Iron is one of the most abundant elements on Earth, and is essential for living organisms: it has a central role in haemoglobin formation and oxygen transport. Iron is truly a Goldilocks nutrient: too little can lead to anemia, too much can lead to liver and heart problems.

Here we provide an overview of this essential nutrient, and what we can do to ensure we consume just the right amount.

• What is iron?
• Iron in the body
• What does iron do?
• How can I get enough iron?
  • Red blood cells, oxygen transport and energy
  • Brain health and cognition
  • Pregnancy and fetus development
  • Iron and the immune system
• Diseases of iron metabolism
  • Not enough iron - iron deficiency
  • Too much iron - iron overload
• Supplements
• Summary
• References

What is iron?

Iron represents about 5% of the earth’s crust, making it one of the most abundant elements on Earth¹. Despite its abundance, iron is strangely a limiting factor for life: in contact with oxygen, iron forms oxide (most commonly seen as rust), which is highly insoluble and not available for organisms.

The Egyptians, Greeks and Romans were aware that iron was important for health, and was commonly used in the 17th century to treat chlorosis (green disease), a condition commonly resulting from iron deficiency. However it wasn’t until the early 20th century that we really understood iron’s central role, when it was confirmed that inorganic iron was needed for haemoglobin formation, a molecule in red blood cells that carries oxygen from our lungs to the rest of the body².

Iron is a transition metal that can easily donate and accept electrons: this ability to move between ferric (Fe3+) and ferrous (Fe2+) state allows iron-containing proteins to participate in oxidation-reduction reactions, many of which are essential for fundamental biological processes in our bodies, such as oxygen transport and respiration³. At the same time, this reactivity can lead to toxicity: in presence of oxygen, iron can produce free radicals which can easily damage cellular structures. Therefore, organisms have developed multiple systems to control iron⁴.

Iron in the body

It is important to remember that our bodies are not very good at getting rid of excess iron and we don’t have a physiological process of iron excretion. The body achieves iron balance through a balanced diet and by regulation of transport and recycling⁵.

In the body, iron is found in two main forms⁶.

• Haem (heme) iron (Fe2+): in this form, iron is bound to hemoproteins. These proteins contain a haem group and have the ability to bind oxygen in the presence of iron atoms. This represents about 70% of the iron in the body. Haemoglobin, found in red blood cells, comprises about 60% of the iron. Other hemoproteins include myoglobin, found in muscle cells (about 10% of the iron) and cytochrome proteins³.
• Non-haem (non-heme) iron (Fe3+): in this form, iron can be found in iron sulfur cluster proteins such as respiratory complexes I-III and coenzyme Q10. It is also bound to transporter proteins such as transferrin and ferritin.

Apart from erythrocytes (red blood cells) and muscle, iron is mainly found in the bone marrow, spleen and liver. This is not surprising considering that the bone marrow is the production site for erythrocytes, and liver and spleen are regulatory and recycling sites on iron, respectively.

When not being used, iron is stored in a storage protein called ferritin. A protein called transferrin, found in the plasma, is responsible for moving iron to the different organs when needed. A hormone called hepcidin, mainly produced in the liver, is a central regulator of iron in the body, controlling absorption and iron transport⁷.

When doctors suspect there might be a problem with iron in the body, they are likely to look at the levels of some of these proteins, as it can help them to understand what might be the issue.

What does iron do?

Although iron is mostly known for its role in oxygen transport around the body and red blood cell (erythrocyte) formation, there are many other important processes where iron is essential.

Red blood cells, oxygen transport and energy

One of the most common symptoms of iron deficiency is fatigue, weakness and shortness of breath. This happens because our body cannot make enough haemoglobin and there is not enough oxygen being transported to the tissues².

How do we make red blood cells?

Most of the iron in the body is used by the bone marrow tissue to make new haemoglobin and red blood cells.). In the lungs, haemoglobin binds to oxygen and transports it to the rest of the tissues in the body.

Haemoglobin is in fact a combination of four chains, each containing an iron atom within a haem group. This incredible structure allows iron to effectively bind to gases such as oxygen and to transport them around the body to where it is needed⁸.

How much haemoglobin we need depends on multiple factors: for example, exposure to high altitude (lower oxygen conditions) and severe blood loss will increase haemoglobin production.

What is Myoglobin?

In contrast to haemoglobin, myoglobin contains just one haem group with one iron atom. The main function of myoglobin is to supply oxygen to the muscles, in particular to heart and skeletal muscle. Myoglobin is very efficient at taking oxygen from blood, and it serves as an oxygen reservoir in muscle⁹.

Energy production inside the cell

Haemoglobin and myoglobin are responsible for delivering oxygen to the cells. Inside the cells, the mitochondria (a cellular structure commonly known as the “powerhouse” of the cell) uses this oxygen to produce ATP. ATP is an essential molecule that our cells use as fuel for pretty much everything. ATP is made via a series of chemical reactions that depend on iron-containing proteins (namely, the mitochondrial complexes I, II and III)¹⁰.

Brain health and cognition

The brain is a highly active tissue which consumes large amounts of oxygen. Therefore, given iron’s role in oxygen transport and energy, it will not come as a surprise that iron is very important for brain health.

Iron is also vital for axon myelination. Myelin is a substance that covers that axon of neurons and facilitates neural transmission: in other words, myelin ensures that neurons in your brain can work properly¹¹.

Iron is also critical for neuronal differentiation and proliferation¹², and for production of several neurotransmitters such as dopamine and norepinephrine³. Iron deficiency, especially during infancy and adolescence when our brains are still developing, has been linked to decreased conscious mental activity and mental developmental problems¹³.

At later stages in life, the concentration of iron in the brain tends to increase, probably due to several factors that can affect the iron regulatory system. The accumulation of iron in neurons might induce cell damage through the excessive production of free radicals¹².

Iron accumulation in the glia (supporting cells in the brain) can lead to inflammation and release of pro-inflammatory cytokines, which in turn can result in a cycle of continuous inflammation and neurodegeneration¹⁴.

Iron accumulation has been associated with increased risk of neurodegenerative diseases such as Alzheimer’s or Parkinson’s¹⁴.

Pregnancy and fetus development

During pregnancy, requirements for iron increase: iron is required for cell division and proliferation, and therefore more iron is needed to support fetal growth and maternal adaptation to pregnancy, such as placental development. The iron demand increases as pregnancy progresses, and it is estimated that an additional 1 gram of iron is needed during pregnancy to maintain the mother’s iron balance and to support the development of the fetus and placenta¹⁵.

In adults, most of the iron goes to produce red blood cells. In infants and children, there is great demand for iron for muscle growth and myoglobin production. Neurological development is high during infancy, which also increases the demand for iron.

Prevalence of iron deficiency is high during pregnancy, and it is estimated that over 20-30% of pregnant women worldwide are anemic due to iron deficiency¹³. While iron supplementation is a common policy worldwide, in the UK, iron supplementation during pregnancy is not recommended unless there is evidence of mothers being anemic¹⁶.

At birth, most full-term babies have enough iron and haemoglobin concentrations for the first 6 months, after which iron stocks will need to be replenished¹³. Breast milk has low amounts of iron, but it is mainly found in iron-binding proteins such as lactoferrin. This makes iron in breastmilk highly bioavailable¹⁷. It is recommended that complementary feeding is introduced about 6 months of age to meet the growing iron requirements¹⁸.

As iron is mainly obtained from the diet, it is very important that children have a diverse diet that includes a variety of iron-rich foods to ensure an appropriate intake of iron. In many Western countries, like the UK, fortified cereals have become a major source of iron for growing children¹⁹.

Iron and the immune system

It’s not common knowledge that iron plays an important role in supporting the immune system and helping us fight infections. Iron is important for cell division and growth, and it’s necessary for differentiation and proliferation of multiple immune cells, such as the T lymphocytes.

As mentioned above, iron can be toxic in the presence of oxygen as it generates free radicals: this is commonly known as the Fenton reaction. Fenton reactions can be harmful when they happen unintentionally; but some of our immune cells, known as neutrophils, use this reaction to generate free radicals that are toxic and lethal for pathogens²⁰.

Iron is involved in the production and regulation of cytokines, the signaling molecules of the immune system, necessary to create the inflammatory response that helps to fight infections²⁰.

How can I get enough iron?

Because biologically available iron is very limited, the human body is very efficient at conserving and recycling iron³. In other words, if you don’t suffer from diseases but have low iron levels, it’s because you don’t get enough from the diet.

Due to the efficient iron recycling system, it is estimated that dietary iron provides about 5% of the iron daily requirement in adults. However, in children, 30% of the daily iron requirement has to come from the diet¹³.

What foods contain iron?

Iron is present in the diet in both haem and non-haem iron²¹.

• Haem (heme) iron: haem iron (bound to haemoproteins) is found only in animal-derived foods: mainly meat, fish and eggs. Liver, particularly from beef, is considered one of the richest sources of iron. Red meats have higher iron than white meats. Haem iron represents about 40% of the total iron content in animal foods.
• Non-haem (non-heme) iron: non-haem iron is found in animal and plant foods. Green leafy vegetables, beans, seeds and whole grains are particularly rich in non-haem iron.

Non-haem iron represents most of the iron we consume, but it has lower absorbability or bioavailability: it is estimated that about 15-40% of haem iron is absorbed, while we only take in less than 15% of non-haem iron⁵. Data suggests that iron bioavailability on an omnivore diet is 14-18%, whereas it is only 5-12% on a vegetarian diet²¹.

Absorption of haem-iron occurs after proteolytic digestion of myoglobin and haemoglobin, which releases the haem group. The haem is maintained in a soluble form so that it is easier to be absorbed by the gut cells²².

The absorption of non-haem iron can be affected by multiple factors present in the diet, both positively and negatively. The effect of these factors is less relevant in the context of an omnivore diet, but are more significant for vegetarian diets, where non-haem is the main iron source.

Enhancers (promoters) of iron absorption found in the diet are:

• Vitamin C (ascorbic acid): vitamin C has been shown to improve absorption of non-haem iron, in part by acting as a weak chelator (sequestering iron) to help to solubilise it in the intestine. Vitamin C has also been shown to improve iron mobilisation²³.
• Carotenoids: studies have shown that carotenoids (such as beta-carotene, lycopene and lutein) can increase the uptake of non-haem iron²⁴.

Inhibitors (detractors) of iron absorption found in the diet are²⁵:

• Tannins: tannins are present in tea and coffee (as tannic acid) as well as in red wine. They are thought to bind non-haem iron in the intestine, therefore sequestering and preventing absorption²¹.
• Phytates: phytate/phytic acid is a compound found in abundance in whole grain cereals and legumes. Phytates have been shown to inhibit iron absorption, possibly by preventing absorption of ferritin deposits, although the exact mechanism is not clear²⁶.

Iron and vegetarian vegan diets

Vegetarian diets are likely to have higher amounts of vitamin C and carotenoids, but they are also more likely to increase consumption of polyphenols and phytic acid, which are found in plant foods²⁷. For people that follow a vegetarian diet, particularly women and children, the intake of iron-fortified foods is highly recommended.

Some gastrointestinal conditions like peptic ulcers, or H.pylori infections are also known to decrease iron absorption²⁸.

The current recommendation for iron is 11mg/day for men. Pre-menopausal women should aim at 16mg/day due to loss during menstruation. Post-menopausal women should aim at 11mg/day²⁹.

Diseases of iron metabolism

Iron metabolism is tightly regulated. When the balance tips to one side or the other, it can lead to serious disorders.

Not enough iron - iron deficiency

It is estimated that over 1.5 billion people worldwide suffer from anaemia, and iron deficiency accounts for 30-50% of the cases³⁰. Although anaemia is especially prevalent in developing countries, it’s still an important problem in the developed world, especially in people with low incomes. Iron deficiency is more common in women than men, due to periodical loss of blood during menstruation. Iron deficiency is relatively common among the elderly population³¹.

People that do not eat animal products, particularly vegans, are also more likely to be iron deficient than meat eaters, due to the lower bioavailability or absorption of non-haem iron⁵.

In developing countries, iron deficiency coexists with infectious diseases such as malaria or hookworm, which have been shown to further affect iron status, particularly in children¹.

Iron deficiency anaemia presents multiple symptoms, including fatigue and exercise-associated dyspnea (shortness of breath), paleness, headache and altered thermoregulation (internal temperature control). These symptoms, along with others, are caused by impairment of oxygen transport. Iron deficiency can also cause cognitive dysfunction, which can lead to neurological damage during brain development in children, as well as worsening cognitive function and dementia in the elderly^1,28.

Oral iron supplementation is the common treatment for iron deficiency. In people with malabsorption, such as the elderly, intravenous iron injection may be more effective.

Too much iron - iron overload

Too much iron in the body is not good for you and can affect and damage the liver, heart and endocrine glands³.

Major causes of iron overload are generally hereditary. Excessive transfusions can also cause iron overload especially in people with chronic kidney disorders³.

Haemochromatosis is an hereditary disease, linked to faulty hepcidin. If this protein is not working properly, the body is unable to detect increasing iron levels and therefore cannot control the iron intake from the diet. In time, this leads to iron accumulation in the organs potentially causing liver and heart damage³².

Beta-thalassemias are hereditary disorders characterised by abnormalities in haemoglobin. This results in ineffective erythropoiesis (new red blood cell formation), resulting in hepcidin suppression and excessive absorption of iron. Beta-thalassemia is prevalent in Mediterranean countries, but it is estimated that about 1.5% of the global population are carriers³³.

Interestingly, iron overload can also lead to chronic fatigue, a symptom generally associated with iron deficiency. In advanced stages of iron overload, it is common to suffer liver cirrhosis and/or diabetes due to organ damage³².

During ageing, iron accumulates selectively in specific areas of the brain. However, greater accumulation occurs in many neurological diseases, and is associated with oxidative stress and cellular damage and with Parkinson’s and Alzheimer’s disease¹⁴.

Supplements

Oral iron supplementation is the quickest and simplest way to increase the dietary intake of iron.

There are multiple types of iron supplements in the market. Iron is better absorbed in an empty stomach, but this can often cause indigestion so many people prefer to take iron with food.

Iron supplementation, particularly at higher doses, is well known for its side effects: 10-40% of people can suffer from constipation, nausea or vomiting²⁸.

Ferrous sulphate is the most common iron supplement, also frequently used in iron fortification as it’s very cost-effective. However, it’s well known for its gastrointestinal-specific side effects and it disagrees with many people³⁴. It’s also known to give a metallic after-taste to food.

Similarly to other minerals, supplements that supply iron in inorganic form tend to have more iron in them, but they’re not soluble and not well absorbed by the body³⁵.

Recently, new natural sources of iron have been explored to try to reduce the side effects of iron salts³⁶.

Fungi are known to take iron from the environment where they grow and store it for use at a later stage. One of these fungi, Aspergillus oryzae, commonly known as koji culture, is widely used in Asian cuisine to produce miso and soya sauce. Koji supplements that contain natural iron have recently been developed. The iron from koji extract has a similar absorption rate to ferrous sulphate but with much lower side effects^37,38.

If you’re taking antacid medication or tetracycline antibiotics, leave at least 2 hours in between the medication and supplementation. These medications can chelate (sequester) the iron, which not only makes the supplement ineffective, but can also have an effect on the medication³⁹.

Summary

Iron is a central nutrient for our health, and its metabolism is tightly regulated: too little iron causes anaemia, too much iron can lead to organ damage. Although iron from vegetable sources is more abundant in the diet, it’s less well absorbed than from meat. People on vegetarian and vegan diets are more likely to suffer from iron deficiency than omnivores, and therefore might want to consider external supplementation.

References

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