Iron Status and Associated Malaria Risk Among African Children.

BACKGROUND: It remains unclear whether improving iron status increases malaria risk, and few studies have looked at the effect of host iron status on subsequent malaria infection. We therefore aimed to determine whether a child's iron status influences their subsequent risk of malaria infection in sub-Saharan Africa. METHODS: We assayed iron and inflammatory biomarkers from community-based cohorts of 1309 Kenyan and 1374 Ugandan children aged 0-7 years and conducted prospective surveillance for episodes of malaria. Poisson regression models were fitted to determine the effect of iron status on the incidence rate ratio (IRR) of malaria using longitudinal data covering a period of 6 months. Models were adjusted for age, sex, parasitemia, inflammation, and study site. RESULTS: At baseline, the prevalence of iron deficiency (ID) was 36.9% and 34.6% in Kenyan and Ugandan children, respectively. ID anemia (IDA) affected 23.6% of Kenyan and 17.6% of Ugandan children. Malaria risk was lower in children with ID (IRR, 0.7; 95% confidence interval [CI], 0.6, 0.8; P < .001) and IDA (IRR, 0.7; 95% CI, 0.6, 0.9; P = .006). Low transferrin saturation (<10%) was similarly associated with lower malaria risk (IRR, 0.8; 95% CI, 0.6, 0.9; P = .016). However, variation in hepcidin, soluble transferrin receptors (sTfR), and hemoglobin/anemia was not associated with altered malaria risk. CONCLUSIONS: ID appears to protect against malaria infection in African children when defined using ferritin and transferrin saturation, but not when defined by hepcidin, sTfR, or hemoglobin. Additional research is required to determine causality. CLINICAL TRIALS REGISTRATION: ISRCTN32849447

Estimating the burden of iron deficiency among African children.

BACKGROUND: Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children. METHODS: We assayed iron and inflammatory biomarkers in 4853 children aged 0-8?years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin <?12??g/L or <?30??g/L in the presence of inflammation in children <?5?years old or <?15??g/L in children ??5?years old). We compared this with a recently proposed gold standard, which uses regression-correction for ferritin levels based on the relationship between ferritin levels, inflammatory markers, and malaria. We further investigated the utility of other iron biomarkers in predicting ID using the inflammation and malaria regression-corrected estimate as a gold standard. RESULTS: The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation <?11% most closely predicted the prevalence of ID according to the regression-correction gold standard. CONCLUSIONS: The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa

Prevalence and predictors of vitamin D deficiency in young African children.

BACKGROUND: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children. METHODS: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses. RESULTS: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants. CONCLUSIONS: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa

Relationship between Energy Balance and Circulating Levels of Hepcidin and Ferritin in the Fasted and Postprandial States

Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −883.45 ± 400.94; p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −148.26 ± 61.20; p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −806.09 ± 395.44; p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −129.40 ± 59.14; p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism

Associations of Habitual Mineral Intake with New-Onset Prediabetes/Diabetes after Acute Pancreatitis

Associations between habitual dietary intake of minerals and glucose metabolism have been extensively studied in relation to metabolic disorders. However, similar research has yet to be conducted in individuals after acute pancreatitis (AP). The main aim was to investigate the associations between habitual intake of 13 minerals and glycaemic status: new-onset prediabetes/diabetes after AP (NODAP), pre-existing prediabetes/type 2 diabetes (T2DM), and normoglycaemia after AP (NAP). Associations between the dietary intake of minerals and markers of glucose metabolism (glycated haemoglobin and fasting plasma glucose) were also studied. The EPIC-Norfolk food frequency questionnaire was used in a cross-sectional fashion to determine the habitual intake of 13 dietary minerals. ANCOVA as well as multiple linear regression analyses were conducted and five statistical models were built to adjust for covariates. The study included 106 individuals after AP. In the NODAP group, intake of 4 minerals was significantly less when compared with the NAP group: iron (B = −0.076, p = 0.013), nitrogen (B = −0.066, p = 0.003), phosphorous (B = −0.046, p = 0.006), and zinc (B = −0.078, p = 0.001). Glycated haemoglobin was significantly associated with iodine intake (B = 17.763, p = 0.032) and manganese intake (B = −17.147, p = 0.003) in the NODAP group. Fasting plasma glucose was significantly associated with manganese intake (B = −2.436, p = 0.027) in the NODAP group. Habitual intake of minerals differs between individuals with NODAP, T2DM, and NAP. Prospective longitudinal studies and randomised controlled trials are now warranted to further investigate the associations between mineral intake and NODAP

Relationship between Habitual Intake of Vitamins and New-Onset Prediabetes/Diabetes after Acute Pancreatitis

Vitamins have many established roles in human health. However, the role of habitual dietary intake of vitamins in glucose homeostasis in individuals after acute pancreatitis (AP) is yet to be elucidated. The aim was to investigate the associations between habitual intake of fat- and water-soluble vitamins/vitamers and markers of glucose metabolism (fasting plasma glucose (FPG), homeostasis model assessment insulin resistance (HOMA-IR) index, and homeostasis model assessment &beta;-cell function (HOMA-&beta;)) in individuals after AP. A total of 106 participants after AP were included in this cross-sectional study and were grouped based on glycaemic status: new-onset prediabetes/diabetes after AP (NODAP), pre-existing prediabetes/type 2 diabetes (T2DM), and normoglycaemia after AP (NAP). Habitual intake of seven fat-soluble vitamins/vitamers and seven water-soluble vitamins were determined by the EPIC-Norfolk food frequency questionnaire. Multiple linear regression analyses were conducted using five statistical models built to adjust for covariates (age, sex, daily energy intake, visceral/subcutaneous fat volume ratio, smoking status, daily alcohol intake, aetiology of AP, number of AP episodes, cholecystectomy, and use of antidiabetic medications). In the NODAP group, three fat-soluble vitamins/vitamers (&alpha;-carotene, &beta;-carotene, and total carotene) were significantly associated with HOMA-&beta;. One water-soluble vitamin (vitamin B3) was also significantly associated with HOMA-&beta; in the NODAP group. None of the studied vitamins were significantly associated with FPG or HOMA-IR in the NODAP group. Prospective longitudinal studies and randomised controlled trials are now warranted to investigate if the observed associations between vitamin/vitamer intake and NODAP are causal and to unveil the specific mechanisms underlying their involvement with NODAP

Dietary Fibre Intake in Type 2 and New-Onset Prediabetes/Diabetes after Acute Pancreatitis: A Nested Cross-Sectional Study

The association between intake of dietary fibre and glucose metabolism has been extensively investigated in numerous metabolic disorders. However, little is known about this association in individuals after an attack of acute pancreatitis (AP). The aim was to investigate the associations between intake of dietary fibre and markers of glucose metabolism in individuals with new-onset prediabetes or diabetes after acute pancreatitis (NODAP), pre-exiting type 2 prediabetes or diabetes, and normoglycaemia after acute pancreatitis. This cross-sectional study was nested within the parent prospective longitudinal cohort study. The studied markers of glucose metabolism were fasting plasma glucose and glycated haemoglobin. Habitual intake of dietary fibre was determined using the EPIC-Norfolk food frequency questionnaire. Multivariable linear regression analyses were conducted. The study included a total of 108 individuals after AP. In the NODAP group, increased intakes of total fibre (β = −0.154, p = 0.006), insoluble fibre (β = −0.133, p = 0.01), and soluble fibre (β = −0.13, p = 0.02) were significantly associated with a reduction in fasting plasma glucose. Increased intakes of vegetables (β = −0.069, p = 0.004) and nuts (β = −0.039, p = 0.038) were significantly associated with a reduction in fasting plasma glucose. Increased intake of nuts (β = −0.054, p = 0.001) was also significantly associated with a reduction in glycated haemoglobin. None of the above associations were significant in the other study groups. Habitual intake of dietary fibre was inversely associated with fasting plasma glucose in individuals with NODAP. Individuals after an attack of AP may benefit from increasing their intake of dietary fibre (specifically, vegetables and nuts) with a view to preventing NODAP

The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia.

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth