1.1. Biological Significance
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.
1.2. Recommended 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.
1.3. Deficiency
Iron deficiency in infants and children is associated with cognitive impairments, including psychomotor[16] and behavioural[17] issues.
2.1. Depression
A high iron intake seems to translate into a lesser chance of depression, according to a (relatively small) meta-analysis on the topic.[18]
3.1. Red 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).[19] The iron in heme can become oxygenated (i.e., bound to oxygen) or unoxygenated in a reversible manner,[20] which is what allows red blood cells to deliver oxygen to body tissues.[21]
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;[22] others derive from a dietary deficiency, such as pernicious anemia (linked to a Vitamin B12 deficiency).[23]
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.[24] 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[25][26][27] — 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.
4Inflammation and Immunology
4.1. Macrophages
Macrophages are immune cells. In addition to eliminating foreign bodies determined to be harmful, they play roles in both inflammation and anti-inflammation[28] and fulfill different maintenance functions,[29] including the recycling of iron.[30]
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.[31] To prevent this, the erythrophagocytic macrophage detects senescent red blood cells and eliminates them.[32]
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.
5Peripheral Organ Systems
5.1. Female 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.[24]
Taking an iron supplement around the time of menstruation appears to reduce anemia, but not as much as taking an iron supplement every day.
6Nutrient-Nutrient Interactions
6.1. Chelation
Several plant-derived compounds can bind iron and sequester it in the intestines, thus reducing its absorption.
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.[33] When mice were fed diets with adequate levels of iron, curcumin did not seem to significanctly hinder iron absorption.[33] Finally, in humans, 500 mg of turmeric did not seem to hinder iron absorption.[34]
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.[34]
Rosemary (source of rosmarinic acid) has also been shown to reduce non-heme iron absorption.[35]
Ingesting iron at the same time as spices rich in phytic acid or phenolic acid may reduce its absorption.
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),[36] but also to raise the PH in the colon and thus increase calcium resorption[37] — 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,[38] but other studies saw no effect on iron metabolism from the prolonged supplementation of around 10 g of psyllium.[39][40][41]
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.
The following beverages are known to inhibit iron absorption when coingested with non-heme iron:
A wide variety of beverages with a high antioxidant content, including coffee and tea, have some acute inhibitory effect on iron.
6.2. Vitamin C
Vitamin C (ascorbic acid) increases the rate at which non-heme iron is absorbed from the intestines into the bloodstream.[45][46] Ascorbate (a mineral salt of ascorbic acid) cycles back and forth between intestinal cells:[47] outside the cells, it reduces iron to a form more readily absorbed;[48] inside the cells, it helps transfer iron to transferrin.[49]
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.[50][51]
