Page 11 - 2019_08-Haematologica-web

Does iron let boys grow faster?!
Günter Weiss1,2
1Department of Internal Medicine II, Innsbruck Medical University and 2Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Innsbruck, Austria
E-mail: GÜNTER WEISS - guenter.weiss@i-med.ac.at doi:10.3324/haematol.2019.222018
Iron is an essential nutrient for the body as it plays a part in multiple enzymatic processes, including DNA synthesis, mitochondrial respiration, oxygen transport, hormone for- mation, and cellular metabolism.1 Iron deficiency and iron deficiency anemia (the latter arising from limited availability of the metal for heme biosynthesis) are global health problems that affect around two billion people. These are particularly important in infants because they have a negative impact on children's growth and mental development.2 Such a situation is highly prevalent in developing countries. Thus, efforts have been made to substitute iron to avoid such developmental defects in children. However, the unbiased administration of iron supplements to children’s diets in tropical regions resulted in a significant increase in morbidity and mortality from infec- tious diseases.3 These can be attributed to the fact that iron is an essential nutrient also for most pathogens but also impacts on the efficacy of anti-microbial immune effector pathways.4,5 Subsequent studies have shown that mild iron deficiency in infants even offers protection from specific infections such as severe malaria.6 This has left physicians with the dilemma as to how to identify children who may benefit from iron supple- mentation while avoiding the risk of an adverse outcome from infection.
Thus, several diagnostic approaches have been adopted to identify those children who may respond to iron supplementa- tion therapy. In this context, the determination of the iron hor- mone hepcidin has attracted great interest. Hepcidin is a liver- derived peptide which controls body iron homeostasis upon binding to the only known cellular iron export protein ferro- portin, resulting in its internalization and degradation.1 Hepcidin expression is induced by body iron loading or inflam- matory signals, including those arising from systemic infec- tions, whereas iron deficiency (as well as, among others, hypoxia and anemia) reduce hepcidin expression.7 Accordingly, low hepcidin levels enable dietary or orally supplemented iron to be absorbed from the duodenum, whereas high-circulating hepcidin levels impair iron transfer from duodenal enterocytes to the circulation.8 In other words, subjects with true iron defi- ciency efficiently absorb iron from the duodenum, whereas persistent inflammation impairs iron uptake from the gut with iron remaining in the intestine.8 This not only results in a blunt- ed response to oral iron therapy, but also increases the availabil- ity of iron for the intestinal microbiome. This leads to subtle alterations of the composition of the microbiota with an increase in pathogenic bacteria and promotion of intestinal inflammation.9 Thus, hepcidin determination in children has been seen to be a reliable diagnostic test to predict the response to oral iron therapy.10 This is also of interest as infection inducible inflammatory signals impact on cytokine formation and stimulate hepcidin production, resulting in the develop- ment of functional iron deficiency, particularly in countries with a high endemic burden of infectious diseases. This functional iron deficiency is characterized by iron retention in reticulo- endothelial cells and the emergence of anemia of inflammation
or anemia of chronic disease which poorly responds to oral iron.11 However, in tropical countries, due to nutritional iron deficiency and/or chronic blood loss on the basis of intestinal infestation with hookworms, counter-regulatory factors can impact on hepcidin levels. Studies in animal models have shown that the inhibitory signals exerted by iron deficiency dominate over hepcidin induction by inflammation.12 This has also been confirmed in clinical trials in young women and in patients with inflammatory bowel disease and low-grade inflammation showing good absorption of oral iron.13,14 This would suggest that low hepcidin levels, even in an inflammato- ry setting, would predict sufficient oral iron absorption.
To gain greater insight into how hepcidin levels are regulat- ed and affected by different factors in a primary care setting, and how these change in early infancy over time, Armitage and co-workers analyzed data from two birth cohorts in The Gambia, Western Africa, adopting a longitudinal approach to the analysis.15 They took repeat measurements of serum con- centrations of hepcidin, iron, the iron storage protein ferritin, and soluble transferrin receptor (sTfR) (which is a marker for the needs of iron for erythropoiesis) and studied the results for associations of these markers with birth weight, growth, sea- sonality, infection, anemia, and nutrition. Children were inves- tigated from birth until one year of age. First, the authors observed that low iron and hepcidin levels at birth were asso- ciated with a lower birthweight, pointing to the importance of sufficient maternal iron supplementation during pregnancy. Second, they also found a decrease in hepcidin, iron and fer- ritin levels over time which is indicative for incorporation of the metal into the growing body. Of note, a greater weight gain was associated with more severe iron deficiency as reflected by low ferritin and hepcidin levels. This also indicat- ed that the faster growth of children is paralleled by or even a consequence of more efficient incorporation of iron in the body where it is used for erythropoiesis and enzymatic com- plexes including myoglobin in muscle cells. However, such faster growing children are more likely to become iron defi- cient because dietary iron availability cannot compensate for the increased incorporation of iron in the body. Thus, such children need specific attention in order to avoid unwanted negative effects of iron deficiency on their development from one year of age onwards; based on the data presented by Armitage et al.,15 these infants can be identified by low hep- cidin levels at the age of 12 months, but this also predicts that they will respond to oral iron therapy.
Most surprisingly, the significant association between growth promotion and iron deficiency was most pronounced in boys. Even at five months of age, a higher prevalence of both iron deficiency and anemia became evident in males as compared to female subjects. Of note, at this early stage, there was a negative association between higher hepcidin levels and gain of weight and length in both sexes, confirming that infec- tion-driven elevation of hepcidin negatively impacts on iron absorption.8
haematologica | 2019; 104(8)
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