Iron

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1Background Information

1.1Sources

Other than fortified cereals, good sources of iron from common foods include (in descending order) oysters, legumes, chocolate, spinach, beef, and potatoes. Meats other than beef have less iron, though they may still be good sources due to the improved bioavailability of heme iron. In contrast, foods such as legumes that are rich in phytic acid and tannins tend to have reduced iron bioavailability.

1.2Biological Activity

Iron is one of the most abundant minerals on Earth (the planet’s crust itself is 4.7% iron).^[1] Because iron acts as an enzyme cofactor, it fulfills essential functions in all known organisms, except for some species of bacteria.^[1][2] In humans, iron also binds with porphyrin to make heme, which is necessary for delivery of oxygen to tissues.^[1][3]

In addition to hemoproteins, iron can also exist in iron-sulfur clusters (ISCs), which are present in more than 200 different proteins, including many enzymes.^[4] Similar to hemoproteins, ISCs exist in nearly all forms of life, including eukaryotes,^[5] bacteria,^[6] and plants.^[7] In humans, these proteins have been associated with energy production; they can be found in mitochondria and seem to be linked to some mitochondrial diseases such as Friedreich’s ataxia.^[8][9]

Because of the conversion of iron between its reduced form (ferrous) and oxidized form (ferric), iron can induce oxidative stress in the body. Beneficial effects can result from this process, but because iron is insoluble, an excess of free iron can also damage proteins and cells.^[10][11]

In humans, in addition to serving as an enzyme cofactor, iron helps to ferry oxygen between tissues and causes oxidative damage (for the purpose of initiating various cellular processes). As a result of this latter function, iron also exists in forms that can cause unnecessary damage to cells when its regulation is thrown into disarray.

1.3Recommended Intake

The Institute of Medicine provides the following recommendations:^[12]

• For infants up to 6 months of age, the adequate intake (AI) is 0.27 mg. Both the Canadian Paediatric Society^[13] and the American Academy of Pediatrics^[14] have suggested that infants fed little to no breast milk may need to drink a specialized infant formulation fortified with iron.

• For infants between 7 and 12 months of age, the estimated average intake (EAR) is 6.9 mg, whereas the recommended daily allowance (RDA) is 11 mg. The large difference in iron requirements between younger and older infants is probably due to both an increase in body mass and an increased capacity to safely store iron.

• For children between 1 and 3, the EAR is 3 mg and the RDA is 7 mg.

• For children between 4 and 8, the EAR is 4.1 mg and the RDA is 10 mg.

• For children and adolescents between 9 and 18, the EAR and RDA differ between the sexes due to menstruation. For males under 14, the RDA is 8 mg, and it increases to 11 mg for ages 14 to 18. For females under 14, the RDA is also 8 mg, but it increases to 15 mg between 14 and 18, with an added recommendation that menstruating females under 14 should increase their intake by approximately 2.5 mg (resulting in an intake of 13.5 mg).

• For men older than 18, the RDA is 8 mg.

• For women between 19 and 50, the RDA is 18 mg. For women older than 50, the RDA is 8 mg, the same as for men. The “50 years of age” boundary is arbitrary and represents menopause.

• For pregnant women, the EAR and the RDA increase to 22–23 mg and 27 mg, respectively.

• For lactating women, the EAR and the RDA decrease to 6.5–7 mg and 9–10 mg, respectively, due to a temporary cessation of menstruation.

For men, iron recommendations are based on age. For women, they are based on age (the estimated ages of first and last menstruation) and the states of pregnancy and lactation.

Someone who gives half a liter (0.5 L) of blood over the course of a year needs an additional 0.6–0.7 mg iron per day.^[15] Someone who frequently partakes in strenuous training needs an additional 30–70% over the EAR.^[12] Although vegetarians and vegans have the same recommended iron intakes as omnivores, they are more likely to be iron deficient because the iron in plants is less bioavailable than the heme iron in animals.

An increase in iron intake may be necessary due to menstruation, pregnancy, and lactation but also due to blood donations, strenuous exercise, and a vegetarian or vegan diet.

1.4Deficiency

Iron deficiency in infants and children is associated with cognitive impairments, including psychomotor^[16] and behavioral^[17] issues.

Iron deficiency frequently results in anemia; without enough iron to produce hemoglobin, the body has a difficult time transporting enough oxygen, which can result in fatigue, cognitive impairment, and several related symptoms. Other health issues that may arise due to iron deficiency are infections, heart failure, restless leg syndrome, and depression. ^[18]

Deficiency can lead to a reduced endogenous antioxidant status, which improves when levels are increased through supplementation.^[19][20][21]

1.5Causes of Deficiency

Blood Donation

Iron deficiency is a common concern with blood donation, and iron levels are routinely checked to ensure that donors are not at risk for anemia. Research has been conducted on the dangers of frequent blood donation.

In one study, 244 elderly participants without iron deficiency were randomized into blood donors or nondonors. Of these, 110 (58 men and 52 women) donated one unit (approximately 485 mL) of blood every 8 to 12 weeks, although only 57 completed five donations within the specified timespan.^[22] Each donation tended to reduce hemoglobin, plasma ferritin, and estimates of iron stores, with the prevalence of iron deficiency increasing to roughly 20% from 0% in the donor group and to roughly 10% from 0% for the nondonor group. Estimates of iron stores suggested that women were more likely to experience a notable reduction than men. Overall, 35% of participants consumed an iron supplement (median of 18 mg per day), and there were no differences in iron stores between users and nonusers for men, but iron supplementation helped to preserve iron levels for women. It’s possible that deficiency rates were higher because the participants who dropped out may have done so to some extent due to iron deficiency.

A follow-up study reported on the 36 participants (20 men, 16 women) who donated at least 15 units of blood over 3.5 years.^[23] Estimates of iron stores suggested a greater reduction in the donor group and somewhat lower hemoglobin, hematocrit, and transferrin saturation for both men and women compared to nondonors. Supplementation did not appear to notably affect hemoglobin or hematocrit changes, though it coincided with a smaller reduction in transferrin saturation in participants who were not anemic. However, when looking at participants who discontinued the study, hemoglobin levels were lower, and many dropouts were due to low hematocrit. It was further estimated that the average man lost 242 ± 17 mg (mean and SD) of iron per donation, and the average woman lost 217 ± 11 mg.

Additionally, observational data collected on blood donors suggests reduced iron levels and a high risk of deficiency.^[24][25][26]

Frequent blood donation can reduce iron levels and result in anemia. Supplementation may be necessary for people at a high risk for deficiency, particularly women.

Surgery Resulting in Blood Loss

Naturally, surgery leading to blood loss can result in anemia. Allogeneic blood transfusion seems to indicate an increased risk of deficiency as compared with the use of autologous blood.^[27]

Celiac Disease and Gluten-Free Diets

Iron deficiency anemia is more common in people with celiac disease, especially in developing countries.^{[28][29][30][31][32][33]} The villus atrophy found in celiac disease and the consequent impaired nutrient absorption are plausible reasons. Greater villus atrophy is associated with greater iron deficiency. Research has also found that folate and vitamin B₁₂ deficiency is more common in celiac disease patients, contributing to the prevalence of anemia.^[29]

Additionally, gluten-free diets may reduce iron intake due to the elimination of many iron-fortified foods and altered dietary choices.^[34] However, this outcome is highly dependent on the personal food choices of each dieter and may be offset by increasing iron intake from other foods.

Gastric Bypass Surgery

Gastric bypass surgery is a cause of a wide variety of nutritional deficiencies due to reduced absorption and reduced food intake, and iron is no exception.^[35] However, the effect on iron seems to be limited to Roux-en-Y gastric bypass because the prevalence of deficiency decreased with sleeve gastrectomy. Overall, this effect is inconsistent and likely depends on the use of prophylactic iron supplements.

Intestinal Inflammation

Intestinal absorption of iron is reduced by excessive inflammatory signaling (particularly of IL-6), which increases the production of hepcidin in hepatocytes.^[36][37] Anemia is more common in both Crohn’s disease and ulcerative colitis.^[38]

Menstruation

Menstruation removes iron from the body at regular intervals, and some evidence indicates that a heavier flow is associated with a greater risk for iron deficiency.^[39][40]

Helicobacter pylori infection

People with Helicobacter pylori infections are more likely to have iron deficiency and anemia, and H. pylori eradication therapy increases serum ferritin and hemoglobin levels independently of iron intake.^[41][42] H. pylori infection can lead to damaged mucosa, gastritis, and low mucosal vitamin C concentrations, both of which could lead to reduced iron absorption.^{[43][44][45][46][47]}

Pregnancy

Pregnancy increases the requirements for iron, and as a consequence, deficiency is more likely to occur when iron intake isn't increased sufficiently.^[48]

2Safety

2.1Toxicity

Excessive iron can catalyze the production of free radicals, which can increase oxidative stress and potentially harm a variety of tissues, including the liver,^[49][50] blood vessels,^[51][52] and colon,^[53] among many others.^[54][55][56] Transferrin, the main carrier of iron in the blood, prevents unintentional reaction. Still, when iron levels become pathologically elevated, a higher proportion of iron is not bound to transferrin (nontransferrin-bound iron), and iron is more available to create free radicals. While iron overload disorders pose the greatest threat, poor transferrin binding can be found in other conditions such as liver diseases and type 2 diabetes in which iron toxicity can further exacerbate the disease.^[57][58][59] 

The body’s endogenous antioxidants act to prevent iron-induced oxidative stress in cells from the body’s labile iron; these antioxidants include superoxide dismutase, catalase, glutathione, glutathione peroxidases, and thioredoxins, as well as ferritin, which safely stores cellular iron.^[60] Antioxidant vitamins and a variety of nonessential exogenous compounds — such as EGCG, curcumin, quercetin, and silymarin — can be used to chelate and/or reduce iron.^{[61][62][63][64][65][66]}

When not safely bound by ferritin and transferrin, iron is liable to produce free radicals, which can damage a wide variety of tissues. Antioxidants and chelators offer some protection.

3Pharmacokinetics

3.1Delivery

Absorption

The paths of absorption differ for heme and nonheme iron. Both are primarily absorbed in the duodenum and to a lesser extent in the upper jejunum, but before nonheme iron can be absorbed into enterocytes, ferric iron must be reduced into ferrous iron by ascorbate ferrireductase.^[67][68] Ferrous iron is absorbed into the enterocytes lining the intestine via the divalent metal transporter 1 (DMT1) and then leaves the cells and enters the bloodstream via ferroportin. The ferrous iron is converted back into ferric iron by hephaestin and heme carrier protein 1 (HPC1), and the iron is liberated by heme oxygenase.^[69][68] Iron that is not used immediately for erythropoiesis (the production of red blood cells) is stored in the liver as ferritin and leaves the hepatocytes via ferroportin. Small amounts of iron are present in a variety of ionic complexes such as peptides, chelates, carboxylates, and phosphates.^[70]

The difference in absorption between heme and nonheme iron has implications for the amount of iron absorbed in the body, which is far greater with heme iron.^[71]

Hepcidin is a 25-amino-acid peptide hormone that plays a large role in iron homeostasis in the body, primarily by preventing iron transport (both from enterocytes and from the liver) into the bloodstream via ferroportin.^[72][68] Hepcidin acts as a regulator of deficiency and excess; when iron levels are high, less hepcidin is produced, and when iron is low, more hepcidin is produced.

Dosing Schedules and Hepcidin

The question of whether different dosing schedules matter for iron absorption has been the subject of much research and may have implications for optimal use of oral iron supplements in correction of iron deficiency.

Alternate Day Versus Daily

In one study, iron-depleted (but not deficient) participants took the same dose of iron every day or on alternate days for 14 and 28 days, respectively. Alternate-day dosing led to reduced hepcidin levels and greater iron absorption.^[73] However, the impact on iron status is unclear because there was no notable difference in serum iron or hemoglobin between groups at the end of their respective dosing periods. The alternate-day group saw a nonsignificantly smaller increase in ferritin. The alternate-day dosing group also experienced less nausea but more headaches. In another study by the same researchers, iron-deficient participants absorbed more iron and had fewer side effects when taking doses on alternate days, but the study was too short to assess the long-term effects on iron status.^[74]

Once Versus Twice Daily

One study failed to find notable differences in iron absorption when the same daily dose was split into two pills, as compared with one.^[73] However, serum hepcidin increased to a lesser extent when taking iron once per day. Each experimental condition lasted for only 3 days, so this study may have been too short to comment on the effect in the long term. An earlier study from the same authors found similar results.^[75]

A study on prevention of anemia in pregnancy used either a single dose of 65 mg of elemental iron or two times that amount (130 mg) divided into two doses.^[76] There was a slightly smaller reduction in hemoglobin in the high-dose group, but the overall differences were comparable. The once-daily group also experienced considerably less nausea.

A different study used a dose of 27 mg given once or twice per day in a randomized, parallel trial. The participants were healthy pregnant women who were carrying twins and therefore had higher iron requirements. Supplementation was started at 12 weeks and persisted until 36 weeks.^[77] There was no notable change in hemoglobin in either group, and the high-dose group saw a much greater increase in ferritin, as could be expected with the higher dose.

Intermittent doses

A meta-analysis looked at intermittent (once, twice, or three times per week) iron supplementation compared with daily supplementation for improving iron status and preventing anemia in adolescent and adult menstruating women.^[78] Overall, there was no notable difference in anemia between groups. However, daily supplementation may be more effective in the long term if iron is taken alone (as opposed to in combination with folic acid). Limited evidence also suggests that daily supplementation may be better for increasing ferritin levels, although more research is needed, and the quality of evidence across studies tended to be low. The meta-analysis also found that side effects were less likely when taking iron weekly rather than daily, suggesting that for people with side effects from iron supplementation, weekly doses may be preferable to and similarly effective as daily doses.^[78]

It's unclear whether the frequency of dosing matters to iron absorption, though less frequent dosing is associated with fewer adverse events in many studies.

3.2Absorption enhancers

Many foods and compounds may increase the absorption of iron.

Animal protein

Early studies using radioisotope-labeled nonheme iron found that adding animal protein to meals can enhance the absorption of nonheme iron.^[79] The increase in absorption varied by condition but was usually doubled (range of 1.7x to 4x). This increase in absorption was observed with veal, fish, beef, and chicken added to meals consisting of maize or black beans. Interestingly, the one test of an animal protein source (beef) on absorption of iron from wheat bread found a lack of effect on absorption.

In a later study, the broader effects were tested over several days.^[80] The participants consumed a wheat roll containing radiolabeled iron at every meal for three different periods of 5 days while on a self-selected diet, a vegetarian diet, or a high-protein diet. Overall, there was a small, nonsignificant increase in iron during the high meat period. This result suggests that the effect is reduced over time or that there may be something about wheat that impairs the absorption-enhancing effect of animal protein, as was found in the previously mentioned study.

One study found that pork also had a mild dose-dependent absorption-enhancing effect. When 25 g, 50 g, and 75 g of pork were eaten during a high-phytate meal based on rice and a wheat bun, iron absorption increased by 15%, 44%, and 57%, respectively.^[81] Another study analyzed 5-day periods of a very high meat diet that supplied 60 g of protein from pork from either Polish or Danish pigs, with a vegetarian diet chosen for comparison. All diets contained wheat products, and the Polish pork contained higher levels of iron and zinc than the Danish pork.^[82] Compared to the vegetarian diet, there was a modest increase in nonheme iron absorption from the meat diets; this increase was somewhat greater with Danish pork and was statistically significant only for Danish pork.

Another study found modestly increased iron absorption from a meal of high-phytate beans when oily fish was added.^[83]

Animal protein increases nonheme iron absorption from the same meal, though the effects in studies using wheat suggest smaller effects than other foods. High-phytate beans saw only a modest absorption-enhancing effect, suggesting that phytate may prevent the positive effects of animal protein on nonheme iron absorption.

Probiotics

One study that used supplementation with Lactobacillus reuteri DSM 17938 at a dose of 3x10⁸ colony-forming units (CFU) in combination with iron found a somewhat greater increase in reticulocyte hemoglobin than when taking iron alone.^[84] 

Another study found that 1x10¹⁰ CFU of freeze-dried Lactobacillus plantarum 299v taken during a meal may have modestly increased iron absorption.^[85] In a different study, iron absorption from a supplemental fruit drink was enhanced by both 1x10¹⁰ and 1x10⁹ CFU of Lactobacillus plantarum 299v, with no difference in absorption between doses.^[86] In contrast, another study gave 1x10¹⁰ CFU of Lactobacillus plantarum 299v to children with iron deficiency who were taking vitamin C and iron. However, that study didn’t find a clear difference in the change in ferritin levels compared with the placebo group.^[87]

A study found that multiple phases of multiple strains of probiotic bacteria coincided with a statistically significant increase in iron and a decrease in ferritin levels in patients with moderate chronic kidney disease, whereas the placebo didn’t change levels of either.^[88] For the first week, the participants took 0.377 g of a mixture of Enterococcus faecium, Lactobacillus acidophilus, and Saccharomyces Boulardii during 3 major meals each day. For the two following weeks, 0.455 g of a combination of Bifidobacterium brevis, Bifidobacterium bifidum, and Bifidobacterium longum and 0.455 g of Lactobacillus rhamnosus and Lactobacillus acidophilus were taken at each meal. The supplements were continued for 3 months, except that two times (2x) the dose was taken at two meals (breakfast and lunch) each day.

Interestingly, 1.9x10⁷ CFU of Bifidobacterium Lactis HN019 and 2.4 g of prebiotic oligosaccharides taken daily for one year by children coincided with a reduction in iron deficiency and anemia, as compared with a placebo, but there was no effect on mean hemoglobin level or serum ferritin.^[89] Another probiotic, Lactobacillus acidophilus, has been shown to increase vitamin B₁₂ and folate levels and consequently hemoglobin, so an increase in hemoglobin or a reduction in the rate of anemia doesn’t necessarily suggest an increase in iron levels.^[90]

A number of bacterial strains seem to be able to increase iron absorption. A reduction of inflammation in enterocytes and the subsequent reduction in hepcidin levels is a plausible mechanism, but this topic requires more research.

Vitamin C

Vitamin C (ascorbic acid) increases the rate at which nonheme iron is absorbed from the intestines into the bloodstream.^[91][92] Ascorbate (a mineral salt of ascorbic acid) cycles back and forth between intestinal cells;^[93] outside the cells, it reduces iron to a form more readily absorbed, and^[94] inside the cells, it helps transfer iron to transferrin.^[95]

Transferrin is a transfer protein that delivers iron to cells, and transferrin iron uptake is regulated by ascorbate, which is why scurvy (which results from a vitamin C deficiency) is often associated with some degree of iron-deficiency anemia.^[96][97]

Vitamin A

In a meta-analysis of 21 clinical trials and 2 cohort studies, vitamin A supplementation to resolve deficiency reduced the risk for anemia and increased hemoglobin and ferritin, though there was insufficient evidence to demonstrate that it reduced iron deficiency specifically.^[98] 

Part of the effect on hemoglobin levels is likely due to the role of vitamin A in hematopoiesis.^[99] However, vitamin A may play a role in increasing absorption, as has been found in some studies.^[100]

Vitamin D

A study on 200 healthy but vitamin-D-deficient adolescents found that supplementation with 1000 IU per day led to considerably reduced iron levels, decreased transferrin saturation, and increased total iron-binding capacity, whereas the control intervention (consumption of 200 mL of milk with only 40 IU of vitamin D daily) didn’t seem to affect these outcomes.^[101]

Another study on pregnant women given 1000 IU of vitamin D found similar ferritin decreases in the supplement and placebo groups and similar hepcidin increases in both groups.^[102] Another study failed to find notable effects of 10 and 25 μg of vitamin D on serum iron, ferritin, hemoglobin, total iron-binding capacity, and transferrin saturation in people with low vitamin D levels.^[103] Yet another study found a reduction in hepcidin with a one-time dose of 250,000 IU one week later but no difference in ferritin levels. ^[104] 

3.3Iron-reducers

Calcium

In one study, a dose of 300 mg of calcium carbonate taken during an iron-enhancing meal (hamburger patty and bun) reduced iron absorption from 37 mg of ferrous sulfate from 2.12% to 1.61%, a difference that was statistically significant. The same dose taken without food reduced the iron absorption from 7.68% to 6.50%, a difference that was not statistically significant.^[105] That same study also found that in people with low iron stores, 600 mg of calcium from calcium carbonate reduced the iron absorption from 18 mg of ferrous sulfate from 13% to 7.3% during the iron-enhancing meal, whereas the absorption increased from 18% to 21.5% when the calcium supplement was taken without food. In people with normal iron stores, the same doses didn’t seem to affect absorption. The same dose of iron and calcium from calcium citrate reduced absorption from 10.1% to 6.1% when taken with food and from 12.9% to 6.6% without food, but neither reduction was statistically significant. For calcium phosphate, iron absorption decreased from 7.3% to 3.2% with food and from 16% to 6% without food, and these differences were statistically significant.

Furthermore, 600 mg of calcium from different supplements reduced natural nonheme iron absorption from a meal from 13.4% (no added calcium) to 9.1% with calcium carbonate, to 11.9% with calcium citrate, and to 8.2% with calcium phosphate; the calcium carbon and phosphate differences were statistically significant but that of calcium citrate was not. The same test performed with an iron-inhibiting meal (egg, muffin, bran flakes, sugar, milk, and coffee) found that iron intake was reduced from 1.2% (no added calcium) to 0.7% with calcium carbonate, to 0.5% with calcium citrate, and to 0.4% with calcium phosphate, and all of the differences were statistically significant.

Absorption from 65 mg of iron from a multivitamin/mineral supplement was drastically reduced by simultaneous delivery of 200 mg of calcium sulfate with 100 mg of magnesium oxide, and absorption from 60 mg of iron was reduced by 350 mg of calcium carbonate taken with 100 mg of magnesium oxide.^[106] The addition of 200 mg of calcium sulfate didn’t suppress the increase in serum iron from 65 mg, but the addition of 350 mg of calcium carbonate did, as did 100 mg of magnesium oxide alone and in combination with both calcium doses and forms. The greatest suppression was observed from calcium carbonate and magnesium oxide, followed by calcium sulfate with magnesium oxide.

Additional tests found that 200 mg of calcium carbonate combined with 100 mg of magnesium hydroxide, 350 mg of calcium carbonate with 100 mg of magnesium oxide, and 250 mg of calcium carbonate with 25 mg of magnesium oxide suppressed iron absorption by more than half.

In another study, 500 mg of elemental calcium from calcium carbonate or hydroxyapatite greatly reduced retention of supplemental iron during a meal.^[107]

A different study found that absorption of 5 mg of nonheme iron with a simultaneous 800-gram dose of various forms of calcium was suppressed by (in order from greatest to least) calcium citrate, gluconate, sulfate, phosphate, carbonate, chloride, and lactate, though the only form that was found to have a statistically significant reduction was calcium citrate.^[108] In another study, doses of 200 to 1500 mg of calcium chloride had only a small inhibitory effect on nonheme iron absorption, and up to 800 mg had a small effect on heme iron absorption, which, although dose dependent, seemed well below that of most other calcium salts.^[109] On the other hand, another study found that doses of as little as 40 mg of calcium chloride notably reduced iron absorption; the possible difference was that this dose was given during a meal, whereas in the the other study, it wasn’t.^[110]

Calcium is a strong inhibitor of iron absorption, and avoiding the simultaneous use of calcium and iron supplements will prevent the reduced absorption of iron.

Coffee and Tea

Coffee may reduce iron absorption,^[111] potentially due to the presence of chlorogenic acid, a known iron chelator.^[112] This mechanism would extend this inhibition to green coffee extract, an even richer source of chlorogenic acid.

• Tea, whether green^[113] or black,^[111] might inhibit iron absorption, possibly due to the presence of catechins^[113] and theaflavins.^[114]

• Infusions of chamomile, lime flower, pennyroyal, peppermint, and vervain may also reduce iron absorption.^[111]

A wide variety of beverages with a high antioxidant content, including coffee and tea, have some acute inhibitory effect on iron.

Curcumin

Curcumin (the most active component of turmeric) has shown the potential to reduce iron absorption in mice but only when high doses (estimated human dose: 8–12 g) were paired with a diet low in iron.^[63] When mice were fed diets with adequate levels of iron, curcumin did not seem to significanctly hinder iron absorption.^[63] Finally, in humans, 500 mg of turmeric did not seem to hinder iron absorption.^[115]

The addition of 4.2 g of ground chili (Capsicum annuum) to a meal fortified with 4 mg of nonheme iron showed a moderate inhibitory effect on iron absorption (38%). Due to the addition of chili, the meal was relatively high in phytic acid.^[115]

Fiber

Psyllium is a dietary fiber (roughly half soluble, half insoluble) that has the potential to reduce nonheme iron absorption (with no effect from vitamin C)^[116] and also to raise the pH in the colon and thus increase calcium resorption^[117] — an increase thought to apply to other minerals as well.

In humans, one study noted a reduction in iron accumulation when nonheme iron was coingested with psyllium,^[118] but other studies saw no effect on iron metabolism from prolonged supplementation of approximately 10 g of psyllium.^{[119][120][121]}

Dietary fiber may have an acute inhibitory effect on iron absorption, but fermentable dietary fibers may increase mineral resorption in the colon.

Rosemary

Rosemary (a source of rosmarinic acid) has also been shown to reduce nonheme iron absorption.^[113]

Ingesting iron at the same time as spices rich in phytic acid or phenolic acid may reduce its absorption.

Quercetin

In a randomized controlled trial, 500 mg of quercetin per day for 12 weeks alleviated iron overload in beta-thalassemia patients, notably reducing serum iron, ferritin, and inflammatory markers.^[122] Quercetin has also been recognized as a strong chelator of iron.^[123]

Zinc

Minerals can compete with each other for absorption pathways, and zinc and iron compete for common transporters such as divalent metal transporter 1 (DMT1), human copper transporter 1 (hCTR1), and Zip14.^[124][125]

While not entirely consistent, there is evidence that simultaneous dosing of iron and zinc leads to reduced iron absorption when the doses are given in water, though absorption doesn’t seem to be affected when the minerals are provided within a food matrix.^[126] Another study didn’t find a difference in absorption or any measure of iron status (besides the unreliable serum iron measure) when 15 mg of zinc was added per day.^[127] Comparisons among groups taking 120 mg of iron with 30 mg of zinc weekly, 120 mg of iron alone weekly, 60 mg iron with 15 mg zinc daily, or 60 mg of iron alone daily showed no notable differences between zinc with iron and iron alone in terms of hemoglobin or ferritin levels.^[128] In another study, 6 weeks of daily supplementation with 22 mg of zinc without iron by participants with low iron reserves reduced plasma iron, ferritin, and transferrin saturation but not hemoglobin.^[129] A daily dose of 10 mg from a zinc supplement given for 3 months in children aged 8–9 years resulted in somewhat reduced serum iron levels, but there were no notable differences as compared with placebo for hemoglobin, ferritin, transferrin, or transferrin saturation.^[130] Interestingly, one study found that daily supplementation with 20 mg of zinc between meals didn’t affect iron absorption from meals containing radioisotope-labeled iron.^[131] However, there was a strong trend towards reduced serum iron and serum ferritin, but not hemoglobin, after 2 months.

Although zinc seems to be able to reduce the absorption of iron, the effect is inconsistent, and the strength of this effect is unclear. Taking zinc between meals is likely a good way to prevent any absorption interference. There does seem to be a notable reduction in serum iron when taking zinc supplements, though this is likely to be independent of any effects on iron absorption and may be potentially linked to competition for transporters in the liver and other unknown consequences.

4Effects on Glucose Metabolism

4.1Glycation

People with iron deficiency anemia and diabetes have higher HbA1c, and markers of iron status are negatively correlated with HbA1c.^{[132][133][134]}PMID10453183

In a randomized, single-blind, placebo-controlled trial, type 2 diabetes patients with anemia saw greater reductions in HbA1c when taking iron supplements than placebo, which also coincided with a greater reduction in fasting blood sugar.^[135]

Another study didn’t find an effect of iron supplementation on HbA1c but wasn’t in type 2 diabetics.^[136] While three uncontrolled studies in people with iron deficiency anemia but without diabetes found a reduction with iron supplementation.^{[137][138][139]}

Resolving iron-deficiency anemia tends to reduce the amount of glycated hemoglobin in circulation. However, due to the role of iron in hemoglobin, it’s likely an effect of increased hemoglobin turnover rather than reductions in glycation. More research is needed.

5Neurology

5.1Depression

A high iron intake seems to translate into a lesser chance of depression, according to a (relatively small) meta-analysis on the topic.^[140]

When it comes to supplementation, one study on women with anemia and depression didn’t find clear evidence for additional improvements in depression scores when 27 mg/d iron was added to vitamin D, compared with taking vitamin D alone.^[141] However, it was unclear to what extent iron supplementation affected the hemoglobin or what the change was in the vitamin D-only group, and so it’s unclear how well this study tests the effects of iron; low hemoglobin can also be caused by low vitamin B12 and folate intake. Additionally, the baseline depression scores were somewhat unbalanced and not particularly high to begin with (no clinical depression), which limits the ability to draw conclusions about iron’s effects in depression.

In the case of postpartum depression, a majority of studies have found a positive association with anemia and iron deficiency, though it’s unclear how potent the relationship is or if there are confounding factors at play.^[142] Controlled trials that give iron as a prophylactic in the postpartum period have found reductions in depression ratings as compared with placebo in both anemic,^[143], and nonanemic participants^[144]. One study found less depression in participants who took intravenous iron than oral iron, the former having led to a greater increase in hemoglobin.^[145] and one case-control study found that women who supplemented with iron during pregnancy were less likely to have postpartum depression than women who didn’t, though it’s possible that this may have been influenced by supplementation of other nutrients.^[146]

Depression is a symptom of iron-deficiency anemia, and increasing iron levels can likely improve the condition.

5.2Restless Leg Syndrome

A meta-analysis looked at randomized, controlled trials that administered iron to patients with restless leg syndrome and compared symptoms to placebo or no iron supplementation after 4 weeks.^[147] The primary outcomes were the change from based in the International Restless Legs Syndrome score (IRLSS) and the percentage of participants who had an improvement in IRLSS score. Secondary outcomes were quality of life, sleep quality, and sleep efficiency. There were 8 trials using intravenous iron and 2 using oral supplements, and overall, there was a modest, statistically significant reduction for IRLSS score for both, with the most evidence for the use of ferric carboxymaltose (FCM) and iron sulfate. Quality of life saw a statistically significant improvement for FCM, though the paper didn’t comment on other forms. Overall, there wasn’t a statistically significant or notable change in sleep quality or periodic limb movement. Iron therapy led to a greater rate of adverse events (RR 2.04 (95% CI 1.46–2.85), which was mostly mild gastrointestinal complaints.

6Cardiovascular Health

6.1Red Blood Cells

In our bodies, iron can bind with porphyrin to make heme. The best-known hemoproteins (proteins with heme) are hemoglobin and myoglobin, found in erythrocytes (the red blood cells).^[148] The iron in heme can become oxygenated (i.e., bound to oxygen) or unoxygenated in a reversible manner,^[149] which is what allows red blood cells to deliver oxygen to body tissues.^[150]

A body without enough red blood cells, or whose red blood cells are unhealthy, suffers from anemia. There are different forms of anemia: some are genetic, such as sickle cell anemia;^[151] others derive from a dietary deficiency, such as pernicious anemia (linked to a Vitamin B12 deficiency).^[152] 

Iron-deficiency anemia, the most common form of anemia worldwide, can be caused by a lack of iron in the diet or by the body having difficulties processing the ingested iron. It primarily affects premenopausal women with low meat intake, due to a combination of iron loss from menstruation and lack of dietary heme iron.^[153] It can be treated by increasing dietary iron, by taking an iron supplement (under medical supervision), or by enhancing the body’s ability to absorb and use iron^{[154][155][156]} — by increasing the bioavailability of plant forms of iron, for instance.

Red blood cells ferry oxygen to body tissues thanks to the iron in hemoglobin and myoglobin. Optimal iron stores in the body support this function; an excess of iron does not necessarily enhance it, but an iron deficiency does hinder it, leading to iron-deficiency anemia.

7Inflammation and Immunology

7.1Macrophages

Macrophages are immune cells. In addition to eliminating foreign bodies determined to be harmful, they play roles in both inflammation and anti-inflammation^[157] and fulfill different maintenance functions,^[158] including the recycling of iron.^[159]

Red blood cells, like all cells, eventually degrade with age — a process known as senescence. As they do, they release their heme, which can then damage tissues and DNA.^[160] To prevent this, the erythrophagocytic macrophage detects senescent red blood cells and eliminates them.^[161]

Some macrophages detect and eliminate damaged or senescent red blood cells, which prevents the iron in those cells from floating free around the body, damaging tissues.

8Peripheral Organ Systems

8.1Female Sex Organs

Taking an iron supplement around the time of menstruation appears to increase both ferritin and hemoglobin and to reduce the risk of anemia (RR 0.73; 95% CI of 0.56–0.95). However, despite similar improvements in hemoglobin, daily supplemention appears to better reduce the risk of anemia.^[153] 

Taking an iron supplement around the time of menstruation appears to reduce anemia, but not as much as taking an iron supplement every day.

9Effects on Exercise Performance

9.1Aerobic performance

Resolving anemia can be expected to improve athletic performance due to the negative effects of low oxygen transport ^[162] but it’s also possible that iron deficiency in the absence of anemia can impair performance. A meta-analysis of 18 trials looked at the effects of iron supplementation on fatigue and physical performance in people with iron deficiency but not anemia.^[163] From 4 studies that looked at fatigue, all found a modest reduction. Performance on a 15 km time trial was evaluated in 2 studies and the results were inclusive. Time to exhaustion was consistently and modestly longer in the 4 studies that measured it, though the result wasn’t statistically significant. It’s unclear if VO_₂ max is meaningfully affected by iron supplementation. Despite the lack of anemia, hemoglobin levels were increased by iron supplementation, suggesting that there may be a benefit to performance by increasing hemoglobin levels within the normal range, though it’s unclear what the effect on non-iron-deficient people would be and where the threshold for iron sufficiency is. Another study found an improvement in endurance during submaximal and maximal exercise when women with low iron levels but who weren’t anemia took 42 mg of iron daily.^[164]