Iron

Iron is an essential trace mineral required for oxygen transport (hemoglobin, myoglobin), mitochondrial electron transport (cytochromes), and numerous iron-sulfur cluster and heme-based enzymes. Iron deficiency is the most common global nutritional deficiency, affecting an estimated 1.2 billion people worldwide per WHO estimates, and the leading cause of nutritional anemia.

Dietary forms and absorption

Dietary iron exists in two chemically distinct forms with different absorption mechanisms. Heme iron — iron bound within the porphyrin ring of hemoglobin and myoglobin in animal products — is absorbed intact by intestinal heme carrier proteins with 15-35% efficiency, largely independent of meal composition. Non-heme iron — ionic iron from plant foods, dairy, and fortified products — requires reduction from ferric (Fe3+) to ferrous (Fe2+) by duodenal cytochrome B, transport across enterocytes via DMT1, and is absorbed at 2-20% efficiency depending on enhancers and inhibitors in the meal.

Hepcidin and iron homeostasis

Hepcidin, a 25-amino-acid peptide hormone produced by hepatocytes, is the master regulator of systemic iron homeostasis. Hepcidin binds ferroportin (the iron export channel on enterocytes, macrophages, and hepatocytes), inducing its internalization and degradation. High hepcidin reduces dietary iron absorption and sequesters iron in macrophages; low hepcidin increases absorption and releases stored iron. Hepcidin is stimulated by body iron stores (via BMP6-SMAD signaling) and inflammation (via IL-6-STAT3), and suppressed by erythropoietic demand and hypoxia.

Requirements and populations at risk

The NAM 2001 DRI set RDAs of 8 mg/day for adult men and postmenopausal women, 18 mg/day for premenopausal women (reflecting menstrual losses), and 27 mg/day for pregnancy. Tolerable Upper Intake Level is 45 mg/day. Populations at elevated risk of iron deficiency: menstruating women, pregnant women, infants after 6 months of age, adolescents during growth spurts, vegetarians and vegans (lower bioavailability from non-heme-only diets), blood donors, endurance athletes (exercise-induced hepcidin elevation plus hemolysis and sweat losses), and patients with gastrointestinal blood loss.

Dietary sources

Per USDA FoodData Central (mg iron per 100 g): beef liver 6.5 (heme), clams 28 (heme), oysters 7 (heme), beef 2-3 (heme), chicken 1 (heme), tuna 1 (heme), fortified breakfast cereals 6-18 (non-heme), lentils (cooked) 3.3 (non-heme), spinach (cooked) 3.6 (non-heme), pumpkin seeds 15 (non-heme), tofu 3 (non-heme), chickpeas 2.9 (non-heme).

Enhancers and inhibitors

Non-heme iron absorption is modulated substantially by co-consumed meal components. Enhancers include: ascorbic acid (vitamin C), which reduces Fe3+ to Fe2+ and chelates iron in absorbable form; meat, poultry, and fish proteins, via the "meat factor" (specific peptides enhance absorption); citric and lactic acids. Inhibitors include: phytate (from whole grains, legumes), tannins and polyphenols (tea, coffee, red wine), calcium (from dairy at high co-doses), and certain dietary fibers.

Clinical deficiency

Iron deficiency progresses through three stages: (1) iron depletion — low ferritin without anemia or functional impairment; (2) iron-deficient erythropoiesis — reduced transferrin saturation, elevated TIBC, elevated zinc protoporphyrin, no anemia; (3) iron deficiency anemia — microcytic hypochromic anemia. Non-anemic iron deficiency is increasingly recognized as clinically relevant, with fatigue, cognitive impairment, and restless leg syndrome improving with iron supplementation even before anemia appears.

Supplementation

Oral iron (ferrous sulfate, gluconate, fumarate, bisglycinate) at 50-200 mg elemental iron daily corrects deficiency over weeks to months. Alternate-day dosing has been shown to achieve higher fractional absorption by avoiding hepcidin upregulation between doses (Moretti et al. 2015, Stoffel et al. 2020). Intravenous iron (ferric carboxymaltose, iron sucrose, low-molecular-weight iron dextran) is used for severe deficiency, intolerance to oral iron, or malabsorption.