Abstract
BackgroundThe contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD.MethodsArchived samples from 199 Tanzanian children, 56% boys aged 3–18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles.FindingsIn univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2–3·93) but which was limited to girls (OR 4·85, 95%CI 1·79–13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status.InterpretationHepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis.FundingFunding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation (“Hepcidin and Iron in Global Health”, OPP1055865).
Highlights
We observed that low hepcidin levels were associated with more severe anemia, occurring in the absence of differences in possible iron markers between the groups
Despite the limitations of iron markers in sickle cell disease (SCD), we can tentatively conclude that high hepcidin levels, and an inability to absorb and incorporate iron, are not likely to be a proximal cause of more severe anemia in this population
Hepcidin in African children without SCD has been suggested as a potential marker to indicate both low iron status, and the ability to receive and utilize iron supplements in anaemic African children. [18,23] Using the same cut off as in this study, more children in HbQ1 group had low hepcidin
Summary
The contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. Findings: In univariable analysis, hepcidin b5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2–3·93) but which was limited to girls (OR 4·85, 95%CI 1·79–13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status. Interpretation: Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis.
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