Iron

---

1Background Information

1.1Sources

Good sources of iron from common foods, besides fortified cereals, include (in descending order) oysters, legumes, chocolate, spinach, beef, and potatoes. Meats besides beef have less iron, though they may still be good sources due to the improved bioavailability of heme iron. In contrast, phytic acid and tannin-rich foods like legumes will 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 works well as an enzyme cofactor, it fulfills essential functions in all known organisms, but for some species of bacteria.^[1][2] In humans, iron also binds with porphyrin to make heme, which is required to deliver oxygen to tissues.^[1][3]

Outside of hemoproteins, iron can also exist in iron-sulfur clusters (ISCs), which are part of over 200 different proteins, including many enzymes.^[4] Like 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 the reduced form (ferrous) and the oxidized form (ferric), iron can induce oxidative stress in the body. Beneficial effects can result, but, since 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 ferry oxygen between tissues and cause 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 both to an increase in body mass and to an increased capacity to store iron safely.

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

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

• For youths between 9 and 18, the EAR and RDA differentiate between sexes, due to menstruation. For males, the RDA is 8 mg under 14, then 11 mg between 14 and 18. For females, the RDA is also 8 mg under 14, but 15 mg between 14 and 18, with an added recommendation that menstruating females under 14 increase their intake by around 2.5 mg (resulting in an intake of 13.5 mg).

• For men over 18, the RDA is 8 mg.

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

For men, iron recommendations are based on age. For women, they are based on age (the ages of first and last menstruations being mere estimations) 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 intakes as omnivores, they are more likely to be deficient, because the iron in plants is less bioavailable than the heme iron in animals.

An increase in iron intake can be made necessary by menstruations, pregnancy, and lactation, but also by 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 behavioural^[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 has been noted to lead to 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 to be blood donors or nondonors. 110 (58 men and 52 women) were to donate 1 unit (about 485 ml) of blood every 8 to 12 weeks, though only 57 completed 5 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 see a notable reduction than men. 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 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 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 as compared with 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 (mean and SD) 242 ± 17 mg of iron per donation, and the average woman lost 217 ± 11.

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 those 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 mean 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 consequently 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 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 seems to be limited to Roux-en-Y gastric bypass, while the prevalence of deficiency decreased with sleeve gastrectomy, though this 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 regularly, and some evidence indicates that a heavier flow is associated with a greater risk for iron deficiency.^[39][40]

Helicobacter pylori infection

Those 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 doesn’t increase sufficiently.^[48]

2Safety

2.1Toxicity

Excessive iron is prone to catalyzing the production of free radicals, increasing oxidative stress, and potentially harming a variety of tissues, including the liver^[49][50], blood vessels,^[51][52] the colon,^[53], among many others.^[54][55][56] Transferrin, the main carrier of iron in the blood, keeps it safe and prevents unintentional reaction. Still, when iron levels become pathologically elevated, a higher proportion of iron is not bound to transferrin (non-transferrin bound iron), and iron is more available to create 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, where 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, particularly superoxide dismutase, catalase, glutathione, glutathione peroxidases, and thioredoxins, as well as ferritin which safely stores cellular iron.^[60] The antioxidant vitamins and a variety of non-essential exogenous compounds can be utilized to chelate and/or reduce iron, such as EGCG, curcumin, quercetin, and silymarin.^{[61][62][63][64][65][66]}

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

3Pharmacokinetics

3.1Delivery

Absorption

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

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

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

Dosing Schedules and Hepcidin

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

Alternate Day Versus Daily

One study had iron-depleted (not deficient) participants take 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, it's unclear how this impacted iron status, with there not being a 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-effect 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 splitting the same daily dose into two pills as compared with one.^[73] However, serum hepcidin increased less when taking iron once per day. Each condition was only 3 days long, 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]

Another study used either a single dose of 65 mg elemental iron or twice that divided into two doses for the purpose of preventing anemia in pregnancy.^[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.

Another study used 27 mg once or twice per day in a randomized, parallel trial. The participants were healthy pregnant women who were having twins, and so would have higher iron requirements than normal. Supplementation took place starting 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 as compared with daily supplementation for improving iron status and preventing anemia in adolescent and adult menstruating women.^[78] Overall, there did not seem to be a notable difference in anemia between groups. However, daily supplementation may be more effective in the long-term when the iron is taken alone (as opposed to in combination with folic acid). Limited evidence also suggested that daily supplementation may be better for increasing ferritin levels, though 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 than daily, overall suggesting that for those with side-effects from iron supplementation, weekly doses may be preferable and similarly effective to daily doses.^[78]

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

3.2Absorption-enhancers

There are many foods and compounds that may increase the absorption of iron.

Animal protein

Early studies using radioisotope-labeled non-heme iron have found that the addition of animal protein to the meal can enhance the absorption of non-heme iron.^[79] The increase in absorption varied by condition, but was in the range of 1.7 to 4-fold and usually at least twice as much; this was observed with veal, fish, beef, and chicken added to meals of maize or black beans. Interestingly, the one test of an animal protein source (beef) on the 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] Participants consumed a wheat roll containing radiolabeled iron at every meal for 3 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 may suggest that the effect is reduced over time, or that there’s something about wheat that impairs the absorption-enhancing effect of animal protein, as was found in the study previously mentioned.

One study found that pork also had a mild, dose-dependent absorption-enhancing effect, with absorption being increased 15% with 25 g, 44 % with 50 g, and 57 % with 75 g during a high-phytate meal based on rice and a wheat bun.^[81] Another study used 5-day periods of a very high meat diet supplying 60 g of protein from pork (either Polish or Danish pigs, the difference being that Polish pork was higher in iron and zinc) at each of 4 meals, or a vegetarian diet during diets heavy in wheat products.^[82] There was a modest increase in non-heme iron absorption, which was somewhat greater with Danish pork, and only statistically significant for Danish pork.

Another study found modestly increased iron absorption from a meal of high-phytate beans when oily fish was added.PMID18460487

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

Probiotics

One study that used Lactobacillus reuteri DSM 17938 at 3x10⁸ colony-forming units (CFU) in combination with iron supplementation found a somewhat greater increase in reticulocyte hemoglobin than when taking iron alone.^[83] 

Another study found that 10¹⁰ CFU of freeze-dried Lactobacillus plantarum 299v taken acutely during a meal may have modestly increased iron absorption.^[84] In another study, iron absorption from a supplemental fruit drink was enhanced by both 10¹⁰ and 10⁹ CFU of Lactobacillus plantarum 299v, with no difference in absorption between doses.^[85] In contrast, another study used 10¹⁰ CFU of the same strain on children with iron deficiency who were taking vitamin C and iron. It didn’t find a clear difference in the change in ferritin levels compared with the placebo group.^[86]

In another study, multiple phases of multiple strains of probiotic bacteria coincided with a notably, statistically significant increase in iron and a decrease in ferritin levels in patients with moderate chronic kidney disease, while the placebo didn’t change levels of either.^[87] For the first week, participants took 0.377 g of a mixture of Enterococcus faecium, Lactobacillus acidophilus, and Saccharomyces Boulardii during 3 major meals each day. For the 2 following weeks, 0.455 g of of combination Bifidobacterium brevis, Bifidobacterium bifidum, Bifidobacterium longum and 0.455 g of Lactobacillus rhamnosus and Lactobacillus acidophilus was taken at each meal. After that, the supplements were continued for 3 months, except that twice the dose was taken at 2 meals (breakfast and lunch) each day.

1.9x10⁷ CFU of Bifidobacterium Lactis HN019 and 2.4 g of prebiotic oligosaccharides daily for one year in children coincided with a reduction in iron deficiency anemia as compared with placebo, though not mean hemoglobin level or serum ferritin.^[88] 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.^[89]

There are a number of bacterial strains that seem to be able to increase iron absorption. The reduction of inflammation in enterocytes and the subsequent reduction in hepcidin levels is a plausible mechanism, though requires more research.

Vitamin C

Vitamin C (ascorbic acid) increases the rate at which non-heme iron is absorbed from the intestines into the bloodstream.^[90][91] Ascorbate (a mineral salt of ascorbic acid) cycles back and forth between intestinal cells:^[92] outside the cells, it reduces iron to a form more readily absorbed;^[93] inside the cells, it helps transfer iron to transferrin.^[94]

Transferrin is a transfer protein that delivers iron to cells, which is why scurvy (which results from a vitamin C deficiency) is often associated with some degree of iron-deficiency anemia.^[95][96]

Vitamin A

In a meta-analysis of 21 clinical trials and 2 cohort studies, vitamin A supplementation used to resolve deficiency reduced the risk for anemia, increased hemoglobin and ferritin, though there was insufficient evidence to demonstrate that it reduced iron deficiency specifically.^[97] 

Part of the effect on hemoglobin levels is likely due to the role of vitamin A in hematopoiesis.^[98] However, there may be a role of vitamin A in increasing absorption as has been found in some studies,^[99]

Vitamin D

A study on 200 healthy but vitamin D-deficient adolescents found that supplementation of 1000 IU per day led to considerably reduced iron levels, transferrin saturation, and increased total iron-binding capacity, while the control (consumption of 200 ml of milk with only 40IU of vitamin D daily) didn’t seem to affect these outcomes.^[100]

Another study on pregnant women given 1000 IU of vitamin D found that ferritin decreased similarly in the supplement and placebo groups, and hepcidin increased similarly.^[101] A 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.^[102] Another study found a reduction in hepcidin with a one-time 250,000 IU one week later, but no difference in ferritin levels. ^[103] 

3.3Iron-reducers

Calcium

300 mg of calcium carbonate reduced the absorption of iron from 37 mg ferrous sulfate from 2.12% to 1.61 during a meal of a hamburger, which was statistically significant, and from 7.68 to 6.50% without food, which wasn’t statistically significant.^[104] It also found that in people with low iron stores, 600 mg of calcium from calcium carbonate reduced the absorption of 18 mg of iron from ferrous sulfate from 13% to 7.3% during a hamburger meal, while there was an increase from 18% to 21.5% without food. In people with normal iron stores, the same doses didn’t seem to affect absorption. The same dose of iron and calcium with calcium citrate reduced absorption from 10.1 to 6.1 during a hamburger meal, and 12.9 to 6.6 without food, neither of which was statistically significant. For calcium phosphate, absorption decreased from 7.3% to 3.2% during the meal and 16% to 6% without food, which was statistically significant.

Furthermore, 600 mg of calcium from different supplements reduced natural non-heme iron absorption from a hamburger meal from 13.4 to 9.1 with calcium carbonate, 11.9 with calcium citrate, and 8.2% with calcium phosphate, with carbon and phosphate being statistically significant and citrate not being. The same test performed with an iron-inhibiting meal containing egg, muffin, bran flakes, sugar, milk, and coffee found that iron intake was reduced from 1.2% to 0.7 with carbonate, to 0.5% with citrate, and 0.4% with phosphate, all being statistically significant.

Absorption of 65 mg of iron from a multivitamin/mineral supplement was drastically reduced with simultaneous use of 200 mg pf calcium sulfate with 100 mg of magnesium oxide, and 60 mg was reduced by 350 mg of calcium carbonate with 100 mg of magnesium oxide.^[105] The addition of 200 mg of calcium sulfate didn’t suppress the increase in serum iron from 65 mg, but 350 mg of calcium carbonate did, and so did 100 mg of magnesium oxide alone and in combination with both calcium doses and forms, the greatest suppression being 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, 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.^[106]

Another study found that absorption of 5 mg non-heme iron with simultaneous calcium doses of 800 mg was suppressed the most with (in order) 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.^[107] In another study, doses of 200 to 1500 mg of calcium chloride had only a small inhibitory effect on non-heme iron absorption, and up to 800 mg had a small effect on heme iron absorption, which, while dose-dependent, seemed well below most other calcium salts.^[108] On the other hand, another study found that doses as little as 40 mg of calcium chloride notably reduced iron absorption, the difference possibly being that this was during a meal, while the other study wasn’t.^[109]

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,^[110] potentially due to the presence of chlorogenic acid, a known iron chelator.^[111] This would extend this inhibition to Green coffee extract, a richer source of chlorogenic acid.

• Tea, be it green^[112] or black,^[110] possibly due to the presence of catechins^[112] and theaflavins.^[113]

• Infusions of chamomile, lime flower, pennyroyal, peppermint, and vervain.^[110]

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 this potential 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.^[114]

The addition of 4.2 g of ground chili (Capsicum annuum) to a meal fortified with 4 mg of non-heme iron showed a moderate inhibitory effect on iron absorption (38%). Due to the addition of chili, the meal was relatively high in phytic acid.^[114]

Fiber

Psyllium is a dietary fiber (roughly half-soluble, half-insoluble). It has the potential to reduce non-heme iron absorption (with no effect from vitamin C),^[115] but also to raise the PH in the colon and thus increase calcium resorption^[116] — an increase thought to apply to other minerals as well.

In humans, one study noted a reduction in iron accumulation when non-heme iron was coingested with psyllium,^[117] but other studies saw no effect on iron metabolism from the prolonged supplementation of around 10 g of psyllium.^{[118][119][120]}

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

Rosemary

Rosemary (source of rosmarinic acid) has also been shown to reduce non-heme iron absorption.^[112]

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

Quercetin

In a randomized, double-blind, placebo-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.^[121] It has been observed that quercetin is a strong chelator of iron.^[122]

Zinc

Minerals can compete with each other for pathways to absorption, and zinc and iron may be competitive at common transporters such as divalent metal transporter 1 (DMT1), human copper transporter 1 (hCTR1) and Zip14.^[123][124]

While not entirely consistent, there is evidence that the simultaneous dosing of iron and zinc leads to reduced iron absorption when provided in water, though absorption doesn’t seem to be affected when the minerals a provided within a food matrix.^[125] Another study didn’t find a difference in absorption or any measure of iron status besides the unreliable serum iron when adding 15 mg of zinc per day.^[126] When taking 120 mg of iron with 30 mg of zinc weekly or 120 mg iron alone weekly, or 60 mg iron with 15 mg zinc, 60 mg of iron alone didn’t find notable differences between zinc with iron compared with iron alone for hemoglobin or ferritin levels^[127] In another study, supplementation of 22 mg of zinc daily without iron by participants with low iron reserves for 6 weeks reduced plasma iron, ferritin, and transferrin saturation, though not hemoglobin.^[128] 10 mg daily from a zinc supplement for 3 months in children aged 8-9 resulted in somewhat reduced serum iron levels, but there were no notable differences as compared with placebo for hemoglobin, ferritin, transferrin, or transferrin saturation.^[129] Interestingly, one study found that supplementation of 20 mg of zinc daily between meals didn’t affect iron absorption from meals with radioisotope-labeled iron.^[130] However, there was a strong trend towards reduced serum iron, serum ferritin, though not hemoglobin after 2 months.

While zinc seems to be able to reduce the absorption of iron, the effect is inconsistent and it’s unclear how potent it is. 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, possibly competition for transporters in the liver, and of unknown consequence.

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.^{[131][132][133]}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.^[134]

Another study didn’t find an effect of iron supplementation on HbA1c but wasn’t in type 2 diabetics.^[135] While three uncontrolled studies in people with iron deficiency anemia but without diabetes found a reduction with iron supplementation.^{[136][137][138]}

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.^[139]

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.^[140] 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.^[141] 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,^[142], and nonanemic participants^[143]. One study found less depression in participants who took intravenous iron than oral iron, the former having led to a greater increase in hemoglobin.^[144] 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.^[145]

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.^[146] 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).^[147] The iron in heme can become oxygenated (i.e., bound to oxygen) or unoxygenated in a reversible manner,^[148] which is what allows red blood cells to deliver oxygen to body tissues.^[149]

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;^[150] others derive from a dietary deficiency, such as pernicious anemia (linked to a Vitamin B12 deficiency).^[151] 

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.^[152] 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^{[153][154][155]} — 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^[156] and fulfill different maintenance functions,^[157] including the recycling of iron.^[158]

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.^[159] To prevent this, the erythrophagocytic macrophage detects senescent red blood cells and eliminates them.^[160]

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.^[152] 

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 ^[161] 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.^[162] 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.^[163]