Iron

• Oxygen Transport
• Energy Production
• Cellular Function

• Immune Function
• Cognitive Development
• Physical Growth
• Hormone Synthesis
• Temperature Regulation

Iron is an essential component of hemoglobin, a protein in red blood cells that transfers oxygen from the lungs to the tissues. As a component of myoglobin, another protein that provides oxygen, iron supports muscle metabolism and healthy connective tissue. Iron is also necessary for physical growth, neurological development, cellular functioning, and synthesis of some hormones. Iron exists in two main forms in the diet: heme iron (found in animal foods) and nonheme iron (found in plant foods and iron-fortified products).

Heme iron is more readily absorbed than nonheme iron. Iron absorption is regulated by hepcidin, a circulating peptide hormone that is the key regulator of both iron absorption and the distribution of iron throughout the body. Iron is stored in the body primarily as ferritin or hemosiderin in the liver, spleen, and bone marrow. Beyond oxygen transport, iron serves as a cofactor for numerous enzymes involved in energy production, DNA synthesis, and metabolism.

Iron-containing enzymes are crucial for the electron transport chain in mitochondria, where cellular energy in the form of ATP is generated. Iron is also essential for proper immune function, affecting the proliferation and maturation of immune cells, particularly lymphocytes. In the brain, iron is necessary for neurotransmitter synthesis, myelination, and metabolic processes. Iron deficiency during critical periods of brain development can lead to long-lasting cognitive and behavioral impairments.

The body maintains iron homeostasis through a complex regulatory system involving absorption, storage, and recycling, as there is no physiological mechanism for iron excretion other than blood loss, sloughing of intestinal cells, or skin desquamation.

Adults: 8-18 mg daily, depending on age, gender, and life stage

Heme iron: 15-35%; Nonheme iron: 2-20%, depending on iron status and dietary factors

Consuming vitamin C (ascorbic acid) with iron-containing foods, Consuming heme iron sources (meat, poultry, seafood) with nonheme iron sources, Taking iron supplements on an empty stomach (if tolerated), Using more bioavailable forms (ferrous sulfate, ferrous gluconate, ferrous fumarate), Avoiding calcium supplements, tea, coffee, and high-phytate foods when taking iron supplements, Using chelated forms like iron bisglycinate for improved absorption with fewer side effects, Taking iron supplements with a small amount of fat to enhance absorption, Addressing low stomach acid if present, as adequate acid is needed for optimal iron absorption, Cooking in cast iron cookware, which can increase the iron content of foods, Fermenting, sprouting, or soaking grains and legumes to reduce phytate content

For maximum absorption, iron supplements should be taken on an empty stomach, ideally 1 hour before or 2 hours after meals. However, if gastrointestinal side effects occur, iron can be taken with food, though absorption may be reduced by 40-50%. Iron supplements should be taken at least 2 hours apart from antacids, calcium supplements, dairy products, tea, coffee, and high-fiber foods. Dividing the daily dose (e.g., taking half in the morning and half in the evening) may improve tolerance and maintain more consistent blood levels.

For those taking multiple supplements, separate iron from zinc, calcium, and magnesium supplements by at least 2 hours, as these minerals compete for absorption pathways. Taking iron supplements with vitamin C (either as a supplement or in foods like orange juice) can significantly enhance absorption. For those with iron deficiency anemia, consistent daily supplementation is typically more effective than intermittent dosing, though the latter may be better tolerated in some individuals.

• Gastrointestinal discomfort
• Nausea
• Constipation
• Diarrhea
• Black stools
• Abdominal pain
• Heartburn
• Temporary tooth staining
• Metallic taste
• Vomiting (less common)
• Fatigue (paradoxical, usually with excessive doses)
• Headache

• Hemochromatosis
• Hemosiderosis
• Polycythemia vera
• Peptic ulcer disease (active)
• Enteritis
• Ulcerative colitis (active phase)
• Regional enteritis
• Iron overload conditions
• Thalassemia (may require specialized management)
• Alcoholic liver disease (may increase risk of iron overload)

• Levodopa (iron reduces absorption)
• Levothyroxine (iron reduces absorption)
• Proton pump inhibitors (reduce iron absorption)
• Tetracycline antibiotics (mutual absorption reduction)
• Quinolone antibiotics (mutual absorption reduction)
• Bisphosphonates (iron reduces absorption)
• Methyldopa (iron reduces absorption)
• ACE inhibitors (reduced absorption)
• Calcium supplements (mutual absorption reduction)
• Zinc supplements (mutual absorption reduction)
• Antacids (reduce iron absorption)
• Chloramphenicol (may delay response to iron therapy)
• Cholestyramine (reduces iron absorption)

45 mg/day for adults (from supplements and food). This upper limit applies to healthy individuals and is based on the risk of gastrointestinal side effects. For treatment of iron deficiency under medical supervision, higher doses are often used. Acute iron toxicity can occur with doses of 60 mg/kg or more, particularly in children, and is a medical emergency.

Chronic iron overload typically occurs only in individuals with hereditary conditions like hemochromatosis or after long-term blood transfusions. Symptoms of acute iron toxicity include severe vomiting, diarrhea, abdominal pain, dehydration, and in severe cases, metabolic acidosis, shock, and death. Chronic iron overload can lead to organ damage, particularly to the liver, heart, and pancreas.

Generally Recognized as Safe (GRAS), approved as a dietary supplement and food additive. The FDA requires warning labels on iron-containing supplements about the risk of accidental overdose in children. Iron supplements containing 30 mg or more per dose must be packaged in individual-dose packaging when intended for retail sale. Certain injectable iron preparations are FDA-approved prescription drugs for specific medical conditions.

Eu: Approved as a food supplement under Directive 2002/46/EC. The European Food Safety Authority (EFSA) has approved health claims related to iron’s contribution to normal cognitive function, energy-yielding metabolism, formation of red blood cells and hemoglobin, oxygen transport, immune system function, and reduction of tiredness and fatigue. Maximum levels in supplements vary by country.

Canada: Approved as a Natural Health Product (NHP) with authorized claims for preventing and treating iron deficiency, maintaining good health, and supporting normal red blood cell formation. Health Canada has established maximum daily doses for different forms of iron.

Australia: Listed on the Australian Register of Therapeutic Goods (ARTG) as a complementary medicine. The Therapeutic Goods Administration (TGA) regulates iron supplements with specific labeling requirements and dosage limitations.

Who: The World Health Organization recommends iron supplementation for specific populations, including pregnant women, young children in areas with high anemia prevalence, and menstruating women and adolescent girls in settings where anemia prevalence is 40% or higher.

Low to medium

$0.05-$0.30 per day for basic forms (ferrous sulfate, ferrous gluconate), $0.30-$1.00 for specialty forms (bisglycinate, carbonyl iron, sucrosomial iron), $1.00-$3.00 for premium forms (heme iron polypeptide, liposomal iron)

Ferrous sulfate provides the most elemental iron per dollar but has higher rates of side effects. For those who tolerate it well, it offers excellent value, particularly for correcting deficiency. Ferrous gluconate and ferrous fumarate offer a middle ground, with slightly better tolerability at a marginally higher cost. Chelated forms like iron bisglycinate cost more but may provide better value due to higher absorption and fewer side effects, potentially improving compliance and long-term outcomes.

Specialty formulations like sucrosomial iron and heme iron polypeptide are significantly more expensive but may be worth the cost for those with significant absorption issues, gastrointestinal sensitivity, or conditions like inflammatory bowel disease. For maintenance dosing in non-deficient individuals, lower-cost options are generally sufficient. For therapeutic dosing in deficiency states, the value equation should consider not just cost but also tolerability, compliance, and speed of repletion. Food sources of iron (particularly heme iron from animal products) can be cost-effective alternatives to supplements for those without significant deficiency.

Cooking in cast iron cookware represents a one-time investment that can increase dietary iron intake over many years. For populations at high risk of deficiency, iron-fortified foods often provide the most cost-effective approach from a public health perspective.

2-3 years for most iron supplements

Store in a cool, dry place away from direct sunlight. Keep container tightly closed. Liquid iron preparations should be kept in dark bottles and may require refrigeration after opening (check product-specific instructions). Keep iron supplements out of reach of children due to toxicity risk.

Moisture (can cause degradation of tablets and capsules), Heat (accelerates oxidation and degradation), Light exposure (particularly for liquid formulations), Air exposure (oxidation of ferrous to ferric forms), Extreme pH conditions (affects stability of certain forms), Interactions with other minerals or compounds in combination supplements, Microbial contamination (particularly for liquid formulations)

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• Hemoglobin concentration (normal range: 12-15.5 g/dL for women, 13.5-17.5 g/dL for men)
• Hematocrit (normal range: 36-44% for women, 41-50% for men)
• Serum ferritin (normal range: 15-200 ng/mL for women, 30-300 ng/mL for men)
• Transferrin saturation (normal range: 20-50%)
• Total iron-binding capacity (TIBC) (normal range: 250-450 mcg/dL)
• Serum iron (normal range: 60-170 mcg/dL for men, 50-130 mcg/dL for women)
• Soluble transferrin receptor (normal range: 0.8-1.8 mg/L)
• Reticulocyte hemoglobin content (normal range: >28 pg/cell)
• Complete blood count (CBC) with red cell indices
• Mean corpuscular volume (MCV) (normal range: 80-100 fL)
• Mean corpuscular hemoglobin (MCH) (normal range: 27-33 pg)
• Mean corpuscular hemoglobin concentration (MCHC) (normal range: 32-36 g/dL)
• Red cell distribution width (RDW) (normal range: 11.5-14.5%)
• Bone marrow iron staining (rarely used, primarily in research or complex cases)
• Hepcidin levels (primarily in research settings)
• Zinc protoporphyrin (ZPP) (normal range: <40 μmol/mol heme)
• Genetic testing for hereditary hemochromatosis and other iron metabolism disorders

Synthesis Methods

Natural Sources

Quality Considerations

Iron has been used medicinally for thousands of years. Ancient Egyptians, Greeks, and Romans used iron-rich mineral waters and iron filings in wine to treat various ailments, particularly those we now recognize as symptoms of anemia. Hippocrates (c. 400 BCE) described a condition that was likely iron deficiency anemia and recommended iron-containing treatments.

In the 17th century, iron was recognized as a treatment for ‘chlorosis’ (an old term for iron-deficiency anemia, particularly in young women), with Thomas Sydenham prescribing iron filings in wine. By the early 19th century, Pierre Blaud developed ‘Blaud’s pills’ (ferrous sulfate and potassium carbonate), which became a standard treatment for anemia. In 1832, Pierre Blaud published his findings on the effectiveness of these iron pills for treating chlorosis. The essential role of iron in hemoglobin formation was established in 1932 by Castle and colleagues.

The connection between iron deficiency and poor work performance was recognized in the early 20th century, leading to interest in iron supplementation for public health. Modern iron supplementation began in earnest in the mid-20th century, with various forms developed to improve absorption and reduce side effects. In the 1950s and 1960s, the relationship between iron status and infection risk became a topic of research, leading to more nuanced approaches to supplementation in malaria-endemic regions. The development of parenteral iron preparations in the latter half of the 20th century provided options for those unable to tolerate oral iron or with conditions affecting absorption.

In recent decades, research has expanded to explore iron’s roles beyond anemia, including cognitive function, exercise performance, restless legs syndrome, and maternal-child health outcomes. Modern formulations focus on enhancing bioavailability while minimizing gastrointestinal side effects, with innovations like sucrosomial iron and heme iron polypeptide representing the continuing evolution of iron supplementation.

Iron supplementation in iron deficiency without anemia: effects on fatigue, cognitive function, and quality of life (ClinicalTrials.gov Identifier: NCT03806738), Oral versus intravenous iron for the treatment of iron deficiency anemia in pregnancy (ClinicalTrials.gov Identifier: NCT04274101), Iron supplementation for the treatment of restless legs syndrome (ClinicalTrials.gov Identifier: NCT03327506), Effect of iron supplementation on physical performance in women with iron deficiency (ClinicalTrials.gov Identifier: NCT04144920), Iron supplementation for the prevention of postpartum depression (ClinicalTrials.gov Identifier: NCT03506581)