Iron Biomarkers Research Articles

An observational and Mendelian randomisation study on iron status and sepsis

Iron deficiency is associated with a substantial burden of morbidity. However, supplementation of iron has been linked to increased rates of serious infection in randomised trials of children in sub-Saharan Africa. Randomised trials in other settings have been inconclusive and it is unknown if changes in levels of iron biomarkers are linked to sepsis in these other settings. We used genetic variants associated with levels of iron biomarkers as instrumental variables in a Mendelian randomisation (MR) analysis to test the hypothesis that increasing levels of iron biomarkers increase the risk of sepsis. In observational and MR analyses we found that increases in iron biomarkers increase the odds of sepsis. In stratified analyses, we show that this risk may be larger in those with iron deficiency and/or anaemia. Taken together, results here suggest a required caution in supplementation of iron and underline the role of iron homeostasis in severe infection.

Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.

Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.

Effect of Deferoxamine on Post-Transfusion Iron, Inflammation, and In Vitro Microbial Growth in a Canine Hemorrhagic Shock Model: A Randomized Controlled Blinded Pilot Study

Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.

Abstract TP117: Temporal Serum Iron And Hemoglobin Changes In Patients From The High Dose Deferoxamine In Intracerebral Hemorrhage Trial

Introduction: Following intracerebral hemorrhage (ICH), elevated cerebral tissue iron concentrations are seen. It is unclear how peripheral serum iron concentrations change over time and how they relate to anemia after ICH. Given the known impacts of iron concentrations and anemia on clinical outcomes, we explored serum iron biomarker and hemoglobin concentration changes after acute ICH. Methods: A post hoc analysis of patients with available serial (baseline and 5 day) serum biomarker data from the multicenter, High Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF) trial was performed. Changes of serum hemoglobin, iron, transferrin, and ferritin were assessed using repeated measure ANOVA analyses. Deferoxamine treatment and poor 90 day modified Rankin Scale 4-6 were separately assessed as between subject factors for these laboratory changes. Results: Of 42 ICH patients analyzed, the mean age was 64, 62% were male, median ICH volume was 15.7mL (IQR 5.7-37.5), and baseline anemia was seen in 19%. We identified significant decrements of hemoglobin (mean difference -1.4 g/dL; 95%CI: -1.9 to -0.9; p&lt;0.0001), iron (mean difference -16.9 ug/dL; 95%CI: -29.7 to -4.1; p=0.01), transferrin (mean difference -43.9 ng/mL; 95%CI: -56.6 to -31.3; p&lt;0.0001), and conversely, significant ferritin elevations (mean difference 104.5 ug/L; 95%CI: 52.5-156.6; p&lt;0.0001) at 5 days. Anemia was identified in 43% of patients at 5 days. Deferoxamine did not have a significant impact on these repeated measures. Patients with poor long-term outcomes had greater decrements in hemoglobin compared to those with good outcomes (mean difference: -1.5 g/dL; 95%CI: -2.6 to -0.3; p=0.01). Conclusions: Serum iron and hemoglobin concentrations decrease significantly over time following ICH. Patients with worse long term ICH outcomes had greater hemoglobin decrements during their hospitalization. The aggregate iron biomarker and hemoglobin concentration changes suggest anemia development may be due to anemia of inflammation. Further work is required to address the pathophysiologic difference between systemic and central iron homeostasis mechanisms following ICH and the impacts that ICH has on inflammation, systemic iron homeostasis, anemia, and clinical outcomes.

Soluble Transferrin Receptor, Antioxidant Status and Cardiometabolic Risk in Apparently Healthy Individuals.

Body iron excess appears to be related to insulin resistance and cardiometabolic risk and increased oxidative stress might be involved in this relationship. Very few studies have described the association between soluble transferrin receptor (sTfR) levels and cardiometabolic risk in the general population or antioxidant status. There were 239 subjects (20-65 years old) included in this cross-sectional study. Linear regressions adjusting for BMI, menopausal status, insulin resistance (HOMA-IR), physical inactivity, alcohol intake and subclinical/chronic inflammation were used to describe the association between sTfR, total antioxidant capacity (TAC), and measures of cardio-metabolic risk. sTfR levels were positively associated with TAC in men (βeta [95% confidence interval ]: 0.31 [0.14 to 0.48]) and women (βeta = 0.24 [0.07 to 0.40]) in non-adjusted and adjusted models (p &lt; 0.05). In men, sTfR levels were inversely associated with waist circumference (βeta [95% confidence interval]: -1.12 [-2.30 to -0.22]) and fasting glucose (-2.7 (-4.82 to -0.57), and positively with LDL cholesterol (12.41 (6.08 to 18.57) before and after adjustments for confounding variables. LDL cholesterol had a significant and positive association with TAC in non-adjusted and adjusted models in men (p &lt; 0.05). sTfR levels are significantly associated with antioxidant status and a few specific cardio-metabolic risk variables, independently of covariates that included serum ferritin and hepcidin. This might imply that iron biomarkers in regard to cardiometabolic risk reflect physiological contexts other than iron metabolism.

Effects of Different Doses, Forms, and Frequencies of Zinc Supplementation on Biomarkers of Iron and Zinc Status among Young Children in Dhaka, Bangladesh

Young children in resource-constrained settings are susceptible to zinc deficiency and its deleterious health effects. The objective of this secondary analysis was to evaluate the effects of the following six interventions on biomarkers of iron and zinc status among a subgroup of young children in Dhaka, Bangladesh, who participated in the Zinc in Powders Trial (ZiPT): (1) standard micronutrient powders (MNPs) containing 4.1 mg zinc and 10 mg iron, daily; (2) high-zinc (10 mg) and low-iron (6 mg) (HiZn LoFe) MNP, daily; (3) HiZn (10 mg) and LoFe (6 mg)/HiZn (10 mg) and no-iron MNPs on alternating days; (4) dispersible zinc tablet (10 mg), daily; (5) dispersible zinc tablet (10 mg), daily for 2 weeks at enrollment and at 12 weeks; (6) placebo powder, daily. At the end of the 24 week intervention period, children in the daily dispersible zinc tablet group exhibited a mean serum zinc concentration (SZC) of 92.5 μg/dL, which was significantly higher than all other groups except the HiZn LoFe MNP alternating group (81.3 μg/dL). MNPs containing 10 mg and 6 mg of iron had a similar impact on biomarkers of iron status, with no evidence of an adverse interaction with zinc.

Dietary Iron Intake and Biomarkers of Iron Status in Slovenian Population: Results of SI.Menu/Nutrihealth Study.

Inadequate iron intake and iron deficiency are recognised as a public health problem in the population at large, and particularly in specific subpopulations. Dietary iron intake was analysed using data of the national Slovenian food consumption study, SI.Menu (n = 1248 subjects; 10−74 years), while iron status was evaluated with laboratory analyses of blood haemoglobin, serum ferritin, and iron concentration in samples, collected in the Nutrihealth study (n = 280, adults). The estimated daily usual population-weighted mean iron intakes ranged from 16.0 mg in adults and the elderly to 16.7 in adolescents, and were lower in females for all three age groups. The main dietary iron sources in all the age groups were bread and bakery products, meat (products), fruit, and vegetables. The highest prevalence of haemoglobin anaemia was observed in females aged 51−64 years (6.7%). Critically depleted iron stores (ferritin concentration < 15 µg/L) were particularly found in premenopausal females (10.1%). Factors influencing low haemoglobin, ferritin, and iron intake were also investigated. We observed significant correlations between iron status with meat and fish intake, and with iron intake from meat and fish, but not with total iron intake. We can conclude that particularly premenopausal females are the most fragile population in terms of inadequate iron intake and iron deficiency, which should be considered in future research and public health strategies.

Multiplexed micronutrient, inflammation, and malarial antigenemia assessment using a plasma fractionation device.

Processing and storing blood samples for future analysis of biomarkers can be challenging in resource limited environments. The preparation of dried blood spots (DBS) from finger-stick collection of whole blood is a widely used and established method as DBS are biosafe, and allow simpler field processing, storage, and transport protocols than serum or plasma. Therefore, DBS are commonly used in population surveys to assess infectious disease and/or micronutrient status. Recently, we reported that DBS can be used with the Q-plex™ Human Micronutrient 7-plex Array (MN 7-plex), a multiplexed immunoassay. This tool can simultaneously quantify seven protein biomarkers related to micronutrient deficiencies (iodine, iron and vitamin A), inflammation, and malarial antigenemia using plasma or serum. Serum ferritin, an iron biomarker, cannot be measured from DBS due to red blood cell (RBC) ferritin content confounding the results. In this study, we assess a simple blood fractionation tool that passively separates plasma from other blood components via diffusion through a membrane into a plasma collection disc (PCD). We evaluated the concordance of MN 7-plex analyte concentrations from matched panels of eighty-eight samples of PCD, DBS, and wet plasma prepared from anticoagulated venous whole blood. The results showed good correlations of >0.93 between the eluates from PCD and DBS for each analyte except ferritin; while correlations seen for plasma/PCD were weaker. However, the recovery rate of the analytes from the PCD were better than those from DBS. The serum ferritin measures from the PCD were highly correlated to wet plasma samples (0.85). This suggests that surveillance for iron status in low resource settings can be improved over the current methods restricted to only measuring sTfR in DBS. When used in combination with the MN 7-plex, all seven biomarkers can be simultaneously measured using eluates from the PCDs.

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

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (β = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (β = -0.37; 95%CI = -0.39, -0.35), hepcidin (β = -0.22, 95%CI = -0.24, -0.20), and TSAT (β = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (β = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (β = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (β = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

Effect of inulin, galacto oligosaccharides and iron fortification on iron deficiency anemia among women of reproductive age; a randomized controlled trial

Iron supplementation and fortification are the well-known approaches to treat iron deficiency anemia (IDA) in women of reproductive age. The objective of the current randomized controlled trial (RCT) was to evaluate the cumulative effects of prebiotics and iron fortification among women of reproductive age. For this purpose, a total of 75 iron deficient women of childbearing age were recruited and randomly divided into 5 groups (4 treatment groups and 1 control group). Four different types of fortified wheat flour were prepared using two iron fortificants (NaFeEDTA and FeSO4) and two prebiotics [inulin and galacto oligosaccharides (GOS)], while control group was treated with iron fortified flour without any prebiotics. Blood samples were collected from overnight fasted women on monthly basis up to 90 days. Hematological indices such as Hemoglobin (Hb), Hematocrit, Red Blood Cell (RBC) Count and Mean Corpuscular Volume (MCV), as well as iron biomarkers including serum iron, ferritin, transferrin, and Total Iron Binding Capacity (TIBC) were evaluated for analyses. The results showed a considerable positive improvement in all iron biomarkers as well as hematological indices among the treatment groups (P-value < 0.05), as compared to the control group. A maximum Hb (11.86 ± 0.24 mg/dL) and hematocrit value (35.06 ± 1.32%), was reported in group G3 which was treated with fortified wheat flour at a dose of 963 mg/kg GOS + 15 ppm FeSO4. On the other hand, highest mean values for RBC Count (4.73 ± 0.41 mil/mm3), MCV (81.41 ± 3.21 fL), serum iron (75.62 ± 2.79 μg/dL), serum transferrin (16.82 ± 0.30 mg/dL), and TIBC (403.68 ± 7.27 μg/dL) were observed in G4 group receiving the fortified wheat flour at a dose of 963 mg/kg GOS + 30 ppm FeSO4 level. The study concluded that prebiotic fortification along with iron salts helps to enhance iron absorption among iron deficiency anemic women of reproductive age.

Erythropoietin as a prophylactic measure against anemia in critically ill patients: A combined prospective and retrospective study

Background &amp; Objective: Critically sick patients often develop moderate to severe anemia, due to various factors. We tested the hypothesis that administering prophylactic recombinant human erythropoietin (rHuEPO) together with early identification and correction of iron deficiency anemia in traumatic brain injury patients would have a positive effect on the incidence of RBCs transfusions.&#x0D; Methodology: One hundred and seventeen head-trauma patients were enrolled. They received 40,000 units of prophylactic rHuEPO, starting on day three after admission and continuing at weekly intervals for 6 weeks, with follow-up of iron biomarkers. Any patient developing iron deficiency anemia was prescribed oral or intravenous iron supplement. The incidence of RBCs transfusion was recorded.&#x0D; Results: The number of RBCs transfusion was significantly less in the prospective group (27.35%) than the retrospective group (42.86%). Hemoglobin and hematocrit levels were significantly less in the first and second weeks after admission and then began to rise. Serum iron, transferrin saturation, and ferritin were at their lowest levels in the fourth week. Meanwhile, total iron binding capacity was higher in the fourth week and lower in the sixth.&#x0D; Conclusion: The administration of prophylactic rHuEPO with early discovery and correction of iron deficiency anemia resulted in a significant reduction in the incidence of RBCs transfusion in the head-trauma patients.&#x0D; Abbreviations: rHuEPO: recombinant human erythropoietin, RBC: red blood cell, ICU: intensive care unit, TBI: traumatic brain injury, GCS: Glasgow Coma Scale, APACHE: Acute Physiology and Chronic Health Evaluation&#x0D; Citation: Amer AF, Elatrozy HI, El Mourad MB. Erythropoietin as a prophylactic measure against anemia in critically ill patients: A combined prospective and retrospective study. Anaesth. pain intensive care 2022;26(5):633−639.&#x0D; DOI: 10.35975/apic.v26i5.1481&#x0D;

Iron-Deficiency Prevalence and Supplementation Practices Among Pregnant Women: A Secondary Data Analysis From a Clinical Trial in Vancouver, Canada

North American public health guidelines recommend supplementation with an iron-containing prenatal multivitamin throughout pregnancy to meet the RDA of 27mg of elemental iron daily. However, whether supplementation with standard prenatal multivitamins is sufficient to prevent maternal iron deficiency is unclear, as needs increase substantially with advancing gestation. This study aimed to assess iron status in early and late pregnancy among 60 pregnant women receiving 27mg/day of elemental iron as part of a randomized trial in Vancouver, Canada. Study visits were conducted at 8-21 (baseline) and 24-38 (endline) weeks of gestation. Venous blood specimens were collected for a complete blood count and measurement of iron and inflammatory biomarkers. Supplementation with any additional iron (beyond 27mg/day) was reported by participants (treatment with additional iron is recommended if ferritin is <30μg/L).Quantile regression was used to explore predictors of endline ferritin concentrations, including ethnicity, education, income, and baseline ferritin measurement. Overall, 60 and 54 women participated in baseline and endline visits, respectively. Rates of probable iron deficiency (ferritin<30μg/L)at baseline and endline were 17 (28%) and 44 (81%), respectively. Less than half (n=18; 41%) of participants with probable iron deficiency at endline reported supplementation with additional iron. Ethnicity was the only significant modifier of endline ferritin, with higher concentrations in those of South, East, and Southeast Asian ethnicity compared to those of European ethnicity (β: 10.4μg/L; 95% CI: 0.3-20.5). Pregnant individuals may require additional supplemental iron beyond 27mg to meet requirements in later pregnancy, given the high rates of iron deficiency observed in this clinical trial, despite consumption meeting 100% of the RDA. This trial was registered at clinicaltrials.gov as NCT04022135.

Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01–1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97–1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94–2.86, P = 0.09) for women and OR 1.21 (CI 0.92–1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.

Reticulocyte Hemoglobin-Equivalent Potentially Detects, Diagnoses and Discriminates between Stages of Iron Deficiency with High Sensitivity and Specificity.

Background: Iron deficiency anemia (IDA) is a global health problem affecting the quality of life of more than 2 billion individuals. The current practice guidelines diagnose and monitor IDA via conventional hematological and iron biomarkers, which take several months before they are corrected under an iron-treatment plan. Reticulocyte hemoglobin equivalent (Ret-He) is used as a marker in most new hematology analyzers to assess iron incorporation into erythrocyte hemoglobin directly. This study aims to examine the efficacy of Ret-He as a marker for iron deficiency (ID) and IDA and investigate whether Ret-He is sensitive to iron therapy. Methods: Two blood samples were drawn from 182 participants for CBC and iron profile measurements. Follow-up samples were drawn from participants with a confirmed diagnosis of ID and/or IDA. Results: Ret-He levels were lower in the ID and IDA groups compared to the control (p < 0.0001), and lower in the IDA group compared to the ID group (p < 0.0001). Ret-He was correlated with ferritin at ID level (<30.0 mg/mL; r = 0.39) and severe IDA (<13.0 ng/mL; p-value < 0.01, r = 0.57). Cut-off values of <28.25 pg for ID and <21.55 pg for IDA showed a higher specificity and sensitivity (ID; AUC: 0.99, sensitivity: 92.73%, specificity: 97.87%) and (IDA; AUC: 0.94, sensitivity: 90.63%, specificity: 92.31%). Finally, Ret-He successfully reflected the iron therapy (p < 0.001) when compared to hemoglobin (Hb) (p = 0.1). Conclusions: Ret-He is a potential marker for detecting and diagnosing different stages of ID with high validity and is very sensitive in reflecting the iron incorporation in a short time.

Erythropoietin as a prophylactic measure against anemia in critically ill patients: A combined prospective and retrospective study.

Background: The aim of this study is to test the hypothesis that administering prophylactic recombinant human erythropoietin (rHuEPO) together with early identification and correction of iron deficiency anemia in traumatic brain injury patients would have an effect on the incidence of RBCs transfusion as a primary outcome.&#x0D; Methodology: One hundred and seventeen head-trauma patients were enrolled. They received 40,000 units of prophylactic rHuEPO, starting on day three after admission and continuing at weekly intervals for 6 weeks, with follow-up of iron biomarkers. Any patient developing iron deficiency anemia was prescribed oral or intravenous iron. The incidence of RBCs transfusion was recorded.&#x0D; Results: The incidence of RBCs transfusion was significantly less in the prospective group (27.35%) than the retrospective group (42.86%). Hemoglobin and hematocrit levels were significantly less in the first and second weeks after admission and then began to elevate. Serum iron, transferrin saturation, and ferritin were at their lowest levels in the fourth week. Meanwhile, total iron binding capacity was higher in the fourth week and lower in the sixth.&#x0D; Conclusion: The administration of prophylactic rHuEPO with early discovery and correction of iron deficiency anemia resulted in a significant reduction in the incidence of RBCs transfusion in head-trauma patients.

Prevalence of and Risk Factors for Iron Deficiency in Twin and Singleton Newborns.

Iron deficiency (ID) in utero and in infancy can cause irreversible neurocognitive damage. Iron status is not routinely tested at birth, so the burden of neonatal ID in the United States is unknown. Infants born from twin or higher-order pregnancies may be at elevated risk of inadequate nutrient endowment at birth. The present study sought to compare the burden of neonatal ID in cord blood serum samples from twin (n = 54) and singleton pregnancies (n = 24). Iron status (serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) biomarker concentrations were measured by immunoassay. The prevalence of ID (SF < 76 ng/mL) among twins was 21% (23/108) and among singletons 20% (5/24). Gestational age at birth, maternal race and infant sex predicted SF levels. Maternal anemia (hemoglobin < 11 g/dL) was observed in 40% of mothers but was not associated with neonatal iron biomarkers. More research is needed to identify risk factors and regulatory mechanisms for inadequate fetal iron accrual to identify higher risk pregnancies and neonates for screening and intervention.

Quintuply-fortified salt for the improvement of micronutrient status among women of reproductive age and preschool-aged children in Punjab, India: protocol for a randomized, controlled, community-based trial

BackgroundMultiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC.MethodsThe study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18–49 years old and 468 PSC 12–59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC.DiscussionIf proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly.Trial registrationClinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Effect of Whole-Body Cryotherapy on Iron Status and Biomarkers of Neuroplasticity in Multiple Sclerosis Women.

The aim of the study was to compare the effect of a series of 20 whole body cryotherapy (WBC) sessions on iron levels and neuroplasticity biomarkers in women with multiple sclerosis (MS) and healthy women. Consent was obtained from the Bioethics Committee at the Regional Medical Chamber in Krakow (87/KBL/OIL/2018; 8 May 2018). The study was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12620001142921; 2 November 2020). The study included 30 people: 15 women with multiple sclerosis (mean age 41.53 ± 6.98 years) and 15 healthy women (mean age 38.47 ± 6.0 years). Both groups attended cryotherapy sessions. Venous blood was collected for analysis before the WBC session and after 20 sessions. In women with MS and healthy women, no significant effect of WBC on changes in the level biomarkers of neuroplasticity was found. There were also no statistically significant differences between the groups of the analyzed indices at the beginning of the study.

Appraising the Causal Association between Systemic Iron Status and Heart Failure Risk: A Mendelian Randomisation Study.

Although observational studies have shown that abnormal systemic iron status is associated with an increased risk of heart failure (HF), it remains unclear whether this relationship represents true causality. We aimed to explore the causal relationship between iron status and HF risk. Two-sample Mendelian randomisation (MR) was applied to obtain a causal estimate. Genetic summary statistical data for the associations (p < 5 × 10−8) between single nucleotide polymorphisms (SNPs) and four iron status parameters were obtained from the Genetics of Iron Status Consortium in genome-wide association studies involving 48,972 subjects. Statistical data on the association of SNPs with HF were extracted from the UK biobank consortium (including 1088 HF cases and 360,106 controls). The results were further tested using MR based on the Bayesian model averaging (MR-BMA) and multivariate MR (MVMR). Of the twelve SNPs considered to be valid instrumental variables, three SNPs (rs1800562, rs855791, and rs1799945) were associated with all four iron biomarkers. Genetically predicted iron status biomarkers were not causally associated with HF risk (all p > 0.05). Sensitivity analysis did not show evidence of potential heterogeneity and horizontal pleiotropy. Convincing evidence to support a causal relationship between iron status and HF risk was not found. The strong relationship between abnormal iron status and HF risk may be explained by an indirect mechanism.