Changes In Iron Status Research Articles

Associations between iron status and psychosocial wellbeing among pregnant women in Cape Coast, Ghana: a longitudinal study.

To determine the associations among iron status, depressive/anxiety symptoms, and quality of life (QoL) throughout pregnancy. This longitudinal study recruited participants in their 1st trimester (< 13 weeks; n=116) and followed in their 2nd (n=71) and 3rd (n=71) trimesters. Sociodemographic, food security, anxiety, depressive symptoms, and QoL questions were collected. Hemoglobin (Hb), ferritin (Ft), and transferrin saturation (TSAT) were determined. Women were categorized as iron improvers or non-improvers based on changes in iron status. Associations were assessed using difference-in-difference analyses. Cape Coast, Ghana between October 2017 to September 2018. Pregnant women, 18-38 years. Improvement in Ft levels from the 1st to 2nd trimester were associated with reduced depressive symptoms (-2.96 vs -0.58, p=0.028), and higher overall QoL (13.99 vs 1.92, p=0.006) particularly role physical (23.32 vs -2.55, p=0.025) and role emotional (27.50 vs 10.06, p=0.025) subscales. Improvement in Hb levels during the same period were linked to less anxiety, particularly fear factor (-2.62 vs -0.51, p=0.020); and worsened physical health aspect of QoL (-21.80 vs -3.75, p=0.005). Improvement in TSAT levels from 2nd to 3rd trimester were associated with increased total anxiety (1.56 vs -0.64, p=0.030) and panic factor (0.45 vs -0.26, p=0.004) and decreased total QoL (-1.08 vs 7.94, p=0.017), specifically role physical (-10.98 vs 11.93, p=0.018). Increases in iron status from first to second trimester were related to improvements in psychosocial wellbeing, implying potential benefit of iron supplementation on affect in early pregnancy. Larger studies are needed to confirm these findings.

Endothelial Hemoglobin Alpha Mediates Iron Regulation of Endothelial Nitric Oxide

Iron deficiency is associated with heart failure, chronic kidney disease, and chronic inflammation. All of these pathologies are associated with endothelial dysfunction and impaired nitric oxide (NO) signaling. Previous clinical studies have found iron deficiency anemia (IDA) increases endothelial NO signaling and attributed this change to the reduction in circulating hemoglobin. However, while free hemoglobin is a potent scavenger of NO, it has been shown in ex vivo preparations that endothelial NO signaling is unaffected by the presence of erythrocytes suggesting changes in circulating hemoglobin do not alter NO signaling. For these reasons we focused on endothelial iron regulation. Using single cell RNA sequencing data of isolated mesenteric and adipose endothelial cells generated by our lab, we have observed arterial endothelial cells have higher transferrin receptor expression compared to capillary, veinous, and lymphatic endothelial cells. This suggests that the arterial endothelium, which controls blood flow and is especially susceptible to endothelial dysfunction, may be particularly sensitive to changes in iron status. Additionally, our lab has previously shown the alpha chain of hemoglobin (Hbα) is expressed in the endothelium of small arteries and scavenges NO. We therefore hypothesized endothelial Hbα, rather than blood hemoglobin is responsible for the increased NO signaling in IDA. We first tested this hypothesis in a mouse model of IDA in which we were able to replete vascular iron stores. C57BL/6 mice were fed an iron deficient (2-6 ppm Fe) or nutrient matched control diet (48 ppm Fe) beginning at weaning. IDA mice underwent phlebotomies (10% blood volume) at 9 and 11 weeks old to aid in the progression of anemia. To restore vascular iron stores, a subset of IDA mice received a single i.p. injection of iron dextran (FeDex; 20 mg/kg) at 12 weeks. One week later complete blood counts were assessed, tissues were collected, and blood flow studies were performed. As expected, IDA mice had low blood hemoglobin (Con: 15.54 ± 0.43 vs. IDA: 6.04 ± 0.35 g/dL; p &amp;lt; 0.0001). FeDex did not rescue the anemia (8.55 ± 0.74 g/dL; p &amp;lt; 0.0001 vs. Con), but did rescue vascular iron stores as measured by ferritin light chain protein. To investigate NO signaling, we used laser speckle contrast imaging to measure changes in in vivo blood flow in response to the NO synthase inhibitor L-NAME. The magnitude of the response to L-NAME is an indicator of NO signaling. IDA mice exhibited an exaggerated response to L-NAME indicating increased NO signaling. Rescuing vascular iron stores with FeDex restored the L-NAME response back to control levels suggesting vascular iron stores, rather than the anemia itself increased NO signaling. In order to investigate the role of endothelial Hbα, we repeated these studies in endothelial specific Hbα knockout mice (Hba1 fl/fl-Cdh5-CreER T2+) developed by us. Lack of endothelial Hbα did not prevent the increased response to L-NAME in IDA mice, but did prevent the rescue by FeDex. These data suggest a model in which endothelial Hbα participates in regulating NO in response to iron, but not the increased NO in IDA.

Low phytic acid pea supplementation as an approach to combating iron deficiency in female runners: A randomized control trial.

Background: Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and the leading cause of anemia globally. Female athletes are at a disproportionate risk for ID due to blood loss through menstruation and decreased iron absorption secondary to exercise. Field peas are a rich source of iron but, similar to iron from other plant-based sources, the iron has limited bioavailability due to high levels of phytic acid, an inherent compound that binds to cations, creating a salt (phytate), which limits absorption during digestion. Aim: The purpose of our research was to investigate the effect of a field pea variety bred to have low levels of phytic acid on plasma ferritin, exercise performance, and body composition in female runners. Methods: Twenty-eight female runners (age:34.6 ± 9.7 years; weight: 65.1 ± 8.1 kg; VO2max: 50.7 ± 8.9 ml/kg/min) underwent measures of ferritin, exercise performance, and body composition before and after being randomly assigned to consume a powder derived from regular peas, low phytic acid peas, or a non-pea control (maltodextrin), plus vitamin C for 8 weeks. Results: The regular pea and low phytic acid pea groups had a 14.4% and 5.1% increase in plasma ferritin, respectively, while the maltodextrin group had a decrease of 2.2%; however, the difference in changes between groups was not statistically significant. No differences between groups were evident in any of the other measures. Conclusion: Larger doses or longer duration of pea supplementation may be necessary to induce meaningful changes in iron status. This trial was registered at ClinicalTrials.gov (NCT04872140).

The impact of recommending iron supplements to women with depleted iron stores in early pregnancy on use of supplements, and factors associated with changes in iron status from early pregnancy to postpartum in a multi-ethnic population-based cohort

BackgroundWe aimed to evaluate the impact of recommending supplementation to pregnant women with serum ferritin (SF) < 20 µg/L in early pregnancy on use of supplements, and to explore which factors were associated with changes in iron status by different iron indicators to 14 weeks postpartum.MethodsA multi-ethnic population-based cohort study of 573 pregnant women examined at mean gestational week (GW) 15 (enrolment), at mean GW 28 and at the postpartum visit (mean 14 weeks after delivery). Women with SF < 20 µg/L at enrolment were recommended 30-50 mg iron supplementation and supplement use was assessed at all visits. Change of SF, soluble transferrin receptor and total body iron from enrolment to postpartum were calculated by subtracting the concentrations at the postpartum visit from that at enrolment. Linear and logistic regression analyses were performed to assess associations between use of supplements in GW 28 and changes in iron status and postpartum iron deficiency/anaemia. Change of iron status was categorized into ‘steady low’, ‘improvement’, ‘deterioration’, and ‘steady high’ based on SF status at enrolment and postpartum. Multinomial logistic regression analyses were performed to identify factors associated with change of iron status.ResultsAt enrolment, 44% had SF < 20 µg/L. Among these women (78% non-Western European origin), use of supplements increased from 25% (enrolment) to 65% (GW 28). Use of supplements in GW 28 was associated with improved iron levels by all three indicators (p < 0.05) and with haemoglobin concentration (p < 0.001) from enrolment to postpartum, and with lower odds of postpartum iron deficiency by SF and TBI (p < 0.05). Factors positively associated with ‘steady low’ were: use of supplements, postpartum haemorrhage, an unhealthy dietary pattern and South Asian ethnicity (p ≤ 0.01 for all); with ‘deterioration’: postpartum haemorrhage, an unhealthy dietary pattern, primiparity and no use of supplements (p < 0.01 for all), and with ‘improvement’: use of supplements, multiparity and South Asian ethnicity (p < 0.03 for all).ConclusionsBoth supplement use and iron status improved from enrolment to the postpartum visit among women recommended supplementation. Dietary pattern, use of supplements, ethnicity, parity and postpartum haemorrhage were identified as factors associated with change in iron status.

Exploration of Menarche, Dietary Iron, and Additional Risk Factors on the Development of Iron Deficiency in Adolescent Girls

Background: Iron deficiency (ID) is estimated to affect between 9 and 16% of adolescent girls in the United States. It occurs during a critical time of increased iron demands related to blood volume expansion, muscle mass increase, and menstrual blood loss. Black girls are disproportionately affected, likely due to social determinants of health. ID is associated with decreased cognitive function, exercise capacity, and fatigue. Unrecognized ID can progress to complications of severe anemia. Despite readily available therapies including both oral and intravenous iron, no universal screening recommendations or evidence-based prediction tools exist to identify adolescent girls at risk for ID. Our objective was to determine the prevalence of, timing of, and clinical risk factors for ID in a large, biracial cohort of adolescent girls. Methods: Existing clinical data and stored serum specimens were obtained from the National Heart Lung and Blood Institute (NHLBI) Growth and Health Study (NGHS). The NGHS was a 10-year longitudinal study initiated in 1985 that enrolled 2,379 girls (51% Black, 49% White) from three cities (San Francisco, Cincinnati, Washington DC). Subjects participated in annual visits with serum samples obtained at Years 1, 3, 5, 7, and 10 with a retention rate of 89% at the 10th annual visit. Clinical data included socioeconomic data, body mass index (BMI), age at menarche, menstrual and pregnancy history, use of oral contraceptive medications, and dietary iron intake. We hypothesized that >10% of NGHS subjects would meet criteria for ID. We further hypothesized that longer duration from onset of menarche, low dietary iron intake, history of pregnancy, and obesity (defined as BMI >30) would be associated with ID. Available serum samples at Year 10 (n=692) were analyzed with Q-Plex Human Micronutrient Array ELISA kits (Quansys Biosciences) to measure iron-related parameters including serum ferritin, soluble transferrin receptor (sTfR1), sTfR1:ferritin index, and C-reactive protein. Subjects with ferritin >150 ng/mL and CRP >5 mg/L were excluded. ID was defined as serum ferritin <15 ng/mL, sTfR1 >5 mg/L, and sTfR1:ferritin index >2. Univariate logistic regression models assessed for the association of ID with established clinical risk factors. Results: Clinical and laboratory data from 510 subjects were included in the final analysis (median age 19 years, 51.4% Black). Of those, 83 (n=16.3%) were found to be iron deficient. ID was not associated with racial group, poverty threshold, BMI, age at menarche, history of pregnancy, oral contraceptive pill use, or average daily iron intake (TABLE). Subjects with later onset of menarche tended to have lower ferritin (OR 1.27 [1.05-1.54], p<0.015, FIGURE). Conclusion: The prevalence of ID in subjects 18 to 19 years of age enrolled in the NGHS was consistent with higher values of previously published prevalence estimates in adolescent girls. Established risk factors for the development of ID, such as earlier onset of menarche, were not clearly associated with ID in this cohort. These findings suggest that universal screening, rather than targeted screening, may be important for the early identification of all girls with ID. Additional clinical data and serum samples from Years 5 and 7 of the NGHS will be obtained to determine the prevalence of ID in the same cohort of subjects at earlier ages and determine changes in iron status over time. The results from this study will inform the development of a risk prediction tool as well as evidenced-based screening recommendations for ID in adolescent girls. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of iron-folic acid treatment for reducing anemia prevalence and improving iron status in women of reproductive age: A one-year longitudinal study.

Anemia control has hitherto been through prophylaxis with weekly iron folic acid (IFA) in Indian women of reproductive age (WRA). Recently, a more precise approach has been proposed, that uses a 'screen and treat with IFA' approach for anemic WRA, combined with continued prophylactic IFA in non-anemic WRA. The efficacy of this approach was assessed in Indian WRA, along with changes in iron status biomarkers. Young WRA (n=470), aged 17-21y, were screened for their venous blood hemoglobin (Hb) and treated with IFA for 90 days according to their grade of anemia, or if non-anemic, administered prophylactic IFA, per Indian policy guidelines, and then followed-up for an additional 9-months. Their Hb, plasma ferritin (PF), transferrin receptor, hepcidin and C-reactive protein concentrations were measured at baseline, during treatment and further follow-up. Anemia was diagnosed using Hb (<12g/dL) and iron deficiency (ID) using PF (<15μg/L) cut-offs after adjustment for inflammation. Co-existence of anemia and ID was labelled iron deficiency anemia (IDA). At baseline, in the whole group anemia, ID and IDA prevalence was 69.6%, 68.7% and 62.4%, respectively. At 90 days, IFA treatment or prophylaxis significantly reduced anemia by 40 percentage points (pp), from 69.6% at baseline to 29.8%; ID by 47.3 pp, and IDA by 48 pp. Moreover, significant treatment effects persisted at 365 days of follow-up. The 'screen and treat with IFA' approach is efficacious in reducing the prevalence of anemia in general among WRA, with persistent and significant effects after 9 months of follow-up. CTRI No:2019/02/017806, http://ctri.nic.in/.

Re\ufeffplacing dietary animal-source proteins with plant-source proteins changes dietary intake and status of vitamins and minerals in healthy adults: a 12-week randomized controlled trial

PurposeA shift towards more plant-based diets promotes both health and sustainability. However, controlled trials addressing the nutritional effects of replacing animal proteins with plant proteins are lacking. We examined the effects of partly replacing animal proteins with plant proteins on critical vitamin and mineral intake and statuses in healthy adults using a whole-diet approach.MethodsVolunteers aged 20–69 years (107 female, 29 male) were randomly allocated into one of three 12-week intervention groups with different dietary protein compositions: ANIMAL: 70% animal-source protein/30% plant-source protein; 50/50: 50% animal/50% plant; PLANT: 30% animal/70% plant; all with designed protein intake of 17 E%. We analysed vitamin B-12, iodine, iron, folate, and zinc intakes from 4-day food records, haemoglobin, ferritin, transferrin receptor, folate, and holotranscobalamin II from fasting blood samples, and iodine from 24-h urine.ResultsAt the end point, vitamin B-12 intake and status were lower in PLANT than in 50/50 or ANIMAL groups (P ≤ 0.007 for all). Vitamin B-12 intake was also lower in 50/50 than in ANIMAL (P < 0.001). Iodine intake and status were lower in both 50/50 and PLANT than in ANIMAL (P ≤ 0.002 for all). Iron and folate intakes were higher in PLANT than in ANIMAL (P < 0.001, P = 0.047), but no significant differences emerged in the respective biomarkers.ConclusionsPartial replacement of animal protein foods with plant protein foods led to marked decreases in the intake and status of vitamin B-12 and iodine. No changes in iron status were seen. More attention needs to be paid to adequate micronutrient intakes when following flexitarian diets.Clinical trial registryNCT03206827; registration date: 2017–06-30.

The Efficacy of Consuming Iron-Fortified Lentils on Body Iron (Fe) Status in Bangladeshi Adolescent Girls: A Sustainable, Food-Based Solution to Iron Deficiency

ObjectivesIron deficiency (ID) and iron deficiency anaemia (IDA) remain a public health concern among women and girls globally, and have numerous impacts on health, nutrition and socioeconomic status. Our objective was to investigate the efficacy of consuming iron-fortified lentils on iron status among rural Bangladeshi adolescent girls. MethodsIn this community-based, double-blind, cluster-randomized controlled trial, girls (13.5 ± 2.0 years) were randomly assigned to three groups that received 1)cooked iron-fortified lentils (160 ppm Fe NaFeEDTA per kg of lentils); 2)cooked non-iron-fortified lentils; or 3)no lentils (usual intake group). We served 200 g of cooked lentils using a local daal recipe on five days/week, for 4 months. Iron status (sFer, sTfR, and Hgb) was assessed at baseline, 2 and 4 months. All analyses were adjusted for inflammation. ResultsThere were no differences in baseline iron status among the three groups. sFer significantly increased by 21.9% (+5.7 μg/L, p < 0.001; 95% CI: 1.7, 9.5 μg/L) from baseline to 4 months in the iron-fortified lentil group, compared to a decline in sFer observed in the non-iron fortified lentil (53.3 vs. 38.6 μg/L, p < 0.01) and no lentil groups (53.6 vs. 39.5 μg/L, p < 0.01). Examining overall changes in iron status over 4 months, we observed maintenance in the iron-fortified group from baseline, compared to a decline in the other groups. ConclusionsWe observed improvement in and maintenance of iron status in a population vulnerable to ID and IDA who consumed iron-fortified lentils for 4 months. Additionally, girls who consumed iron-fortified lentils had a 60% lower chance of developing clinical and subclinical ID (sFer < 15, 15–30 μg/L), and a 70% lower chance of developing sub-clinical IDA (sFer 15–30 μg/L + Hgb < 12 g/dL) compared to those who did not. Funding SourcesGlobal Institute for Food Security.

Association of common\xa0TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians

Genome-wide association studies in Europeans and Asians have identified numerous variants in the transmembrane protease serine 6 (TMPRSS6) and transferrin (TF) genes that are associated with changes in iron status. We sought to investigate the effects of common TMPRSS6 and TF gene SNPs on iron status indicators in a cohort of healthy Africans from rural Gambia. We measured iron biomarkers and haematology traits on individuals participating in the Keneba Biobank with genotype data on TMPRSS6 (rs2235321, rs855791, rs4820268, rs2235324, rs2413450 and rs5756506) and TF (rs3811647 and rs1799852), n = 1316. After controlling for inflammation, age and sex, we analysed the effects of carrying either single or multiple iron-lowering alleles on iron status. TMPRSS6 rs2235321 significantly affected plasma hepcidin concentrations (AA genotypes having lower hepcidin levels; F ratio 3.7, P = 0.014) with greater impact in individuals with low haemoglobin or ferritin. No other TMPRSS6 variant affected hepcidin. None of the TMPRSS6 variants nor a TMPRSS6 allele risk score affected other iron biomarkers or haematological traits. TF rs3811647 AA carriers had 21% higher transferrin (F ratio 16.0, P < 0.0001), 24% higher unsaturated iron-binding capacity (F ratio 12.8, P < 0.0001) and 25% lower transferrin saturation (F ratio 4.3, P < 0.0001) compared to GG carriers. TF rs3811647 was strongly associated with transferrin, unsaturated iron-binding capacity (UIBC) and transferrin saturation (TSAT) with a single allele effect of 8–12%. There was no association between either TF SNP and any haematological traits or iron biomarkers. We identified meaningful associations between TMPRSS6 rs2235321 and hepcidin and replicated the previous findings on the effects of TF rs3811647 on transferrin and iron binding capacity. However, the effects are subtle and contribute little to population variance. Further genetic and functional studies, including polymorphisms frequent in Africa populations, are needed to identify markers for genetically stratified approaches to prevention or treatment of iron deficiency anaemia.

Iron status and self‐reported fatigue in blood donors

Three blood centers randomly assigned 692 frequent donors to education or iron supplementation treatments. Biomarkers for iron status were measured during 20 to 24 months of follow-up. A fatigue score was derived from an 11-item questionnaire at baseline and final visits, and associations between iron status and fatigue were assessed. Final lab and questionnaire data were evaluable from 337 subjects. At baseline, female sex, older age, and anemia were associated with fatigue, but iron status was not. Mean (±SD) fatigue score change was 0.0 (±0.5). Mean (±SD) increase in iron stores was 1.0 (±3.5) mg/kg, but changes in body iron stores were not associated with fatigue score changes (0.01 per mg/kg; 95% CI, -0.01 to 0.02) or with fatigue (RR, 1.01; 95% CI, 0.99 to 1.04). The only factor associated with fatigue score changes was baseline fatigue (0.36; 95% CI, 0.25 to 0.48). Among high-frequency donors, neither iron status at baseline nor changes in iron status predicted fatigue during follow-up, with improvements limited to those with higher levels of baseline fatigue. Assessment of the association between iron and fatigue in blood donors benefits from careful consideration of study design and the study population.

Increased Iron Status during a Feeding Trial of Iron-Biofortified Beans Increases Physical Work Efficiency in Rwandan Women

ABSTRACTBackgroundIron-biofortified staple foods can improve iron status and resolve iron deficiency. However, whether improved iron status from iron biofortification can improve physical performance remains unclear.ObjectiveThis study aimed to examine whether changes in iron status from an iron-biofortified bean intervention affect work efficiency.MethodsA total of 125 iron-depleted (ferritin <20 μg/L) female Rwandan university students (18–26 y) were selected from a larger sample randomly assigned to consume iron-biofortified beans (Fe-Bean; 86.1 mg Fe/kg) or conventional beans (control: 50.6 mg Fe/kg) twice daily for 18 wk (average of 314 g beans consumed/d). Blood biomarkers of iron status (primary outcome) and physical work efficiency (secondary outcome) were measured before and after the intervention. Work performed was assessed during 5-min steady-state periods at 0-, 25-, and 40-W workloads using a mechanically braked cycle ergometer. Work efficiency was calculated at 25 W and 40 W as the work accomplished divided by the energy expended at that workload above that expended at 0 W. General linear models were used to evaluate the relation between changes in iron status biomarkers and work efficiency.ResultsThe Fe-Bean intervention had significant positive effects on hemoglobin, serum ferritin, and body iron stores but did not affect work efficiency. However, 18-wk change in hemoglobin was positively related to work efficiency at 40 W in the full sample (n = 119; estimate: 0.24 g/L; 95% CI: 0.01, 0.48 g/L; P = 0.044) and among women who were anemic (hemoglobin <120 g/L) at baseline (n = 43; estimate: 0.64 g/L; 95% CI: 0.05, 1.23 g/L; P = 0.036). Among women who were nonanemic at baseline, change in serum ferritin was positively related to change in work efficiency at 40 W (n = 60; estimate: 0.50 μg/L; 95% CI: 0.06, 0.95 μg/L; P = 0.027).ConclusionsIncreasing iron status during an iron-biofortified bean feeding trial improves work efficiency in iron-depleted, sedentary women. This trial was registered at clinicaltrials.gov as NCT01594359.

Changes in Iron Status of Hypertensive Patients

Changes in Iron Status of Hypertensive Patients

Distinct TP53 Mutation Subtypes Differentially Influence Cellular Iron Metabolism

The most commonly mutated gene in all human cancers is the tumor suppressor gene TP53; however, in addition to the loss of tumor suppressor functions, mutations in TP53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how TP53 mutation status influences the molecular control of iron homeostasis. The effect of TP53 mutation type on cellular iron homeostasis was examined using cell lines with inducible versions of either wild-type TP53 or a representative mutated TP53 gene from exemplary “hotspot” mutations in the DNA binding domain (R248, R273, and R175) as well as H193Y. The introduction of distinct TP53 mutation types alone was sufficient to disrupt cellular iron metabolism. These effects were mediated, at least in part, due to differences in the responsiveness of iron regulatory proteins (IRPs) to cellular iron availability. IRPs are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability, cells harboring either a wild-type TP53 or R273H TP53 mutation displayed canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels were affected by changes in iron status in cells harboring the R175H mutation type. However, all mutation types exhibited robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing distinct TP53 mutations. As TP53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.

Abstract 4365: Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism

Abstract The most commonly mutated gene in all human cancers is the tumor suppressor gene p53, but in addition to loss of tumor suppressor functions, mutations in p53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how p53 mutation status influences the molecular control of iron homeostasis. Though hundreds of p53 mutations have been identified, the majority occur within the DNA binding domain and can be subdivided into two broad classes: contact (e.g., R273H) or conformational (e.g., R175H). By generating cell lines with inducible versions of some of the most common conformational and contact-type p53 mutations we have established that introduction of specific p53 mutation types alone is sufficient to disrupt cellular iron metabolism. We also demonstrate these effects are mediated at least in part due to differences in the responsiveness of Iron Regulatory Proteins (IRP) to cellular iron availability. IRP are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability cells harboring either a wild-type p53 or contact (R273H) p53 mutation display canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels are affected by changes in iron status in cells harboring the conformational type mutant (R175H). Yet, both contact and conformational mutants exhibit robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing conformational type p53 mutants. Preliminary proteomics data suggests that lack of IRP responsiveness in cells expressing conformational p53 mutations may result from impaired iron-sulfur cluster biogenesis. These findings are currently being explored as a means of exploiting distinct p53 mutation types to more favorably induce iron-mediated cell death via the activation of ferroptosis. As p53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers. Citation Format: Eshan Dandekar, Aishwarya Srinivasan, Stephen Clarke, Mckale Montgomery. Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4365.

PS1120 IRON MOBILIZATION IN A REAL LIFE COHORT OF APLASTIC ANEMIA PATIENTS TREATED WITH ELTROMBOPAG

Background:Most aplastic anemia (AA) patients are heavily transfusion dependent of both platelets and red blood cells (RBC), and iron overload may become an issue. Excess iron not only hampers the function of several systems (liver, heart, kidney, endocrine system), but has also a negative effect on normal hematopoiesis, which is already particularly poor in AA patients. TPO mimetic eltrombopag (EPAG) improves hematopoiesis in about 40% of patients with both relapsed/refractory and newly‐diagnosed AA, and recent reports demonstrated iron‐mobilizing activity in vitro; furthermore, harmonic oscillation of serum ferritin concomitant to EPAG initiation and discontinuation have been also observed in vivo, indicating an iron mobilization effectAims:To evaluate iron mobilization mediated by EPAG in a real life cohort of AA patientsMethods:Clinical and hematologic parameters, including iron panel, of 10 AA patients treated with EPAG at our Institution in the last 18 months were collected. Changes in iron status and their relationship with EPAG treatment were systematically recordedResults:Table 1 shows hematologic parameters and iron status at baseline and after EPAG treatment. Median age was 43 years (23–91), and male to female ratio 1:1. At the time of EPAG initiation 6 cases presented with severe AA and 60% were RBC transfusion dependent. Three patients were therapy naïve and received EPAG together with frontline IST, starting at 150 mg/day since day+14; seven cases were relapsed/refractory ones, previously treated with ATG and cyclosporine (2), cyclosporine alone (2), or steroids only (2). As regards iron status, ferritin levels and plasma iron increased from EPAG start to month +1 and +3 (p = 0.04), and transferrin saturation was persistently augmented versus baseline at month +1,+3, and +6 (p = 0.01, p = 0.03, P = 0.04, respectively). Considering non transfused patients, we observed a similar increase of these parameters after EPAG start, although baseline values were lower than in transfusion‐dependent cases. At month +12 an amelioration of iron status was observed, both in transfusion dependent and not, particularly iron and transferring saturation that did not further increase. Notably, iron chelation was performed in 2 transfused cases only, possibly accounting for this improvement. Considering hematologic parameters, Hb, ANC, and PLT values significantly ameliorated from baseline to month +3, and along the follow up. Mean Hb increase from baseline was 0.7 ± 1.6 g/dL, mean ANC increase 0.3 ± 0.48x109/L, and mean PLT 27 ± 38x109/L. Transfusion requirement was progressively lost, and ORR increased from 56% at month+3 to 100% at month +6 and thereafter (although CR was observed in 1 patient only)Summary/Conclusion:In our real life cohort of AA patients we observed an increase of iron and transferrin saturation levels soon after EPAG initiation, irrespective of the transfusion status. This data support the iron‐mobilizing effect of EPAGimage

Dynamic iron status after acute heart failure

Iron deficiency (ID) is common in heart failure (HF), and is associated with unfavourable clinical outcomes. Although it is recommended to screen for ID in HF, there is no clear consensus on the optimal timing of its assessment. To analyse changes in iron status during a short-term follow-up in patients admitted for acute HF. Iron status (serum ferritin concentration and transferrin saturation) was determined in 110 consecutive patients (median age: 81 years) admitted to a referral centre for acute HF, at three timepoints (admission, discharge and 1 month after discharge). ID was defined according to the guidelines. The prevalence rates of ID at admission, discharge and 1 month were, respectively, 75% (95% confidence interval [CI] 67-83%), 61% (95% CI: 52-70%), and 70% (95% CI: 61-79%) (P=0.008). Changes in prevalence were significant between admission and discharge (P=0.0018). Despite a similar ID prevalence at admission and 1 month (P=0.34), iron status changed in 25% of patients. Between admission and discharge, variation in C-reactive protein correlated significantly with that of ferritin (ρ=0.30; P=0.001). Advanced age, anaemia, low ferritin concentration and low creatinine clearance were associated with the persistence of ID from admission to 1 month. Iron status is dynamic in patients admitted for acute HF. Although ID was as frequent at admission as at 1 month after discharge, iron status varied in 25% of patients.

Changes in Iron Status Are Related to Changes in Brain Activity and Behavior in Rwandan Female University Students: Results from a Randomized Controlled Efficacy Trial Involving Iron-Biofortified Beans

ABSTRACTBackgroundEvidence suggests that iron deficiency (ID) affects cognitive performance, as measured in behavior. Although such effects must be mediated by changes in the brain, very few studies have included measures of brain activity to assess this relation.ObjectiveWe tested the hypothesis that provision of iron-biofortified beans would result in improvements in measures of iron status, brain dynamics, and behavior.MethodsA double-blind, randomized, intervention study was conducted in 55 women aged 18–27 y with low iron status (serum ferritin <20 µg/L). Women were randomly assigned to consume iron-biofortified (86.1 ppm iron) or comparison beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed by hemoglobin, ferritin, transferrin receptor, and body iron; cognitive performance with 5 computerized tasks; and brain dynamics by concurrent electroencephalography (EEG). All measures were taken at baseline and endline.ResultsThe groups did not differ on any measures at baseline. Intention-to-treat analyses revealed significant (all P < 0.05) improvements in hemoglobin (partial effect size attributable to the independent variable, η2 = 0.16), ferritin (η2 = 0.17), and body iron (η2 = 0.10), speed of responding in attentional and mnemonic tasks (η2 = 0.04-0.29), sensitivity and efficiency of memory retrieval (η2 = 0.12-0.55), and measures of EEG amplitude and spectral power (η2 = 0.08 to 0.49). Mediation models provided evidence in support of the hypothesis that changes in iron status produce changes in behavior by way of changes in brain activity.ConclusionsBehavioral performance and brain activity, as measured by EEG, are sensitive to iron status, and the consumption of iron-biofortified beans for 18 wk resulted in improvements in measures of both, relative to what was obtained with a comparison bean, in a sample of female university students. Furthermore, the results support the conclusion that changes in brain activity resulting from consumption of biofortified beans mediate the relations between changes in iron biomarkers and changes in cognition. Clinical trial registry: ClinicalTrials.gov Reg No. NCT01594359.

Amino acid profile in patients with thalassemia major analyzed by liquid chromatography-tandem mass spectrometry

Patients with thalassemia major develop secondary iron overload due to ineffective erythropoiesis and recurrent transfusions. Excessive iron overload results in increased non-transferrin-bound iron, which induces tissue injury as it catalyzes the formation of free radical ions. Iron accumulation can impair the structural and functional integrity of the intestines and reduce amino acid availability. Iron overload can be alleviated by iron chelation. Transferrin is the body’s natural chelator that predominantly comprises amino acids glycine and aspartic acid. Research has shown lower transferrin levels in patients with iron overload. The present study aimed to assess the changes in iron status and the amino acid profile in patients with thalassemia major. Serum iron; unsaturated iron-binding capacity; total iron-binding capacity; and serum ferritin, glycine, and aspartic acid were assessed in a cohort of 21 patients (13 patients with beta thalassemia major and 8 with beta Hb E thalassemia). The results showed significant changes in iron status: elevated ferritin post-transfusion and decreased ferritin and elevated glycine levels after chelation. Future studies are required to assess the changes in other amino acids.

Total iron-binding capacity is a novel prognostic marker after curative gastrectomy for gastric cancer.

Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer. We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors' associations with prognosis after surgery. Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (< 260µg/dl) that was not associated with Hgb or Fe level. Patients with low TIBC were significantly associated with older age (≥ 65years old; P = 0.0085), low albumin (< 3.9g/dl; P = 0.0388) and high CRP (≥ 0.15mg/dl; P = 0.0018) in multivariate analysis. Low Fe (< 60µg/dl) was not associated with disease-free survival (DFS) or overall survival (OS); however, low Fe was associated with longer cancer-specific survival in Stage III GC patients (P = 0.0333). Both low Hgb and low TIBC were significantly associated with shorter DFS (Hgb: P = 0.0433; TIBC: P < 0.0001) and shorter OS (Hgb: P = 0.0352; TIBC: P < 0.0001). Low TIBC were significantly associated with shorter DFS (HR 2.167, 95% CI 1.231-3.639, P = 0.0086) and shorter OS (HR 2.065, 95% CI 1.144-3.570, P = 0.0173) in multivariate Cox hazard regression analysis. Preoperative serum TIBC level of GC patients who undergo curative gastrectomy is a novel prognostic marker in univariate and multivariate analyses.

Efficacy of iron supplementation may be misinterpreted using conventional measures of iron status in iron-depleted, nonanemic women undergoing aerobic exercise training

Background: Despite its known detrimental effects, iron deficiency remains the most common micronutrient deficiency in the world. Many interventions that aim to improve iron status involve physically active populations. Intense aerobic exercise training negatively affects iron status; however, the impact of regular moderate aerobic exercise on the effectiveness of iron supplementation remains unclear.Objective: This study aimed to determine whether aerobic training modifies the assessment of the effectiveness of iron supplementation in improving conventional iron status measures.Design: Seventy-two iron-depleted, nonanemic Chinese women [serum ferritin (sFer) <25 μg/L and hemoglobin >110 g/L] were included in an 8-wk, partially blinded, randomized controlled trial with a 2 × 2 factorial design including iron supplements (42 mg elemental Fe/d) or placebo and aerobic training (five 25-min sessions/wk at 75-85% of maximum heart rate) or no training. Linear mixed models were used to evaluate the relation between supplement type, training, and changes in iron status over time, measured by sFer, hemoglobin, soluble transferrin receptor (sTfR), and estimated total body iron.Results: After treatment, both the iron-supplemented trained and untrained groups showed significantly improved sFer, sTfR, and body iron values compared with either of the placebo groups. Similarly, trained participants had significantly higher aerobic fitness measures than untrained participants. Training modified the sFer response to supplementation (training by supplement interaction, P = 0.07), with the iron-supplemented trained group having significantly lower sFer than the iron-supplemented untrained group at week 8 (mean ± SD: 31.8 ± 13.5 and 47.6 ± 15.7 μg/L, respectively; P = 0.042), whereas there was no significant difference between the placebo trained and untrained groups (21.3 ± 12.2 and 20.3 ± 7.0 μg/L, respectively; P = 1.00).Conclusions: Regular aerobic training reduces the apparent effectiveness of iron supplementation in improving sFer and calls into question whether conventional measures of iron status accurately reflect iron metabolism in physically active, nonanemic women. This trial was registered at clinicaltrials.gov as NCT03002090.