebral vasodilation, and fetal death [62,63].

Normal serum iron levels are 50–120 mcg/dL. Mild-to-moderate systemic iron toxicity is possible when serum iron levels are 350–500 mcg/dL. Hepatotoxicity is usually observed at levels higher than 500 mcg/dL, and levels higher than 800 mcg/dL are associated with severe toxicity. Patients with serum iron levels exceeding 500 mcg/dL require age-appropriate intensive care, including chelation therapy with deferoxamine, but patients with symptoms of toxicity should be treated regardless of serum iron level [82]. Excessive iron has a corrosive effect on the GI tract leading to nausea, vomiting, diarrhea, melena, and hematemesis. Iron overload can damage organs, such as the liver, heart, and pancreas, as well as endocrine glands and joints.