Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children

Abstract

Iron deficiency anemia (IDA) is the most prevalent nutritional condition worldwide. We studied the contribution of hepcidin-mediated iron blockade to IDA in African children. We measured hepcidin and hemoglobin weekly, and hematological, inflammatory, and iron biomarkers at baseline, 7 weeks, and 12 weeks in 407 anemic (hemoglobin < 11 g/dl), otherwise healthy Gambian children (6 to 27 months). Each child maintained remarkably constant hepcidin levels (P < 0.0001 for between-child variance), with half consistently maintaining levels that indicate physiological blockade of iron absorption. Hepcidin was strongly predicted by nurse-ascribed adverse events with dominant signals from respiratory infections and fevers (all P < 0.0001). Diarrhea and fecal calprotectin were not associated with hepcidin. In multivariate analysis, C-reactive protein was the dominant predictor of hepcidin and contributed to iron blockade even at very low levels. We conclude that even low-grade inflammation, especially associated with respiratory infections, contributes to IDA in African children.

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

“…45 We hypothesize that the high hepcidin levels in young children relative to adolescents might result in a survival advantage during a critical period of high vulnerability for serious infections. 44,45 We observed a positive correlation of CRP levels (between 0.1 and 5 mg/L) with serum hepcidin levels, suggesting that, as described earlier, 46 even minor infections and/or inflammation induce hepcidin production in children, consistent with the suggested protective antimicrobial activity of hepcidin. 2 Importantly, the relatively high hepcidin levels for ferritin in young children as compared to adolescents did not result in IDA in these subjects, despite the enormous growth during infancy that is accompanied by a considerable increase of circulating blood volume and other tissues requiring iron.…”

“…The TSAT/hepcidin ratio was statistically significantly correlated with multiple biochemical correlates in both males and females after adjustment for age and time of blood sampling ( Table 6). The sexspecific multivariable models including these parameters explained 46.0% and 22.8% of the TSAT/hepcidin ratio variation in males and females, respectively (Table S7).…”

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

“…This may relate to higher contents of bioavailable iron in typical European weaning diets. A recent study in Gambian infants (6–27 months) found that respiratory infections and fever incidence (but not diarrhoea or faecal calprotectin—a marker of intestinal inflammation) were strongly associated with raised hepcidin; inflammation (marked by CRP), even if very low-grade, was the dominant predictor of hepcidin [90]. Chronic, even mild, inflammation may therefore play a key role in inhibiting dietary iron uptake, contributing to the declining iron status of early childhood in such settings.…”

“…It is likely that childhood infections similarly encompass hepcidin induction. Indeed, associations between elevated hepcidin and respiratory infection or fever, but not diarrhoea, in young children were recently reported [90].…”

“…Recurrent or chronic infections, or other drivers of persistent inflammation, even if mild, may also lead to raised hepcidin and relative inhibition of dietary iron absorption [90,106]. The specific relationship between hepcidin upregulation and iron absorption may be context dependent.…”