Measures Of Iron Status Research Articles

A young child formula supplemented with a synbiotic mixture of scGOS/lcFOS and Bifidobacterium breve M-16V improves the gut microbiota and iron status in healthy toddlers.

Early-life gut microbiota development depends on a highly synchronized microbial colonization process in which diet is a key regulator. Microbiota transition toward a more adult-like state in toddlerhood goes hand in hand with the transition from a milk-based diet to a family diet. Microbiota development during the first year of life has been extensively researched; however, studies during toddlerhood remain sparse. Young children's requirement for micronutrients, such as dietary iron, is higher than adults. However, their intake is usually sub-optimal based on regular dietary consumption. The Child Health and Residence Microbes (CHaRM) study, conducted as an adjunct to the GUMLi (Growing Up Milk "Lite") trial, was a double-blind randomized controlled trial to investigate the effects on body composition of toddler milk compared to unfortified standard cow's milk in healthy children between 1 and 2 years of age in Brisbane (Australia). In this trial, fortified milk with reduced protein content and added synbiotics [Bifidobacterium breve M-16V, short-chain galactooligosaccharides, and long-chain fructooligosaccharides (ratio 9:1)] and micronutrients were compared to standard unfortified cow's milk. In the present study, the effects of the intervention on the gut microbiota and its relationship with iron status in toddlers were investigated in a subset of 29 children (18 in the Active group and 11 in the Control group) who completed the CHaRM study. The toddler microbiota consisted mainly of members of the phyla Firmicutes, Bacteroidota, and Actinobacteriota. The abundance of the B. breve species was quantified and was found to be lower in the Control group than in the Active group. Analysis of blood iron markers showed an improved iron status in the Active group. We observed a positive correlation between Bifidobacterium abundance and blood iron status. PICRUSt, a predictive functionality algorithm based on 16S ribosomal gene sequencing, was used to correlate potential microbial functions with iron status measurements. This analysis showed that the abundance of predicted genes encoding for enterobactin, a class of siderophores specific to Enterobacteriaceae, is inversely correlated with the relative abundance of members of the genus Bifidobacterium. These findings suggest that healthy children who consume a young child formula fortified with synbiotics as part of a healthy diet have improved iron availability and absorption in the gut and an increased abundance of Bifidobacterium in their gut microbiome.

Effectiveness of zinc protoporphyrin/heme ratio and ferritin for assessing iron status in preterm infants.

Since iron is crucial for many tissue processes, we, therefore, aimed to assess ferritin and the zinc protoporphyrin to heme ratio (ZnPP/H) as indicators of iron status in preterm newborns, particularly during certain inflammatory episodes. From 170 preterm babies, paired ferritin and ZnPP/H measurements were collected twice (on the first postnatal day and six weeks later). To compare these measures and assess the impact of anemia, sepsis, and packed red blood cell transfusion (PRBT), three different scenarios were considered. Compared to the non-anemic group, the anemic patients' serum ferritin level was considerably lower (p = 0.044), whereas the anemic patients' ZPP/H ratio was significantly greater (p < 0.001). In neonates with sepsis, ferritin levels were considerably greater in both anemic and non-anemic septic neonates compared to neonates without sepsis (p < 0.001 for each). Regarding ZPP/H ratio, no appreciable variations were found between the two groups. In addition, serum ferritin significantly increased following each PRBT (p < 0.001 for each). As a result of each PRBT, the ZPP/H ratio considerably decreased (p < 0.001). As a measure of iron status during particular inflammatory processes like infection and PRBT, ZnPP/H may be more accurate.

Maternal hemoglobin and iron status in early pregnancy and risk of respiratory tract infections in childhood: A population-based prospective cohort study.

Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age. In a population-based cohort study among 5134 mother-child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied. After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects. High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections.

Iron Deficiency and Iron Deficiency Anemia in Women with and without Obesity: NHANES 2001-2006.

Obesity has been linked to numerous health and nutritional problems, including impaired iron metabolism, a common cause of anemia. We aimed to determine the prevalence of anemia, iron deficiency (ID), and iron deficiency anemia (IDA) among women aged 20-49 years based on body mass index (BMI) status. We used measures of iron status and body mass index from the 2001-2006 National Health and Nutrition Examination Survey (NHANES). Mean serum ferritin, erythrocyte protoporphyrin, and soluble transferrin receptor were higher, while those of serum iron, percent transferrin saturation, and mean cell volume (MCV) were lower in women with obesity than those with normal weight (all p < 0.016). ID based on the ferritin model was 12.5 ± 1.0% vs. 22.9 ± 1.6% (p < 0.001); 9.0 ± 0.9% vs. 20.0 ± 1.3% (p < 0.001) based on the MCV model; and 8.1 ± 1.0% vs. 10.5 ± 1.2% (p > 0.05) based on the BII model for women with normal weight and women with obesity, respectively. Anemia prevalence was 5.5 ± 0.8% (normal) vs. 9.3 ± 1.0% (obese) (p = 0.005). The IDA estimates based on the ferritin and MCV models were similar but higher than that from the BII model (p < 0.001). Generally, the prevalence rates of ID and anemia (and IDA) were higher for women with obesity, but the method used to define deficiency mattered. The choice of iron indices is important for estimating ID and IDA in populations with obesity.

Development of Iron Status Measures during Youth: Associations with Sex, Neighborhood Socioeconomic Status, Cognitive Performance, and Brain Structure

BackgroundIron is essential to brain function, and iron deficiency during youth may adversely impact neurodevelopment. Understanding the developmental time course of iron status and its association with neurocognitive functioning is important for identifying windows for intervention. ObjectivesThis study aimed to characterize developmental change in iron status and understand its association with cognitive performance and brain structure during adolescence using data from a large pediatric health network. MethodsThis study included a cross-sectional sample of 4899 participants (2178 males; aged 8–22 y at the time of participation, M [SD] = 14.24 [3.7]) who were recruited from the Children’s Hospital of Philadelphia network. Prospectively collected research data were enriched with electronic medical record data that included hematological measures related to iron status, including serum hemoglobin, ferritin, and transferrin (33,015 total samples). At the time of participation, cognitive performance was assessed using the Penn Computerized Neurocognitive Battery, and brain white matter integrity was assessed using diffusion-weighted MRI in a subset of individuals. ResultsDevelopmental trajectories were characterized for all metrics and revealed that sex differences emerged after menarche such that females had reduced iron status relative to males [all R2partial > 0.008; all false discovery rates (FDRs) < 0.05]. Higher socioeconomic status was associated with higher hemoglobin concentrations throughout development (R2partial = 0.005; FDR < 0.001), and the association was greatest during adolescence. Higher hemoglobin concentrations were associated with better cognitive performance during adolescence (R2partial = 0.02; FDR < 0.001) and mediated the association between sex and cognition (mediation effect = −0.107; 95% CI: −0.191, −0.02). Higher hemoglobin concentration was also associated with greater brain white matter integrity in the neuroimaging subsample (R2partial = 0.06, FDR = 0.028). ConclusionsIron status evolves during youth and is lowest in females and individuals of low socioeconomic status during adolescence. Diminished iron status during adolescence has consequences for neurocognition, suggesting that this critical period of neurodevelopment may be an important window for intervention that has the potential to reduce health disparities in at-risk populations.

Eligibility Considerations for Female Whole Blood Donors: Hemoglobin Levels and Iron Status in a Nationally Representative Population.

Blood collection from minority populations improves the transfusion support of patients with sickle cell disease and thalassemia, but efforts are challenged by high deferral rates for hemoglobin (Hb) eligibility thresholds. This study sought to evaluate hemoglobin and iron status of a representative US female population to assess the suitability of 12.0 g/dL as minimum hemoglobin. Data were extracted from the National Health and Nutrition Examination Surveys (NHANES), 1999-2010. A national sample designed to reflect potential female blood donors (weight ≥110 lbs, not pregnant, no infectious marker reactivity, and no blood donation in past year) aged 16 to 49 years was analyzed for Hb and serum ferritin (SF) measures by race/ethnicity (N=6937). Mean Hb and SF and the prevalence of iron deficiency ([ID] SF<12 ng/mL and SF<26 ng/mL) and low Hb (<12.5 g/dL and <12.0 g/dL) were estimated. Multivariable modified Poisson regression compared the prevalence for ID or low Hb at each cutoff by race/ethnicity. Mean SF values were higher and ID prevalence was lower in Non-Hispanic (NH) White (SF=45.3 ng/mL, SF<12 ng/mL=8.2%) than NH Black (SF=39.6 ng/mL, SF<12 ng/mL=14.2%) and Hispanic (SF=36.5 ng/mL, SF<12 ng/mL=12.7%) females. Compared to NH White females (13.7 g/dL), mean Hb was lower in NH Black (12.6 g/dL) and Hispanic females (13.4 g/dL). The percentage with Hb<12.5 g/dL was >4 times greater in NH Black (39.1%) and >2 times greater in Hispanic females (16.5%) compared to NH White (8.6%). Within 0.5 g/dL incremental categories of Hb, NH Black had higher mean SF levels and lower prevalence of SF<12 ng/mL or <26 ng/mL compared to NH White and Hispanic females. At Hb of 12.0 to 12.4g/dL, NH Black females had better measures of iron status (SF=39.1 ng/mL, %SF<12 ng/mL=12.0%) than NH White (SF=33.6 ng/mL, %SF<12 ng/mL=15.8%) and Hispanic (SF=30.4 ng/mL, %SF<12 ng/mL=15.5%) females whose Hb was 12.5 to 12.9 g/dL. Adjusting for age and Hb, the prevalence ratio for low SF was significantly lower in NH Black compared to NH White females at both SF<26 ng/mL (adjusted prevalence ratio [aPR]=0.83, 95%CI=0.76-0.92) and SF<12 ng/mL (aPR=0.66, 95%CI=0.52-0.83). NH Black females with Hb 12.0 to 12.4g/dL have better iron stores than NH White and Hispanic females whose Hb is 12.5 to 12.9 g/dL. The distribution of Hb and iron may support the safe collection of blood for female donors below the current Hb eligibility requirement of 12.5 g/dL.

Efficacy and utility of a tool for both measurement of vitamin B6, B12, D, folate and iron status and assessment of diet quality in athletes.

NutriProfiel® is a tool to measure micronutrient status and to assess diet quality. It consists of measurement of micronutrient status in blood and a short food frequency questionnaire (FFQ) ('Eetscore-FFQ'). Based on the results, individuals receive a dietary advice. In this study, we evaluated the application of NutriProfiel in athletes ('NutriProfiel-Sport') by assessing the coverage of nutrient intake of the Eetscore-FFQ (part 1) and by evaluating athlete's dietary behaviour after using NutriProfiel-Sport and their satisfaction with this tool (part 2). For part 1, data of 419 athletes were used. We evaluated the coverage of nutrient intake of the Eetscore-FFQ using first and second MOMents (MOM1 and MOM2) sum scores of food items in the questionnaire. Forty-eight athletes were involved in part 2. They gave blood samples for micronutrient status measurement and were asked to complete the Eetscore-FFQ at baseline and after 3 months, as well as a questionnaire on their satisfaction with NutriProfiel-Sport. Results showed that for most nutrients, MOM1 and MOM2 scores were above 80 %, meaning that nutrient intake was sufficiently covered by the Eetscore-FFQ. No difference in diet quality was observed between baseline and after 3 months. Nevertheless, a majority of athletes reported the NutriProfiel-Sport results and advice as useful. On a scale from 0 to 10, NutriProfiel-Sport was graded with a mean (±sd) score of 7⋅6 (±0⋅8). In conclusion, NutriProfiel-Sport is a potential valuable and appreciated tool for athletes and the Eetscore-FFQ as part of this tool sufficiently covers nutrient intake in athletes.

Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Background: Iron overload (IO) is an important clinical consequence of transfusion-dependent myelodysplastic syndromes (MDS). For patients with high transfusion burden (HTB), limited treatment options are available to effectively treat anemia and reduce transfusion dependence. Transfusion dependence is an independent predictor of poor prognosis in MDS. It is associated with IO and elevated ferritin, a marker of intracellular iron storage that also predicts poor prognosis in MDS. When adjusting for transfusion burden, each 500 µg/L increase in ferritin above 1000 µg/L is associated with a 30% greater risk of death (Malcovati et al. 2006). IO also disrupts osteoprogenitors and erythroid precursors within the osteohematopoietic niche, leading to abnormal bone turnover and ineffective erythropoiesis (Bulycheva 2015). While iron chelators have shown some efficacy in managing IO, they introduce toxicities and have little effect on transfusion burden. Unmet need remains for treatments that effectively address anemia, IO, and reduce transfusion dependence in patients with MDS, especially those with HTB. KER-050 is designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche, and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. To date, clinical data indicate that KER-050 induces sustained increases in reticulocytes and hemoglobin. Preliminary findings also show potential for KER-050 to induce erythroid response and reduce transfusion burden in patients with MDS, including those with HTB (Tan et al., 2022). KER-050 may also impact iron metabolism and this presentation explores the effects of KER-050 on indices of IO. Methods: This Phase 2 study is evaluating KER-050 in participants with very low- to intermediate-risk MDS. Data presented are from Part 1 Dose Escalation which included 16 weeks of KER-050 treatment across 5 cohorts (0.75 to 5 mg/kg). Iron chelator therapy was permitted at the discretion of the investigator provided patients had been on a stable dose for 8 weeks prior to C1D1. Markers of IO and hematopoiesis were assessed as exploratory endpoints over the 16-week treatment period. Analyses presented evaluate the effect of KER-050 on these markers. Baseline markers of bone turnover were also assessed. Results: A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1). HTB patients had the highest baseline serum iron and ferritin levels. Preliminary findings indicate that KER-050 treatment was associated with decreases in serum ferritin for patients both with and without iron chelator therapy. Patients achieving transfusion independence (TI) experienced a 39.5% reduction (mean change: -619.4 ng/ml, range: -2118.4 to +243 ng/mL) in serum ferritin at Week 12 that was generally sustained at Week 16 and 20 (Figure 1). Similarly, over the same time period, serum iron and transferrin saturation (TSAT) decreased by 4.03 µmol/L (8.38%) and 5.3%, respectively, in patients achieving TI. Soluble transferrin receptor (sTfR) increased by 32.2% and remained elevated at subsequent visits. Summary: Preliminary data from the 16-week Dose Escalation in this ongoing phase 2 study reveal differences in baseline iron biomarkers indicative of increasing iron overload with increasing transfusion burden. While nearly half of HTB patients received iron chelator therapy, this group had markedly elevated ferritin compared to NT and LTB patients at baseline. KER-050 treatment was associated with reductions in serum ferritin, irrespective of the use of iron chelation. Patients achieving TI experienced decreases in ferritin, iron and TSAT concurrent with increases in sTfR that were generally maintained through follow-up. The data suggest that, in addition to improving hematopoiesis and transfusion burden in MDS patients, KER-050 may reduce iron overload, a serious clinical complication impacting the survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fortification of salt with iron and iodine versus fortification of salt with iodine alone for improving iron and iodine status.

Fortification of salt with iron and iodine versus fortification of salt with iodine alone for improving iron and iodine status.

Ensuring the Efficacious Iron Fortification of Foods: A Tale of Two Barriers.

Iron fortification of foods has always been a challenge. This is because iron fortification compounds vary widely in relative absorption; because many foods undergo unacceptable changes in color or flavor from the addition of iron; and because many of the iron-fortified foods contain potent inhibitors of iron absorption. These technical barriers have largely been overcome, and efficacious iron-fortified foods, that maintain or improve the iron status of women or children in long-term feeding studies, can be designed. Commercially fortified infant foods are efficacious, and other commercial iron-fortified foods targeted at women and children will provide a useful amount of iron provided the fortification level is adjusted according to the relative absorption of the iron compound. Technologies for the large-scale fortification of wheat and maize flour are also well established, and iron fortification of rice, using the recently developed extruded premix technique, is showing great promise. However, some important knowledge gaps still remain, and further research and development is needed in relation to iron (and iodine)-fortified salt and iron-fortified liquid milk. The usefulness of less-soluble iron compounds, such as ferrous fumarate, to fortify foods for infants and young children in low- and middle-income countries (LMICs) also needs further investigation. A more formidable barrier to efficacious iron-fortified food has been reported in recent years. This is the infection-initiated inflammation barrier, which inhibits iron absorption in response to infection. This barrier is particularly important in LMICs where infections such as malaria and HIV are widespread, and gastrointestinal infections are common due to poor quality water supplies and sanitation. Another source of inflammation in such countries is the high prevalence of obesity in women. Most countries in sub-Saharan Africa have high inflammation which not only decreases the efficacy of iron-fortified and iron-biofortified foods but complicates the monitoring of large-scale iron fortification programs. This is because iron deficiency anemia cannot be differentiated from the more prominent anemia of inflammation and because inflammation confounds the measurement of iron status. There is an urgent need to better quantify the impact of inflammation on the efficacy of iron-fortified foods. However, at present, in LMICs with high inflammation exposure, infection control, cleaner water, improved sanitation, and a decrease in obesity prevalence will undoubtedly have a greater impact on iron status and anemia than the iron fortification of foods.

Pediatric Heart Failure: Cardiac Ejection Fraction with Cardiomyopathy Decreased to 21% in Iron Deficient from 37% in Iron Sufficient Children

▪Introduction: The overall aim of our study was to determine if iron deficiency has harmful effects on cardiac function in children with chronic heart failure. Heart failure in children is a complex, heterogeneous disorder leading to a final common pathway of cardiomyocyte dysfunction and attrition. Cellular, animal, and human studies have shown that iron deficiency causes cardiomyocyte dysfunction that can be reversed with iron treatment. Cellular studies of human iron-deficient cardiomyocytes have shown that supplemental iron restores impaired contractility and relaxation. Animal studies have found that cardiomyocyte-specific deletions or alterations of critical iron proteins (transferrin receptor 1, hepcidin, ferroportin) produce cardiomyocyte iron deficiency (without anemia) and result in ultimately fatal cardiac dysfunction that can be rescued with intravenous (IV) iron. Over half of adults with chronic heart failure are iron deficient. Meta-analysis of small randomized clinical trials has shown that IV iron significantly reduces recurrent hospitalization, cardiovascular mortality, and all-cause mortality in iron deficient adults with heart failure. European Society of Cardiology, American College of Cardiology and American Heart Association guidelines recommend consideration of IV iron therapy for adult iron-deficient patients with heart failure.The prevalence and consequences of iron deficiency in children with heart failure have not been established. Previously, two small retrospective studies of children with heart failure have reported that 56% to 96% were iron deficient, with increased morbidity and mortality. The goals of our study of children with heart failure were to determine (i) how often iron status is assessed, (ii) the prevalence of iron deficiency, and (iii) the effects of iron deficiency on cardiac function in patients with cardiomyopathy.Methods: We retrospectively reviewed electronic medical records to identify pediatric patients ages 1-21 years old seen at Columbia University Irving Medical Center Pediatric Heart Failure clinic with absolute iron deficiency during 2010-2020. Heart failure was defined as presence of symptoms or systolic dysfunction by echocardiography. Patients were excluded with a history of heart transplant, isolated diastolic failure, or renal failure requiring dialysis. In adults with heart failure, a transferrin saturation <20% has a sensitivity of 94% and a specificity of 84% in identifying absolute iron deficiency, as determined from a bone marrow aspirate, and iron stores were present in 100% of patients with a transferrin saturation ≥30% (Circ Heart Fail. 2018;11:e0045). In children with heart failure, we used these criteria to define absolute iron deficiency as a transferrin saturation <20% and iron sufficiency as a transferrin saturation ≥30%.Patients with an intermediate transferrin saturation are likely a mixture of absolute and functional iron deficiency, and of iron sufficiency and were excluded from our analysis of cardiomyopathy. Cardiac ejection fraction was evaluated by an echocardiogram performed within 3 months of measurement of transferrin saturation.Results: Of 579 patients with heart failure, only 159 (27%) had any type of laboratory iron studies. Of patients with iron studies, 81 (51%) were evaluated as outpatients; 49% as inpatients. The cause of heart failure was cardiomyopathy (52%), congenital heart disease (34%), acute myocarditis (6%), and other (8%).In the 82 patients with heart failure due to cardiomyopathy, 39 (48%) were iron deficient and 16 (20%) iron sufficient. In the iron deficient children with cardiomyopathy, the left ventricular ejection fraction was lower than in the iron sufficient patients (median 21% vs. 37%; p=0.03 (Mann-Whitney); Figure). The groups did not differ significantly with respect to hemoglobin (Figure), sex, age, or New York Heart Association class.Conclusion: We report a clinically important decrease in cardiac ejection fraction in children with heart failure due to cardiomyopathy who have absolute iron deficiency. Potentially, iron treatment could safely and effectively reverse the harmful effect of iron deficiency on heart function and prospective randomized trials of oral and intravenous iron therapy are urgently needed. Measurement of iron status should routinely be included in the evaluation of children with heart failure. [Display omitted] DisclosuresNeunert: Novartis: Research Funding.

Effect of Iron deficiency on health-related quality of life in chronic heart failure patients regardless of anaemia status

Abstract Background Chronic Heart Failure (CHF) patients have marked functional limitations causing a significant impact on Health Related Quality of Life (HRQoL) in these patients. Iron Defeciency is very common in Heart Failure patients &amp; it is suggested that it affects HRQoL in CHF patients regardless of the Anemia status . Objective To evaluate the impact of iron deficiency (ID) on health-related quality of life (HRQoL) in chronic heart failure (CHF) patients using Minnesota Living with Heart Failure questionnaire (MLHFQ) in patients with normal hemoglobin levels . Methods From October 2018 to August 2019 ,100 patients with CHF from out- patient clinics in ASU university hospitals were subjected to history taking , examination , Echocardiography , measurement of Iron status using serum ferritin, Assessment of Health Related Quality of Life (HRQoL) using Minnesota Living with Heart Failure Questionnaire (MLHFQ) . Patients then were divided into 2 equal groups depending on their serum ferritin level &amp; comparison of MLHFQ score between the 2 groups was done . Results The study population was divided into 2 groups: Iron Defecient (ID) (n = 50) &amp; non Iron Defecient (non ID) (n = 50) , 61 patients were males &amp; 39 were females. The MLHFQ scores were 66.9 ± 9.1 among ID patients vs 46.9 ± 7.3 in non ID patients (p value &amp;lt; 0.001) indicating worse HRQoL in ID group . The physical domain (p value &amp;lt; 0.001) was markedly affected than the emotional domain (p value 0.006) of the MLHFQ score . Conclusion In CHF patients , HRQoL was markedly affected among ID patients than non ID patients with physical factors more affected than the emotional factors .

Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia.

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged <5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a 2-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10; interquartile range [IQR]: 0.03-0.19) than those with CM (0.24; IQR: 0.14-0.69; P=0.006) or asymptomatic malaria (0.19; IQR: 0.09-0.46; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL; IQR: 4.7-49.8) and hepcidin/ferritin ratios (0.03; IQR: 0.01-0.22) than those with NTS alone (105.8 ng/mL; IQR: 17.3-233.3; P=0.02 and 0.31; IQR: 0.06-0.66; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole, we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long‐term study

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation.MethodsWe retrospectively analysed the long‐term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin < 100 μg/L or ferritin 100–300 μg/L and transferrin saturation (TSAT) < 20%] who were on stable targeted PAH therapy, compared with matched controls without ID. Patients with ID received a single infusion of FCM (500 to 1000 mg). Clinical measures monitored included exercise capacity, World Health Organization (WHO) functional class, ESC/ERS risk status, and hospitalizations. The observation period was up to 18 months.ResultsOne hundred and seventeen patients (mean age 60.9 ± 16.1 years; 64.1% females) with confirmed PAH and on stable targeted therapy for ≥3 months were included (58 with and 59 patients without ID who did not receive FCM). In patients with ID, iron supplementation with FCM resulted in an immediate and sustained improvement of iron status for up to 18 months (serum iron, ferritin, TSAT, all P < 0.01). Fourteen patients in the FCM group received a second FCM infusion after 9.6 ± 4.8 months due to recurrent ID. At 6 and 18 months after FCM infusion, 6 min walk distance improved from 377.5 ± 15.9 at baseline to 412.5 ± 15.1 and 400.8 ± 14.5 m, respectively (both P < 0.05). WHO functional class (P < 0.05) and ESC/ERS risk status also improved, and there was a reduction of hospitalizations for worsening PAH in the 12 months post vs. prior to iron repletion (P = 0.029). No significant changes were observed in the control group. FCM was well tolerated in all patients, with no severe adverse events.ConclusionsIn addition to targeted therapy, correction of ID by parenteral iron supplementation with FCM appears feasible and safe, has sustained effects on iron status, and may improve the clinical status and hospitalization rates in patients with PAH. Larger controlled studies are required to confirm this finding.

Iron Status in Early Infancy Is Associated With Attentional Flexibility and Cognitive Achievement in Rural Gambia

ObjectivesTo determine the relationship between iron status in early infancy (1–5 months) and longitudinal trajectories of cognitive development (5–18 months) in a cohort of infants from rural Gambia. MethodsThis study used data from the Brain Imaging for Global Health (BRIGHT) study, which recruited pregnant women (n = 223) and followed up mothers and their children to 18 months of age (n = 191). Infant blood samples collected at 1 and 5 months of age were analysed for soluble transferrin receptor (sTfR) and ferritin using a COBAS INTEGRA 400 (Roche). Cognitive development was measured at 5, 8, 12 and 18 months of age using the Mullen Scales of Early Learning (MSEL) and an eye tracking measure of attentional flexibility (disengagement time). For each outcome measure, mixed effects models of individual developmental trajectories from 5–18 months of age were developed. Each model had a different measure of iron status as the primary exposure (ferritin or sTfR at 1 or 5 months of age) and was adjusted for confounding factors. ResultsPrevalence of iron deficiency (ferritin < 12μg/L or < 30 μg/L if CRP > 5mg/L) increased from 0% to 29.5% between 1 and 5 months of age. In mixed effects models, a -1mg/L difference in sTfR (indicating better iron status) at 1 month of age was associated as with a 31.2ms difference in disengagement time (SE = 13.1, p = 0.017) at each time point from 5–18 months of age, but was not associated with MSEL developmental trajectory. A -1mg/L difference in sTfR at 5 months of age associated with a 0.6 point difference in MSEL score from 5–18 months of age (SE = 0.180, p = 0.001) and a 10.6ms difference in disengagement time (SE = 4.8, p = 0.028) across the same period. There was no relationship between ferritin concentration at 1 or 5 months and trajectories of either MSEL or disengagement time (all p > 0.05). ConclusionsInfants under 6 months of age in rural Gambia are at risk of iron deficiency. Poor iron status in early infancy, measured by sTfR but not ferritin, is associated with both global cognition and a specific measure of attentional flexibility, from 5–18 months of age. Maintenance of adequate iron in infants up to 6 months of age may benefit the developing brain. Funding SourcesBill and Melinda Gates Foundation and Medical Research Council (UK).

Optimal serum ferritin level range: iron status measure and inflammatory biomarker.

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and of inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease (PAD) offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha (TNF-a), and high sensitivity C-reactive protein (hsCRP) were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels < 100 ng/mL. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20—100 ng/mL with % transferrin levels from 20–50%, to ensure adequate iron status and that ferritin levels above 194 ng/mL associate with all-cause mortality in population cohorts.

Are Pregnant Women Who Are Living with Overweight or Obesity at Greater Risk of Developing Iron Deficiency/Anaemia?

Low-grade inflammation is often present in people living with obesity. Inflammation can impact iron uptake and metabolism through elevation of hepcidin levels. Obesity is a major public health issue globally, with pregnant women often affected by the condition. Maternal obesity is associated with increased pregnancy risks including iron deficiency (ID) and iron-deficiency anaemia (IDA)—conditions already highly prevalent in pregnant women and their newborns. This comprehensive review assesses whether the inflammatory state induced by obesity could contribute to an increased incidence of ID/IDA in pregnant women and their children. We discuss the challenges in accurate measurement of iron status in the presence of inflammation, and available iron repletion strategies and their effectiveness in pregnant women living with obesity. We suggest that pre-pregnancy obesity and overweight/obese pregnancies carry a greater risk of ID/IDA for the mother during pregnancy and postpartum period, as well as for the baby. We propose iron status and weight gain during pregnancy should be monitored more closely in women who are living with overweight or obesity.

Anthropometric Markers and Iron Status of 6-12-Year-Old Thai Children: Associations and Predictors.

Introduction Obesity may be associated with poor iron status. The objective of this study was to investigate the association between different indices of iron status and anthropometric measurements in Thai children. Materials and Methods Anthropometry (weight, height, waist circumference (WC), and body composition assessed by bioelectrical impedance analysis) and iron indices were measured in 336 Thai children aged 6–12 years. Iron deficiency (ID) was defined using two or more of the following: (1) %transferrin saturation (%Tsat) < 16%; (2) serum ferritin (SF) < 15 μg/mL; and (3) soluble transferrin receptor (sTfR) > 5 mg/L. Iron deficiency anaemia (IDA) was defined as haemoglobin < WHO age cutoff combined with ID. Overweight and obesity were defined as body mass index (BMI) standard deviation score (SDS) ≥ +1 SDS or +2 SDS, respectively (WHO growth reference). Results BMI SDS was significantly positively correlated with sTfR and SF (sTfR, r: 0.209, p < 0.001; SF, r: 0.214, p < 0.001) and negatively correlated with %Tsat (r: −0.132, p = 0.013). Correlations between WC SDS and %fat mass and each iron marker were similar. The percentage with low SF was significantly lower than that using other individual markers. ID prevalence was not significantly different between normal-weight and overweight/obesity groups although a significantly higher proportion of overweight/obese children had sTfR >5 mg/L. Puberty and menarche were significant predictors of ID (puberty adjusted OR: 2.20, 95% CI: 0.43, 11.25; menarche adjusted OR: 6.11, 95% CI: 1.21, 30.94). Conclusion Greater adiposity was associated with poorer iron status. However, SF may not be a good indicator of iron status in Thai children, particularly in those who are overweight/obese, whereas sTfR merits further investigation.

Evidence of Genetic Transmission in African Iron Overload

AbstractIron overload in Africa was previously regarded as purely due to excessive iron in traditional beer, but we recently found evidence that transferrin saturation and unsaturated iron binding capacity may be influenced by an interaction between dietary iron content and a gene distinct from any HLA-linked locus. To determine if serum ferritin follows a genetic pattern and to confirm our previous observations, we studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was characterized with repeated morning measurements of serum ferritin, transferrin saturation, and unsaturated iron binding capacity after supplementation with vitamin C. For each measure of iron status, segregation analysis was consistent with an interaction between a postulated iron-loading gene and dietary iron content (P < .01). In the most likely model, transferrin saturation is 75% and serum ferritin is 985 ’g/L in a 40-year-old male heterozygote with an estimated beer consumption of 10,000 L, whereas the saturation is 36% and serum ferritin is 233 ’g/L in an unaffected individual with identical age, sex, and beer consumption. This segregation analysis provides further evidence for a genetic influence on iron overload in Africans.

Long-Term Eltrombopag for Bone Marrow Failure Depletes Total Body Iron

Eltrombopag (EPAG) is a non-peptide, thrombopoietin receptor agonist approved for several forms of thrombocytopenia, as well as severe aplastic anemia in first line (combined with immunosuppressive therapy) and refractory (single agent) settings. It is effective in moderate aplastic anemia and under investigation for myelodysplastic syndrome (MDS) and other marrow failure conditions. Although aplastic anemia (AA) patients often respond to EPAG and become drug-independent, this may take months to years, and some patients remain either continuously or intermittently EPAG-dependent. Previously, we and others have reported that EPAG chelates and mobilizes iron in a cohort of AA patients. We present a larger cohort of AA/MDS patients from 4 prospective clinical trials of EPAG, and report declining iron stores on extended EPAG therapy, including some patients developing frank iron deficiency anemia (IDA) responsive to oral or parenteral supplementation, and others normalizing prior severe iron overload during extended EPAG therapy. We report the kinetics of this effect and analyze its impact, if any, upon response and relapse. 317 patients were treated with EPAG for unilineage cytopenia, AA or MDS. 206 AA patients treated on non-EPAG protocols served as historical controls. Average follow-up was 42.9 months (2.2-206.7) for EPAG and 69.6 months (6.1-196) for controls. Average time on EPAG was 9.0 months (0.4-81.1); 73 patients (23.0%) were treated for ≥ 7 months. Average baseline serum ferritin (SF) was 1757 ng/mL (29-18977) for EPAG; 1628 ng/mL (14-8438) for controls (N.S.), with iron overload (SF ≥ 1000 ng/mL) in 56.5% of EPAG patients; 53.9% of controls (N.S.). On EPAG, serum iron (2x over baseline, P &amp;lt; 1.3 x 10-39) and transferrin saturation (85.1% of patients have 100% saturation) are elevated due to binding by EPAG, while serum ferritin (SF) does not correlate with iron or transferrin saturation. These effects resolve following EPAG therapy: iron is 15% lower than baseline (P = 5.1 x 10-5), median saturation is 40%, and SF and iron correlate. No such dissociation is noted for historical controls. This implies that SF is the most reliable measure of iron status while on EPAG due to its chelating properties. EPAG duration correlates with SF fold-reduction (R2 = 0.19, P &amp;lt; 4 x 10-14). SF levels during EPAG treatment follow first order (exponential) kinetics (R2 = 0.35, P &amp;lt; 2 x 10-20), with a clearance half-life of 15.3 months, independent of baseline SF. There is minimal correlation of treatment response with SF kinetics (P = 0.04). In comparison, historical responders demonstrate a significantly slower SF clearance (P &amp;lt; 8 x 10-10) with a half-life of 47.5 months. SF half-life on EPAG is comparable to that of chelators such as deferoxamine or deferasirox used for transfusion-related iron overload in AA/MDS. This similarity in kinetics and the fact that this effect is independent of treatment response (and thus transfusion burden) support a role for EPAG in actively depleting total body iron. Of 305 evaluable patients, 62 (9.8%) had iron-depletion as measured by ferritin. 30 (7.5%) were during EPAG treatment with a median time of 55.0 months. 11 (3.6%) of patients experienced falling hemoglobin or other signs of anemia. 9 started iron supplementation or discontinued EPAG, with improvement in the 5 patients who have had follow-up. Patients with EPAG-induced IDA follow the same kinetics (15.5-month half-life) as the general cohort. Logistic models do not predict response based upon either baseline ferritin or kinetics. Furthermore, neither logistic nor Kaplan-Meier models identify any timepoint ferritin, baseline iron overload, or kinetics as predictors of relapse risk. While iron and ferritin may be biomarkers of disease and transfusion burden, they do not appear to drive outcomes, and do not support the recent hypothesis that response of marrow failure to EPAG is based on iron chelation and reversal the toxic impact of intracellular iron on hematopoietic stem cells. Our data suggest a potential role for EPAG or its derivatives as iron chelators. More importantly, they demonstrate that EPAG can deplete iron stores, paradoxically requiring supplementation in previously overloaded patients. In addition to relapse, IDA should also be considered in responders on long term EPAG with declining hemoglobin. We recommend maintaining SF greater than 100 ng/mL so that these patients may continue this life-saving therapy. Figure 1 Disclosures Young: Novartis: Research Funding. Dunbar:Novartis: Research Funding.