The Danger of Iron Supplementation

Iron deficiency is the most common form of malnutrition in the world, affecting more than 2 billion people globally(1). According to the WHO(6), if the amount of absorbable iron in the diet cannot be immediately improved, iron supplementation will be a necessary component of programs to control iron deficiency anemia. Moreover, they recommend supplementation with iron to high-risk groups: pregnant women and children 6 months to 2 years, as well as women in reproductive age, preschool children, school-age children, and adolescents in areas with a high prevalence of anemia(6).

Less might mean More

This may sound like a definite solution, but here's the problem: Low iron measurement does not always indicate low iron status. During presence of infection and inflammation, the immune system cells (Macrophages) induces the production of inflammatory hormones called cytokines, particularly known as Interleukin 6 or IL-6(2).

The presence of cytokines signals the liver to release another hormone called hepcidin, which has the ability to regulate iron levels by inhibiting dietary iron absorption and locking iron into the cells(2).

The competition for IRON

Ferritin is the storage room for iron in our cells. However, pathogens can also access stored iron and use it for their own nourishment, which is why our immune system (macrophages) has this amazing mechanism to release inflammatory hormones which leads to cascade of reactions to deprive bacteria of iron.

The Downside: False Positive results

Though this mechanism prevents iron from circulating to deprive pathogens from iron needed for nourishment, This could be interpreted as low iron status(2).

Supplementation of iron may lead to iron overload that could overwhelm the capacity of hepcidin to inhibit iron absorption(1). Thus the mechanism to lower iron in circulation will be beneficial in infections, but when iron intake is too high, hepcidin might not be sufficient to deprive pathogens from iron(2). This is the reason why some iron supplementation programs in developing countries failed to correct iron levels. In worst cases, supplementation was discontinued after a remarkable number of deaths occured.

Guidelines should be Revisited

It is alarming that the simple screening for iron deficiency pushes health workers in low-income countries to address iron deficiency problems without considering the presence of infections. To prevent this problem, the WHO guidelines on Iron-supplementation include complementary parasite control measures along with iron-supplementation ONLY when parasitic infections are endemic(6). In other words, efforts to control infection will only be given when the prevalence of parasitic infection reaches 20-30% or greater(6).

The Good News

The good news is that there are some precaution ways to attenuate detrimental effects of iron overload. One technique is to use “slow-release” iron compounds such as sodium iron ethylenediaminetetraacetate and iron polymaltose(5). These types of supplements results in lower free-iron levels compared to ferrous sulfate supplementation(5). Similarly, taking iron supplements with food results to less circulating iron and helps prevent pathogens from getting stronger.

and ....The Bad News

The bad news is that low-income countries have poor planning and resources on parasitic infection tests. When most funds are directed towards supplementation, the complementary parasite control is neglected. Moreover, biomarkers for low iron status and anemia will show false-positive results in the presence of infection. When interpreting iron status, inflammation markers such as C-reactive protein should be used along with iron measurements(3). A positive inflammation means false-positive iron-deficiency and requires medical intervention(3).

Take home message:

What can individuals and health professionals do to ensure safety on iron-supplementation? Whether it is an individual or in public health problem, infection and inflammatory markers should be cleared before initializing iron-supplementation(7). The best and safest way to obtain iron is through the diet together with vitamin C-rich foods to increase its absorption(4). This may take time to restore iron levels to normal though. When necessary, iron supplements can be taken BUT with caution and should be instructed to be taken with food(7). Most of all, remember that all supplements are indicated only for deficient individuals where food cannot meet nutrient needs.

References

1) Daba, A., Gkouvatsos, K., Sebastiani, G., & Pantopoulos, K. (2013). Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing. Journal of Molecular Medicine (Berlin, Germany), 91(1), 95–102. doi:10.1007/s00109-012-0937-5

2) De Domenico I, Zhang TY, Koening CL, Branch RW, London N, Lo E, Daynes RA, Kushner JP, Li D, Ward DM, Kaplan J. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010;120(7):2395-405

3) Engle-stone, R., Nankap, M., Ndjebayi, A. O., Erhardt, J. G., & Brown, K. H. (2013). Plasma Ferritin and Soluble Transferrin Receptor Concentrations and Body Iron Stores Identify Similar Risk Factors for Iron Deficiency but Result in Different Estimates of the National Prevalence of Iron Deficiency and Iron-Deficiency Anemia among Women and, (8), 369–377. doi:10.3945/jn.112.167775.iron

4) Gropper, S. S., & Smith, J. L. (2013). Advanced nutrition and human metabolism. (6th ed., p. 474). Belmont CA: Wadsworth Cengage Learning.

5) Schumann, K., Solomons, N. W., Orozco, M., Romero-Abal, M. E., & Weiss, G. (2013). Differences in circulating non-transferrin-bound iron after oral administration of ferrous sulfate, sodium iron EDTA, or iron polymaltose in women with marginal iron stores. Food and Nutrition Bulletin, 34(2)

6) Stoltzfus, R. J., & Dreyfuss, M. L. (n.d.). Guidelines for the Use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia.

7) Zlotkin, S., Newton, S., Aimone, A. M., Azindow, I., Amenga-Etego, S., Tchum, K., Owusu-Agyei, S. (2013). Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial. JAMA : The Journal of the American Medical Association, 310(9), 938–47. doi:10.1001/jama.2013.277129

8) Reis Lemos, A., Ismael, L.A., Boato, C.C., Borges, M.T., Rondo, P.H. (2010). Review Article Hepcidin as a Biochemical Parameter for the Assessment of Iron Deficiency Anemia, Rev Assoc Med Bras 2010; 56(5): 596-9