Journal articles: 'Hepcidin, ERFE, sTfR, Iron metabolism'

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Garbowski, Maciej W., Olivier Hermine, Maria Domenica Cappellini, Raffaella Origa, Gian Luca Forni, Ersi Voskaridou, Frédéric Galactéros, et al. "GDF15 and Erythroferrone Mark Erythropoietic Response to ACE-011 (Sotatercept) in Thalassemia." Blood 132, Supplement 1 (November 29, 2018): 3633. http://dx.doi.org/10.1182/blood-2018-99-111770.

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Abstract Background The hemoglobin (Hb) response to the activin receptor type IIA ligand trap ACE-011 (Sotatercept) in non-transfusion-dependent thalassemia (NTDT), and the transfusion requirement response in TDT are described, but the mechanisms of action, clinical predictors and markers of response, are unclear. In principle, ACE-011 may act on early and/or late erythroblasts to decrease ineffective erythropoiesis (IE), both in healthy subjects and in thalassemia. As erythropoiesis intimately links to iron metabolism, changes in markers of iron metabolism relative to those of erythropoiesis may inform the mechanisms and developmental stage at which ACE-011 acts. Methods Markers of IE and iron metabolism in 46 thalassemia patients (30 NTDT, 16 TDT) were taken before and during a median follow up of 722.5 days, (IQR 830.5, range 152-1427) of escalating doses of ACE-011 (3-weekly 0.1 to 1.0 mg/kg s.c. injections), depending on the protocol, as part of the approved study (Cappellini, et al. 2018 under review). Markers of erythropoiesis included Hb, Reticulocytes (Ret), soluble transferrin receptor 1 (sTfR), growth differentiation factor 11 and 15 (GDF11, GDF15), erythroferrone (ERFE). Markers of iron metabolism included plasma hepcidin, serum ferritin (SF), transferrin saturation (TSAT), and non-transferrin-bound iron (NTBI). Data were analyzed using longitudinal multilevel model for change (LMMC) on STATA (Version 14) as generalized linear mixed model with random and fixed effects to account for repeated measures and highly complex temporal data structure. Final LMMCs were built to explain the change in Hb from baseline and the behavior of key biomarkers. Independent variables were entered into the models based on the study design (predictors from design) and theoretical background (predictors of interest and control variables). P value <0.05 was considered statistically significant. Results Predictors of response. In NTDT, Hb response associated positively with dose and duration of exposure (both at p<0.0001), and negatively with baseline EPO (p=0.002), GDF15 (p<0.0001) or TSAT. In TDT, accounting for transfusion effect, baseline GDF15 and EPO positively predicted Hb response while ERFE was a negative predictor (all at p<0.0001). Biomarker changes with time In NTDT, significant changes with time on study were increases in Hb, sTfR, ERFE and Ret and decreases in hepcidin, bilirubin, and NTBI. GDF15 showed no change. In TDT, GDF15, sTfR and ERFE increased, whereas hepcidin decreased. The Hb change was insignificant in TDT (as expected per protocol) and was dose-independent, however the mean 41% reduction in transfusion iron load rate (ILR) was dose dependent, implying an equivalent net production of Hb in TDT (Table 1). Other significant relationships Absolute hepcidin level in NTDT and TDT was negatively predicted by ERFE (p<0.0001): the first longitudinal demonstration of this association in thalassemia patients. GDF11, the target for ACE-011 that was shown previously to negatively regulate erythroid differentiation (Dussiot et al, Nat Med 2014), fell significantly on study (preliminary data). Significant reduction in indirect bilirubin in NTDT, implying reduced hemolysis, suggests improved quality of produced erythrocytes. Interpretation and conclusions NTDT patients allow a cleaner interpretation of biomarker changes as these are confounded in TDT by increased bone marrow stress from less transfusion. In NTDT, sTfR and ERFE (total erythropoiesis) increase on study while GDF15 (IE) and EPO do not. Thus Hb gain may result from increased effectiveness of late stage erythropoiesis (sTfR+ and ERFE+) possibly from decreased apoptosis and more rapid maturation (Carrancio et al, BJH 2014) in this compartment. We speculate that increased survival of those erythroid progenitor cells expressing TfR (and hence sTfR) and ERFE (hence increased ERFE) also explains the observed hepcidin reduction. Despite exposure to lower hepcidin, there is no iron loading: NTBI falls against stable SF in NTDT, consistent with shunting of iron into the sink of effective erythropoiesis. The reduction in GDF11 in vivo, not previously reported for ACE-011, is also consistent with increased apoptosis of the early progenitor pool and with improved erythroblast differentiation relative to proliferation as suggested in murine β-thalassemia treated with ACE-011 (Dussiot, et al. Nat Med 2014). Disclosures Garbowski: Vifor: Consultancy. Hermine:Erythec: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Novartis: Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Origa:Bluebird Bio: Consultancy; Novartis: Honoraria; Cerus Corporation: Research Funding; Apopharma: Honoraria. Forni:Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy; Apopharma: Other: DSM Board. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Galactéros:Addmedica: Other: grant; Novartis: Other: grant. Taher:Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceutical: Research Funding; Protagonist Therapeutics: Consultancy; Celgene Corp.: Research Funding; Ionis Pharmaceuticals: Consultancy. Ribeil:bluebird bio: Consultancy; Vitalaire: Other: grant; Addmedica: Other: grant; Cydan: Consultancy; Novartis: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zou:Celgene Corporation: Employment, Equity Ownership. Zinger:Celgene Corporation: Employment. Schwickart:Celgene Corporation: Employment, Equity Ownership. Sung:Celgene Corporation: Employment, Equity Ownership. Porter:Novartis: Consultancy; Cerus: Honoraria; Agios: Honoraria.

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Styczyński, Jan, Artur Słomka, Monika Łęcka, Katarzyna Albrecht, Michał Romiszewski, Monika Pogorzała, Małgorzata Kubicka, et al. "Soluble Hemojuvelin and Ferritin: Potential Prognostic Markers in Pediatric Hematopoietic Cell Transplantation." Cancers 15, no. 4 (February 7, 2023): 1041. http://dx.doi.org/10.3390/cancers15041041.

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Objective: Iron overload (IO) is a common and life-threatening complication resulting from the therapy of AL and HCT patients. This study aimed to evaluate the prognostic value of 12 serum biomarkers of iron metabolism in pediatric patients treated for AL or undergoing HCT. Patients: Overall, 50 patients with AL after intensive treatment and 32 patients after HCT were prospectively included in the study. AL patients at diagnosis and healthy controls served as reference groups. Methods: The impact of the following 12 serum iron metabolism parameters on the outcome of AL/HCT patients was analyzed: iron, transferrin (Tf), total iron-binding capacity (TIBC), ferritin, ferritin heavy chains (FTH1), ferritin light chains (FTL), hepcidin, soluble hemojuvelin (sHJV), soluble ferroportin-1 (sFPN1), erythroferrone (ERFE), erythropoietin (EPO), and soluble transferrin receptor (sTfR). Results: With a median follow-up of 2.2 years, high levels of ferritin and low levels of sHJV had an adverse prognostic impact on OS and EFS in children after HCT. If these patients were combined with those with AL after intensive chemotherapy, the results were confirmed for OS and EFS both for ferritin and sHJV. Conclusions: Among the 12 analyzed serum parameters of iron metabolism, increased levels of ferritin and decreased levels of sHJV had an adverse prognostic impact on survival in children after HCT. More data are needed to clarify the relationship between ferritin, sHJV, and mortality of AL children after intensive chemotherapy, and more extensive prospective studies are required to prove sHJV predictivity.

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Huang, Yumei, Rongrong Liu, Xiaoyun Wei, Jiaodi Liu, Lingyuan Pan, Gaohui Yang, and Yongrong Lai. "Erythropoiesis and Iron Homeostasis in Non-Transfusion-Dependent Thalassemia Patients with Extramedullary Hematopoiesis." BioMed Research International 2019 (January 30, 2019): 1–9. http://dx.doi.org/10.1155/2019/4504302.

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Background. Extramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH. Materials and Methods. 52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed. Results. EMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity. Conclusions. GDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.

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Delaney, Katherine, Ronnie Guillet, Eva Pressman, Elizabeta Nemeth, and Kimberly O'Brien. "Erythroferrone Is Associated with Maternal Erythropoietic Drive During Pregnancy." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 968. http://dx.doi.org/10.1093/cdn/nzaa054_040.

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Abstract Objectives Iron (Fe) homeostasis must be tightly regulated during pregnancy to meet both maternal and fetal Fe demands. Several hormones are known to impact Fe homeostasis including hepcidin, erythropoietin and erythroferrone (ERFE). Few data are available on determinants of ERFE in pregnant women or in their newborns at birth. The objective of this study was to characterize concentrations of ERFE across gestation and evaluate this hormone in relation to other Fe status biomarkers and regulatory hormones in mothers across pregnancy. Methods ERFE was measured in serum from pregnant adolescents (n = 166, age 14–19) or women carrying multiple fetuses (n = 61, age 20–46). ERFE concentrations across gestation (wks 8 – 42.1) were compared to Fe status and nutritional indicators (hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), total body Fe (TBI), TR-F index (sTfR/log(SF)), folate and vitamin B-12), as well as regulatory hormones (erythropoietin (EPO), hepcidin) and inflammatory markers (IL-6, C-reactive protein (CRP)). Results ERFE concentrations increased significantly across pregnancy in women carrying multiple fetuses (P < 0.01), but did not change across pregnancy in the adolescents (P = 0.3). In both populations, 16% (n = 30) of women were anemic at midgestation (MG) and 24% (n = 75) at delivery. ERFE concentrations were significantly increased in anemic women at both MG (P = 0.02) and at delivery (P = 0.02). At MG (median 26 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P = 0.002). Maternal TfR, IL-6 and serum Fe were the strongest determinants of maternal MG ERFE, and explained 29% of variance in ERFE. At delivery (median 38 wks), ERFE was significantly positively associated with TfR (P < 0.001) and EPO (P < 0.001), which together explained 18% of variance in ERFE at delivery. ERFE was not significantly associated with hepcidin at either MG (P = 0.87) or delivery (P = 0.52). Conclusions ERFE was significantly higher in anemic women across pregnancy and, as expected, was positively associated with indicators of erythropoietic drive. ERFE however, was not significantly associated with hepcidin, possibly because hepcidin is regulated by multiple competing signals. More research is needed to understand the relationship between maternal ERFE and neonatal Fe status at birth. Funding Sources Funded by the NIH (NIDDK/NICHD).

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Nemeth, Elizabeta, Tomas Ganz, and Léon Kautz. "Erythron to the Liver: Send Iron." Blood 124, no. 21 (December 6, 2014): SCI—37—SCI—37. http://dx.doi.org/10.1182/blood.v124.21.sci-37.sci-37.

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For successful expansion of erythropoiesis, the activity of the hormone erythropoietin (EPO) must be coordinated with the supply of iron to erythroid precursors. Increased iron supply for erythropoiesis is ensured by the suppression of hepcidin, the iron-regulatory hormone produced by the liver. Low hepcidin levels allow greater absorption of dietary iron and greater mobilization of iron from the stores in the spleen and the liver. The mechanisms coordinating erythropoietic activity with iron delivery are not well understood. We recently identified erythroferrone as a new mediator of hepcidin suppression during stress erythropoiesis1. Erythroferrone (ERFE) is a member of the C1q/TNF-related protein (CTRP) family of metabolic mediators. ERFE is produced in response to EPO by erythroblasts of the bone marrow and spleen of mice. The induction of ERFE by EPO was dependent on Jak2/Stat5 signaling. Ex vivo treatment of human erythroblasts with EPO also resulted in a dramatic induction of ERFE expression. The essential role of ERFE in acute hepcidin suppression by erythropoiesis was demonstrated in ERFE-deficient mice. In contrast to wild-type mice which suppressed hepcidin ~10-fold within hours after hemorrhage or erythropoietin injection, no hepcidin suppression was observed in ERFE knockout mice within 24 h. As a consequence, ERFE-deficient mice exhibited delayed recovery of hemoglobin after hemorrhage or severe inflammation. Treatment of mice or hepatocytes with recombinant ERFE protein confirmed the hepcidin-suppressive activity of the protein. It remains to be seen whether administration of ERFE protein would be useful for the treatment of anemia of inflammation mediated by elevated hepcidin. In iron-loading anemias including β-thalassemia, hepcidin is chronically suppressed by the exuberant but ineffective erythropoietic activity. This is the cause of iron overload in untransfused thalassemia patients and may contribute to iron loading even in transfused patients. We found that ERFE expression is greatly increased in the bone marrow and spleen of mice with β-thalassemia intermedia (th3 model). Transgenic ablation of ERFE in th3 mice normalized hepcidin and partially corrected their iron overload. Although human studies of the role of ERFE in health and disease are clearly needed, ERFE is a promising candidate for the pathological suppressor of hepcidin in anemias with ineffective erythropoiesis. References: 1. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014; 46: 678-684. Disclosures Nemeth: Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Merganser Biotech: Equity Ownership. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Keryx Pharma: Consultancy; Merganser Biotech: Consultancy, Equity Ownership.

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Thompson, Alexis A., Tomas Ganz, Mary Therese Forsyth, Elizabeta Nemeth, and Sherif M. Badawy. "Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?" Blood 134, Supplement_1 (November 13, 2019): 816. http://dx.doi.org/10.1182/blood-2019-129658.

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BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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Sangkhae, Veena, Vivian Yu, Richard Coffey, Tomas Ganz, and Elizabeta Nemeth. "Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis." Blood 138, Supplement 1 (November 5, 2021): 757. http://dx.doi.org/10.1182/blood-2021-153902.

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Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

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Oarbeascoa, Gillen, Sara Redondo, Maria Jose Morán-Jiménez, Amalia Domingo, Cristina Muñoz-Linares, Maria Isabel Moreno-Carralero, Jose Maria Bellon, Juan Francisco del Campo Rincon, Jose Luis Díez-Martín, and Patricia Font. "Hepcidin and Erythroferrone in the Anemia of Low-Risk Myelodysplastic Syndromes." Blood 132, Supplement 1 (November 29, 2018): 3085. http://dx.doi.org/10.1182/blood-2018-99-116992.

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Abstract BACKGROUND: Anemia is the most common manifestation of low-risk myelodysplastic syndromes (MDS). Iron-overload in MDS can occur before transfusion dependence in the context of ineffective erythropoiesis. Significantly lower hepcidin levels have been described in patients with sideroblastic refractory anemia compared to higher risk MDS, promoting inadequate iron absorption that leads to higher iron overload. Erythroferrone (ERFE) is a hormone that stimulates erythropoiesis and regulates iron homeostasis; in physiological conditions, is stimulated by erythropoietin and increases iron absorption inhibiting hepcidin. There are no studies describing the activity of ERFE in MDS. The objective of this study was to describe the relationship among hepcidin, ERFE and iron overload in 31 patients with low-risk MDS. METHODS: 50 samples were analized, 31 from patients (16 males, 17 females) with low-risk MDS: 10 low IPSS-R and 21 very-low IPSS-R; and 19 from healthy controls. 13 patients showed severe anemia with transfusion dependence, 4 patients received only erythropoiesis stimulating agents (ESA) and 14 patients did not receive any treatment for the anemia. Patient characteristics are summarized in table 1. Hepcidin levels were measured using the DRG Hepcidin 25 (bioactive) HS ELISA Kit (DRG Diagnostics GmbH), and ERFE was measured with the FAM132B (Human) OKEH02395 ELISA kit (Aviva Systems). For the analysis, two groups of patients were considered: 13 with severe and transfusion dependent anemia and 18 with mild/moderate anemia. RESULTS: Patients with severe anemia showed higher serum ferritin levels (median 2143ng/mL vs 204ng/mL, p<0.001) compared to patients without transfusion dependence. Hepcidin levels were significantly higher in patients with transfusion dependent anemia (mean 59.85 vs 16.11ng/mL, p=0.001) compared to patients with transfusion independence, and were also higher in these last patients compared to healthy controls (mean 16.11 vs 10.6ng/mL, p<0.001). Regarding ERFE, patients with transfusion dependent anemia showed significantly higher ERFE levels (mean 281.92 vs. 62.83pg/mL, p=0.016) than patients with mild/moderate anemia. However, there were no significant differences between patients with mild/moderate anemia and healthy controls. There was no correlation between hepcidin and ERFE levels (p=0.46). CONCLUSIONS: To the best of our knowledge, this is the first simultaneous analysis of hepcidine and ERFE in MDS. Patients with severe anemia showed significantly higher ERFE levels compared to those with moderate anemia, suggesting a higher erythropoietic stimulus. Patients with severe anemia showed significantly superior hepcidin levels, hindering iron absorption in situations of massive iron overload. Accordingly, ERFE did not show negative correlation with hepcidin in either cohort, supporting the abnormal iron metabolism in MDS. Larger studies are required to define the relationship between hepcidin and ERFE in low-risk MDS. Disclosures No relevant conflicts of interest to declare.

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Сахин, В. Т., М. А. Григорьев, Е. В. Крюков, С. П. Казаков, and О. А. Рукавицын. "Influence of Hepcidin and Soluble Transferrin Receptor on the Development of Anemia of Chronic Diseasesin Rheumatic Patients." Гематология. Трансфузиология. Восточная Европа, no. 3 (November 10, 2020): 311–18. http://dx.doi.org/10.34883/pi.2020.6.3.016.

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Цель. Оценить взаимосвязь между гепцидином, растворимым рецептором трансферрина (sTfR) и показателями обмена железа, концентрацией гемоглобина и числом эритроцитов у ревматических пациентов.Материалы и методы. Обследованы 63 пациента ревматологического профиля: 26 мужчин (45 (36–54,9) лет), 37 женщин (49 (38–60) лет). Пациенты разделены на две группы: 1-я группа – 41 пациент с анемией, 2-я группа (контрольная) – 22 пациента без анемии. Выполнен сравнительный анализ показателей гемограммы, обмена железа (железо, ферритин, трансферрин, общая железосвязывающая способность сыворотки крови – ОЖСС, коэффициент насыщения трансферрина железом – КНТ), гепцидина, растворимого рецептора трансферрина (sTfR), С-реактивного белка (СРБ). Выполнен корреляционный анализ между гепцидином, sTfR и показателями гемограммы и обмена железом.Результаты. У пациентов с анемией в сравнении с контрольной группой выше концентрации гепцидина (504,9 (23,5–916,5) и 232(0,0–858) нг/мл), sTfR (8,6 (3,9–7,1) и 2,2 (1,5–3,1) нмоль/л),а также ферритина (292,7 (146,1–335,1) и 78,5 (36–90,7) мкг/л), СРБ (59,4 (10,9–100,2)и 4,6 (1,2–5,8) мг/л). Для железа, ОЖСС, КНТ, трансферрина не выявлено межгрупповых различий (p>0,05). Выявлена корреляция между числом эритроцитов и гепцидином (r=–0,5), sTfR (r=–0,5). Выявлена корреляция между концентрацией гемоглобина и гепцидином (r=–0,7), sTfR (r=–0,7). Для концентрации гепцидина установлена прямая взаимосвязь с ферритином (r=0,6) и СРБ (r=0,3) и обратная взаимосвязь с ОЖСС (r=–0,6) и трансферрином (r=–0,6). Не выявлено взаимосвязи между гепцидином и железом, КНТ. В отношении концентрации sTfR установлена прямая корреляционная связь с ферритином (r=0,4) и СРБ (r=0,3) и обратная корреляционная связь с железом (r=–0,6) и КНТ (r=–0,5). Не выявлено взаимосвязи между sTfR и ОЖСС, трансферрином.Влияние гепцидина и растворимого рецептора трансферринана развитие анемии хронических заболеваний у ревматических пациентов. Заключение. Показан многокомпонентный генез анемии у ревматических пациентов. Установлено значение увеличения секреции гепцидина, sTfR, нарушений в обмене железа на развитие анемии. Установлено супрессорное влияние гепцидина на выработку клеток эритрона. Доказано слабое влияние воспаления на концентрацию sTfR. Purpose. To assess the relationship between hepcidin, soluble transferrin receptor (sTfR), and indicators of iron metabolism, hemoglobin concentration, and erythrocyte number in rheumatic patients.Materials and Methods. The study involved 63 rheumatic patients: 26 men (45 (36–54.9) years old), 37 women (49 (38–60) years old). The patients were divided into two groups: group 1 – 41 patients with anemia, group 2 (control) – 22 patients without anemia. Comparative analysis of hemogram parameters, iron metabolism (iron, ferritin, transferrin, total iron-binding capacity of blood serum – TIBC, iron transferrin saturation index (TSI), hepcidin, soluble transferrin receptor (sTfR), C-reactive protein (CRP) was performed. Correlation analysis was performed between hepcidin, sTfR, and hemogram and iron metabolism parameters.Results. In patients with anemia, the concentration of hepcidin (504.9 (23.5–916.5) and 232 (0.0–858) ng/ml), sTfR (8.6 (3.9–7.1) and 2.2 (1.5–3.1) nmol/L), ferritin (292.7(146.1–335.1) and78.5(36–90.7) μg/L), CRP (59.4 (10.9–100.2) and 4.6 (1.2–5.8) mg/L) is higher in comparison with the control group. There were no intergroup differences for iron, TIBS, CST, transferrin (p>0.05). The correlation was found between the number of erythrocytes and hepcidin (r=–0.5), sTfR (r=–0.5). The correlation was found between the concentration of hemoglobin and hepcidin (r=–0.7), sTfR (r=–0.7). For the concentration of hepcidin, a direct relationship with ferritin (r=0.6) and CRP (r=0.3) and the inverse relationship with TIBC (r=–0.6) and transferrin (r=–0.6) were revealed. No relationship was found between hepcidin and iron, TSI. In relation to the concentration of sTfR, a direct correlation was revealed with ferritin (r=0.4) and CRP (r=0.3) and the inverse correlation with iron (r=–0.6) and CST (r=–0.5). No relationship was found between sTfR and TIBC, transferrin Conclusion. There was showed the multicomponent genesis of anemia in rheumatic patients. The significance of the increase of the secretion of hepcidin, sTfR, disorders of iron metabolism for the development of anemia was revealed. The suppressive effect of hepcidin on the production of erythron cells was also revealed. A weak effect of inflammation on the concentration of sTfR was proved.

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Sakhin, V. T., E. V. Kryukov, M. A. Grigoryev, S. P. Kazakov, A. V. Sotnikov, A. V. Gordienko, and O. A. Rukavitsyn. "Iron metabolism, cytokine secretion in patients with rheumatologic pathology." Clinical Medicine (Russian Journal) 98, no. 9-10 (March 28, 2021): 691–98. http://dx.doi.org/10.30629/0023-2149-2020-98-9-10-691-698.

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Aim. To study the eff ect of hepcidin, soluble transferrin receptor (sTfR ), and cytokines on iron metabolism and the development of anemia in rheumatologic patients, to propose a working version of the classifi cation of anemia of chronic diseases (ACD) according to the major nosotropic factor.Material and methods. 126 patients with rheumatic disease, 34 men (45.8 (36–54.9) years old), 92 women (49.5 (38–60) years old) were examined. Group 1 included 41 patients with ACD. Group 2 included 29 patients with the combination of ACD and IDA and 34 patients with iron defi ciency anemia (IDA). Group 3 included 34 patients with IDA and 29 — with the combination of ACD and IDA. Control group included 22 patients without anemia. Comparative analysis between groups with and without anemia and correlation analysis of hemogram parameters, iron metabolism, C-reactive protein (CRP), hepcidin, sTfR , interleukin-6 (IL-6), IL-1β, IL-10, interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) were performed.Results. In the ACD group, the concentrations of hepcidin, ferritin, CRP, IL-6 were increased in comparison with other groups. The correlation was revealed between erythrocytes, hemoglobin and IL-6 (r = −0.3 and −0.6), IL-10 (r = −0.4 and −0.4), INF-γ (r = −0.4 and −0.3), TNF-α (r = −0.3 and −0.3), hepcidin (r = −0.5 and −0.7), sTfR (r = −0.5 and −0.7). Dependence was shown between IL-6 and iron (r = –0.6), transferrin saturation index (TSI) (r = −0.5), ferritin (r = −0.5), CRP (r = 0.5), between TNF-α and TIBС (r = −0.6), transferrin (r = −0.6), ferritin (r = −0.7), between IL-1β and TIBC, ferritin, transferrin (r = −0.4). The correlation was noted between hepcidin and IL-6 (r = 0.5), IL-10 (r = 0.4), between sTfR and IL-6 (r = 0.4), IL-10 (r = 0.6), INF-γ (r = 0.4).Conclusion. The multicomponent genesis of anemia in patients with rheumatologic disease was detected. The signifi cance of disorders in iron metabolism, the eff ect of hepcidin, sTfR and cytokines on the development of anemia was found. A working version of ACD classifi cation (with a predominant iron defi ciency, with violations of the regulatory mechanisms of erythropoiesis, with insuffi cient production of erythropoietin) has been put forward.

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Tomczyk, Maja, Jakub Kortas, Damian Flis, Barbara Kaczorowska-Hac, Agata Grzybkowska, Andzelika Borkowska, Ewa Lewicka, Alicja Dabrowska-Kugacka, and Jędrzej Antosiewicz. "Marathon Run-induced Changes in the Erythropoietin-Erythroferrone-Hepcidin Axis are Iron Dependent." International Journal of Environmental Research and Public Health 17, no. 8 (April 17, 2020): 2781. http://dx.doi.org/10.3390/ijerph17082781.

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Alterations in iron metabolism after physical activity are manifested through the rise of blood hepcidin (Hpc) levels. However, in many athletes, no changes in Hpc levels are observed after exercise despite the presence of inflammation. The missing links could be erythropoietin (EPO) and erythroferrone (ERFE), which down-regulate Hpc biosynthesis. EPO, ERFE and Hpc biosynthesis is modified by serum iron through transferrin receptor 2. Consequently, we investigated whether marathon-induced changes in EPO, ERFE and Hpc levels are blood iron-dependent. Twenty-nine healthy male marathon runners were analyzed. Serum iron, ferritin, transferrin, EPO, ERFE and Hpc levels were assessed before, immediately after, and 9 ± 2 days after the marathon. The runners whose serum Hpc decreased after the marathon (n = 15), showed a significant increase in ERFE levels. In athletes whose serum iron levels were below 105 µg/day (n = 15), serum EPO (p = 0.00) and ERFE levels (p = 0.00) increased with no changes in Hpc concentration. However, in athletes with low serum iron, no changes in EPO levels were observed when serum ferritin exceeded 70 ng/mL (n = 7). Conversely, an increase in ERFE levels was observed in marathoners with low serum iron, independently of serum ferritin (n = 7). This indicates modulation of blood iron may affect exercise-induced changes in the EPO/ERFE/Hpc axis. Further study is needed to fully understand the physiological meaning of the interdependence between iron and the EPO/ERFE/Hpc axis.

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Russo, Roberta, Immacolata Andolfo, Luigia De Falco, Francesco Manna, Antonella Gambale, Mariasole Bruno, Gianluca De Rosa, Domenico Girelli, Lucia De Franceschi, and Achille Iolascon. "Erfe-Encoding FAM132B in Congenital Dyserythropoietic Anemia Type II." Blood 126, no. 23 (December 3, 2015): 535. http://dx.doi.org/10.1182/blood.v126.23.535.535.

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Abstract Recessive mutations in SEC23B gene cause congenital dyserythropoietic anemia type II (CDAII), a rare hereditary disorder hallmarked by ineffective erythropoiesis, iron overload, and reduced expression of hepatic hormone hepcidin (Iolascon, 2013). The most recently described hepcidin regulator is the erythroblast-derived hormone erythroferrone (ERFE), a member of TNF-α superfamily that specifically inhibits hepcidin production in experimental models (Kautz, 2014). However, the function of ERFE in humans remains to be investigated. To determine whether dysregulation of ERFE expression is associated with ineffective erythropoiesis and iron-loading in CDAII, we studied the ERFE-encoding FAM132B gene expression in 48 SEC23B-related CDAII patients and 29 age and gender matched healthy controls (HCs). Twelve new cases and four novel SEC23B mutations were described. Samples were obtained after informed consent, according to the Declaration of Helsinki. Genomic DNA, mutational screening, RNA isolation, cDNA preparation, and qRT-PCR were performed as previously described (Russo, 2013). All patients were young adults (17.0±2.5 years at diagnosis), with increased serum ferritin (395.4±67.6 ng/mL) and transferrin saturation (71.9±5.4 %). We observed a statistically significant overexpression of FAM132B gene in peripheral blood mononuclear cells from CDAII patients (9.09±0.08) compared to HCs (8.32±0.12, p<0.0001). A similar trend was obtained when evaluating FAM132B expression in reticulocytes from a subset of patients and HCs. Of note, a statistically significant correlation between peripheral blood and reticulocyte FAM132B expression from the same patients was observed (Spearman ρ= 0.78, p=0.02). Although the role of ERFE in peripheral blood is still unknown, our observations suggested that the evaluation of FAM132B mRNA in peripheral blood is a reliable and easy-to-measure marker of ERFE levels. When we divided CDAII patients into two sub-groups accordingly to FAM132B gene expression, we observed a statistically significant reduction in hemoglobin (Hb) level in the high-FAM132B subset (8.6±0.4 g/dL) respect to low-FAM132B one (10.1±0.5 g/dL, p=0.02). Of note, the expression level of FAM132B did not correlate with the transfusion regimen. The higher amount of ERFE reflects the increased iron demand for Hb production as well as the expanding abnormal erythropoiesis, as attested by the increased RDW and sTfR (although not significant) in high-FAM132B patients. This in turn leads to reduced hepcidin in high-FAM132B group (4.2±1.8 nM) compared to low-FAM132B one (5.9±1.8 nM, p=0.05), resulting in augmented iron delivery to the erythron. Although the iron balance data do not differ significantly between the two groups, a tendency to decreased hepcidin/ferritin ratio and increased transferrin saturation was observed in high-FAM132B patients. Thus, FAM132B overexpression seems to contribute to the inappropriate suppression of hepcidin with subsequent hemosiderosis observed in CDAII. Consistent with our previous studies, we observed a reduced SEC23B expression in our patients compared to HC. Indeed, FAM132B and SEC23B gene expression exhibited an inverse correlation (Spearman ρ=-0.36, p=0.01). We confirmed the ex vivo data about inverse correlation between FAM132B and SEC23B expression observed in our patients by establishing K562 SEC23B-silenced cells. To knockdown SEC23B gene expression in K562 cells two different pGIPZ Lentiviral shRNAmir for SEC23B (shSEC23B-70/-74) were used. We observed a higher expression of FAM132B at 5 days of erythroid differentiation in K562 SEC23B-silenced cell compared to not-silenced ones. Conversely, SEC23B expression was lower in both shSEC23B compared to sh-CTR at 2 and 5 days of differentiation. Although the mechanisms of hemin-induced differentiation are quite different from EPO-induced ones, we can hypothesize that FAM132B over-expression is related to the maturative arrest and the subsequent increased number of erythroid precursors. This study provides the first analysis on ERFE regulation in humans. Our data suggest that ERFE over-expression in CDAII patients is the result of both physiological and pathological mechanisms leading to hepcidin suppression in condition of dyserythropoiesis. Nevertheless, it seems that ERFE cannot be the main erythroid regulator of hepcidin suppression, at least in CDAII patients. Disclosures No relevant conflicts of interest to declare.

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Li, Yihang, Gregory R. Booth, Qi Feng, and Robert E. Fleming. "Hypoferremia of Fasting in Mice Is Associated with Increased Hepcidin and Decreased Erythroferrone Expression." Blood 124, no. 21 (December 6, 2014): 4026. http://dx.doi.org/10.1182/blood.v124.21.4026.4026.

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Abstract Background: Protein-calorie restriction in humans is associated with changes in iron metabolism that differ from dietary iron-deficiency. Dietary iron absorption and tissue iron distribution and are regulated by the hepatocellular peptide hormone hepcidin, which mediates a decrease in circulating iron concentrations and increase in cellular iron stores. Hepcidin is upregulated in response to increased serum and tissue iron, upregulated in response to ER-stress via the transcription factor CREB-H, and down-regulated in response to erythroid iron demand via the circulating signaling molecule erythroferrone/myonectin (ERFE). An overnight fast was reported to decrease expression of skeletal muscle ERFE in mice. Objective: The aim of this study was to investigate the regulation of hepcidin in the hypoferremia of fasting. Design/Methods: We analyzed parameters of iron homeostasis in five 5 week old male AKR mice fasted for 18 hours overnight (and allowed access to water) compared with mice with access to chow ad libitum. Serum and tissue iron concentrations were measured. Liver hepcidin mRNA was quantified by real-time RT-PCR and verified by Northern blot analysis. Marrow ERFE and liver CREB-H mRNA expression was quantified by RT-PCR and normalized to beta actin. Results: As anticipated, fasted mice had significantly lower serum iron concentrations (203 vs 321 mcg/dL, P<0.001) and transferrin saturations (64.4 vs 79.6%, P<0.05). Duodenal iron concentrations were increased in fasted mice, 2.3-fold (P<0.01). Histochemical staining demonstrated iron retention in the absorptive enterocytes. Liver (916 vs 735 mcg/g, P=0.1) and splenic (480 vs 414 mcg/g, P=0.001) iron concentrations were modestly higher in the fasted mice. Despite hypoferremia, the fasted mice demonstrated increased liver hepcidin expression (1.9 fold, P < 0.05). Liver CREB-H mRNA expression was increased ~10 fold, P<0.01; however there was no change in liver XBP-1 processing (marker of ER stress). Marrow ERFE expression was downregulated by approximately one third (P<0.01). Conclusions: The fasting state in mice is associated with increased hepcidin expression, iron retention in absorptive enterocytes, and decreased circulating iron. These observations suggest that the hypoferremia of fasting is not consequent to limited iron availability, but rather to hepcidin-mediated retention of iron in the duodenum and storage tissues. They moreover support a role for nutritional state, independent of iron status, as a regulator of hepcidin and mediated by changes in expression of ERFE and CREB-H. Disclosures No relevant conflicts of interest to declare.

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Gajewska, Joanna, Jadwiga Ambroszkiewicz, Witold Klemarczyk, Ewa Głąb-Jabłońska, Halina Weker, and Magdalena Chełchowska. "Ferroportin-Hepcidin Axis in Prepubertal Obese Children with Sufficient Daily Iron Intake." International Journal of Environmental Research and Public Health 15, no. 10 (October 1, 2018): 2156. http://dx.doi.org/10.3390/ijerph15102156.

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Iron metabolism may be disrupted in obesity, therefore, the present study assessed the iron status, especially ferroportin and hepcidin concentrations, as well as associations between the ferroportin-hepcidin axis and other iron markers in prepubertal obese children. The following were determined: serum ferroportin, hepcidin, ferritin, soluble transferrin receptor (sTfR), iron concentrations and values of hematological parameters as well as the daily dietary intake in 40 obese and 40 normal-weight children. The ferroportin/hepcidin and ferritin/hepcidin ratios were almost two-fold lower in obese children (p = 0.001; p = 0.026, respectively). Similar iron concentrations (13.2 vs. 15.2 µmol/L, p = 0.324), the sTfR/ferritin index (0.033 vs. 0.041, p = 0.384) and values of hematological parameters were found in obese and control groups, respectively. Iron daily intake in the obese children examined was consistent with recommendations. In this group, the ferroportin/hepcidin ratio positively correlated with energy intake (p = 0.012), dietary iron (p = 0.003) and vitamin B12 (p = 0.024). In the multivariate regression model an association between the ferroportin/hepcidin ratio and the sTfR/ferritin index in obese children (β = 0.399, p = 0.017) was found. These associations did not exist in the controls. The results obtained suggest that in obese children with sufficient iron intake, the altered ferroportin-hepcidin axis may occur without signs of iron deficiency or iron deficiency anemia. The role of other micronutrients, besides dietary iron, may also be considered in the iron status of these children.

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Diepeveen, Laura, Rian Roelofs, Nicolai Grebenchtchikov, Rachel van Swelm, Leon Kautz, and Dorine Swinkels. "Differentiating iron-loading anemias using a newly developed and analytically validated ELISA for human serum erythroferrone." PLOS ONE 16, no. 7 (July 20, 2021): e0254851. http://dx.doi.org/10.1371/journal.pone.0254851.

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Erythroferrone (ERFE), the erythroid regulator of iron metabolism, inhibits hepcidin to increase iron availability for erythropoiesis. ERFE plays a pathological role during ineffective erythropoiesis as occurs in X-linked sideroblastic anemia (XLSA) and β-thalassemia. Its measurement might serve as an indicator of severity for these diseases. However, for reliable quantification of ERFE analytical characterization is indispensable to determine the assay’s limitations and define proper methodology. We developed a sandwich ELISA for human serum ERFE using polyclonal antibodies and report its extensive analytical validation. This new assay showed, for the first time, the differentiation of XLSA and β-thalassemia major patients from healthy controls (p = 0.03) and from each other (p<0.01), showing the assay provides biological plausible results. Despite poor dilution linearity, parallelism and recovery in patient serum matrix, which indicated presence of a matrix effect and/or different immunoreactivity of the antibodies to the recombinant standard and the endogenous analyte, our assay correlated well with two other existing ERFE ELISAs (both R2 = 0.83). Nevertheless, employment of one optimal dilution of all serum samples is warranted to obtain reliable results. When adequately performed, the assay can be used to further unravel the human erythropoiesis-hepcidin-iron axis in various disorders and assess the added diagnostic value of ERFE.

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Castro-Mollo, Melanie, Marc Ruiz Martinez, Maria Feola, Anisa Azatovna Gumerova, Carla Casu, Robert E. Fleming, Stefano Rivella, Tony Yuen, Mone Zaidi, and Yelena Ginzburg. "Erythroferrone Regulates Bone Remodeling in β-Thalassemia." Blood 134, Supplement_1 (November 13, 2019): 2. http://dx.doi.org/10.1182/blood-2019-125822.

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Erythropoiesis normally occurs in the bone marrow within the pelvis and femur, and both erythropoiesis and bone metabolism are susceptible to changes in iron homeostasis. Thus, hematopoietic and osteoid systems require coordination of iron metabolism during stress or ineffective erythropoiesis. Recently, a more extensive understanding of the crosstalk between iron metabolism and erythropoiesis revealed that a bone marrow secreted protein, erythroferrone (ERFE), is a negative regulator of hepcidin [Kautz Nat Gen 2014]. Hepcidin in turn is the main negative regulator of iron absorption and recycling [Nemeth Science 2004] and its suppression enables an increase in iron availability during stress erythropoiesis. Diseases of ineffective erythropoiesis, such as β-thalassemia, with chronic erythroid expansion, are associated with thinning of cortical bone, leading to decreased bone mineral density [Haidar Bone 2011; Vogiatzi Bone 2006]. Mechanisms underlying coordination of erythropoiesis and bone metabolism are incompletely understood. However, because ERFE functions to suppress hepcidin by sequestering BMPs [Arezes Blood 2018], and because BMPs are crucially important for bone metabolism [Hogan Genes Dev 1996], we hypothesize that ERFE may be involved in coordinating iron metabolism, erythropoiesis, and bone homeostasis. Lastly, osteoblast expression of TfR2 was found to inhibit bone formation by activating BMP-p38MAPK signaling and expression of the Wnt inhibitor Sclerostin, protein product of the SOST gene [Rauner Nat Med 2019]. We thus propose to explore the role of ERFE in disordered bone metabolism in β-thalassemia. In vitro data demonstrates that osteoblasts from wild type (WT) mice express ERFE and this expression is enhanced by BMP2/6/7 (Figure 1a and 1b). Furthermore, osteoblasts from ERFE-/- mice exhibit enhanced bone mineralization (6.8-fold increased von Kossa staining, measured by image J) (Figure 1c), increased expression of osteoblast-specific markers (e.g. osterix (OSX))(Figure 1d), and higher SOST expression (Figure 1e) relative to WT osteoblasts. We anticipate that if TfR2 is central to bone metabolism, ERFE-/- osteoblasts may exhibit a decrease in TfR2; our results demonstrate only a trend toward decreased TfR2 in ERFE-/- osteoblasts (Figure 1f). In addition, we propose that ERFE is a negative regulator of osteoblast activity, predicting that ERFE loss in th3/+ mice would enhance bone mineral density. To this end, we analyzed bone mineral density and histomorphometry in WT, ERFE-/-, th3/+, and th3/+ERFE-/- mice. Surprisingly, although no differences are evident between WT, ERFE-/-, and th3/+ femora, th3/+ERFE-/- mice exhibit a decrease in bone mineral density and bone volume / total volume (BV/TV) (Figure 2a-2b) with a trend toward enhanced femoral mineral apposition rate (Figure 2c) relative to th3/+ mice. These results indicate enhanced osteoblast activity without increased bone formation. Because bone mineralization is a composite of the relative osteoblast and osteoclast activity, we hypothesize that osteoclast activity is further enhanced in th3/+ ERFE-/- mice. TRAP staining demonstrates a significantly increased number of osteoclasts in ERFE-/- relative to WT as well as th3/+ ERFE-/- relative to th3/+ femora (Figure 2d). Our studies demonstrate that ERFE, like other members of the TNFα superfamily [Lu J Bone Miner Res 2011], negatively regulates OSX which is critical for osteoblast function (Figure 3a). Thus, suppression of ERFE results in more OSX (Figure 1d), enhanced mineralization (Figure 1c), and higher SOST expression (Figure 1e) which results in the secretion of Sclerostin (Figure 3b). Sclerostin both feeds back to suppress Wnt signaling to decrease osteoblast function and increases RANKL production to stimulate osteoclast differentiation (Figure 3b). Taken together, ERFE functions as a negative regulator of both osteoblast and especially osteoclast activity such that its loss leads to more osteoclast activity and results in decreased bone mineral density in β-thalassemia. These findings provide novel insights into the complex interplay between regulation of iron metabolism and bone homeostasis in diseases of dysregulated erythropoiesis, when ERFE expression is increased, and support the rationale to further explore the role of ERFE and TfR2 in this crosstalk in β-thalassemia. Disclosures Fleming: Protagonist: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Consultancy; Ultragenyx: Consultancy. Rivella:Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy; Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Ginzburg:La Jolla Pharma: Membership on an entity's Board of Directors or advisory committees.

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Delaye, Jean-Baptiste, Hugo Alarcan, Nicolas Vallet, Charlotte Veyrat-Durebex, Louis Bernard, Olivier Hérault, Martine Ropert, et al. "Specific changes of erythroid regulators and hepcidin in patients infected by SARS-COV-2." Journal of Investigative Medicine 70, no. 4 (March 15, 2022): 934–38. http://dx.doi.org/10.1136/jim-2021-002270.

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Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19−) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55–70.48) vs 14.2 (IQR 5.95–18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01–0.73) vs 0.89 (IQR 0.19–3.82) ng/mL, p=0.035; 2003 (IQR 1355–2447) vs 4713 (IQR 2082–7774) pg/mL, p=0015), respectively) compared with the COVID-19− group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19−, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19− group.

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Ruiz Martinez, Marc, Wenbin An, Maria Feola, Tomas Ganz, and Yelena Ginzburg. "Additive Effects of Decreased TfR1 and Ablated Erfe Improve Both Ineffective Erythropoiesis and Iron Overload in β-Thalassemic Mice." Blood 132, Supplement 1 (November 29, 2018): 847. http://dx.doi.org/10.1182/blood-2018-99-119426.

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Abstract Patients with β-thalassemias manifest anemia, ineffective erythropoiesis, extramedullary hematopoiesis, splenomegaly, and systemic iron overload. Even in non-transfusion dependent patients, iron overload in β-thalassemia develops because of increased intestinal iron absorption, leading to multiple organ dysfunction if untreated and accounts for most of the deaths in this disease. The main regulator of body iron content and distribution is hepcidin, inhibiting iron absorption in duodenal enterocytes and release of stored iron from macrophages and hepatocytes. Despite iron overload in patients and mice with β-thalassemia, hepcidin levels are insufficiently increased, as ineffective erythropoiesis dominates hepcidin regulation. Relatively low hepcidin causes iron overload in β-thalassemia. Recent evidence demonstrates that erythroferrone (ERFE), an erythroid regulator of hepcidin, is increased in bone marrow and serum from β-thalassemic patients and th3/+ mice [Kautz Nat Gen 2014] and its loss results in increased hepcidin, partially reversing iron overload in th3/+ mice [Kautz Blood 2015]. In addition, bone marrow ERFE expression normalizes in TfR1 haploinsufficient th3/+ mice [Li Blood 2017]. We hypothesize that the loss of ERFE and TfR1 influences erythropoiesis and iron metabolism in complementary ways in th3/+ mice, and therefore aim to explore iron- and erythropoiesis-related parameters in th3/+ TfR1+/- ERFE-/- (triple mutant (TM)) mice. All models are on a C57BL6 background and have been crossed to generate 4-6 mice for analysis at 6 weeks of age. We confirm our previous reports [Li Blood 2017] that th3/+TfR1+/- mice have increased RBC count and hemoglobin, decreased MCV and reticulocyte count (Table I), and reduce splenomegaly (Fig 1a and 1b) relative to th3/+ mice. We also confirm that th3/+ ERFE-/- mice do not reverse splenomegaly or improve peripheral blood circulating erythroid parameters compared to th3/+ mice [Kautz Blood 2015] (Table I) but exhibit further increase in TfR1 in late stage erythroid precursors (Fig 1c). Analysis of the bone marrow reveals that total erythroid mass is unaltered in triple mutants relative to th3/+, th3/+ ERFE-/-, and th3/+ TfR1+/- mice, but the number of late erythroblasts (poly-E and ortho-E stages) is normalized to WT levels (Fig 1d), strongly suggesting that, unlike in th3/+ erythropoiesis, where the block in differentiation occurs at the poly-E stage, th3/+ TfR1+/- and especially triple mutant mice restore differentiation at this stage to generate a higher hemoglobin. No differences in erythroblast apoptosis or ROS concentration are evident in triple mutant relative to th3/+ ERFE-/- or th3/+ TfR1+/- mice. We also analyzed markers of Epo responsiveness and demonstrate that serum Epo and EpoR expression are increased in th3/+ relative to WT mice (Fig 1e and 1f), but while serum Epo is decreased, EpoR is further increased (Fig 1f). These findings suggest that Epo responsiveness is more optimized in triple mutant erythroblasts, enabling a smaller proportion of late stage erythroblasts to produce circulating RBCs with relatively less serum Epo. Remarkably, while neither th3/+ ERFE-/- and th3/+ TfR1+/- mice reverse iron overload or impact hepcidin expression at 6 weeks of age, triple mutant mice demonstrate fully normalized ratio of hepcidin expression relative to liver iron concentration (LIC) (Fig 1g). Taken together, these experiments provide evidence of the differential and additive effects of TfR1 and ERFE loss in th3/+ mice, with a predominantly erythropoietic benefit of TfR1 loss, a predominantly iron-homeostatic benefit of ERFE loss, and synergy of both in optimizing Epo responsiveness. Disclosures Ganz: Intrinsic LifeScience: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Silarus Pharma: Consultancy, Equity Ownership; Keryx Pharma: Consultancy, Research Funding; Gilead: Consultancy; Ablynx: Consultancy; Vifor: Consultancy; Akebia: Consultancy, Research Funding; La Jolla Pharma: Consultancy, Patents & Royalties: Patent licensed to La Jolla Pharma by UCLA.

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Zaninoni, Anna, Roberta Russo, Roberta Marra, Elisa Fermo, Immacolata Andolfo, Anna Paola Marcello, Dario Consonni, et al. "Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency." Blood 138, Supplement 1 (November 5, 2021): 1993. http://dx.doi.org/10.1182/blood-2021-151635.

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Abstract Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias (CDA), and some forms of congenital hemolytic anemias. Among them pyruvate kinase deficiency (PKD) has been shown to develop iron overload also in absence of transfusions suggesting dyserythropoietic features. Moreover, severe forms can be misdiagnosed as CDA due to bone marrow abnormalities and ineffective erythropoiesis further supporting this evidences. The hormone erythroferrone (hERFE) is produced by erythroblasts in response to erythropoietin (EPO), and acts by suppressing hepcidin, thereby increasing iron absorption and mobilisation for erythropoiesis demand. The ERFE-hepcidin axis seems to play a crucial role in the pathogenesis of these disorders; an increased erythroferrone release by immature erythroid cells results in hepcidin suppression and secondary iron overload that could finally results in ineffective erythropoiesis and anemia. To investigate the pathophysiological basis of iron overload in PKD, we analysed the levels of hERFE, EPO, hepcidin, and soluble transferrin receptor (sTFR) in a large group of 41 PKD patients equally distributed by gender, age and severity. The results were analysed in comparison with two groups of patients affected by hemolytic anemia with overt dyserythropoiesis (42 patients with CDA type II) and with congenital hemolytic anemia due to RBC membrane defects (51 patients with hereditary spherocytosis [HS]), respectively. Demographic, hematologic, and biochemical features of the three groups of patients are reported in the table. Among the PKD patients, 18/41 were <18 yrs, median Hb level at the time of the study was 9.05g/dL (range 5.5-14.5), 12 underwent splenectomy, 28 ever received at least three transfusions their life, 14 of them transfusion dependent (>6 tx/yrs). Mean ferritin levels at the time of the study were 546 ng/ml (range 59-4990), 15/41 patients requiring chelation therapy for iron overload developed also in absence of transfusions. As expected, CDAII patients showed decreased hepcidin levels (3.74 ng/mL; n.v. 17.25, P<0.001) associated with increased erythropoietin (62.7 IU/L, n.v. 6.5, P=0.01) and hERFE (24.8 ng/mL, n.v. 1, P<0.0001). On the contrary, HS showed increased hepcidin, with less marked increased of ERFE (9.9 ng/mL, P=0.02) and EPO (36.4IU/L, P=0.005). In PKD patients we observed decreased hepcidin levels (7.15 ng/mL, P=0.03)), increased hERFE (18ng/mL, P<0.0001) and EPO (75.6 IU/L, P=0.009). Instead, sTFR was equally increased in the three groups of patients (Figure). Interestingly, by comparing the three groups of patients, PKD showed dyserythropoietic features as evidenced by the observation of intermediate values between HS and CDAII of hepcidin (P=0.007 PKD v CDAII and P=0.0002 PKD vs HS), hEFRE, and sTFR. This study provides the first analysis of the main regulators of systemic iron homeostasis in PK deficiency compared either with the model of a structural RBC defect (HS) or with the typical model of dyserythropoietic anemia with ineffective erythropoiesis, such as CDAII. These data provide evidence of the dyserythropoietic features of PK deficiency, underlining the need of accurate diagnosis and paving the way of novel therapeutic approaches in PK deficiency. Zaninoni A. and Russo R. equally contributed to the study Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Barcellini: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Jasuja, Reema, Anagha Sawant, Debra D. Pittman, and Jie Quan. "Transcriptomic Analysis Reveals Erythroferrone Modulates BMP6 Signaling Pathways Involved in Iron Homeostasis and Metabolism." Blood 132, Supplement 1 (November 29, 2018): 1049. http://dx.doi.org/10.1182/blood-2018-99-118724.

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Abstract Introduction: Erythroferrone (ERFE), the recently identified erythroid regulator of iron absorption, is a member of the C1q/TNF-related protein (CTRP) family. It is produced in erythroblasts in response to an increased erythropoietic drive, downregulates hepcidin expression and thereby promotes intestinal iron absorption and mobilization. The levels of Erfe are inappropriately high under conditions of ineffective erythropoiesis in inherited anemias such as thalassemia and congenital dyserythropoietic anemias. However, the mechanism of Erfe mediated Hepcidin inhibition remains unknown. Here, we use transcriptomic analysis of the human hepatoma cell line, Huh7 to identify genes and pathways involved in hepatocyte response to Erfe. Methods: Huh7 cells were seeded in a 6-well cell culture plate. Twenty four hours later, the cells were washed with PBS, and treated with a recombinant murine ERFE monomeric Fc (mEFRE-FC, 10µg/ml) protein or a control IgG (10 ug/ml) for 1h, 6h or 24h in growth media. RNA was isolated, followed by RNA quantification and quality assessment using a 2100 Agilent Bioanalyzer. ERFE is known to regulate Hepcidin antimicrobial peptide (HAMP) transcription and a treatment effect on HAMP expression was demonstrated by qPCR prior to sequencing. A total of 27 mRNA sequencing libraries were constructed from 1ug of human total RNA with the Illumina TruSeq Stranded mRNA Sample Prep protocol and single-end 75 bp reads were generated on an Illumina NextSeq 500. DESeq2 statistical package was used for differential expression testing. Multiple comparisons were adjusted for using a false discovery rate of 5%. Additionally, results were filtered to consider only those genes that demonstrated a fold-change point estimate >2 in either direction. Pathway analysis was performed using the Biological Process gene sets from the Gene Ontology annotation. Results: Compared to control treated Huh7 cells, 3 transcripts were differentially regulated following a one hour treatment with mERFE-Fc, ID1 (Log2 fold-change -1.55, q-value 4.99E-09), BPIFB2 (Log2 fold-change -1.88, q-value 0.036) and ANO1 (Log2 fold-change -1.43, q-value 0.019). A larger number of genes were differentially regulated with longer treatments, 32 genes at 6h and 828 genes at 24h. Among selected genes differentially expressed at 24h, between control treated and Erfe treated cells, we observed a significant reduction in expression of genes known to be directly upregulated by bone morphogenetic proteins (BMPs), including DNA binding protein inhibitor ID1(ID1), DNA binding protein inhibitor ID2 (ID2), DNA binding protein inhibitor ID3 (ID3) and HAMP. BMP6 has been demonstrated to regulate several biological processes such as iron metabolism in the liver, adipogenesis, and insulin sensitization. Interestingly, we also observed upregulation of SLC27A1 (or FATP1, fatty acid transporter, Log2 fold-change 2.27, q-value 0.003), GDNF (Log2 fold-change 2.57, q-value 2.4E-05), GIPR (Log2 fold-change 2.53, q-value 7.9E-07) upon treatment with Erfe at 24h. Previous work has demonstrated that all of these genes are downregulated by BMP6 treatment 1-3. Pathway analysis indicated a number of genes differentially regulated in the GOBP (gene ontology biological processes) iron ion homeostasis pathway, BMP signaling or TGF-β receptor signaling pathway. This assessment further indicated downregulation of cellular hormone levels and metabolic processes and ion homeostasis as biological processes impacted by erythroferrone. Conclusions: Significant differences in gene expression occur in hepatocytes upon interaction with erythroferrone. Many genes in the iron homeostasis, BMP6 signaling metabolic processes were also differentially regulated. This further supports the mechanism of ERFE on iron homeostasis. Disclosures Jasuja: Pfizer: Employment. Sawant:Pfizer: Employment. Pittman:Pfizer: Employment. Quan:Pfizer: Employment.

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Horiguchi, Hiroto, Masayoshi Kobune, Kento Ono, Saori Shimoyama, Chisa Fujita, Akari Goto, Hiroshi Ikeda, and Satoshi Iyama. "CD34+ Positive Myelodysplastic Cells with Ring Sideroblasts or SF3B1 Mutation Produce High Erythroferrone and GDF15." Blood 136, Supplement 1 (November 5, 2020): 28–29. http://dx.doi.org/10.1182/blood-2020-134861.

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Background. Iron absorption from gastrointestinal tract was enhanced in a subset of patients with myelodysplastic syndrome (MDS) exhibiting ineffective erythropoiesis. Duodenal iron absorption was achieved via an iron transporter divalent metal transporter (DMT)-1 and ferroportin which was downregulated by hepatic hepcidin. Recently, three erythroid regulators such as growth differentiation factor 15 (GDF15), twisted gastrulation protein homolog 1 (TWSG1) and erythroferrone (ERFE) which down regulated hepatic hepcidin production has been identified. However, it has been not yet clarified which molecules could contribute to the increased iron absorption in patients with MDS. Materials and Methods. In the present study, we examined the expression level of GDF15, TWSG1 and ERFE mRNA during ex vivo erythroid differentiation from sodium butyrate (SB)-treated K562 and CD34+ bone marrow (BM) cells in the presence of 4 U/mL erythropoietin (EPO), 100 U/mL interleukin-3, 10 ng/mL stem cell factor, 20 ng/mL insulin-like growth factor (IGF)-1 and 500 micro g/mL iron-saturated transferrin. We further analyzed the expression level of GDF15 and ERFE by using a GEO dataset (GSE58831). GEO dataset was downloaded as a matrix by GEOquery package (Bioconductor). The numerical data of the matrix were normalized by quantile normalization using limma package. Clinical and sequencing data were downloaded from supplementary materials. Those were combined with a GEO dataset (GSE58831) before analysis. Results. The levels of ERFE and GDF15 mRNA were dramatically increased during erythroid differentiation from SB-treated K562 and normal CD34+ cells in response to EPO in vitro. Using GEO data sets (GSE58831), the levels of ERFE and GDF15 mRNA in CD34+ cells derived from MDS patients were significantly elevated as compared with that from healthy volunteers. Importantly, the levels of ERFE and GDF15 mRNA in CD34+ cells in a subset of MDS with ring sideroblasts (RS) or SF3B1 mutation were significantly and highly elevated as compared with other subsets of MDS (GSE58831). Additionally, the supernatant derived from SB-treated K562 reduced hepcidin level in HepG2 in the presence of EPO. Conclusion. These results suggested that productions of ERFE and GDF15 in CD34+ MDS cells with RS or SF3B1 mutation may be associated with abnormal iron metabolism via hepcidin reduction. These findings may be useful to understanding the high ferritin level in a subset of MDS patients. Figure 1 Disclosures Kobune: Takeda Pharmaceutical Company: Research Funding; Alexion Pharmaceuticals Inc: Research Funding; Novartis Pharma K.K.: Research Funding; ONO PHARMACEUTICAL CO., LTD: Research Funding. Ikeda:Alexion Pharmaceuticals Inc: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharma K.K.: Research Funding; Sanofi K.K.: Research Funding; ONO PHARMACEUTICAL CO., LTD: Research Funding.

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Cavallaro, Flaminia, Lorena Duca, Laura Francesca Pisani, Roberta Rigolini, Luisa Spina, Gian Eugenio Tontini, Nadia Munizio, et al. "Anti-TNF-Mediated Modulation of Prohepcidin Improves Iron Availability in Inflammatory Bowel Disease, in an IL-6-Mediated Fashion." Canadian Journal of Gastroenterology and Hepatology 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/6843976.

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Background. Anaemia is common in inflammatory bowel disease (IBD), frequently resulting from a combination of iron deficiency and of anaemia of chronic disease (ACD). ACD is characterized by macrophage iron retention induced by proinflammatory cytokines. Hepcidin is the master inducer of iron accumulation during ACD, and its production is mainly regulated by IL-6 and the novel erythroid hormone erythroferrone (ERFE). This study evaluates whether anti-TNF monoclonal antibodies therapy modurates hepcidin production and the levels of its main regulators, leading to a restoration of iron homeostasis. Methods. Sera were collected from 21 IBD patients, before each anti-TNF administration, for the first 6 weeks of therapy. Prohepcidin, erythropoietin, erythroferrone, C reactive protein, interleukin-6, iron markers, and haemoglobin levels were measured and clinical activity indexes were evaluated. Results. Serum prohepcidin, IL-6, CRP, and ferritin were significantly reduced after 6-week treatment; an increase in serum iron and total transferrin was observed. No changes in the EPO-ERFE axis were found. Remarkably, haemoglobin was significantly increased. Conclusions. Anti-TNF therapy improves iron metabolism and, subsequently, anaemia in IBD. This effect appears to be related to the modulation of the cytokine network and specifically IL-6 leading to a relevant decrease of hepcidin, a master regulator of ACD.

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Inoyatova, F. I., N. A. Ikramova, G. Z. Inogamova, Kh M. Kadyrkhodzhayeva, F. G. Abdullayeva, N. K. Valiyeva, and A. Kh Akhmedova. "The informativity of the markers of iron metabolism in the differential diagnosis of anemia of inflammation in children with chronic HBV infection." Journal Infectology 12, no. 5 (January 21, 2021): 40–47. http://dx.doi.org/10.22625/2072-6732-2020-12-5-40-47.

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Objective: To assess diagnostic importance of iron metabolism markers in the progression of anemia of inflammation (AI) in children with chronic HBV infection.Materials and methods: Among 148 examined children with chronic HBV infection 140 had AI, 60.7% of them with refractory (RA) and 39.3% with non-refractory (nRA) progression variant. Complete blood count was performed using hematologic automatic analyzer. Virologic verification of HBV was done by ELISA and PCR. ELISA was used to determine 25-hepcidin, serum iron, ferritin, trasferrin, sTfR, IL-1, IL-6. The index sTfR/log10Ft was calculated.Results: Performing the examination of children with chronic HBV infection we determined high prevalence of AI, equal to 94.6%, which was characterized by normocyte normochromic progression, thrombocytopenia, thrombocrit decrease in case of RA, and microcyte hypochromic progression with erythrocyte anisocytosis in case of nRA. Despite the high inflammatory index induced by HBV viral replication, children with RA had characteristic decrease in 25-hepcidin and transferrin parameters with background high values of ferritin, while nRA was characterized by rise of 25-hepcidin and transferrin spectrum with low values of serum iron and ferritin.Conclusions. In the genesis of AI in chronic HBV cases two pathogenic variants were determined: true iron deficiency with ferromarkers in the type of IDA characteristic for nRA and redistribution iron deficiency compliant to hemosiderosis characteristic for RA. Priority in the differential diagnosis of AI variants is given to the comparison of sTfR/log10Ft index parameters (RA<1.0; nRA>2.0) with reference level of 25-hepcidin<28,68ng/ml in case of RA, and >56,37ng/ml in case of nRA.

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Mangaonkar, Abhishek, Niren Patel, Hongyan Xu, Kavita Natrajan, Betsy Clair, Leigh G. Wells, Latanya Bowman, Nadine Barret, and Abdullah Kutlar. "Plasma Biomarkers of Iron Regulation, Overload, and Inflammation in Sickle Cell Disease." Blood 124, no. 21 (December 6, 2014): 1380. http://dx.doi.org/10.1182/blood.v124.21.1380.1380.

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Abstract Transfusional iron overload has been increasingly recognized among patients with sickle cell disease (SCD) over the past two decades. We recently reported on the prevalence of iron overload among 635 adult SCD patients followed at our center and found that 80 patients (12%) had developed iron overload as a result of repeated blood transfusions. Fifty six (70%) of these subjects developed iron overload as a result of episodic, mostly unnecessary transfusions at outlying hospitals. There have been reports of association of increased morbidity and mortality among iron overloaded SCD patients; it has also been hypothesized that SCD patients tend to develop fewer complications of iron overload, compared to transfusion dependent beta thalassemia, primarily due to the chronic inflammatory state with resultant upregulation of hepcidin, and lower extra-hepatic iron loading. We studied biomarkers of iron metabolism, iron regulation, and inflammatory markers in 22 patients with SCD (SS) and iron overload (two consecutive ferritin levels of >1000 ng/ml and significant transfusion history) and compared these with 14 SCD patients without iron overload (ferritin <1000 ng/ml, and no significant transfusion history). Serum Fe, ferritin, %transferrin saturation (Tf) and total iron binding capacity, as well as high sensitivity C reactive protein (hsCRP) were performed by routine laboratory methods. Plasma concentrations of soluble transferrin receptor (sTfR), interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF-15) were measured using commercially available ELISA kits (R&D Systems, Minneapolis, USA). Plasma hepcidin was measured using a commercially available kit from DRG Diagnostics (Marburg, Germany). The results are summarized below: Abstract 1380. TableAgeyearsFerritin ng/ml% sathsCRPmg/dLHepcidinng/mlsTfRnmol/LGDF-15pg/mlIL-6pg/mlCases (n=22)33.42083.560.40.8829.872.21201.55.2Controls (n=14)29.0401.840.40.9512.477.11115.34.1p-value0.236.14E-050.020.80.0020.20.550.24 As expected, ferritin and % Tf saturation were significantly higher in the iron overloaded group. Hepcidin levels were also significantly higher in cases vs. controls, indicative of appropriate upregulation of hepcidin in Fe overload. sTfR and GDF-15 levels, as well as the inflammatory markers (hsCRP and IL-6) did not differ significantly between Fe overloaded and non-iron overloaded SCD patients. The two groups did not differ significantly in terms of the measures of disease severity (number of pain crises/year and number of hospitalizations/year). We further looked at the ratio of hepcidin/ferritin, sTfR/log ferritin, GDF-15/hepcidin, and tested the correlation between GDF-15 and hepcidin levels and ferritin and hepcidin levels; the ratio of hepcidin to ferritin was not different between cases and controls (0.019 and 0.021, respectively, p=0.73). sTfR to log ferritin ratio was significantly lower in cases compared to controls (22.3 vs 33.24, p=0.0004). GDF-15/hepcidin ratio was also found to be significantly lower in cases (262.1 vs 1896.7, p=0.01). Additionally, GDF-15 and hepcidin levels correlated significantly in controls but not iron overloaded SCD patients (p=0.04 vs p=0.7). Similarly, hepcidin and ferritin levels were significantly correlated in controls (p=0.03) but not in cases (p=0.8). Our results suggest that i) hepcidin levels are appropriately upregulated in iron overloaded SCD patients, ii) inflammatory markers (hsCRP and IL-6) were not significantly different between iron overloaded and non-iron overloaded patients, suggesting that systemic inflammation is not the driving factor behind hepcidin upregulation in iron overloaded SCD patients; however, a local/paracrine effect of IL-6 on hepatocytes secondary to Fe related inflammation in the liver cannot be excluded; and iii) GDF-15 and sTfR levels are not different between cases and controls, indicating that erythropoiesis does not differ between Fe overloaded and non-iron overloaded SCD patients. The observation that the correlation between GDF-15 and hepcidin levels is lost in iron overloaded SCD patients suggests that erythropoiesis does not contribute to hepcidin regulation in these subjects. This can further be clarified by studying the role of the newly described erythroid regulator of hepcidin, erythroferrone in SCD with and without iron overload. Disclosures No relevant conflicts of interest to declare.

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Barad, Alexa, Ronnie Guillet, Eva Pressman, Tomas Ganz, Elizabeta Nemeth, and Kimberly O'Brien. "Placental Ferroportin Protein Abundance Is Associated With Neonatal Rather Than Maternal Iron Status in Women at High Risk for Gestational Iron Insufficiency." Current Developments in Nutrition 6, Supplement_1 (June 2022): 622. http://dx.doi.org/10.1093/cdn/nzac061.006.

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Abstract Objectives Murine data suggest that the placenta prioritizes iron (Fe) for its own needs when Fe is limited by upregulating transferrin receptor 1 (TFR1) and downregulating the Fe exporter ferroportin (FPN). Human data on the impact of maternal and neonatal Fe status on placental FPN are conflicting. The study aims were to identify determinants of placental FPN protein abundance in women at risk of Fe insufficiency and to assess the utility of the placental Fe deficiency index (PIDI), which is the FPN/TFR1 ratio, as a measure of maternal/fetal Fe insufficiency. Methods FPN and TFR1 protein abundance was measured by semi-quantitative western blots in placentae collected from 43 neonates born to teens (17.4 ± 1.1 y) carrying singletons (39.9 ± 1.3 weeks of gestation at birth) and from 57 neonates born to 26 women (31.3 ± 6.3 y) carrying multiples (35.5 ± 2.7 weeks of gestation at birth). Fe status biomarkers (Hb, SF, sTfR, TBI) and hormones (hepcidin, EPO, ERFE) were assessed in maternal and cord blood. Results FPN and TFR1 were detected in all samples analyzed between 30.4–41.7 weeks of gestation. In both cohorts, FPN protein abundance was associated with neonatal but not maternal factors. Higher FPN was associated with lower cord Hb (p = 0.03) in the multiples cohort and with higher cord EPO (p = 0.002) in the teens. In contrast, TFR1 was inversely associated with maternal Fe status; multiples cohort (SF, p = 0.01; sTfR, p = 0.01; TBI, p = 0.003; hepcidin p = 0.01), teens (SF, p = 0.01). The PIDI was predicted by maternal and neonatal Fe status but in opposite directions. In the multiples cohort, Fe deficient women (mid-gestation sTfR > 8.5 mg/L, delivery SF < 12 μg/L or TBI < 0 mg/kg) had a lower PIDI (p = 0.02, p = 0.003, p = 0.04) but lower cord Hb was associated with a higher PIDI (p = 0.004). In the teens, lower mid-gestation hepcidin was associated with a lower PIDI (p = 0.009) but higher cord EPO was associated with a higher PIDI (p = 0.006). Conclusions Placental FPN protein was inversely associated with neonatal Fe status. The PIDI captures fetal and maternal regulation of placental Fe trafficking as it reflects Fe export to the fetus relative to Fe import from maternal circulation. More data are needed to assess the utility of the PIDI as an indicator of Fe insufficiency during pregnancy and how it relates to neonatal outcomes that are driven by placental health. Funding Sources USDA, Gerber Foundation, NIH NICHD.

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Papassotiriou, Ioannis, Pagona Flevari, Christos Poziopoulos, Sofia Zaliou, Vasilis Tsaousis, Katerina Larissi, Maria Dimopoulou, et al. "Non Invasive Evaluation of Bone Marrow Activity in Patients with Sickle Cell Disease: Correlation with Disease Features, Genotype, Markers of Erythropoiesis, Iron Metabolism and Hydroxyurea Treatment." Blood 134, Supplement_1 (November 13, 2019): 4821. http://dx.doi.org/10.1182/blood-2019-121622.

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Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by pathological polymerization of hemoglobin, increased red cell rigidity and poor microvascular blood flow with consequent tissue ischemia and infarction. Thus, hemolytic anemia, vaso-occlusion and vasculopathy are the hallmarks of its clinical presentation. The transferrin receptor (TfR) mediates the transport of iron into cells and the circulating TfR can be measured as soluble transferrin receptor (sTfR). sTfR levels are frequently used to establish the diagnosis of iron deficiency anemia, especially in the context of inflammation, but they also reflect bone marrow erythropoietic activity (BMA) and mass. Erythropoietic activity has been found to be the most important determinant of sTfR levels. In this context, we aimed to study and evaluate bone marrow activity in patients with compound heterozygous HbS and beta-thalassemia (HbS/βthal) based in sTfR measurements and explore possible correlations with of key features of the disease such as: the hemolytic component, vaso-occlusive crises (VOC), acute chest syndrome, venous thrombosis, arterial thrombosis including stroke, avascular necrosis, pulmonary hypertension, hydroxyurea therapy, inflammation and renal injury. along with other biomarkers of erythropoiesis and iron metabolism such as Placental Growth Factor (PlGF), Growth Differentiation Factor-15 (GDF-15), Ferritin and Hepcidin-25. Patients and Methods: Ninety adult Caucasian patients with HbS/βthal [49 patients under hydroxyurea (HU+) treatment and 41 patients without hydroxyurea (HU-) treatment], were included in this study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients has received any transfusions at least 6-monthes before enrollment in the study. Along with hematologic and blood chemistry parameters determination, levels of circulating sTfR, PlGF, GDF-15 and Hepcidin-25 were measured in patients with HbS/βthal and controls using RUO and IVD immunoenzymatic techniques. BMA activity was calculated from the established formula: patient-sTFR/meanControl-sTFR. Results: We found that: sTfR levels were markedly elevated in all patients with HbS/βthal compared to controls (4.8±2.2 vs. 1.0±0.2 mg/L, p<0.001), resulting in a 1.6-11.9 fold increase of BMA. No correlation was found between BMA and disease features as well as regarding hydroxyurea treatment BMA (p>0.434). BMA correlated significantly with the markers of the erythropoietic and hemolytic component such as: Hemoglobin (r=-0.434, p<0.001); Reticulocyte Production Index (r=0.645, p<0.001); LDH (r=0.570, p<0.001); Billirubin (r=0.540, p<0.001), PlGF (r=0.597, p<0.001) and Hb A levels (r=-0.493, p<0.001), while no correlation was found between BMA and Hb F levels. Furthermore, BMA values correlated significantly only with GDF-15 (r=0.466, p<0.001), while interestingly no correlation was found between BMA and Ferritin and Hepcidin-25 levels alone (r=0.101, p>0.351 and r=-0.043, p>0.710, respectively), but a negative correlation was found between BMA and Hepcidin-25/Ferritin ratio, (r=-0.330, p=0.005). Conclusions: Our findings demonstrate that all patients with HbS/βthal studied have a significantly increased degree of erythroid BMA as assessed by measurements of sTfR levels. Erythroid BMA correlated significantly with Hepcidin/Ferritin ratio, which is an index of the degree of Hepcidin expression relative to iron overload. The correlation of erythroid BMA with Hb A levels, indicate the important role of βthal genotype in HbS/βthal disease. Furthermore, BMA is not related to hydroxyurea therapy and/or iron metabolism parameters in these patients. This implicates a likely complex action of hydroxyurea, which causes intermittent cytotoxic suppression of erythroid progenitors and cell stress signaling. The latter affects erythropoiesis, leading to recruitment of erythroid progenitors with increased HbF levels, although the number of erythroid progenitors -the main source of sTfR- remains stable. Disclosures Voskaridou: Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Miura, Shogo, Masayoshi Kobune, Soushi Ibata, Masahiro Yoshida, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, et al. "CD34/EPO-R Double Positive MDS Cells Produce Erythroferrone in Response to Erythropoietin." Blood 128, no. 22 (December 2, 2016): 2455. http://dx.doi.org/10.1182/blood.v128.22.2455.2455.

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Abstract Background. It has been reported that iron absorption from gastrointestinal tract was enhanced in a subset of patients with myelodysplastic syndrome (MDS) exhibiting ineffective erythropoiesis. Iron absorption was achieved via an iron transporter ferroportin which was downregulated by hepcidin. Recently, three erythroid regulators such as growth differentiation factor 15 (GDF15), twisted gastrulation protein homolog 1 (TWSG1) and erythroferrone (ERFE) which down regulated hepatic hepcidin production has been identified. However, it has been not yet clarified which molecules could contribute to the increased iron absorption in patients with MDS. Materials and Methods. In the present study, we examined the expression level of GDF15, TWSG1 and ERFE mRNA during ex vivo erythroid differentiation from CD34+ bone marrow (BM) cells in the presence of 4 U/mL erythropoietin (EPO), 100 U/mL interleukin-3, 10 ng/mL stem cell factor, 20 ng/mL insulin-like growth factor (IGF)-1 and 500 micro g/mL iron-saturated transferrin. We further analyzed the expression level of GDF15 and ERFE in BM mononuclear cells (MNCs) derived from BM derived from MDS patients and lymphoma patients without BM involvement as a control by using quantitive RT-PCR. The expression of EPO-R was analyzed by flow cytometry. The CD34+ MDS cells were seeded on fibronectin substratum in 5 mL of a serum-free medium supplemented with 50 ng/mL human thrombopoietin (TPO), 10 ng/mL human SCF, 50 ng/mL human Fms-related tyrosin kinase 3 ligand (FLT3LG) and 100 ng/mL human delta like protein 4 (DLL4) with or without 4 U/mL EPO. For analysis of CD34+ cells, a GEO dataset (GSE58831) was downloaded as a matrix by GEOquery package (Bioconductor). The numerical data of the matrix were normalized by quantile normalization using limma package. Clinical and sequencing data were downloaded from supplementary materials. Those were combined with a GEO dataset (GSE58831) before analysis. Results. The level of ERFE mRNA was dramatically increased during erythroid differentiation from control CD34+ cells in response to EPO in vitro (Figure 1) although increase of the level of GDF15 and TWSG1 was marginal. Moreover, the level of ERFE mRNA in BM MNCs derived from MDS patients was significantly higher than that from control. Furthermore, the expression level of ERFE mRNA correlated with the percentage of CD34+ cells, but not percentage of erythroblasts derived from MDS patients. Using GEO data sets (GSE58831), the level of ERFE mRNA in CD34+ cells derived from MDS patients was significantly elevated as compared with that from healthy volunteers. Importantly, flow cytometric analysis indicated that CD34+ MDS cells highly expressed EPO receptors and the level of ERFE mRNA in CD34+ cells in a subset of MDS patients was enhanced after exposure of EPO ex vivo. In addition, the level of ERFE mRNA positively correlated with the level of EPO-R in CD34+ MDS cells (GSE58831). Conclusion. These results indicated that CD34+/EPO-R+ double positive MDS cells is one of the major sources of ERFN. The level of ERFE in CD34+ MDS cells may be associated with abnormal iron metabolism in MDS patients. These finding may be important for understanding the abnormal iron metabolism and predicting the efficacy of EPO administration. Disclosures No relevant conflicts of interest to declare.

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Skenderi, Papanikolaou, Nomikos, Kotsis, and Tsironi. "Iron Homeostasis in Elite Athletes and Ultramarathon Runners." Proceedings 25, no. 1 (September 3, 2019): 32. http://dx.doi.org/10.3390/proceedings2019025032.

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AIM: The present study was aimed at determining the effect of two different types of exercise (elite athletes playing football and ultramarathon runners on iron metabolism and, especially, the role of hepcidin in iron homeostasis. MATERIAL & METHOD: Two groups of athletes were investigated. The first group consisted of 19 male elite football athletes and the second group of 41 ultramarathon runners. In both cases, blood samples were taken pre-race (t1), immediately post-race (t2), and 24 hours post-race for football athletes or 36-48 hours post-race for ultramarathon athletes (t3). RESULTS: The iron levels in time t3 were found to have statistically significant decreases compared with the iron levels in pre-race and post-race period. Moreover, ferritin levels increased significantly in times t2 and t3. Hepcidin levels increased in time t2 in football players (from 27.45 ± 12.98 to 37.42 ± 13.74 ng/mL) and decreased in time t3. However, in ultramarathon runners, hepcidin levels significantly increased in time t2 (from 29.16 ± 10.92 to 58.81 ± 16.97 ng/mL) and remained increased in time t3 (37.69 ± 16.38 ng/mL), despite a trend for decrease. In football players, sTfR levels did not change, contrary to ultramarathon runners, where sTfR levels were found decreased in times t2 and t3. CONCLUSIONS: Iron metabolism in athletes can be impacted by the type of exercise. Ferritin is not a reliable marker for iron balance because, in the present study, it is more likely an acute-phase protein. The main regulator of iron homeostasis, hepcidin, increased, showing the body’s response to inflammation, by trapping iron in the macrophages and by altering iron absorption. Finally, a strenuous and prolonged exercise can lead to sports anemia.

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Grammer, Tanja B., Hubert Scharnagl, Alexander Dressel, Marcus E. Kleber, Günther Silbernagel, Stefan Pilz, Andreas Tomaschitz, et al. "Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study)." Clinical Chemistry 65, no. 7 (July 1, 2019): 849–61. http://dx.doi.org/10.1373/clinchem.2018.297242.

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Abstract BACKGROUND Anemia has been shown to be a risk factor for coronary artery disease (CAD) and mortality, whereas the role of iron metabolism remains controversial. METHODS We analyzed iron metabolism and its associations with cardiovascular death and total mortality in patients undergoing coronary angiography with a median follow-up of 9.9 years. Hemoglobin and iron status were determined in 1480 patients with stable CAD and in 682 individuals in whom significant CAD had been excluded by angiography. RESULTS Multivariate-adjusted hazard ratios (HRs) for total mortality in the lowest quartiles of iron, transferrin saturation, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were 1.22 (95% CI, 0.96–1.60), 1.23 (95% CI, 0.97–1.56), 1.27 (95% CI, 1.02–1.58), 1.26 (95% CI, 0.97–1.65), and 0.99 (95% CI, 0.79–1.24), respectively, compared to the second or third quartile, which served as reference (1.00) because of a J-shaped association. The corresponding HRs for total mortality in the highest quartiles were 1.44 (95% CI, 1.10–1.87), 1.37 (95% CI, 1.05–1.77), 1.17 (95% CI, 0.92–1.50), 1.76 (95% CI, 1.39–2.22), and 0.83 (95% CI, 0.63–1.09). HRs for cardiovascular death were similar. For hepcidin, the adjusted HRs for total mortality and cardiovascular deaths were 0.62 (95% CI, 0.49–0.78) and 0.70 (95% CI, 0.52–0.90) in the highest quartile compared to the lowest one. CONCLUSIONS In stable patients undergoing angiography, serum iron, transferrin saturation, sTfR, and ferritin had J-shaped associations and hemoglobin only a marginal association with cardiovascular and total mortality. Hepcidin was continuously and inversely related to mortality.

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Sacri, Anne-Sylvia, Thibaud Lefebvre, Mariane De Montalembert, Alain Bocquet, Piotr Gembara, Brigitte Pinçant, Serge Hercberg, et al. "Hepcidin, Soluble Transferrin Receptor, and Other Biomarkers of Iron Status Distributions in Healthy 2 Years Old Infants from a National Ambulatory Study in France." Blood 134, Supplement_1 (November 13, 2019): 4809. http://dx.doi.org/10.1182/blood-2019-128982.

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Background: Adequate evaluation of iron status in young children is of paramount importance given the frequency of iron deficiency (ID) and its potential short- and long-term neurocognitive adverse effects when occurs early. Iron metabolism is complex and the correct evaluation of iron status may be difficult, notably when inflammation is present. Soluble transferrin receptor (sTfR) is not modified by inflammation but lacks specificity in ID, and its combination with serum ferritin (SF) by the TfR-F index (TfR/logSF) has been proposed to improve diagnosis performances [Punnonen Blood 1997]. Hepcidin has been identified in the two last decades has the key regulator of iron homeostasis mainly by controlling iron release from macrophages via ferroportin degradation, as well as enterocytes absorption [Ganz Blood 2011]. Scarce studies have been published on hepcidin in healthy children in industrialized countries [Uijterschout Pediatr Res 2014]. The distribution of sTfR and hepcidin in healthy young children is unknown, including according to gender. Aims: Our objective was to describe hepcidin, sTfR and other iron status biomarkers (serum ferritin [SF], hemoglobin (Hb), transferrin saturation, zinc protoporphyrin [ZnPP]) distributions in a population of healthy infants aged 2 years old. Methods: In a cross-sectional observational study conducted in primary care pediatricians' offices throughout France from 2016 to 2017, infants aged 2 years old were consecutively included to undergo a blood sampling in the morning fasting. They were excluded if they were affected by a chronical disease involving iron metabolism, had fever in the last 15 days or biological inflammation defined as a CRP≥10 mg/L, and had no measurement for hepcidin. Hepcidin and ZnPP in erythrocytes were measured after a <24 hours frozen transport at -80°C in the dark by liquid chromatography-tandem mass spectrometry (LC-MS/MS, limit of detection = 0.75 ng/mL, intra- and inter-assay precision ≤ 12.3% and 9.9% [Lefebvre Clin Chem Lab Med 2015]) and by a fluorimetric method, respectively. Hb and mean corpuscular Hb concentration were measured immediately after the sample by spectrophotometric methods. The other iron biomarkers were immediately measured after refrigerated or frozen transport using immuno-turbidimetric method for transferrin (limit of detection = 0.1 g/L, intra- and inter-assay precision ≤1.2 and 2.6%) and sTfR (limit of detection 0.5 mg/L, intra- and inter-assay precision ≤2.1 and 3.6%), and electro‐chemiluminescence immunoassay for SF (limit of detection = 0.5 μg/L, intra- and inter-assay precision ≤1.1% and 5.7%). The distribution of biomarkers were described, including after classical mathematical transformation. Results: Among the 539 included children, the mean age was 24 months (SD 0.6), 49% were girls. Prevalence of ID (SF <10 µg/L) and anemia (Hb <11 g/dL) was 7% (37/539, 95% CI 4.9-9.3) and 3% (19/536, 95% CI 2.1-5.5), respectively. Hepcidin (ng/mL) median was 3.3 (IQR: 1.0-7.1; min-max: 0.75-104.1) and its mean was 6.7 (SD 10.7). Hepcidin was neither normally nor log-normally distributed (Figure 1.A, 1.B). sTfR median was 4.1 (IQR: 3.6-4.8; min-max: 1.2-13.5) and its mean was 4.2 (SD 1.1). TfR-F index median was 1.2 (IQR: 1.0-1.5; min-max: 0.3-8.4) and its mean was 1.4 (SD 0.6). No statistically significant difference was found between girls and boys for hepcidin, sTfR, and TfR-F index distributions (all p t-tests > 0.3). Distributions of other iron biomarkers were closed to those reported in the literature. Conclusion: We described for the first time in a nationwide ambulatory study hepcidin and TfR/logSF distributions in a population of 2 year-old healthy infants with a low ID prevalence. Hepcidin had a right-skewed distribution and its normalisation was not obtained by usual transformations. Low values, partly corresponding to the limit of detection, were over-represented despite the low proportion of ID defined by SF level. High values were also observed despite the exclusion of infants with CRP>10 mg/L. We did not find significant variations according to gender. Our results will help define normal values at this age to better interpret iron status. Disclosures Sacri: Secteur Francais des Aliments de l Enfance: Research Funding; French Ministry of Health DGOS PHRC regional 2014 no. AOR14053: Research Funding. De Montalembert:Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Addmedica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chalumeau:French Ministry of Health DGOS PHRC regional 2014 no. AOR14053: Research Funding; Secteur Francais des Aliments de l Enfance: Research Funding.

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Weiler, Hope A., Sonia Jean-Philippe, Tamara R. Cohen, Catherine A. Vanstone, and Sherry Agellon. "Depleted iron stores and iron deficiency anemia associated with reduced ferritin and hepcidin and elevated soluble transferrin receptors in a multiethnic group of preschool-age children." Applied Physiology, Nutrition, and Metabolism 40, no. 9 (September 2015): 887–94. http://dx.doi.org/10.1139/apnm-2014-0328.

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Iron deficiency anemia is prevalent in subgroups of the Canadian population. The objective of this study was to examine iron status and anemia in preschool-age children. Healthy children (n = 430, 2–5 years old, Montreal, Quebec, Canada) were sampled from randomly selected daycares. Anthropometry, demographics, and diet were assessed. Biochemistry included hemoglobin, ferritin, soluble transferrin receptors (sTfR), ferritin index, markers of inflammation (C-reactive protein, interleukin 6 (IL-6), and tumour necrosis factor alpha (TNFα)), and hepcidin. Iron deficiency and anemia cutoffs conformed to the World Health Organization criteria. Differences among categories were tested using mixed-model ANOVA or χ2tests. Children were 3.8 ± 1.0 years of age, with a body mass index z score of 0.48 ± 0.97, and 51% were white. Adjusted intakes of iron indicated <1% were at risk for deficiency. Hemoglobin was higher in white children, whereas ferritin was higher with greater age and female sex. Inflammatory markers and hepcidin did not vary with any demographic variable. The prevalence of iron deficiency was 16.5% (95% confidence interval (CI), 13.0–20.0). Three percent (95% CI, 1.4–4.6) of children had iron deficiency anemia and 12.8% (95% CI, 9.6–16.0) had unexplained anemia. Children with iron deficiency, with and without anemia, had lower plasma ferritin and hepcidin but higher sTfR, ferritin index, and IL-6, whereas those with unexplained anemia had elevated TNFα. We conclude that iron deficiency anemia is not very common in young children in Montreal. While iron deficiency without anemia is more common than iron deficiency with anemia, the correspondingly reduced circulating hepcidin would have enabled heightened absorption of dietary iron in support of erythropoiesis.

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Zapora-Kurel, Agnieszka, Łukasz Kuźma, Magdalena Zakrzewska, Marcin Żórawski, Sławomir Dobrzycki, Małgorzata Twardowska-Kawalec, and Jolanta Małyszko. "Novel Iron Parameters in Patients with Type 2 Diabetes Mellitus in Relation to Kidney Function." Journal of Clinical Medicine 10, no. 16 (August 22, 2021): 3732. http://dx.doi.org/10.3390/jcm10163732.

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Background/aims: Anemia of chronic disease is a common feature in diabetes and chronic kidney disease. Hepcidin is the key element involved in iron metabolism; however, studies on new indices of iron status are still ongoing. The aim of the study was to assess novel iron parameters in patients with type 2 diabetes mellitus in relation to kidney function. Methods: The study included 80 type 2 diabetic patients and 23 healthy volunteers. Standard laboratory measurements were used to measure the iron status, complete blood count, creatinine, the estimated glomerular filtration rate (eGFR), serum lipids, and brain natriuretic peptides (BNPs). Commercially available kits were used to measure hepcidin-25, the soluble transferrin receptor (sTfR), growth differentiation factor-15 (GDF-15), and hypoxia-inducible factor-1 alpha. Results: Anemia was present in 65% of the studied patients. The control group was found to have significantly higher hepcidin, sTfR, and GDF-15, and lower hemoglobin and iron. When compared with patients with eGFR values ≥60 mL/min/1.73 m2 and <60 mL/min/1.73 m2, we found that patients with higher eGFR had higher hemoglobin, ferritin, and HIF-1 alpha, lower BNP, and were younger. We found that levels of HIF-1 alpha are negligible in the studied population and were related to age only in patients with eGFR values ≥60 mL/min/1.73 m2. Conclusion: A comprehensive assessment of iron status is rarely performed. Novel biomarkers of iron metabolism are not generally related to kidney function. Whether the assessment of HIF-1 alpha would be a marker of efficient anemia therapy with HIF-prolyl hydroxylase inhibitors is still a matter for further study.

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Sakhin, V. T., M. A. Grigoriev, E. V. Kryukov, S. P. Kazakov, A. V. Sotnikov, A. V. Gordienko, and O. A. Rukavitsyn. "Pathogenetic features of anemia of chronic diseases in patients with malignant neoplasms and rheumatic pathology." Oncohematology 15, no. 4 (December 7, 2020): 82–90. http://dx.doi.org/10.17650/1818-8346-2020-15-4-82-90.

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Objective: to study the importance of cytokines, hepcidin, a soluble transferrin receptor, iron metabolism in the development of anemia of chronic diseases in patients with malignant neoplasms and rheumatic pathology, to identify the leading factors in the development of anemia for each of the studied groups and to develop a working classification of anemia of chronic diseases.Materials and methods. 63 patients with rheumatic pathology were examined. The study group included 41 (17 men/24 women, average age 53.4 ± 4 years) patients with anemia, the control group included 22 (9 men/13 women, age 49.3 ± 1.78 years) patients without anemia. The patients (n = 63) with stage II–IV malignant neoplasms were examined. The study group included 41 patients with anemia (34 men/7 women, age 67.1 ± 9.9 years), in the control group 22 patients without it (17 men/5 women, age 60.2 ± 14.9 years). The number of red blood cells, the hemoglobin level, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, concentrations of serum iron, total iron binding capacity (TIBC), ferritin, transferrin, C-reactive protein (CRP), transferrin saturation index (TSI), and soluble transferrin receptor (sTfR), hepcidin, interleukin (IL) – 6, – 10, tumor necrosis factor-α (TNF-α) were determined. Mann – Whitney U Test was applied to check for statistically significant differences in study samples.Results. Compared with the control group, elevated concentrations of ferritin, CRP, hepcidin, sTfR and IL-6 (p <0.05) were found for patients with rheumatic pathology and anemia and no differences were found in the concentrations of iron, TIBC, TSI, transferrin. For patients with solid malignant neoplasms and anemia, lower concentrations of iron, TIBC, TSI and higher concentrations of CRP, hepcidin, sTfR, IL-6, IL-10, TNF-α (p <0.05) are shown in comparison with the control group and there were no differences in the concentrations of ferritin, transferrin (p >0.05).Conclusion. The multicomponent anemia genesis in patients with cancer and rheumatic pathology is shown. The contribution of each mechanism to the development of anemia may vary depending on the specific nosological form. In patients with cancer, functional iron deficiency, activation of IL-6, IL-10, TNF-α synthesis and an increase in hepcidin synthesis lead to the development of anemia of chronic diseases. In patients with a rheumatic profile and anemia, a more pronounced synthesis of hepcidin and an increase IL-6 concentration are indicated. A working version of the classification of anemia of chronic diseases based on the leading pathogenetic factor is proposed (with a predominant iron deficiency, with impaired regulatory mechanisms of erythropoiesis, with insufficient production of erythropoietin).

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Galushko, E., A. Semashko, A. Gordeev, and A. Lila. "POS0567 HEPCIDIN IS POTENTIAL BIOMARKER TO DISTINGUISH BETWEEN IRON DEFICIENCY ANEMIA AND ANEMIA OF INFLAMMATION IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 518.2–518. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3303.

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Background:Anemia of inflammation (AI) and iron deficiency anemia (IDA) are the two most prevalent forms of anemia in patients with rheumatoid arthritis (RA). Diagnosis becomes challenging if AI is associated with true ID (AI/ID), as there is still a lack of a gold standard for differentiation between AI and AI/ID. However, as therapies to overcome anemia differ, proper diagnosis and understanding of underlying pathophysiological regulations are necessary.Objectives:The aim of the study was to evaluate the clinical efficiency of hepcidin, a key regulator of iron metabolism, in the diagnosis of IDA, as well as the differential diagnosis of AI/ID and AI in patients with RA.Methods:The study was undertaken 96 patients with RA, 67 of them were diagnosed anemia according to WHO criteria (104,3±21,4 g/l). Anemic patients and anemia-free patients with RA (n=29) were comparable (p>0.05) in age (44.4±14.8 and 49.8±9.3 years), disease duration (73.5±65.4 and 59.8±48.3 months) and DAS28 (6.3±1.6 and 5.9±1.9). All cases were subjected to following tests: complete blood count with peripheral smear, serum C-reactive protein, serum interleukin-6, iron studies, serum soluble transferrin receptor (sTfR), and serum hepcidin. Patients with RA and anemia were divided two groups: 25 patients with IDA and 42 - with AI. The AI cases were subdivided into pure AI and AI with coexistent ID (n=15).Results:The mean serum hepcidin concentration was significantly increased in pure AI patients (123.85±25.8 ng/mL) as compared to those in IDA patients (63.9±22.8 ng/mL, P < 0.05) and anemia-free patients with RA (88.1±39.09 ng/mL). Also, compared to pure AI patients [normal sTfR levels (<3 µg/mL)], the serum hepcidin concentration was reduced significantly in AI patients with ID [high sTfR levels (≥3 µg/mL)] with a mean of 79.0±23.97 ng/mL.Conclusion:Hepcidin measurement can provide a useful tool for differentiating AI from IDA and also help to identify an iron deficiency in AI patients. This might aid in the appropriate selection of therapy for these patients.Disclosure of Interests:None declared

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Suárez-Ortegón, Milton Fabian, Alejandra Arbeláez, José María Moreno-Navarrete, José Guillermo Ortega-Ávila, Mildrey Mosquera, and José Manuel Fernández-Real. "Soluble Transferrin Receptor, Antioxidant Status and Cardiometabolic Risk in Apparently Healthy Individuals." Antioxidants 12, no. 1 (December 22, 2022): 19. http://dx.doi.org/10.3390/antiox12010019.

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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 < 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 < 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.

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Sanyear, Chanita, Buraporn Chiawtada, Punnee Butthep, Saovaros Svasti, Suthat Fucharoen, and Patarabutr Masaratana. "The hypoferremic response to acute inflammation is maintained in thalassemia mice even under parenteral iron loading." PeerJ 9 (April 30, 2021): e11367. http://dx.doi.org/10.7717/peerj.11367.

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Background Hepcidin controls iron homeostasis by inducing the degradation of the iron efflux protein, ferroportin (FPN1), and subsequently reducing serum iron levels. Hepcidin expression is influenced by multiple factors, including iron stores, ineffective erythropoiesis, and inflammation. However, the interactions between these factors under thalassemic condition remain unclear. This study aimed to determine the hypoferremic and transcriptional responses of iron homeostasis to acute inflammatory induction by lipopolysaccharide (LPS) in thalassemic (Hbbth3/+) mice with/without parenteral iron loading with iron dextran. Methods Wild type and Hbbth3/+ mice were intramuscularly injected with 5 mg of iron dextran once daily for two consecutive days. After a 2-week equilibration, acute inflammation was induced by an intraperitoneal injection of a single dose of 1 µg/g body weight of LPS. Control groups for both iron loading and acute inflammation received equal volume(s) of saline solution. Blood and tissue samples were collected at 6 hours after LPS (or saline) injection. Iron parameters and mRNA expression of hepcidin as well as genes involved in iron transport and metabolism in wild type and Hbbth3/+ mice were analyzed and compared by Kruskal–Wallis test with pairwise Mann–Whitney U test. Results We found the inductive effects of LPS on liver IL-6 mRNA expression to be more pronounced under parenteral iron loading. Upon LPS administration, splenic erythroferrone (ERFE) mRNA levels were reduced only in iron-treated mice, whereas, liver bone morphogenetic protein 6 (BMP6) mRNA levels were decreased under both control and parenteral iron loading conditions. Despite the altered expression of the aforementioned hepcidin regulators, the stimulatory effect of LPS on hepcidin mRNA expression was blunt in iron-treated Hbbth3/+ mice. Contrary to the blunted hepcidin response, LPS treatment suppressed FPN1 mRNA expression in the liver, spleen, and duodenum, as well as reduced serum iron levels of Hbbth3/+ mice with parenteral iron loading. Conclusion Our study suggests that a hypoferremic response to LPS-induced acute inflammation is maintained in thalassemic mice with parenteral iron loading in a hepcidin-independent manner.

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Skrypnik, Katarzyna, Paweł Bogdański, Magdalena Sobieska, and Joanna Suliburska. "Hepcidin and Erythroferrone Correlate with Hepatic Iron Transporters in Rats Supplemented with Multispecies Probiotics." Molecules 25, no. 7 (April 5, 2020): 1674. http://dx.doi.org/10.3390/molecules25071674.

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The influence of probiotic supplementation on iron metabolism remains poorly investigated. However, a range of studies, especially on Lactobacillus plantarum 299v (Lp229v), have indicated a possible positive impact of probiotics on iron absorption. The aim of the study was to determine the effect of multistrain probiotic supply on iron balance. Thirty Wistar rats were randomized into three groups: placebo (KK group), and multistrain probiotic per os in a daily dose of 2.5 × 109 colony forming units (CFU) (PA group) or 1 × 1010 CFU (PB group). Multistrain probiotic consisted of nine bacterial strains: Bifidobacterium bifidum W23, B. lactis W51, B. lactis W52, Lactobacillus acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, Lactococcus lactis W19, and Lc. lactis W58, in equal proportions. After six weeks, blood and organ samples were collected. No differences were found between the three groups in terms of serum concentrations of hepcidin (HEPC), lactoferrin (LTF), homocysteine (HCY), ferritin (Ft), or erythroferrone (ErFe), or in liver content of divalent metal transporter 1 (DMT1), transferrin receptors 1 and 2 (TfR), or ZRT/IRT-like protein 14 (ZIP14) proteins. In the overall sample, positive correlations were noted between the serum concentrations of hepcidin and lactoferrin, and hepcidin and ferritin; serum concentration of hepcidin and DMT1 and TfR1 in the liver; and serum concentration of erythroferrone and TfR2 in the liver. The correlations of serum hepcidin and erythroferrone with liver DMT1 and TfR represent significant mechanisms of Fe homeostasis. Our study has shown that multistrain probiotic supplementation used in the experiment did not disrupt the biochemical and hepatic regulatory processes of Fe balance and did not demonstrate significant influence on selected parameters of Fe metabolism.

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Shi, Jimin, Xuying Pei, Yi Luo, Yamin Tan, Yanmin Zhao, Jingsong He, Weiyan Zheng, et al. "Iron Metabolism before Allo-HSCT in Patients with Acute Leukemia and Impact of Iron Overload on Transplantation." Blood 128, no. 22 (December 2, 2016): 2461. http://dx.doi.org/10.1182/blood.v128.22.2461.2461.

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Abstract Objective: Iron overload is common in patients with acute leukemia who undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). We performed a comprehensive analysis of iron parameters to assess these patients' iron metabolism, and studied the prognostic impact of pretransplant iron overload on the outcome of transplantation. Methods: In this retrospective study, we studied 124 patients undergoing myeloablative allo-HSCT between 2012 and 2014. Serum iron (SI), serum ferritin (SF), hepcidin (Hepc) and soluble transferrin receptor (sTfR) were measured before transplant. We analyzed the effect of elevated pretransplant ferritin on acute graft versus host disease (aGVHD), infectious complications, overall survival (OS) and non-relapse mortality (NRM). Results: Date of 124 patients (including 56 cases of acute lymphocytic leukemia and 68 cases of acute myeloid leukemia) were analyzed. Median SI, SF, Hepc and sTfR values were 12.15 umol/L, 667.05 ng/ml, 369.50 ng/L and 7.69 ng/ml, respectively. Iron overload (defined as SF>1000 ng/ml) were observed in 27.42% of patients. Pretransplant iron overload was significantly associated with increased risk of bacterial infections during the early post-transplant period, and with reduced risk of aGVHD. Pretransplant iron overload increased NRM and reduced OS, but there were no significant differences. Conclusion: Patients with acute leukemia regularly develop iron overload before they undergoing allo-HSCT. Pretransplant iron overload was correlated with transplantation outcome. Disclosures No relevant conflicts of interest to declare.

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Ruiz Martinez, Marc, Wenbin An, Maria Feola, Jeffrey A. Glassberg, and Yelena Ginzburg. "Hepcidin Predicts Decrease in Erythroid Expansion in Sickle Cell Disease Patients Treated with Inhaled Steroids." Blood 132, Supplement 1 (November 29, 2018): 2339. http://dx.doi.org/10.1182/blood-2018-99-115234.

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Abstract Sickle cell disease (SCD) is a recessively inherited hemoglobin disorder; the most common and severe form is a consequence of homozygous βS mutation. High concentration of hemoglobin S damages RBC membranes, leading to hemolysis, vaso-occlusion, and inflammation, which together result in anemia, recurrent painful crises, and multiple end-organ damage (i.e. brain, kidney, lung, and bone). Anemia in SCD is multi-factorial. Causes include hemolysis, ineffective erythropoiesis, impaired iron utilization, insufficient erythropoietin responsiveness, and low oxygen affinity [Sherwood Blood 1986]. RBC transfusions are used to ameliorate symptoms and complications but indications are not clearly defined for adults. We postulate that impaired iron utilization in SCD is a consequence of complex regulation of hepcidin, the main hormone regulating circulating and systemic iron. We aim to explore correlation between hepcidin, inflammation and erythropoiesis to enhance our understanding of iron metabolism, hepcidin regulation, and pathophysiology of anemia in SCD. Ultimately this may yield more specific indications for RBC transfusion, and pave the way for novel therapeutic approaches. High hepcidin results in the sequestration of iron within macrophages and prevents further iron absorption in the gastrointestinal tract. Hepcidin expression is enhanced by iron and inflammation and suppressed by hypoxia and erythropoiesis. Distinguishing the relative contribution of these competing effects on hepcidin in SCD is complicated. For example, adult SCD patients in steady state have significantly lower hepcidin relative to heterozygous controls and do not correlate with markers of inflammation and erythropoiesis [Kroot Haematologica 2009]. In a randomized, placebo-controlled trial, inhaled steroids (mometasone) were administered to non-asthmatic SCD patients [Glassberg Am J Hematol 2017]. The results demonstrate improved pain scores and reduced hemolysis in the treated group although the mechanism of this effect is not known. In a subsequent analysis, markers of inflammation are suppressed in the treated group, correlating with macrophage activation. We thus evaluate hepcidin expression in stored serum samples from this trial of SCD patients treated with inhaled steroids or placebo. Samples before and after treatment were analyzed. Serum hepcidin quantification was performed with Hepcidin-25 ELISA kit (Intrinsic Lifesciences LLC). In addition, we evaluate if and how hepcidin levels correlate with pro-inflammatory markers measured with olink inflammation assay. Serum hepcidin concentration is not different in steroid- vs. placebo-treated SCD patients before or after treatment and no significant difference is observed in the hepcidin ratio after:before treatment between the two groups (Fig 1a). However, in the steroid group, hepcidin concentrations are increased in a higher proportion of patients although the difference does not reach statistical significance (Fig 1b). We thus hypothesize that hepcidin levels may be a marker of increased erythropoiesis relative to inflammation in SCD. Both IL-6 (Fig 2a) and IL-10 (Fig 2b), cytokines known to induce hepcidin expression during inflammation, decrease after treatment with steroids relative to placebo, and neither correlates with hepcidin concentration after treatment (Table I). Hepcidin is however inversely correlated with adenosine deaminase (ADA) and hemoglobin S and directly correlative with fibroblast growth factor 23 (FGF23), monocyte chemoattractant protein 1 (MCP1), and hemoglobin F in both placebo- and steroid-treated groups (Table I), potentially suggesting that hepcidin inversely correlates with expanded erythropoiesis. We thus use the newly available human ELISA kit for erythroferrone (ERFE) (Intrinsic Lifesciences LLC), a recently identified erythroid regulator of hepcidin [Kautz Nat Gen 2014], to evaluate correlation with hepcidin. Our results demonstrate that serum ERFE concentration decreases in steroid- (Fig 3a) but not placebo-treated SCD patients (Fig 3b), and no correlation with hepcidin is observed. Taken together, these data for the first time demonstrate a decrease in erythropoiesis and erythroid-regulation-induced hepcidin suppression in inhaled-steroid-treated SCD patients. Disclosures No relevant conflicts of interest to declare.

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Gromadzka, Grażyna, Diana Wierzbicka, Tomasz Litwin, and Adam Przybyłkowski. "Iron metabolism is disturbed and anti-copper treatment improves but does not normalize iron metabolism in Wilson’s disease." BioMetals 34, no. 2 (February 8, 2021): 407–14. http://dx.doi.org/10.1007/s10534-021-00289-x.

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AbstractWilson’s disease (WD) is a rare hereditary disorder of copper metabolism. Some data suggest that iron metabolism is disturbed in WD and this may affect the course of the disease. The current study aimed to determine whether anti-copper treatment could affect iron metabolism in WD. One hundred thirty-eight WD patients and 102 controls were examined. Serum ceruloplasmin and copper were measured by colorimetric enzyme assay or atomic adsorption spectroscopy, respectively. Routine and non-routine parameters of iron metabolism were measured by standard laboratory methods or enzyme immunoassay, respectively. WD patients, both newly diagnosed and treated, had less serum copper and ceruloplasmin than controls (90.0, 63.0, 22.0 mg/dL, respectively, p < 0.001); in the treated patients blood copper and ceruloplasmin were lower than in untreated patients (p < 0.001). Untreated patients (n = 39) had a higher median blood iron (126.0 vs 103.5 ug/dL, p < 0.05), ferritin (158.9 vs 47.5 ng/mL, p < 0.001), hepcidin (32, 6 vs 12.1 ng/mL, p < 0.001) and sTfR (0.8 vs. 0.7 ug/mL, p < 0.001) and lower blood transferrin (2.4 vs. 2.7 g/L, p < 0.001), TIBC (303.0 vs 338.0 ug/dL, p < 0.001), hemoglobin (13.1 vs 13.9 g/dL, p < 0.01) and RBC (4.3 vs. 4.6, p < 0.002) than controls. Treated patients (n = 99) had a significantly lower median iron (88.0 vs. 126.0 ug/dL, p < 0.001), ferritin (77.0 vs. 158.9 ng/mL, p < 0.005) and hepcidin (16.7 vs. 32.6 ng/mL, p < 001) and higher transferrin (2.8 vs. 2.4 g/L, p < 0.005), TIBC (336.0 vs 303.0 ug/dL, p < 0.001), RBC (4.8 vs. 4.3 M/L, p < 0.001) and hemoglobin (14.4 vs. 13.1 g/dL, p < 0.001) than untreated; the median iron (p < 0.005) was lower, and ferritin (p < 0.005), RBC (p < 0.005) and hepcidin (p < 0.002) were higher in them than in the control group. Changes in copper metabolism are accompanied by changes in iron metabolism in WD. Anti-copper treatment improves but does not normalize iron metabolism.

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Kralova, Barbora, Ondrej Jahoda, Jihyun Song, Katarina Hlusickova Kapralova, Lucie Sochorcova, Josef T. Prchal, Vladimir Divoky, and Monika Horvathova. "Aging-Related Changes in Erythropoietic Activity and Iron Metabolism in a Mouse Model of Congenital Erythrocytosis with Human Gain-of-Function Erythropoietin Receptor." Blood 138, Supplement 1 (November 5, 2021): 938. http://dx.doi.org/10.1182/blood-2021-146747.

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Abstract We previously created and characterized a mouse model of congenital erythrocytosis with low erythropoietin (EPO) levels from a gain-of-function mutation of the human erythropoietin receptor gene (mtHEPOR) (Divoky et al. PNAS. 2001; 98:986; Divoky et al. JMM Berl. 2016; 94:597). These mice develop fetal erythrocytosis, followed by transient amelioration of erythrocytosis in perinatal life, and reappearance at 3-6 weeks of age. Similarly, erythrocytosis is observed in heterozygous mtHEPOR patients postnatally but not at birth. We previously reported dynamic changes of the erythron with iron homeostasis during ontogenesis in these mice (Kralova et al. Blood 2017; 130: 170). We observed that while perinatal mtHEPOR mice exhibit relative iron deficiency, aged mice had iron overload. Here, we evaluated developmentally-determined factors associated with hyperactivation of EPOR signaling which could cause a transition from iron deficiency (neonates) to hyperferremia and increased iron deposition (aged mice). To assess the consequences of different levels of EPOR-JAK2-STAT5 signaling, we studied hetero- and homozygous mtHEPOR mice that differ in their severity of erythrocytosis. We found that prenatally and perinatally, mtHEPOR hetero- and homozygous mice have increased erythroferrone (Erfe) transcripts and reduced hepcidin, consistent with the known inverse correlation between Erfe and hepcidin and in accordance with increased numbers of immature erythroid progenitors in the fetal hepatic circulation. At birth, previously normal Epo expression decreased and remained low in adulthood. Iron deficiency, observed in mtHEPOR hetero- and homozygotes at postnatal day 7, was likely related to increased iron consumption by augmented erythropoiesis at this stage. Postnatally, hepcidin levels increased in mutant mice, accompanied by low Erfe induction and iron accumulation in the liver and spleen as reflected by the upregulation of hepatic Bmp6 expression in mature adult (aged ~6.5 months) and old (~16 months) mtHEPOR homozygotes. We hypothesized that this could be a consequence of diminished iron consumption due to a progressive decline of erythropoiesis in mtHEPOR mice, possibly mediated by premature aging of erythroid progenitors with cell-autonomously increased proliferative history and/or increased inflammation. Indeed, young mutant erythrocytes had decreased erythrocyte survival and expression of a senescent marker CD47, an inhibitor of erythrocytes' phagocytosis. Additionally, a progressive decline in the percentage of Ter119-positive bone marrow cells and immature erythroblasts was observed in mtHEPOR hetero- and homozygotes with aging. Clonogenic assays of old mice revealed suppression of early (BFU-E) and late (CFU-E) erythroid progenitors and myeloid bias of hematopoiesis, paralleled by the up-regulation of PU.1 expression, elevation of platelet counts, and an increase in megakaryocytes chiefly in the bone marrow of mtHEPOR homozygotes. Serum levels of inflammatory cytokines did not indicate systemic inflammation; however, induced transcripts of IL-6, Inf-γ, Tgf-β, and Tnf-α, mainly in mtHEPOR homozygotes showed local bone marrow inflammatory stress. These data indicate progressive attenuation of erythroid drive in mtHEPOR homozygotes, and less so in mtHEPOR heterozygotes, paralleled by a decline in hematocrit levels with aging. In response to attenuated erythropoietic activity, iron consumption was reduced in mtHEPOR mice, leading to iron accumulation in the liver and spleen accompanied by markedly increased hepcidin synthesis. Our data suggest that even in the absence of systemic inflammation, albeit with possible paracrine inflammatory signals, known to affect bone marrow remodeling and hematopoietic aging, life-lasting prolonged activation of EPOR-JAK2-STAT5 signaling promoted exhaustion of erythroid progenitors and resulted in an age-related decline of accelerated erythropoiesis in this mouse model of congenital erythrocytosis with human gain-of-function EPOR. Grant support: Czech grant agencies projects GA17-05988S, NV19-07-00412 and LTAUSA17142, Palacky University project IGA_LF_2021_004. Disclosures No relevant conflicts of interest to declare.

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Tarancon-Diez, Laura, Miguel Genebat, Manuela Roman-Enry, Elena Vázquez-Alejo, Maria de la Sierra Espinar-Buitrago, Manuel Leal, and Mª Ángeles Muñoz-Fernandez. "Threshold Ferritin Concentrations Reflecting Early Iron Deficiency Based on Hepcidin and Soluble Transferrin Receptor Serum Levels in Patients with Absolute Iron Deficiency." Nutrients 14, no. 22 (November 10, 2022): 4739. http://dx.doi.org/10.3390/nu14224739.

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(1) Background: The serum ferritin cut-off to define absolute iron deficiency is not well-established. The aim of the present study was to determine a clinically relevant ferritin threshold by using early serum biomarkers of iron deficiency such as hepcidin and the soluble transferrin receptor; (2) Methods: Two hundred and twenty-eight asymptomatic subjects attending a hospital as outpatients between 1st April 2020 and 27th February 2022 were selected. Iron metabolism parameters as part of the blood analysis were requested by their doctor and included in the study. Then, they were classified into groups according to their ferritin levels and iron-related biomarkers in serum were determined, quantified, and compared between ferritin score groups and anemic subjects. (3) Results: Serum ferritin levels below 50 ng/mL establish the point from which the serum biomarker, the soluble transferrin receptor to hepcidin ratio (sTfR/Hep ratio), begins to correlate significantly with ferritin levels. (4) Conclusion: Ferritin levels ≤ 50 ng/mL are indicative of early iron deficiency; hence, this should be considered as a clinically relevant cut-off for iron deficiency.

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Vega-Sánchez, Rodrigo, Mari Cruz Tolentino-Dolores, Blanca Cerezo-Rodríguez, Georgette Chehaibar-Besil, and María Eugenia Flores-Quijano. "Erythropoiesis and Red Cell Indices Undergo Adjustments during Pregnancy in Response to Maternal Body Size but not Inflammation." Nutrients 12, no. 4 (April 1, 2020): 975. http://dx.doi.org/10.3390/nu12040975.

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During human pregnancy, iron requirements gradually increase, leading to higher amounts of erythropoietin (EPO) and reticulocytes, and changes in erythrocyte size and density. Women with pregestational obesity experience “obesity hypoferremia” during pregnancy, which alters iron homeostasis. In this study we aimed to describe the relationship between EPO and iron nutrition status during nonanemic pregnancy, and to explore whether obesity and inflammation influence erythropoiesis and red cell indices. We conducted a secondary analysis of a cohort followed throughout pregnancy. Participants were nonanemic women assigned to two study groups based on pregestational body mass index (pgBMI): adequate weight (AW, n = 53) or obesity (Ob, n = 40). All received a multivitamin supplement. At gestational ages (GA) 13, 21, 28 and 34, we measured hemoglobin and red cell indices with an ACT-5DIFF hematology counter, and reticulocyte percentage by manual cell counting. EPO, interleukin (IL–6) and markers of iron status, i.e., hepcidin, serum transferrin receptor (sTfr) and ferritin, were measured by ELISA. Bivariate correlations showed that EPO was positively associated with pgBMI, GA, sTfr and IL-6, but negatively associated with hepcidin, ferritin and hemoglobin, and unrelated to iron intake. Generalized linear models adjusted for confounding factors showed that EPO and erythrocyte concentrations were significantly higher in women in the Ob group, while mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and red cell distribution width (RDW) were lower; reticulocytes and mean corpuscular hemoglobin concentration (MCHC) were not different. Differences were not altered when controlling for inflammation (IL–6). These changes suggest that, in addition to altering iron metabolism, a larger maternal body size during pregnancy results in higher erythropoiesis without increasing hemoglobin, which is exhibited in the latter being distributed among more and smaller erythrocytes.

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Brugnara, Carlo. "Iron Deficiency and Erythropoiesis: New Diagnostic Approaches." Clinical Chemistry 49, no. 10 (October 1, 2003): 1573–78. http://dx.doi.org/10.1373/49.10.1573.

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Abstract Iron deficiency anemia is one of the most common diseases worldwide. In the majority of cases, the presence of hypochromic microcytic anemia and biochemical evidence for depletion of body iron stores makes the diagnosis relatively straightforward. However, in several clinical conditions, classic biochemical indices such as serum iron, transferrin saturation, and ferritin may not be informative or may not change rapidly enough to reflect transient iron-deficient states (functional iron deficiency), such as the ones that develop during recombinant human erythropoietin (r-HuEPO) therapy. The identification and treatment of iron deficiency in settings such as r-HuEPO therapy, anemia of chronic disease, and iron deficiency of early childhood may be improved by the use of red cell and reticulocyte cellular indices, which reflect in almost real time the development of iron deficiency and the response to iron therapy. In the anemia of chronic disease, measurements of plasma cytokines and iron metabolism regulators such as hepcidin (when available) may be helpful in the characterization of the pathophysiologic basis of this condition. The ratio of serum transferrin receptor (sTfR) to serum ferritin (R/F ratio) has been shown to have excellent performance in estimating body iron stores, but it cannot be used widely because of the lack of standardization for sTfR assays. The combination of hematologic markers such as reticulocyte hemoglobin content, which decreases with iron deficiency, and R/F ratio may allow for a more precise classification of anemias.

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Сахин, В. Т., М. А. Григорьев, Е. В. Крюков, С. П. Казаков, and О. А. Рукавицын. "Features of Cytokine Secretion and Their Influence on the Indicators of Iron Metabolism and Development of Anemia in patients with Rheumatic Pathology." Гематология. Трансфузиология. Восточная Европа, no. 1 (May 25, 2020): 140–48. http://dx.doi.org/10.34883/pi.2020.6.1.014.

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Цель. Изучить особенности секреции интерлейкина-6 (ИЛ-6), интерлейкина-10 (ИЛ-10), интерлейкина-1β (ИЛ-1β), интерферона-гамма (ИФН-γ), фактора некроза опухоли-альфа (ФНО-α) у пациентов с ревматическими заболеваниями и сопутствующей анемией хронических заболеваний (АХЗ), исследовать их влияние на обмен железа и эритропоэз.Материалы и методы. Обследованы 63 пациента ревматологического профиля, 26 мужчин (45 (36–54,9) лет), 37 женщин (49 (38–60) лет). Пациенты разделены на две группы: 1-я группа – 41 пациент с анемией, 2-я группа (контрольная) – 22 пациента без анемии. Выполнен сравнительный анализ показателей гемограммы, обмена железа (железо, ферритин, трансферрин, общая железосвязывающая способность (ОЖСС), коэффициент насыщения трансферрина железом (КНТ), гепцидин, растворимый рецептор трансферрина (sTfR), С-реактивный белок (СРБ)) и цитокинов. Выполнен корреляционный анализ между цитокинами и показателями гемограммы, обмена железа, гепцидином, sTfR, СРБ.Результаты. У пациентов с анемией в сравнении со 2-й группой выше концентрации фер ритина (292,7 (146,1–335,1) и 78,5 (36–90,7) мкг/л), СРБ (59,4 (10,9–100,2) и 4,6 (1,2–5,8) мг/л),гепцидина (504,9 (23,5–916,5) и 232 (0,0–858) нг/мл), sTfR (8,6 (3,9–7,1) и 2,2 (1,5–3,1) нмоль/л).Для железа, ОЖСС, КНТ, трансферрина не выявлено межгрупповых различий (p>0,05). Концентрация ИЛ-6 у пациентов с анемией больше в сравнении со 2-й группой (35,8 (2,1–41,1) и 2,7 (1,5–3)). Для ИЛ-10, ИЛ-1β, ИФН-γ, ФНО-α не выявлено межгрупповых различий (p>0,05). Выявлена корреляция между числом эритроцитов и ИЛ-6 (r=–0,3), ИЛ-10 (r=–0,4), ИНФ-γ (r=–0,4), ФНО-α (r=–0,3). Доказана взаимосвязь между концентрацией гемоглобина и ИЛ-6 (r=–0,6), ИЛ-10 (r=–0,4), ИНФ-γ (r=–0,3), ФНО-α (r=–0,3), ИЛ-1β (r=–0,4), между концентрацией железа и ИЛ-6 (r=–0,6), ИЛ-10 (r=–0,4). Установлена корреляция между ОЖСС и ИЛ-6 (r=–0,3), ИЛ-10 (r=–0,3), ИНФ-γ (r=–0,3), ФНО-α (r=–0,6) и ИЛ-1β (r=–0,4). Для ферритина установлена корреляция с ИЛ-6 и ИЛ-10 (r=0,5), ИНФ-γ (r=0,3), ИЛ-1β (r=0,4), ФНО-α (r=0,7). Доказана взаимосвязь между трансферрином и ИЛ-6, ИЛ-10, ИНФ-γ (r=–0,3), ИЛ-1β (r=–0,4), ФНО-α (r=–0,6).Заключение. Показано влияние цитокинов на развитие анемии у ревматических пациентов посредством их влияния на эритропоэз и обмен железа. Предложен рабочий вариант классификации АХЗ на основании ведущего патогенетического фактора (АХЗ с преимущественным дефицитом железа, АХЗ с нарушениями регуляторных механизмов эритропоэза, АХЗ с недостаточной продукцией эритропоэтина). Purpose. To study the features of secretion of interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin- 1β (IL-1β), interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) in patients with rheumatic diseases and concomitant anemia of chronic diseases (ACD), to study their effect on iron metabolism and erythropoiesis.Materials and methods. We examined 63 rheumatologic patients; 26 men (45 (36–54.9) years old), 37 women (49 (38–60) years old). Patients were divided into two groups: group 1 – 41 patients with anemia, group 2 (control) – 22 patients without anemia. A comparative analysis of hemogram and iron metabolism (iron, ferritin, transferrin, total iron binding capacity – TIBC, transferrin saturation index – TSI), hepcidin, soluble transferrin receptor (sTfR), C-reactive protein (CRP), and cytokines was performed. A correlation analysis between cytokines and hemogram, iron metabolism, hepcidin, sTfR, CRP was performed.Results. In comparison with the 2nd group, patients with anemia have higher concentrations of ferritin (292.7 (146.1–335.1) and 78.5 (36–90.7) mcg/l), CRP (59.4 (10.9–100.2) and 4.6 (1.2–5.8) mg/L),hepcidin (504.9 (23.5–916.5) and 232 (0.0–858) ng/ml), sTfR (8.6 (3.9–7.1) and 2.2 (1.5–3.1) nmol/L).For iron, TIBC, TSI, transferrin, no intergroup differences were found (p>0.05). The concentration of IL-6 in patients with anemia is higher in comparison with the 2nd group (35.8 (2.1–41.1) and 2.7 (1.5–3)). No intergroup differences were found for IL-10, IL-1β, IFN-γ, TNF-α (p>0.05). A correlation was found between the number of red blood cells and IL-6 (r=–0.3), IL-10 (r=–0.4), INF-γ (r=–0.4), TNF-α (r=–0,3). The relationship between the concentration of hemoglobin and IL-6 (r=–0.6), IL-10 (r=–0.4), INF-γ (r=–0.3), TNF-α (r=–0,3), IL-1β (r=–0.4), between the concentration of iron and IL-6 (r=–0.6), IL-10 (r=–0.4) was proven. A correlation was revealed between TIBC and IL-6 (r=–0.3), IL-10 (r=–0.3), INF-γ (r=–0.3), TNF-α (r=–0,6) and IL-1β (r=–0.4). For ferritin, a correlation was revealed with IL-6 and IL-10 (r=0.5), INF-γ (r=0.3), IL-1β (r=0.4), TNF-α (r=0,7). The relationship between transferrin and IL-6, IL-10, INF-γ (r=–0.3), IL-1β (r=–0.4), TNF-α (r=–0.6) was proven.Conclusion. The effect of cytokines on the development of anemia in rheumatic patients through their effect on erythropoiesis and iron metabolism was showed. A working version of the classification of ACD on the base of the leading pathogenetic factor was proposed (ACD with predominant iron deficiency, ACD with impaired regulatory mechanisms of erythropoiesis, ACD with insufficient production of erythropoietin).

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Adamkiewicz, Daniel, Abhishek A. Mangaonkar, James Son, Hongyan Xu, Leigh Wells, Latanya Bowman, and Abdullah Kutlar. "Transfusional Iron Overload in Sickle Cell Patients:Outcomes of Chelation Therapy." Blood 138, Supplement 1 (November 5, 2021): 4177. http://dx.doi.org/10.1182/blood-2021-151743.

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Abstract Iron (Fe) overload is not rare among sickle cell disease (SCD) patients. It results from either chronic transfusions for primary or secondary stroke prevention, or more commonly sporadic, mostly unnecessary transfusions and are associated with significant morbidity, secondary to hepatic, cardiac and renal Fe deposition. Previous studies at our Center showed that 12% of the adult SCD population had Fe overload, and vast majority of these (80%) resulted from episodic transfusions (Son et al, 2013). Subsequent studies showed that the Fe regulatory peptide, hepcidin was appropriately upregulated in SCD subjects with Fe overload, and the plasma levels of the glycoprotein hormone erythroferrone (ERFE) was not as high as that found in patients with transfusion dependent beta thalassemia (TDT) due to the absence of significant ineffective erythropoiesis in SCD (Thawer et al, 2017, Mangaonkar et al, Brit. J. Haematol, 2020). We report on the utilization and outcomes in Fe overloaded SCD patients who were prescribed the oral chelating agent deferasirox. 22 patients were prescribed deferasirox; median age was 38, 12 female 10 male. 21 had Hb SS, and 1 had s-b 0 thalassemia. Deferasirox dose ranged from 720-2500 mg/day (12 to 28 mg/Kg/day). Nonadherence was ascertained by patients' own admission. Figures 1-3 show the pre and post ferritin levels in subjects who were on deferasirox, and in controls; patients who took deferasirox had a more pronounced decrease in their ferritin (p=.004 vs p=.74). Although hepatic MRI for liver iron content (LIC) was not available on all patients, in those who underwent MRI there was a correlation between LIC and serum ferritin obtained at close temporal proximity (Fig. 4). Most common side effects of deferasirox were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), which were seen less commonly with the newer oral formulation (Jadenu). Several conclusions can be drawn from our observation on relatively small number of patients: 1) Deferasirox is effective in decreasing Fe overload as shown by serum ferritin levels 2) Second generation of oral deferasirox is better tolerated, and therefore is associated with improved adherence, 3) Documentation of a decrease in LIC with chelation will be important for the reversal of Fe induced organ damage, and 4) Parallel studies of the levels of Fe regulatory peptides hepcidin and erythroferrone (ERFE) will clarify the effect of chelation therapy on biomarkers of Fe metabolism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Zviahina, O., and S. Shevchuk. "AB0487 HEPSIDINE LEVEL IN PATIENTS WITH ANKYLOSING SPONDYLITIS, RELATIONSHIP WITH HEMOPOESIS AND FERROKINETICS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1270.1–1271. http://dx.doi.org/10.1136/annrheumdis-2021-eular.382.

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Background:Hypoferimia, as a manifestation of systemic inflammation, is quite common in patients with ankylosing spondylitis (AS). Anemic syndrome can be represented by anemia of chronic disease (ACD), iron deficiency anemia (IDA) and their combination. Its frequency of occurrences ranges from 18.5 to 45.8 %. The discovery of the hormone hepcidin in 2001 changed the perception of iron metabolism disorders and demonstrated its association with the inflammatory component. Over the last decade, scientific databases have accumulated a lot of information about hepcidin and its role in the development of anemia and the response to inflammation. However, in the context of the AS, such data are contradictory and therefore need further study.Objectives:To determine the level of hepcidin in patients with ankylosing spondylitis and to assess its relationship with hematopoiesis and ferrokinetics.Methods:The hepcidin levels of 76 patients with ankylosing spondylitis (13 women and 63 men with a mean age of 43.67±0.97 years). The diagnosis of AS was made according to the New York modified criteria of 1984. All patients were divided into three groups: without anemia (n=47), with anemia (n=29) and the control group, representative by age and sex (n=26). According to the percentile analysis, all patients were divided into a group with an optimal <25 ng/ml, extremely high - 25-35 ng/ml and a high level of hepcidin > 35 ng/ml. In addition to hepcidin, hematopoiesis and ferrokinetic parameters were measured in each patient: hemoglobin (Hb), erythrocyte, MCV, serum iron, total serum iron-binding capacity (TIBC), serum ferritin, transferrin saturation (TS). Statistical processing of the obtained results was performed with the use of statistical software package “Microsoft Office Excel 2007”.Results:When conducting a percentile comparison in 95 % of people in the control group, the level of hepcidin was in the range of 17.97-38.8 ng/ml (P5 - P95), and in patients with AS in 95 % - 14.62-87.38 ng/ml. At P95, the level of hepcidin in patients with AS was 2.3 times higher than in P95 control group. Comparing the mean values of hepcidin, a significant difference was found between the group of patients without anemia, where it was 36.08±2.57 ng/ml and the group of patients with anemia, where the level of hepcidin was 51.77±4.62 ng/ml. The lowest level of hepcidin was in patients with IDA (35.8 ±7.50 ng/ml), and the highest (62.78±5.94 ng/ml) - among patients with ACD. The group of patients with ACD and iron deficiency, according to the levels of hepcidin (48.53±9.50 ng/ml) took an intermediate place.In terms of hematopoiesis and ferrokinetics, the level of hemoglobin and erythrocytes did not differ significantly between the groups of optimal, extremely high and high levels of hepcidin. According to the levels of serum iron, TS and ferritin in the group of patients with anemia, a significant association with hepcidin was established (with increasing levels of hepcidin, the values of serum iron, TS and ferritin also increased). In contrast,sTfR levels were the highest in the group with optimal hepcidin levels (6.02±0.71 mg/l) and decreased to 4.88±0.64 mg/l in the group with high hepcidin levels. Such changes in hematopoiesis and ferrokinetics were explained by the accumulation of mostly people with symptoms of ACD in the group with high levels of hepcidin, and the group with optimal levels of hepcidin consisted mainly of patients with IDA.Conclusion:Patients with AS have elevated serum hepcidin levels, it is higher in individuals with anemic syndrome than in patients without anemia and is associated with serum iron, TS and ferritin levels.Disclosure of Interests:None declared.

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Delaney, Katherine, Ronnie Guillet, Chang Cao, Eva Pressman, and Kimberly O'Brien. "Maternal Red Blood Cell Catabolism as a Source of Fetal Iron." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 969. http://dx.doi.org/10.1093/cdn/nzaa054_041.

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Abstract Objectives The developing fetus is reliant on maternal iron (Fe) supply across gestation. Fetal Fe may be obtained from maternal red blood cell (RBC) catabolism, dietary sources or maternal stores. Relative use of these Fe pools has not been explored in humans. The objective of this study was to label the maternal RBC pool in early gestation and evaluate determinants of RBC enrichment across. A second objective was to compare fetal uptake of Fe from RBC catabolism vs recent maternal diet. Methods Fifteen women (age 17–34 y) were dosed with an oral stable ,57Fe isotope during the early second trimester of pregnancy (wk 15 ± 0.7) to label the maternal RBC pool. Enrichment of ,57Fe in maternal RBCs was monitored at regular intervals across pregnancy and in neonatal RBC's at birth. All women ingested an additional stable isotope (,58Fe) in late gestation (wk 34 ± 0.7) to quantify rapid transfer of dietary Fe to the fetus. The net amounts of each isotope in the mother and neonate were calculated using hemoglobin (Hb) concentration, body weight and estimated blood volumes. Hb, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin and erythroferrone (ERFE) were assessed in maternal and cord blood. Results In this population, 25% of women were anemic at delivery (Hb < 11 g/dL), and 36% of the newborns were anemic at birth (wk 39 ± 1.8) (Hb < 13 g/dL). During the third trimester of pregnancy, 25% of women were Fe deficient (SF < 12 mg/L). In the group as a whole, RBC ,57Fe enrichment decreased (b = −0.2, P = 0.06) on average by 2% across the 22 wk study interval (from 13.1% to 9.6%). Of the net amount of ,57Fe released from RBC catabolism, 25.4% [95% CI: 10.0%–64.4%] was transferred to the neonate. Neonatal RBC ,57Fe enrichment was significantly inversely associated with maternal and neonatal SF, which captured 87% of the variance in neonatal RBC ,57Fe enrichment (P < 0.01). Maternal SF was significantly inversely associated with neonatal RBC ,58Fe enrichment from the dietary source in late gestation. Maternal SF captured 55% of the variance in neonatal RBC ,58Fe enrichment (P = 0.01). Conclusions Women with low Fe stores exhibited a greater loss of RBC enrichment across gestation and a higher transfer of Fe from both catabolized RBC's and dietary sources to the fetus. More research on the determinants of placental Fe trafficking of different sources of maternal Fe is needed. Funding Sources Work funded by the NIH/NIDDK.

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Hoeks, Marlijn, Tim Bagguley, Rian Roelofs, Louise De Swart, David Bowen, Argiris Symeonidis, Corine van Marrewijk, et al. "Elevated Labile Plasma Iron (LPI) Levels in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Are Associated with Decreased Quality of Life and Reduced Survival." Blood 132, Supplement 1 (November 29, 2018): 4392. http://dx.doi.org/10.1182/blood-2018-99-118070.

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Abstract Background: Patients with lower-risk MDS (LR-MDS) are prone to iron toxicity due to long-term iron accumulation either caused by RBC transfusions or ineffective erythropoiesis. Nontransferrin bound iron (NTBI), including labile plasma iron (LPI), are toxic iron species that may mediate cellular damage via oxidative stress. The EUMDS registry collects prospective observational data on newly diagnosed LR-MDS patients from 145 centers in 17 countries since 2008. Methods: We analyzed serum from 247 LR-MDS patients collected at six-month intervals for ferritin, transferrin saturation (TSAT), hepcidin-25, soluble transferin receptor (sTfR) and toxic iron species (NTBI and LPI) in order to evaluate temporal changes in iron metabolism, the presence of potentially toxic forms of iron and their impact on survival, and quality of life. In addition, we measured the impact of iron chelation on the iron species levels and its impact on the outcome parameters. Results: The median age was 73 years (range: 37 to 95 years) and 66% were males. WHO2001 MDS-subtypes were RCMD (45%), RARS (22%), RA (18%), RAEB-1 (7%), 5q-syndrome (4%) and RCMD-RS (4%). The IPSS-R categories were: (very) low risk: 66%; intermediate risk: 11%; (very) high risk: 2% and unknown: 20%. The median EQ5D index score was 0.80 (p10 to p90: 0.52 to 1.00). The table shows iron parameters at registration, 1 and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and according to: MDS-RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Mean serum ferritin levels were increased in TD patients, compared to TI patients (Table). Increase of ferritin levels over time was high in both TD groups, but the increase was more pronounced in the RS subgroup. Elevated CRP levels (> 10mg/L) were observed in TD nonRS patients, especially during the first year after diagnosis. Markedly increased mean TSAT levels (>75%) occurred in the subgroup of TD-RS patients throughout the observation period. Hepcidin levels were most markedly elevated in TD nonRS patients at registration and remained elevated during follow-up (Table). Hepcidin levels were low in MDS-RS TI patients at all time points compared to nonRS MDS patients and decreased over time as a result of an increased (ineffective) erythropoiesis (Table). This is supported by the highest levels of STfR also noted in this patient category (data not shown). The highest NTBI and LPI levels were observed in TD-RS patients compared to the other 3 subgroups (Table). Both NTBI and LPI levels had a strong correlation (p <0.001) with TSAT. Elevated LPI levels in combination with high TSAT levels (>80%) occurred almost exclusively in patients with MDS-RS and/or previous transfusions. Both the EQ5D index score and EQ-VAS showed a negative correlation (r) with LPI levels with r = -0.09 (p = 0.028) and r = -0.07 (p=0.046) respectively. This negative effect of elevated LPI levels was most pronounced in the TD RS subgroup with a negative correlation of -0.17 for the EQ5D index score and -0.2 for the VAS score. In total 16 patients received iron chelation during the sample collection period (11 patients deferasirox, 4 patients desferioxamine and 1 patient unknown). LPI levels were normal in 14 out of the 17 samples collected during deferasirox treatment and in 2 out of 5 samples collected during desferoxamine treatment. The Kaplan-Meier curves (Figure) demonstrate the prognostic impact of elevated LPI levels by transfusion status as a time dependent variable; once a subject had an elevated LPI level, they remained in this group. Patients were censored at time of starting iron chelation (16 patients). In a multivariate analysis comparing elevated LPI levels and transfusion dependency to the control group with undetectable LPI and no transfusion showed a significantly decreased survival in all 3 risk groups after adjustment for age at diagnosis, baseline IPSS-R category and ESA treatment status; for details, see supplementary table. Conclusion: This study illustrates labile plasma iron species as a clinically relevant assay for identification of the toxic fraction of overt iron overload and its negative impact on HRQoL and overall survival in transfusion dependent and transfusion independent patients. Table. Table. Disclosures Culligan: Merck Sharp & Dohme (MSD): Honoraria; Abbvie: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Pfizer: Honoraria; Celgene: Other: Support to attend conferences; JAZZ: Honoraria; Daiichi-Sankyo: Other: Support to attend conferences. Garelius:novartis: Honoraria. de Witte:Celgene: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding.

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Capel-Casbas, Maria J., Jose J. Duran, Jorge Diaz, Gerardo Ruiz, Ramon Simon, Francisco Rodriguez, Josep Piqueras, Dolors Pelegri, and Nuria Pujol-Moix. "Latent Iron Metabolism Disturbances in Fertile Women and Its Detection with the Automated Hematology Instrument LH750®." Blood 106, no. 11 (November 16, 2005): 3707. http://dx.doi.org/10.1182/blood.v106.11.3707.3707.

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Abstract Today, one of the healthcare challenges is to detect diseases before they occur so they can be prevented. It is well known the high frequency of iron deficiency (ID) with anemia (IDA) or without anemia, Latent Iron deficiency (LID) in fertile women, due to menstruation and sometimes due to poor diet. Also well known is the relatively high frequency of anemia in chronic diseases (ACD) or the previous clinical stage without anemia that we will call Latent Functional Iron Deficiency (LFID) and hemochromatosis (HEM) in the general population. In this study we were trying to see how frequently iron metabolism disturbances were present: LFID, LID and HEM in fertile, non-anemic women. Patients and Methods: We collected 211 consecutive random women with an age between 12 and 45 years old with a hemoglobin (Hb) between 12 g/dL and 13 g/dL. We have tested all of them for the complete blood count, reticulocyte count and reticulocyte derived parameters (MRV, IRF, etc.), iron profile: serum iron (Fe), Transferrin (Tf), Ferritin (Fer), Transferrin Saturation (TfS%). We analyzed the most common genetic abnormalities related to Hereditary Hemochromatosis in all the women with Ferritin higher than 100 with normal or high iron, and we froze serum for further analysis: Soluble Transferrin receptor (sTfR), Hepcidin, CRP, etc. We then studied what are the best possible parameters and cut-offs to help in the detection of suspect iron metabolism disturbances. RESULTS: we found 31 LID (14.7%), 7 Latent Functional Iron deficiency (LFID)(3.3%), 9 Hemochromatosis (HH) (4.3%) and 164 with normal Iron profiles (77.7%). From the 9 Hemochromatosis the genetic studies we studied, shown three heterozygotic and two homozygotic mutation for the H 63 D and one heterozygotic mutation for the gen C 282 T. We found differences statistically significant to differentiate the abnormalities analyzed as compared to normals (N) with these parameters or combination of them: LID vs N: MCV, MCH, MCHC, RDW. LFID vs N: MCV, MCH, MCHC, RDW and combined parameters, like Maf (Hb x MCV). HH vs N: MCV, MCH, MCHC and MRV. Some of the discriminant functions we found increase significantly the sensitivity and specificity of the parameters used alone Stats Latent Iron deficiency vs Normal Female Stat / Parameter Hb x MCV/100 (R) MCV MCH MCHC RDW Mean LID 10,8 86,8 29,0 33,3 14,5 Mean Normal 11,2 88,9 30,0 33,7 14,1 p Student test (*U Mann) p 0,0209 p 0,05 p 0,0095 p 0,0029 p 0,0054 * Cut off < 10,5 <82,77 <29,5 <33,66 >13,99 Stats Latent Functional Iron Deficiency and HH / Disease LFID LFID LFID HH HH HH Stat / Parameter HbxMCV/100 (R) HbxMCVx(1/RDW)(R) RDW MRVxMCV/100 (R) MCH MRV Mean 10,7 7,2 14,9 104,0 31,3 113,2 Mean Normal 11,2 8,0 14,1 93,0 30,0 104.7 p Student test (*U Mann) p 0,075 NS p 0,036 p 0,0291 * p 0,0069 p 0,0016 p 0,0097 Cut off <10,5 <7,49 >13,61 >92,4 >30,26 >106,4

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Journal articles on the topic 'Hepcidin, ERFE, sTfR, Iron metabolism'

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