Low Hepcidin Levels in Severely Anemic Malawian Children with High Incidence of Infectious Diseases and Bone Marrow Iron Deficiency

Abstract

IntroductionA reliable diagnostic biomarker of iron status is required for severely anemic children living in malarious areas because presumptive treatment with iron may increase their infection risk if they are not iron deficient. Current biomarkers are limited because they are altered by host inflammation. In this study hepcidin concentrations were assessed in severely anemic children living in a highly malarious area of Malawi and evaluated against bone marrow iron in order to determine the usefulness of hepcidin as a point of care test.Methods207 severely anemic children were assessed for levels of hepcidin, ferritin, serum transferrin receptor, erythropoietin, hematological indices, C-reactive protein, interleukin-6, malaria parasites and HIV infection. Deficiency of bone marrow iron stores was graded and erythroblast iron incorporation estimated. Interaction of covariates was assessed by structural-equation-modeling.Results and ConclusionHepcidin was a poor predictor of bone marrow iron deficiency (sensitivity 66.7%; specificity 48.5%), and of iron incorporation (sensitivity 54.2%; specificity 61.8%), and therefore would have limitations as a point of care test in this category of children. As upregulation of hepcidin by inflammation and iron status was blunted by erythropoietin in this population, enhanced iron absorption through the low hepcidin values may increase infection risk. Current recommendations to treat all severely anemic children living in malarious areas with iron should therefore be reconsidered.

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

“…Consistent with previous studies, 27,29 we observed that the suppression of hepcidin starting at day 7 was negatively correlated with the increase in EPO. More interestingly, we show herein that this suppression is also negatively correlated with the expression of the recently described erythroid factor ERFE in the bone marrow and in the spleen.…”

“…The circulating levels of hepcidin more than doubled 3 to 5 days after infection, but the mechanisms involved in this upregulation remain unclear. Although IL-6 has been shown to be correlated with hepcidin in some studies, [27][28][29] in another study serum IL-6 and urinary hepcidin were not significantly associated. 23 Furthermore, in one ex vivo study, human peripheral blood mononuclear cells co-incubated with Plasmodiuminfected RBCs exhibited a significant upregulation of hepcidin mRNA without a concomitant IL-6 mRNA increase.…”

“…28 Finally, a group of children with severe malarial anemia exhibited very low serum hepcidin levels. 29 Taken together, these studies clearly indicate that during severe malarial anemia, the signaling pathway that suppresses hepcidin can override the activation pathway associated with parasiteinduced inflammation.…”

“…In the two human studies that monitored erythropoietin (EPO) levels and serum hepcidin in malaria infection, EPO and hepcidin were negatively correlated. 27,29 One animal study has also demonstrated a significant negative correlation between serum EPO and hepcidin in mice infected with Plasmodium berghei. 24 We recently showed that high levels of EPO cause hepcidin suppression indirectly by inducing the production of the erythroid regulator erythroferrone (ERFE) by erythroid progenitors in the bone marrow and the spleen.…”

“…Stimulation of erythropoietic activity translates into a dramatic increase of EPO expression and extramedullary erythropoiesis. These manifestations are reminiscent of severe anemia observed in some children living in endemic areas of malaria, 27,29 and is accompanied by a strong repression of hepcidin expression, both at the mRNA and the protein level. There is, therefore, a turning point post-infection where the signaling pathway that suppresses hepcidin overrides the activation pathway associated with blood-stage parasitemia.…”