Iron in Health and Disease


Iron

Iron is the most abundant element on earth (by mass), and the 4th most abundant metal on the earth's crust. It is a transition metal that can readily donate and accept electrons to participate in oxidation–reduction reactions, which are essential for many fundamental biologic processes. Iron is a mineral and is naturally present in many foods. Dietary iron has two main forms: haem and non-haem. Plants and iron-fortified foods contain nonheme iron only, whereas meat, seafood, and poultry contain both haem and non-haem iron.



Role

In humans, iron is incorporated into proteins as a component of haem, iron sulfur clusters, or other functional groups. These iron-containing proteins are required for vital cellular and organismal functions including oxygen transport, mitochondrial respiration, metabolism, nucleic acid replication and repair, host defence, and cell signalling.

Approximately 1–2 mg of iron is provided by dietary absorption in the duodenum, which is balanced by an unregulated loss of 1–2mg, primarily through epithelial shedding and blood loss. Since body iron losses are not regulated, the major avenues for regulating systemic iron balance are in controlling dietary iron uptake, and iron release from the recycling of macrophages and hepatocytes.


Dietary iron is absorbed in several forms: inorganic, haem, and ferritin. Inorganic dietary iron is mainly present in the oxidized or ferric form (Fe3+) and must be reduced to ferrous form (to Fe2+) prior to intestinal uptake. Most of the 3 to 4 grams of elemental iron in adults is present in haemoglobin over (60%). The remaining iron is stored in cells, largely in the form of ferritin, an inert form that limits the production of damaging redox reactive species.


At the systemic level, the iron hormone hepcidin is a major regulator of body iron. Hepcidin controls iron entry into circulation by binding to irons transporter ferroportin, inducing its internalization and degradation in lysosomes. In this way, hepcidin expression inhibits iron absorption from the diet, and iron release from recycling macrophages and other body stores.



Sources

The richest sources of haem iron in the diet include lean meat and seafood. Dietary sources of nonheme iron include nuts, beans, vegetables, and fortified grain products. Haem iron has higher bioavailability than nonheme iron. The bioavailability of iron is approximately 14% to 18% from mixed diets that include substantial amounts of meat, seafood, and vitamin C (ascorbic acid, which enhances the bioavailability of non-haem iron) and 5% to 12% from vegetarian diets. Phytate (present in grains and beans) and certain polyphenols in some foods (such as cereals and legumes) reduces the bioavailability of non-haem iron. Unlike other inhibitors of iron absorption, calcium might reduce the bioavailability of both non-haem and haem iron.


Iron supplements, especially those designed for women, typically provide 18 mg iron (100% of the RDA). Multivitamin supplements for men or seniors frequently contain less or no iron. Because of its higher solubility, ferrous iron in dietary supplements is more bioavailable than ferric iron. High doses of supplemental iron (45 mg/day or more) may cause gastrointestinal side effects, such as nausea and constipation.


Role in Health and Disease

Iron deficiency is the most frequently encountered nutritional deficiency in man, manifesting clinically as iron deficiency anaemia (IDA). According to the World Health Organization, anaemia affects nearly one quarter of the world’s population, with 50% of cases attributable to iron deficiency. Iron deficiency anaemia can cause gastrointestinal disturbances, weakness, fatigue, impaired cognitive function, immune function, and body temperature regulation. In infants and children, IDA can result in psychomotor and cognitive abnormalities that, without treatment, can lead to learning difficulties.

Iron deficiency can be due to insufficient dietary iron absorption nutritional deficiency, increased requirements during pregnancy and rapid growth in children, or increased blood loss. Anaemia can also be caused by functional iron deficiency, characterized by reduced levels of circulating iron that limit erythropoiesis despite adequate stores of total body iron.


The liver is a main storage depot for iron (25%) and is the primary organ that clears excess circulating non-transferrin bound iron (NTBI) in conditions of iron overload. When the iron storage and antioxidant capacity of the liver is exceeded, iron overload can lead to oxidant-mediated liver injury, cirrhosis, and hepatocellular carcinoma. Major causes of systemic iron overload are hereditary hemochromatosis, iron loading anaemias and transfusional or other secondary forms of iron overload. In these disorders, iron exceeds the buffering capacity of transferrin leading to highly reactive forms of NTBI that are taken up in the liver, heart, and endocrine glands, where the excess iron fuels oxidative damage and organ dysfunction and disease states.



In the heart, iron accumulation is associated with cardiomyopathy, which is a major cause of morbidity and mortality. Some epidemiologic studies in the general population have demonstrated an association between increased haem iron intake, body iron stores, and cardiovascular risk; though other studies have produced conflicting results. In the brain, iron overload has been associated with many neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. Evidence of a mechanistic role has been observed, with a possibility that proteins associated with Alzheimer’s and Parkinson’s, are upregulated due to iron loading.


Like humans, microorganisms require iron for survival. It has been hypothesized that one function of the hepcidin ferroportin system in humans is to restrict iron availability to invading organisms. This notion is supported by evidence from iron studies in the developing world, where increased rates of infection, morbidity and mortality from malaria, diarrheal illnesses and tuberculosis were observed, following iron supplementation.

Requirements

The Recommended Dietary Allowances (RDAs) for vegetarians are 1.8 times higher than for omnivores, given the lower bioavailability of non-haem iron from plant-based foods. The RDA of iron for men aged 19+ and women over 51+ is 8mg, and 18mg for women aged 19-50 years.


Conclusion

Many plant foods contain high amounts of iron; legumes, whole grains and dark green leafy vegetables. It is therefore possible to achieve enough dietary iron on a plant-based diet. Lower iron stores may be protective against non-communicable diseases, such as heart disease, cancer and neurological disorders. A plant-based diet contains a vast number of molecules with iron-chelating and antioxidant properties that can protect cells against oxidative stress-induced damage by modulating cellular iron homeostasis. Therefore, it is advisable for all individuals to regularly control their iron status and improve their diet regarding the content and bioavailability of iron, by consuming more plants and less meat.

References

Daher, R., Manceau, H., & Karim, Z. (2017). Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med, 46(12 Pt 2), e272-e278. doi:10.1016/j.lpm.2017.10.006


Dev, S., & Babitt, J. L. (2017). Overview of iron metabolism in health and disease. Hemodial Int, 21 Suppl 1, S6-S20. doi:10.1111/hdi.12542


Galaris, D., Barbouti, A., & Pantopoulos, K. (2019). Iron homeostasis and oxidative stress: An intimate relationship. Biochim Biophys Acta Mol Cell Res, 1866(12), 118535. doi:10.1016/j.bbamcr.2019.118535


Haider, L. M., Schwingshackl, L., Hoffmann, G., & Ekmekcioglu, C. (2018). The effect of vegetarian diets on iron status in adults: A systematic review and meta-analysis. Crit Rev Food Sci Nutr, 58(8), 1359-1374. doi:10.1080/10408398.2016.1259210


Mann, J. & Truswell, S. (2017). Essentials of human nutrition. (5th ed.). London, United Kingdom: Oxford University Press.

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