An Insight into the Relationships between Hepcidin, Anemia, Infections and Inflammatory Cytokines in Pediatric Refugees: A Cross-Sectional Study

Abstract

BackgroundHepcidin, a key regulator of iron homeostasis, is increased in response to inflammation and some infections, but the in vivo role of hepcidin, particularly in children with iron deficiency anemia (IDA) is unclear. We investigated the relationships between hepcidin, cytokines and iron status in a pediatric population with a high prevalence of both anemia and co-morbid infections.Methodology/Principal FindingsAfrican refugee children <16 years were consecutively recruited at the initial post-resettlement health check with 181 children meeting inclusion criteria. Data on hematological parameters, cytokine levels and co-morbid infections (Helicobacter pylori, helminth and malaria) were obtained and urinary hepcidin assays performed. The primary outcome measure was urinary hepcidin levels in children with and without iron deficiency (ID) and/or ID anaemia (IDA). The secondary outcome measures included were the relationship between co-morbid infections and (i) ID and IDA, (ii) urinary hepcidin levels and (iii) cytokine levels. IDA was present in 25/181 (13.8%). Children with IDA had significantly lower hepcidin levels (IDA median hepcidin 0.14 nmol/mmol Cr (interquartile range 0.05–0.061) versus non-IDA 2.96 nmol/mmol Cr, (IQR 0.95–6.72), p<0.001). Hemoglobin, log-ferritin, iron, mean cell volume (MCV) and transferrin saturation were positively associated with log-hepcidin levels (log-ferritin beta coefficient (β): 1.30, 95% CI 1.02 to 1.57) and transferrin was inversely associated (β: −0.12, 95% CI −0.15 to −0.08). Cytokine levels (including IL-6) and co-morbid infections were not associated with IDA or hepcidin levels.Conclusions/SignificanceThis is the largest pediatric study of the in vivo associations between hepcidin, iron status and cytokines. Gastro-intestinal infections (H. pylori and helminths) did not elevate urinary hepcidin or IL-6 levels in refugee children, nor were they associated with IDA. Longitudinal and mechanistic studies of IDA will further elucidate the role of hepcidin in paediatric iron regulation.

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications

“…While this paper was under revision, a study on anemia in pediatric refugees was published that found an association of decreased urinary hepcidin levels with hemoglobin, ferritin, and serum iron but not to IL-6 concentrations. 42 This is in accordance with our observed lack of differences in circulating IL-6 levels between ACD (high serum hepcidin) and ACD/IDA subjects (low serum hepcidin), suggesting that the erythroid demand for iron is a more powerful regulator of hepcidin expression than inflammation-induced hepcidin formation. However, as a limitation of this study, we were not able to distinguish between the effects of a putative erythropoietic stimulation and the effects of iron deficiency on hepcidin expression when analyzing the combined effects of bleeding and inflammation, although EPO levels were significantly higher in ACD/IDA compared with ACD subjects.…”

Role of hepcidin in the diagnosis of sepsis and septic shock in children

“…Moreover, we were not able to examine WBC, CRP, and PCT levels due to inadequate blood volume collected from the healthy children. The levels of the biomarkers at the time the samples were taken may not reflect their actual levels because our data are cross-sectional, the half-lives of sepsis markers are different (14,(25)(26)(27), and the majority of patients had received antibiotic and fluid therapy prior to the PICU. Hepcidin is severely affected by anemia parameters such as serum and storage iron levels of patients regardless of the level of inflammation.…”

Serum hepcidin, iron metabolism and infection parameters in children with anemia of inflammation and with iron deficiency anemia

“…It takes place in oxygen transport, protein synthesis, and function of enzymes. Adequate iron stores are necessary for normal childhood growth and development [1,2]. Although the biological importance of iron has been known since ancient times, there have been new developments in the field of absorption and storage of the iron during the the last decade, especially in the last 2-3 years.…”

“…Ferroportin exports iron into plasma from duodenocytes, hepatocytes and erythrophagocytosing macrophages [5]. Measurement of hepcidin concentrations in serum or urine is thought to be useful to differentiate iron-deficiency anemia from anemia of infection [2]. Ferroportin is the sole known iron exporter.…”

“…However, there are not enough studies investigating the effectiveness of serum hepcidin levels in iron-deficiency anemia and anemia of inflammation in children [1,2,[8][9][10][11].…”