Rapid growth is a dominant predictor of hepcidin suppression and declining ferritin in Gambian infants

Abstract

Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, seasonality, and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth cohorts of infants in rural Gambia (n=114 and n=193). This setting is characterized by extreme seasonality, prevalent childhood anemia, undernutrition, and frequent infection. Plasma was collected from infants at birth and at regular intervals, up to 12 months of age. Hepcidin, ferritin and plasma iron concentrations declined markedly during infancy, with reciprocal increases in soluble transferrin receptor and transferrin concentrations, indicating declining iron stores and increasing tissue iron demand. In cross-sectional analyses at 5 and 12 months of age, we identified expected relationships of hepcidin with iron and inflammatory markers, but also observed significant negative associations between hepcidin and antecedent weight gain. Correspondingly, longitudinal fixed effects modeling demonstrated weight gain to be the most notable dynamic predictor of decreasing hepcidin and ferritin through infancy across both cohorts. Infants who grow rapidly in this setting are at particular risk of depletion of iron stores, but since hepcidin concentrations decrease with weight gain, they may also be the most responsive to oral iron interventions.

Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

“…A recent study of Armitage et al indeed observed that antecedent weight gain was negatively associated with serum hepcidin levels in Gambian infants. 39 However, the virulence of infectious organisms depends on their ability to assimilate iron from their host.…”

“…Analyses were stratified by sex because of sex-specific differences in hepcidin levels and iron homeostasis that have been described earlier. 20,26,27,30,38,39 SPSS version 22 was used for data analysis.…”

“…The wide reference ranges reflect the substantial interindividual variation in serum hepcidin concentrations. Because of the earlier described sex-specific differences in both adults and children 20,26,27,30,39 regarding serum hepcidin levels, all analyses were stratified for sex. As shown in Table 2 and Table S2, we did not observe a difference in serum hepcidin levels between males and females.…”

Does iron let boys grow faster?!

“…To gain greater insight into how hepcidin levels are regulated 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 concentrations 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, seasonality, infection, anemia, and nutrition. Children were investigated from birth until one year of age.…”

“…However, such faster growing children are more likely to become iron deficient 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 hepcidin levels at the age of 12 months, but this also predicts that they will respond to oral iron therapy.…”