Iron

Last Updated: December 18, 2023

Iron is an essential mineral best known for helping red blood cells to carry oxygen. Except in the case of deficiency, iron supplementation has no proven benefit; on the contrary, it can lead to side effects and increased oxidative stress.

Iron is most often used for

What is iron?

Iron is one of the most abundant minerals on Earth. It occurs naturally in various foods such as oysters, legumes, chocolate, spinach, beef, and potatoes, and is added to some foods (e.g., cereals) as a fortification measure. Iron is also sold as a supplement in the form of capsules, tablets, or liquid. In hospital settings, it can be administered through intravenous (IV) or intramuscular (IM) injection.[1]

Dietary iron comes in two primary forms: heme iron and non-heme iron. Heme iron is more readily absorbed; it is formed when iron binds to a heterocyclic organic compound called porphyrin. Heme iron is a component of hemoproteins like hemoglobin (Hb), an oxygen transport protein, and myoglobin, an oxygen-storage protein found in muscle tissues. Animal products (e.g., meat, poultry, and fish) contain both heme and non-heme iron, whereas plant-based and iron-fortified foods only provide non-heme iron, which is less easily absorbed by the body.[1]

Additionally, iron is a constituent of the iron-sulfur clusters (ISCs)[5] found in many proteins; iron is also present in proteins responsible for iron storage and transport (i.e., transferrin, lactoferrin, ferritin, hemosiderin).[6]

What are iron’s main benefits?

Iron plays a pivotal role in numerous biological functions and is often the first-line treatment for iron deficiency anemia (IDA). While specific guidelines exist for treating IDA with iron, there is still insufficient evidence to prove the benefits of iron supplementation in individuals with iron deficiency (ID) who are not anemic.[7]

In clinical practice, iron is commonly prescribed to menstruating women due to the increased blood loss, and during pregnancy to meet heightened metabolic demands and prevent IDA, which could have serious consequences for both the mother and the baby.[8][9]

ID is also a risk factor for heart failure (HF). Iron supplementation in individuals affected by HF appears to reduce the rates of hospitalization and the severity of HF symptoms.[10][11] Hemoglobin, ferritin and left ventricular ejection fraction (LVEF) levels also seem to be increased by iron,[10] and one meta-analysis also noted that exercise capacity and quality of life were improved after iron supplementation in people with HF.[11]

Iron is also a key component in the brain, and studies involving children have shown that supplementation may improve memory and concentration.[12] However, more quality research is needed to verify these results.

The question of whether iron supplementation benefits infants and young adults remains a topic of debate necessitating further research. One meta-analysis, which included children and adolescents ranging from 1 month to 19 years old, found that iron supplementation increased Hb and ferritin levels, particularly with frequent supplementation over longer periods, and resulted in reduced prevalence of overall anemia, ID, and IDA.[13]

Finally, one meta-analysis demonstrated that both oral and IV iron supplementation appeared to improve symptoms of restless leg syndrome (RLS). Specifically, IV supplementation with ferric carboxymaltose (FCM) was associated with a significant improvement in quality of life (QOL) scores, although it had no noticeable effect on sleep quality.[14]

What are iron’s main drawbacks?

Iron supplements should be used cautiously, only when required, and in accordance with recommended doses. Prolonged use of iron supplements or an excess of iron in the system can lead to adverse side effects.

Iron supplements frequently result in gastrointestinal discomfort, including symptoms such as nausea, abdominal pain, dark stool, heartburn, and constipation, and other side effects such as headache. This can be a significant challenge for individuals with IDA, who may find it difficult to adhere to their treatment recommendations.[12]

Although ferritin, hemosiderin, and transferrin play essential roles in regulating iron levels in the system, an excessive amount of free iron can trigger the production of free radicals and increase oxidative stress. This can potentially lead to damage to proteins and cells, and harm the body.[15][16] Diseases characterized by iron overload include hemochromatosis, a hereditary disease in which iron builds up to toxic levels in the body, which can lead to damage to organs such as liver, joints pancreas or heart.[17]

Additionally, multiple observational studies have reported that regular consumption of dietary iron, especially heme iron sourced from meat products, may predispose one to numerous diseases (e.g., type 2 diabetes, cardiovascular disease, coronary heart disease) and may increase the risk of some cancers (e.g., breast, colorectal, and esophageal cancer). However, the majority of these claims are based on self-reported food diaries or food questionnaires, and the level of evidence is weak. Furthermore, it’s important to highlight that processed meat does not only contain heme iron, but other potentially harmful substances (e.g., nitrite, nitrate, heterocyclic amines) which may be confounding factors that also raise the risk of some diseases.[17]

In children, low doses of iron may cause diarrhea, but they do not appear to increase the risk of infections at the recommended dosage. Nevertheless, the World Health Organization (WHO) advises monitoring children in countries at high risk of malaria when receiving iron supplementation, as it may both increase the risk of contracting the disease and potentially worsen its effects. The mechanism by which iron interacts with malaria is still not fully understood.[12][18]

How does iron work?

Understanding the process of iron absorption in the body is key to grasping its mechanism of action. The disparity in absorption between heme and non-heme iron has implications for the amount of elemental iron absorbed in the body, with heme iron, typically found in animal products, being absorbed more efficiently.[19]

Both heme and non-heme iron are primarily absorbed in the duodenum and, to a lesser extent, in the upper jejunum (the first and second sections of the small intestine, respectively). Heme iron enters the gastrointestinal tract as ferrous iron (i.e., with a 2+ oxidation state), which is more easily absorbed, while non-heme iron is typically ingested in its ferric (3+) form. However, for non-heme iron to be absorbed, it must first be reduced into ferrous iron by reductase enzymes (e.g., ascorbate ferrireductase), or other compounds like vitamin C. Ferrous iron is then taken up by enterocytes lining the intestine through the divalent metal transporter 1 (DMT1), and then leaves these cells and enters the bloodstream via ferroportin. Once in the bloodstream, iron is converted back from ferrous to ferric iron and transported by transferrin to various organs and tissues.[20]

After absorption, iron plays a crucial role in several reactions and biological processes within the body, many of which are centered around iron’s roles in protein function and oxygen transport and storage. Iron is required to form hemoglobin (an oxygen-transporter protein) and myoglobin (an oxygen-storage protein). Inadequate iron intake can hinder the production of healthy red blood cells, potentially leading to anemia. In mitochondria, iron serves as a cofactor in proteins that contain iron-sulfur clusters (e.g., flavoproteins), other heme-containing proteins involved in the electron transport chain (e.g., cytochrome c oxidase), and proteins that contain iron ions (e.g., monooxygenases and dioxygenases).[21][10] Additionally, iron is involved in cell growth and differentiation, electron transfer reactions for energy production, and the regulation of the expression of some genes.[15]

Iron is also an essential nutrient for brain development and function. It plays a role in energy (ATP) production and neurotransmitter synthesis, as well as in the uptake and degradation of neurotransmitters, all of which are involved in behavior, memory, learning, and sensory systems.[12][22]

It’s important to note that when iron supplements are taken to treat IDA, it usually takes about 3 months to replenish iron stores, and hemoglobin levels will increase gradually in the first month of supplementation.[23]

What else is Iron known as?
Note that Iron is also known as:
  • Ferrous Sulfate
  • Ferrous Fumarate
  • Ferrous Gluconate
  • Ferrous Bisglycinate
  • Elemental Iron
  • Heme Iron Polypeptide
Dosage information

The recommended daily allowance (RDA) depends on gender, age, and whether you are pregnant or lactating:[1][2]

AgeMaleFemalePregnancyLactation
0–6 months0.27 mg*0.27 mg*
7–12 months11 mg11 mg
1–3 years7 mg7 mg
4–8 years10 mg10 mg
9–13 years8 mg8 mg
14–18 years11 mg15 mg27 mg10 mg
19–50 years8 mg18 mg27 mg9 mg
51+ years8 mg8 mg

These values correspond to the RDA for total iron, which encompasses both dietary iron (iron assimilated from iron-rich foods) and iron supplements. The need for supplementation depends on the amount of iron absorbed from one's diet. It’s important to avoid exceeding the RDA to prevent excessive iron intake.[1]

Notably, for infants up to 6 months of age, these values specifically refer to adequate intake (AI), because there is insufficient evidence to establish an RDA for this age group.[1] The Institute of Medicine (IOM) determined the daily AI by multiplying the average iron content in human milk (0.35 mg/L) by the average milk intake of exclusively breastfed infants (0.78 L/day), resulting in an AI of 0.27 mg/day of iron. These values don’t account for potential variations in the iron concentration of human milk.[3]

For preterm breastfed infants, a daily oral iron dosage of approximately 2 mg/kg is estimated to be appropriate for preventing iron deficiency (ID) or iron deficiency anemia (IDA) in preterm breastfed babies. Term breastfed infants typically do not require additional iron until around 4 months, at which point supplementation with 1 mg/kg of iron may or may not be required depending on the infant's health status. Formula-fed preterm and term infants may require different dosages if iron supplementation is needed.[2]

It is worth noting that iron is most effective when administered on an empty stomach or 2 hours after a meal. However, if iron supplements are poorly tolerated due to gastrointestinal side effects, a dose reduction or administration after a meal may be more suitable.[4]

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References
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Examine Database References
  1. Depression Symptoms - McClung JP, Karl JP, Cable SJ, Williams KW, Nindl BC, Young AJ, Lieberman HRRandomized, double-blind, placebo-controlled trial of iron supplementation in female soldiers during military training: effects on iron status, physical performance, and moodAm J Clin Nutr.(2009 Jul)
  2. Aerobic Exercise Metrics - Waldvogel S, Pedrazzini B, Vaucher P, Bize R, Cornuz J, Tissot JD, Favrat BClinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trialBMC Med.(2012 Jan 24)
  3. Fatigue (non-anemic) - Favrat B, Balck K, Breymann C, Hedenus M, Keller T, Mezzacasa A, Gasche CEvaluation of a single dose of ferric carboxymaltose in fatigued, iron-deficient women--PREFER a randomized, placebo-controlled studyPLoS One.(2014 Apr 21)
  4. Hemoglobin - Andersen CT, Marsden DM, Duggan CP, Liu E, Mozaffarian D, Fawzi WWOral iron supplementation and anaemia in children according to schedule, duration, dose and cosupplementation: a systematic review and meta-analysis of 129 randomised trials.BMJ Glob Health.(2023-Feb)
  5. Hemoglobin - Ali SA, Razzaq S, Aziz S, Allana A, Ali AA, Naeem S, Khowaja N, Ur Rehman FRole of iron in the reduction of anemia among women of reproductive age in low-middle income countries: insights from systematic review and meta-analysis.BMC Womens Health.(2023-Apr-17)
  6. Heart Rate - Brownlie T 4th, Utermohlen V, Hinton PS, Giordano C, Haas JDMarginal iron deficiency without anemia impairs aerobic adaptation among previously untrained womenAm J Clin Nutr.(2002 Apr)
  7. Muscular Endurance - Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G, Haas JDIron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted, nonanemic womenAm J Clin Nutr.(2003 Feb)
  8. Anxiety Symptoms - Vaucher P, Druais PL, Waldvogel S, Favrat BEffect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trialCMAJ.(2012 Aug 7)
  9. Fatigue (non-anemic) - Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, Bischoff T, de Vevey M, Studer JP, Herzig L, Chapuis C, Tissot J, Pécoud A, Favrat BIron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trialBMJ.(2003 May 24)
  10. Fatigue (non-anemic) - Krayenbuehl PA, Battegay E, Breymann C, Furrer J, Schulthess GIntravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentrationBlood.(2011 Sep 22)
  11. Fatigue (non-anemic) - Houston BL, Hurrie D, Graham J, Perija B, Rimmer E, Rabbani R, Bernstein CN, Turgeon AF, Fergusson DA, Houston DS, Abou-Setta AM, Zarychanski REfficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trialsBMJ Open.(2018 Apr 5)
  12. Aerobic Exercise Metrics - Woods A, Garvican-Lewis LA, Saunders PU, Lovell G, Hughes D, Fazakerley R, Anderson B, Gore CJ, Thompson KGFour weeks of IV iron supplementation reduces perceived fatigue and mood disturbance in distance runnersPLoS One.(2014 Sep 23)
  13. Fibromyalgia Symptoms - Chad S Boomershine, Todd A Koch, David MorrisA Blinded, Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Ferric Carboxymaltose in Iron-Deficient Patients with FibromyalgiaRheumatol Ther.(2018 Jun)
  14. Hemoglobin - Silva Neto LGR, Santos Neto JED, Bueno NB, de Oliveira SL, Ataide TDREffects of iron supplementation versus dietary iron on the nutritional iron status: Systematic review with meta-analysis of randomized controlled trials.Crit Rev Food Sci Nutr.(2019)
  15. Hemoglobin - Fischer JAJ, Cherian AM, Bone JN, Karakochuk CDThe effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials.Nutr Rev.(2023-Jul-10)
  16. Hemoglobin - Fernández-Gaxiola AC, De-Regil LMIntermittent iron supplementation for reducing anaemia and its associated impairments in adolescent and adult menstruating womenCochrane Database Syst Rev.(2019 Jan 31)
  17. Infant Birth Weight - Hansen R, Sejer EPF, Holm C, Schroll JBIron supplements in pregnant women with normal iron status: A systematic review and meta-analysis.Acta Obstet Gynecol Scand.(2023-Sep)
  18. Restless Leg Syndrome Symptoms - Tomer Avni, Shelley Reich, Nirit Lev, Anat Gafter-GviliIron supplementation for restless legs syndrome - A systematic review and meta-analysisEur J Intern Med.(2019 May)
  19. Attention - Gutema BT, Sorrie MB, Megersa ND, Yesera GE, Yeshitila YG, Pauwels NS, De Henauw S, Abbeddou SEffects of iron supplementation on cognitive development in school-age children: Systematic review and meta-analysis.PLoS One.(2023)
  20. Attention - Chen Z, Yang H, Wang D, Sudfeld CR, Zhao A, Xin Y, Chen JC, Fawzi WW, Xing Y, Li ZEffect of Oral Iron Supplementation on Cognitive Function among Children and Adolescents in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.Nutrients.(2022-Dec-15)
  21. All-Cause Mortality - Mei Z, Chen J, Luo S, Jin L, Liu Q, Chen YComparative efficacy of intravenous and oral iron supplements for the treatment of iron deficiency in patients with heart failure: A network meta-analysis of randomized controlled trials.Pharmacol Res.(2022-Aug)
  22. All-Cause Mortality - Hamza M, Sattar Y, Manasrah N, Patel NN, Rashdi A, Khanal R, Naveed H, Zafar M, Khan AM, Alharbi A, Aamir M, Gonuguntla K, Raina S, Balla SMeta-Analysis of Efficacy and Safety of Intravenous Iron in Patients With Iron Deficiency and Heart Failure With Reduced Ejection Fraction.Am J Cardiol.(2023-Sep-01)
  23. Cardiovascular Mortality - Hamed M, Elseidy SA, Ahmed A, Thakker R, Mansoor H, Khalili H, Mohsen A, Mamas MA, Banerjee S, Kumbhani DJ, Elgendy IY, Elbadawi AIntravenous iron therapy among patients with heart failure and iron deficiency: An updated meta-analysis of randomized controlled trials.Heliyon.(2023-Jun)