The Importance of Iron

Iron is an essential nutrient required by every human cell1. Its atomic structure gives rise to a number of biochemically useful properties, including the unusual capacity to both donate and accept electrons, and to reversibly bind to ligands such as oxygen and nitrogen2. As such, iron plays a vital role in the transport and storage of oxygen, in oxidative metabolism and in cellular growth and proliferation. ​

Physiological iron

Body iron content is approximately 3–4g, which corresponds to a concentration of 40–50mg of iron per kilogram of body weight3. Approximately 60% is present in the form of haemoglobin in circulating red blood cells; however, the body exploits the unique properties of iron by incorporating it into hundreds of different enzymatic and non-enzymatic proteins that are crucial to a wide range of physiological functions2.

Table 1. The biological uses of iron.

The biochemical reactivity of iron – namely its ability to both donate and accept electrons – means that it can be harmful when present in high concentrations. Unbound iron can catalyse the formation of reactive oxygen species that cause intra- and extra-cellular damage4. Thus, when not bound to functional proteins (functional iron), free iron is sequestered by the iron transport protein transferrin (transport iron) or stored by ferritin or as haemosiderin (storage iron)3. As such, iron deficiency can have multiple aetiologies, depending on the type of iron that is deficient (see ‘Absolute versus functional iron deficiency’).


Finely tuned inter-relationships between mechanisms are needed to maintain iron at optimal levels, preventing damage caused by either too much or too little iron (see ‘Iron absorption, metabolism and homeostasis’).

 

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Table 2. The typical distribution of the three main types of iron in healthy adults3

Iron metabolism

The majority of iron in the body is contained within erythrocytes where it is incorporated into haem protein complexes that transport oxygen as haemoglobin and myoglobin. Iron is central to this function, with oxygen molecules binding directly to the core iron atom5. Erythrocytes have a life span of approximately 120 days, after which they are broken down by the macrophages of the reticuloendothelial system5. During this process, haem iron is released and recycled, either through incorporation into newly formed erythrocytes in the bone marrow or as storage iron in the liver. Approximately 20–25mg of iron is effectively recycled in this way every day5,6.

Some iron is, however, lost from the body through normal shedding of skin and gut lumen cells, and this may be exacerbated by loss of haemoglobin through bleeding3. Since iron loss is not actively controlled, maintenance of appropriate iron levels is achieved by controlling iron absorption from the gut.

Iron is absorbed in amounts inversely proportional to body iron stores. Individuals with high iron levels will, therefore, absorb proportionally less dietary iron than someone who is iron deficient7 and this can be monitored by measuring serum ferritin5. Iron absorption is further affected by factors including erythropoiesis, hypoxia, pregnancy, inflammation, and the combination of modifying molecules – such as amino acids, vitamins and pharmaceuticals – in the gut3,5.

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As such, the measurement of factors related to these stimuli may be highly informative when determining iron status. The above figure illustrates the overall movement of iron during its metabolism8.

Iron deficiency

Iron deficiency is in the top 20 risk factors for the global distribution of burden of disease9. It is the most common nutritional disorder in the world and the leading cause of anaemia – most preschool children and pregnant women in non-industrialised countries, and at least 30–40% in industrialised countries, are iron deficient10.

Iron deficiency also occurs frequently across multiple therapeutic areas, including in patients with chronic diseases such as inflammatory bowel disease, heart failure and chronic kidney disease1. In such conditions, inadequately managed iron deficiency has been associated with poor patient outcomes, including increased hospitalisation, reduced quality of life and even higher death rates11-13.

The many and varied roles of iron in the body mean that iron irregularities are of considerable clinical importance.

Iron overload and oxidative stress

Excessive iron intake – caused by dietary iron overload, excessive oral or parenteral iron supplementation and blood transfusion – can be highly toxic3.

Genetic factors can also influence iron retention, with diseases such as haemochromatosis characterised by excessive iron absorption that leads to life-threatening organ damage.

Iron presents an unusual problem in that the properties that make it essential in so many physiological processes, also allow it to act as a toxin. The unique ability of iron to change its oxidation state allows many iron-dependent proteins to adapt to changing environments. However, when not bound to protein, this same ability can lead to the production of ‘free radicals’ – an unwanted bi-product of the reaction between free iron and hydrogen peroxide. This, in turn, can lead to the detrimental oxidation of molecules including DNA, lipids and carbohydrates, which causes damage to cells and tissues3. This process is called ‘oxidative stress’ and is implicated in a range of diseases, including cardiovascular disease, diabetes and cancer.

Concerns have been raised regarding the potential for parenteral iron to lead to oxidative stress. The risk of oxidative stress relates to the specific nature of the iron formulation being employed. This is covered in more detail in ‘Iron deficiency management’.

References
  1. 1. Donovan, A., Roy, C. N. & Andrews, N. C. The ins and outs of iron homeostasis. Physiology 21, 115-123, doi:10.1152/physiol.00052.2005 (2006).
  2. 2. Beard, J. L. Iron biology in immune function, muscle metabolism and neuronal functioning. The Journal of nutrition 131, 568S-579S; discussion 580S (2001).
  3. 3. Crichton, R. D., Bo.G; Geisser, P. Iron Therapy With Speacial Emphasis on Intravenous Administration. Fourth Edition edn, (Bremen: UNI-MED, 2008).
  4. 4. Vaziri, N. D. Understanding Iron: Promoting Its Safe Use in Patients With Chronic Kidney Failure Treated by Hemodialysis. American journal of kidney diseases : the official journal of the National Kidney Foundation, doi:10.1053/j.ajkd.2012.10.027 (2013).
  5. 5. Hunt, J. R. in Encyclopedia of Human Nutrition 82-89 (Elsevier Ltd, 2005).
  6. 6. Janssen, M. C. & Swinkels, D. W. Hereditary haemochromatosis. Best practice & research. Clinical gastroenterology 23, 171-183, doi:10.1016/j.bpg.2009.02.004 (2009).
  7. 7. Beard, J. & Han, O. Systemic iron status. Biochimica et biophysica acta 1790, 584-588, doi:10.1016/j.bbagen.2008.09.005 (2009).
  8. 8. Horl, W. H. Anaemia management and mortality risk in chronic kidney disease. Nature reviews. Nephrology, doi:10.1038/nrneph.2013.21 (2013).
  9. 9. Institute for Health Metrics and Evaluation. GBD 2010 change in leading causes and risks between 1990 and 2010, 2010).
  10. 10. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. (WHO/NMH/NHD/MNM/11.1), (2011).
  11. 11. Jankowska, E. A. et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. European heart journal 31, 1872-1880, doi:10.1093/eurheartj/ehq158 (2010).
  12. 12. Kulnigg, S. & Gasche, C. Systematic review: managing anaemia in Crohn's disease. Alimentary pharmacology & therapeutics 24, 1507-1523, doi:10.1111/j.1365-2036.2006.03146.x (2006).
  13. 13. Okonko, D. O., Mandal, A. K., Missouris, C. G. & Poole-Wilson, P. A. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. Journal of the American College of Cardiology 58, 1241-1251, doi:10.1016/j.jacc.2011.04.040 (2011).