An Analytical Study to Explore Iron Stores in a Population of Nowshera Based on Age and Gender Perspective

OBJECTIVES: To analyze the impact of age and gender on iron stores in a population of the Nowshera region. METHODOLOGY: This cross sectional study was conducted in the Department of Pathology Qazi Hussain Ahmed Medical Complex Nowshera from 1st January 2019 to 31st March 2020. All patients were selected by convenience sampling in the Pathology department irrespective of age and gender. Both descriptive and inferential statistics were applied to analyze data by the latest SPSS version 25. RESULTS: Out of the total study population males were 70 (27.1%) and females 188 (77.9%) with median age 30 years. The median ferritin level was 12.8 ng/ml. Out of total, 142 (55%) of cases were with serum ferritin less than 15ng/ml. A significant (p=0.03) gender based median ferritin level difference was observed with 1.5 times more probability of low iron stores in females as compared to males (OR=1.5). No statistically significant difference in body iron stores exists in different age groups. CONCLUSION: A significant difference was noted in the iron stores in gender groups and the probability of depleted/low iron stores was higher in female gender as compared to male gender in all age groups in our population.

Comparative study of efficacy and safety of parenteral iron sucrose versus ferric carboxymaltose in treatment of postpartum iron deficiency anaemia

Background: Postpartum anaemia often leads to multiple clinical complications in mother as well as infant and iron supplementation with parenteral iron is the preferred treatment modality. The present study was planned to compare the efficacy and tolerability of IV iron sucrose and IV ferric carboxymaltose in treatment of postpartum iron deficiency anaemia.Methods: This randomized, parallel, open label, prospective 4-weeks study was conducted from June 2019 to December 2020 in women with postpartum anaemia admitted to obstetrics and gynaecology inpatient department of a tertiary care hospital. Women with postpartum iron deficiency anaemia (N=60) were randomly divided into two groups; receiving Injection iron sucrose (N=30, maximum dose 500 mg) or Injection ferric carboxymaltose (N=30, maximum dose 500 mg). Change in haemoglobin and serum ferritin levels from baseline to the end of 2 and 4 weeks of treatment were evaluated.Results: The results showed early, sustained and significant increase in the haemoglobin levels in both the groups. However, the difference was not significant between groups (p=0.2). Evaluation of replenishment of iron stores (serum ferritin) showed improvement in both the groups, however in FCM group the rise was found to be significant (p<0.05).Conclusions: FCM in a lower dose of 500mg was found to be safe and effective in significantly improving haemoglobin concentration as well as in replenishing iron stores in patients with postpartum anaemia.

Effect of maternal hemoglobin and iron status on fetal hemoglobin, iron status, growth and maturity

Background: Iron deficiency anemia during pregnancy is a major health issue in India. However, the status of iron stores in infants born to iron depleted mothers remains controversial and inadequately investigated. The present study is therefore an attempt to understand whether maternal anemia and iron stores have any significant effect on iron status and growth of fetus.Methods: This is a prospective, cross-sectional, hospital based study conducted at Mata Chanan Devi Hosital, Janakpuri, New Delhi. Hemoglobin and iron profile of 100 newborns and their mothers were taken. Mothers were divided into anemic and non anemic group to see the effect of maternal anemia on fetus.Results: A total of 100 newborns and their mothers were analysed. Cord hemoglobin and iron profile was significantly reduced in anemic compared to non anemic group. Birth weight of newborn was significantly reduced only in moderately anemic group as compared to non anemic group but there was no difference seen in length and head circumference.Conclusions: Maternal serum ferritin levels should be measured for the diagnosis of occult iron deficiency in the fetus so that timely measures can be taken to prevent iron deficiency anemia in the newborn.

Ferritin trajectories over repeated whole blood donations: results from the FIND+ study

Background: Whole blood donors lose approximately 200-250 mg of iron per donation. Depending on post-donation erythropoiesis, available iron stores, and iron absorption rates, optimal donation intervals may differ between donors. This project aims to define subpopulations of donors with different ferritin trajectories over repeated donations. Methods: Ferritin levels of 300 new whole blood donors were measured from stored (lookback) samples from each donation over a two-year period in an observational cohort study. Latent classes of ferritin level trajectories were investigated using growth mixture models for male and female donors, separately. Associations of ferritin levels with subsequent iron deficiency and/or low haemoglobin were assessed with generalized linear mixed models. Results: In both genders two groups of donors were identified using group-based trajectory modelling. Ferritin levels showed rather linear reductions among 42.9% of male donors and 87.7% of female donors. For the remaining groups of donors, steeper declines in ferritin levels were observed. Ferritin levels at baseline and the end of follow-up varied greatly between groups. Conclusion: Repeated ferritin measurements show depleting iron stores in all new whole blood donors, the level at which mainly depends on baseline ferritin levels. Tailored, less intensive donation strategies might help to prevent low iron in donors, and could be supported with ferritin monitoring and/or iron supplementation.

INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis—a protocol for a prospective open-label blinded endpoint randomised controlled trial

Background The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation Methods In a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 μg/L and ≤ 2000 μg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 μg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed. Discussion The INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory. Trial registration This trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987. Registered 29 June 2020.

Decreased Serum Iron Concentration and Total Iron Binding Capacity Are Associated With Serious Crohn’s Disease

Background: This study aimed to investigate whether serum indicators related to iron stores in the body are associated with clinical and endoscopic disease severity.Methods: Eighty-four patients with Crohn’s disease (CD) and twenty-four healthy volunteers were included. The indicators related to iron stores were detected within one week after endoscopic and CT enterography examinations.Results: Patients were divided into three groups according to the CDAI scores. Serum iron levels were decreased in all patient groups (p<0.05), and the values of remission group were higher than those of moderate group (p<0.001). The total iron binding capacity （TIBC） values of the moderate group were lower than those of the controls and the other patient groups (p<0.05). None of the indicators differed significantly among the patients classified by SES-CD (p>0.05). Underweight, decreased serum iron and TIBC were independent risk factors for moderate clinical disease. Combined detection of decreased serum iron and TIBC was helpful in differentiating severe patients. The sensitivity and specificity were 32.7% and 100%, respectively (AUC = 0.812, p<0.01).Conclusions: Decreases in serum iron and TIBC were associated with the clinical activity of CD. Combined detection of the two indicators was conducive to screening patients with serious disease.

Luspatercept Redistributes Body Iron to the Liver in Transfusion-Dependent-Thalassemia (TDT) during Erythropoietic Response

Introduction: Luspatercept inhibits select ligands of the TGF-β superfamily implicated in thalassemic erythropoiesis and promotes late-stage erythroid maturation (Suragani RN, et al. Nat Med 2014;20:408-414). This leads to greater red blood cell (RBC) output from thalassemic marrow and reduces transfusion dependence in TDT (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231). The underlying mechanisms for this clinical outcome are not well understood in a syndrome involving significant iron overload and cyclical stimulation of erythropoiesis between transfusions. Here we report novel physiological and clinical insights from a BELIEVE trial (NCT02604433) biomarker analysis, which demonstrate that hepcidin and erythropoietic changes in TDT lead to iron redistribution from macrophages to hepatocytes on luspatercept. Methods: 336 TDT patients ≥ 18 years of age who took part in the BELIEVE study, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (Cappellini et al. 2020), were randomized 2:1 to receive luspatercept or placebo subcutaneously every 21 days for 48 weeks. This ethically approved study was conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent. Transfusion iron loading rate (ILR) was calculated assuming 1 unit = 200 mg Fe. Liver iron content (LIC) was measured by R2 MRI and R2* MRI, and total body iron stores by Angelucci formula. Serum was assayed for ferritin (SF) nephelometrically (Covance lab), and hepcidin, erythroferrone (ERFE), growth differentiation factor (GDF)15, and transferrin receptor (sTfR1) by ELISA at Intertek (San Diego, CA). Median and interquartile ranges are shown; P value &lt; 0.05 was deemed significant. Results: Within 48 weeks on luspatercept, transfusion iron loading fell by 1.6 g (8 RBC units, ILR difference −0.08 mg Fe/kg/d ± 0.07, range −0.4 to 0.2). Regardless of thalassemic genotype, SF fell by 269.3 ± 963.7 and earliest at 12 weeks by 103.6 ± 690.3 µg/L (both P &lt; 0.0001), with no change on placebo, indicating reduced macrophage iron. However, despite unchanged chelation exposure, no reduction in LIC (5.7 to 6.7 mg/g dw) or calculated body iron stores (3.6 to 4.2 g, not significant) occurred on luspatercept, even though saved iron loading from transfusion was 44% (1.6 g/3.6 g) of baseline body iron stores. On luspatercept, but not placebo, hepcidin fell by 53%, while erythropoietin (EPO), ERFE, GDF15, sTfR1, and reticulocytes rose by 93%, 51%, 59%, 66%, and 112%, respectively (all P &lt; 0.0001). 71% (120/169) patients with and 47% without (17/36) ILR reduction had negative SF trends (P &lt; 0.0001). In patients with SF reduction on luspatercept, bilirubin and LDH rose 50% and 67% (P &lt; 0.0001) indicating increased RBC hemolysis from residual (effective and ineffective) erythropoiesis. ILR change correlated with changes in EPO, hepcidin, sTfR1, and bilirubin, but not with changes in ERFE, GDF15, reticulocytes, or LDH (Figure A). Hepcidin reduction was related to LIC increase post splenectomy (Figure B), suggesting a role for the spleen in preventing hemolytic iron redistribution to the liver. Decrease in SF thus associates with erythroid iron incorporation (sTfR1), hence RBC production that reduces transfusion needs (falling ILR) but enhances hemolytic rerouting of iron to the liver. In a mixed-effect linear regression analysis, transfusion, LIC, baseline SF, time, and treatment predicted SF changes in a benchmark model. We found high baseline LIC lessens the SF outcome, and hepcidin, EPO, and bilirubin jointly explained 66% of the treatment effect of luspatercept on SF. Conclusions: Luspatercept-increased ERFE, likely as a result of increased production or higher frequency of late-stage erythroblasts, partially reduces hepcidin production. Lower hepcidin mobilizes iron stores to facilitate bulk hemoglobinization, erythropoietic response, and transfusion burden reduction. Luspatercept leads to SF reduction that marks hepcidin-dependent iron egress from macrophage compartment to plasma. This relocated iron, variably utilized by thalassemic erythron, refluxes back to plasma for hepatocyte and extrahepatic iron uptake, or as heme iron shunts into the liver through hemolytic pathways from intramarrow ineffective erythropoiesis or peripheral breakdown of newly made thalassemic RBC. Macrophage to hepatocyte iron redistribution in TDT appears to be a mechanism of luspatercept. Figure 1 Figure 1. Disclosures Garbowski: Imara: Consultancy; Vifor: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Suragani: Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Shetty: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Vodala: BMS: Current Employment, Other: stock options. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Schwickart: BMS (Celgene): Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other, Patents & Royalties; Exelixis: Current Employment, Current equity holder in publicly-traded company. Porter: Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.