Imbalance of Iron Availability and Demand in Patients With Acute and Chronic Heart Failure.

BACKGROUND: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand. METHODS AND RESULTS: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF. CONCLUSIONS: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.

Increased erythroferrone levels in malarial anaemia.

We assessed the diagnostic potential of erythroferrone as a biomarker for iron homeostasis comparing iron deficiency cases with anaemia of inflammation and controls. The dysregulation of the hepcidin axis was observed by Latour et al. in a mouse model of malarial anaemia induced by prolonged Plasmodium infection leading to increased erythroferrone concentrations. In line with that, we found significantly higher erythroferrone levels in cases with malaria and anaemia in an African population, compared to asymptomatic controls. Therefore, our findings extend the previous ones of the mouse model, suggesting also a dysregulation of the hepcidin axis in humans, which should be further corroborated in prospective studies and may lay the basis for the development of improved treatment strategies according to ERFE concentrations in such patients.

Real-world experience of intravenous iron sucrose supplementation and dynamics of soluble transferrin receptor and hepcidin in a Spanish cohort of absolute iron deficient patients.

The study evaluated the safety and effectiveness of the generic intravenous (IV) iron treatment (Feriv®), in a Spanish cohort with absolute iron deficiency (ID) (serum ferritin <50 ng/ml, with or without anaemia) (n = 122; 91% women; median age of 44 years [IQR: 33.7-54]). Iron-related biomarkers were measured before treatment (baseline), 2 weeks after beginning the protocol (intermediate control, IC) and between 7 and 10 days after treatment completion (final time-point). Primary efficacy endpoints were ferritin levels ≥ 50 ng/ml, anaemia restoration or an increase in haemoglobin (Hb) of at least one point in patients without baseline anaemia. After treatment, iron-related biomarkers improved, including ferritin, Hb, sideremia, transferrin, transferrin saturation index, soluble transferrin receptor (sTfR), and hepcidin. Baseline ferritin concentration (13.5 ng/ml [IQR: 8-24.2]) increased at the IC and continued rising at the final time-point, reaching a median ferritin of 222 ng/ml and 97.3% of patients ≥ 50 ng/ml. At the final time-point, anaemia prevalence decreased from 26.2% to 5%, while the 34.1% without baseline anaemia showed an increase in Hb of at least one point. Headache was the only drug-adverse event recorded in 2.3% of patients. At a late time-point (27.5 median weeks after ending therapy [IQR: 22-40]), evaluated in a subgroup of 66 patients, 18% had ferritin levels < 50 ng/ml. Multivariate analysis showed that low baseline ferritin and high sTfR/hepcidin ratio tended to be independently associated with ID recurrence. Feriv® is a safe, effective first-line treatment for absolute ID, with improvement of serum ferritin and Hb. ID recurrence was associated with the baseline degree of iron stores depletion, indicated by serum ferritin, and sTfR/hepcidin ratio.

CORRELATION BETWEEN HEPCIDIN AND PROCALCITONIN AND THEIR DIAGNOSTIC ROLE IN PATIENTS WITH COVID-19.

OBJECTIVE: The aim: The purpose of this study is to find out the association between procalcitonin and hepcidin in patients with COVID-19, in addition to their role as diagnostic markers. PATIENTS AND METHODS: Materials and methods: A total of 75 patients infected with coronavirus were included in the current study, their age is ranging between 20 to 78 years. Those patients was hospitalized in Al-Sadr Teaching Hospital in Najaf, in Iraq. This study also included 50 healthy subjects which are volunteers and considered as a (control group). Biomarker (procalcitonin and hepcidin) measurements were achieved by electrochemiluminescent immunoassay (ECLIA) in the Elecsys immunoassay system. RESULTS: Results: The present study showed a significant increase the serum cencentration of hepcidin and procalcitonin in patients with COVID-19 as compared tohealthy subjects. There was a highly significant increasing(p < 0.01) in hepcidin and PCT level in patients with severe infection comparing to other catgaries.The current study also revealed that the sensitivity values of the markers were: 0.88%, 0.85 for procalcitonin and hepcidin respectively, which indicate high diagnostic power. CONCLUSION: Conclusions: Serum levels of hepcidin and procalcitonin are increased as inflammatory markers in COVID-19 patients with relatively high sensitivity. It seems that these imflammatory markers obviously elevate in the severe cases COVID-19dusease.

Effect of ultramarathon running on iron metabolism.

BACKGROUND: Iron is a vital trace element for energy production and oxygen transportation; importantly, it is essential to athletic performance. Maintaining iron balance is tightly controlled at systemic and cellular levels. This study aimed to determine serum iron tests, hepcidin levels, and cellular iron import and export activities in peripheral blood mononuclear cells (PBMCs) in ultramarathon runners to elucidate the association of systemic inflammation response and iron metabolism. METHODS: Sixteen amateur runners were enrolled. Blood samples were taken 1 week before, immediately, and 24 h after the run. Plasma hepcidin levels were measured by enzyme-linked immunosorbent assay. The expression levels of divalent metal iron transporter 1 (DMT1), ZRT/IRT-like protein 14 (ZIP14), transferrin receptor 1 (TfR1), and ferroportin (FPN) in PBMCs were measured using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Serum iron concentrations and transferrin saturation significantly decreased immediately after the race and dramatically recovered 24 h post-race. Serum ferritin levels had a statistically significant rise immediately after the race and remained high 24 h after the completion of the race. Ultramarathons were associated with increased plasma interleukin-6 concentrations corresponding to the state of severe systemic inflammation and therefore boosted plasma hepcidin levels. The expression levels of DMT1 and FPN mRNA were markedly decreased immediately and 24 h after the race. The ZIP14 and TfR1 mRNA expression in PBMCs significantly decreased immediately after the race and returned to the baseline level at 24 h post-race. Positive significant correlations were observed between plasma hepcidin and ferritin levels. CONCLUSION: Iron homeostasis and systemic inflammatory response are closely interconnected. Cellular iron import and export mRNA activities in PBMCs were acutely inhibited during an ultramarathon.

The Key Role of Hepcidin-25 in Anemia in Multiple Myeloma Patients with Renal Impairment.

Background and objectives: Anemia is common in multiple myeloma (MM) and is caused by a complex pathomechanism, including impaired iron homeostasis. Our aim is to evaluate the biomarkers of iron turnover: serum soluble transferrin receptor (sTfR) and hepcidin-25 in patients at various stages of MM in relation with markers of anemia, iron status, inflammation, renal impairment and burden of the disease and as predictors of mortality. Materials and methods: Seventy-three MM patients (six with smoldering and 67 with symptomatic disease) were recruited and observed for up to 27 months. Control group included 21 healthy individuals. Serum sTfR and hepcidin were measured with immunoenzymatic assays. Results: MM patients with and without anemia had higher sTFR compared to controls, while only anemic patients had higher hepcidin-25. Both hepcidin-25 and sTfR were higher in anemic than non-anemic patients. Higher hepcidin-25 (but not sTfR) was associated with increasing MM advancement (from smoldering to International Staging System stage III disease) and with poor response to MM treatment, which was accompanied by lower blood hemoglobin and increased anisocytosis. Neither serum hepcidin-25 nor sTfR were correlated with markers of renal impairment. Hepcidin-25 predicted blood hemoglobin in MM patients independently of other predictors, including markers of renal impairment, inflammation and MM burden. Moreover, both blood hemoglobin and serum hepcidin-25 were independently associated with patients' 2-year survival. Conclusions: Our results suggest that hepcidin-25 is involved in anemia in MM and its concentrations are not affected by kidney impairment. Moreover, serum hepcidin-25 may be an early predictor of survival in this disease, independent of hemoglobin concentration. It should be further evaluated whether including hepcidin improves the early diagnosis of anemia in MM.

Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia.

Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.

Iron supplementation ameliorates aloin-induced iron deficiency anemia in rats.

Aloin, an anthraquinone glycoside, is one of other C-glycosides found in the leaf exudate of Aloe plant. Aloin possesses several biologic activities, including antitumor activity in vitro and in vivo. However, aloin treatment has shown iron deficiency anemia and erythropoiesis in vivo. The present study was undertaken to verify if iron supplementation could alleviate these perturbations, compared to doxorubicin, an anthracycline analog. Oral iron supplementation (20.56 mg elemental Fe/kg bw) to aloin-treated rats normalized red blood corpuscles count, hemoglobin concentration, and serum levels of total iron binding capacity and saturated transferrin, as well as hepatic iron content, hepcidin level, and mRNA expression of ferritin heavy chain (Ferr-H) and transferrin receptor-1 (TfR-1) genes. Although, serum hyperferremia, and leukocytosis were maintained, yet the spleen iron overload was substantially modulated. However, combined aloin and iron treatment increased iron storage levels in the heart and bone marrow, compared to aloin treatment per se. On other hand, oral iron supplementation to rats treated with doxorubicin (15 mg/kg bw) lessened the increase in the spleen iron content concomitantly with hepatic hepcidin level, rebound hepatic iron content to normal level, and by contrast augmented serum levels of iron and transferrin saturation. Also, activated Ferr-H mRNA expression and repressed TfR-1 mRNA expression were recorded, compared to doxorubicin treatment per se. Histopathological examination of the major body iron stores in rats supplemented with iron along with aloin or doxorubicin showed an increase in extramedullary hematopoiesis. In conclusion, iron supplementation restores the disturbances in iron homeostasis and erythropoiesis induced by aloin treatment.

Etiology of Anemia in Older Mexican Adults: The Role of Hepcidin, Vitamin A and Vitamin D.

Anemia in older adults is a growing public health issue in Mexico; however, its etiology remains largely unknown. Vitamin A deficiency (VAD) and vitamin D deficiency (VDD) have been implicated in the development of anemia, though by different mechanisms. The aim of this study is to analyze the etiology of anemia and anemia-related factors in older Mexican adults. This is a cross-sectional study of 803 older adults from the southern region of Mexico in 2015. The anemia etiologies analyzed were chronic kidney disease (CKD), nutritional deficiencies (ND), anemia of inflammation (AI), anemia of multiple causes (AMC) and unexplained anemia (UEA). VAD was considered to be s-retinol ≤ 20 µg/dL, and VDD if 25(OH)D < 50 nmol/L. IL-6 and hepcidin were also measured. Multinomial regression models were generated and adjusted for confounders. Anemia was present in 35.7% of OA, independent of sex. UEA, CKD, AI and ND were confirmed in 45%, 29.3%, 14.6% and 7% of older adults with anemia, respectively. Hepcidin and log IL-6 were associated with AI (p < 0.05) and CKD (p < 0.001). VAD was associated with AI (p < 0.001), and VDD with ND and AMC (p < 0.05). Log-IL6 was associated with UEA (p < 0.001). In conclusion, anemia in older adults has an inflammatory component. VAD was associated to AI and VDD with ND and AMC.

Effect of ß-hydroxybutyrate monoester on markers of iron metabolism in new-onset prediabetes: findings from a randomised placebo-controlled trial.

Background: People with prediabetes often have altered iron metabolism and may benefit from mild exogenous ketosis, which can now be successfully achieved thanks to recent developments in chemistry of food components. Objective: The objective was to investigate the effect of acute exogenous ketone monoester (ß-hydroxybutyrate) on plasma levels of markers of iron metabolism in people with prediabetes. Methods: Eighteen participants with new-onset prediabetes after acute pancreatitis aged 18 years or above took part in randomised controlled cross-over trial in Auckland, New Zealand. After an overnight fast, participants consumed the exogenous ketone supplement or placebo. Blood samples were collected in the fasted state (0 minutes) and then serially every 30 minutes for 150 minutes. Both participants and study personnel were blinded to the intervention/placebo allocation. Repeated measures analysis of variance was performed using total area under the curve to determine the change in hepcidin and ferritin over time after consumption of the exogenous ketone supplement and placebo. Results: Consumption of the exogenous ketone supplement significantly elevated blood levels of ß-hydroxybutyrate from 0.20 mmol L-1 at baseline to 3.50 mmol L-1 at 30 minutes (p < 0.05) and remained significantly elevated for the duration of the trial. The total area under the curve of hepcidin was 340.5 ± 121.1 ng mL-1 after the exogenous ketone supplementation as compared with 343.2 ± 119.6 ng mL-1 min-1 after the use of placebo (p = 0.91). The total area under the curve of ferritin was 786.7 ± 129.1 ng mL-1 min-1 after the exogenous ketone supplementation as compared with 776.9 ± 131.4 ng mL-1 min-1 after the use of placebo (p = 0.10). Conclusion: Acute supplementation of ß-hydroxybutyrate did not significantly affect the circulating levels of hepcidin or ferritin in people with prediabetes. Long-term effects of ß-hydroxybutyrate warrant investigations in the future.

Increased serum catalytic iron may mediate tissue injury and death in patients with COVID-19.

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.

Associations of Food and Nutrient Intake with Serum Hepcidin and the Risk of Gestational Iron-Deficiency Anemia among Pregnant Women: A Population-Based Study.

Hepcidin is a regulator of iron metabolism. Diet affects the body's iron status, but how it influences hepcidin concentrations and the risk of gestational iron-deficiency anemia (IDA) remains unclear. We investigated relationships of food and nutrient intake with serum hepcidin levels in relation to the iron status at a population scale. A retrospective cross-sectional study was conducted based on data obtained from the Nationwide Nutrition and Health Survey in pregnant women, Taiwan (2017~2020). In total, 1430 pregnant women aged 20~45 years with a singleton pregnancy were included. Data from blood biochemistry, 24-h dietary recall, and a food frequency questionnaire were collected during a prenatal checkup. Adjusted multivariate linear and logistic regression analyses were employed to measure the beta coefficient (ß) and 95% confidence interval (CI) of serum hepcidin and the odds ratio (OR) of IDA. In IDA women, serum hepcidin levels were positively correlated with the intake frequency of Chinese dim sum and related foods (ß = 0.037 (95% CI = 0.015~0.058), p = 0.001) and dark leafy vegetables (ß = 0.013 (0.001~0.025), p = 0.040), but they were negatively correlated with noodles and related products (ß = -0.022 (-0.043~-0.001), p = 0.038). An adjusted multivariate logistic regression analysis showed that dietary protein [OR: 0.990 (0.981~1.000), p = 0.041], total fiber [OR: 0.975 (0.953~0.998), p = 0.031], and rice/rice porridge [OR: 1.007 (1.00~1.014), p = 0.041] predicted gestational IDA. Total carbohydrates [OR: 1.003 (1.000~1.006), p = 0.036], proteins [OR: 0.992 (0.985~0.999), p = 0.028], gourds/shoots/root vegetables [OR: 1.007 (0.092~1.010), p = 0.005], and to a lesser extent, savory and sweet glutinous rice products [OR: 0.069 (0.937~1.002), p = 0.067] and dark leafy vegetables [OR: 1.005 (0.999~1.011), p = 0.088] predicted IDA. The risk of IDA due to vegetable consumption decreased with an increasing vitamin C intake (p for trend = 0.024). Carbohydrates and vegetables may affect the gestational iron status through influencing hepcidin levels. Vitamin C may lower the risk of gestational IDA due to high vegetable consumption.

Comparative Evaluation of Sucrosomial Iron and Iron Oxide Nanoparticles as Oral Supplements in Iron Deficiency Anemia in Piglets.

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.

Does the Combined Effect of Resistance Training with EPO and Iron Sulfate Improve Iron Metabolism in Older Individuals with End-Stage Renal Disease?

We sought to investigate the effects of resistance training (RT) combined with erythropoietin (EPO) and iron sulfate on the hemoglobin, hepcidin, ferritin, iron status, and inflammatory profile in older individuals with end-stage renal disease (ESRD). ESRD patients (n: 157; age: 66.8 ± 3.6; body mass: 73 ± 15; body mass index: 27 ± 3), were assigned to control (CTL; n: 76) and exercise groups (RT; n: 81). The CTL group was divided according to the iron treatment received: without iron treatment (CTL-none; n = 19), treated only with iron sulfate or EPO (CTL-EPO or IRON; n = 19), and treated with both iron sulfate and EPO (CTL-EPO + IRON; n = 76). The RT group followed the same pattern: (RT-none; n = 20), (RT-EPO or IRON; n = 18), and (RT-EPO + IRON; n = 86). RT consisted of 24 weeks/3 days per week at moderate intensity of full-body resistance exercises prior to the hemodialysis section. The RT group, regardless of the iron treatment, improved iron metabolism in older individuals with ESRD. These results provide some clues on the effects of RT and its combination with EPO and iron sulfate in this population, highlighting RT as an important coadjutant in ESRD-iron deficiency.

Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study.

Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment.

Differentiating iron-loading anemias using a newly developed and analytically validated ELISA for human serum erythroferrone.

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 ß-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 ß-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.

Erythroferrone and hepcidin as mediators between erythropoiesis and iron metabolism during allogeneic hematopoietic stem cell transplant.

Hematopoietic cell transplantation (HCT) brings important alterations in erythropoiesis and iron metabolism. Hepcidin, which regulates iron metabolism, increases in iron overload or inflammation and decreases with iron deficiency or activated erythropoiesis. Erythroferrone (ERFE) is the erythroid regulator of hepcidin. We investigated erythropoiesis and iron metabolism after allogeneic HCT in 70 patients randomized between erythropoietin (EPO) treatment or no EPO, by serially measuring hepcidin, ERFE, CRP (inflammation), soluble transferrin receptor (sTfR, erythropoiesis), serum iron and transferrin saturation (Tsat; iron for erythropoiesis) and ferritin (iron stores). We identified biological and clinical factors associated with serum hepcidin and ERFE levels. Serum ERFE correlated overall with sTfR and reticulocytes and inversely with hepcidin. Erythroferrone paralleled sTfR levels, dropping during conditioning and recovering with engraftment. Inversely, hepcidin peaked after conditioning and decreased during engraftment. Erythroferrone and hepcidin were not significantly different with or without EPO. Multivariate analyses showed that the major determinant of ERFE was erythropoiesis (sTfR, reticulocytes or serum Epo). Pretransplant hepcidin was associated with previous RBC transfusions and ferritin. After transplantation, the major determinants of hepcidin were iron status (ferritin at all time points and Tsat at day 56) and erythropoiesis (sTfR or reticulocytes or ERFE), while the impact of inflammation was less clear and clinical parameters had no detectable influence. Hepcidin remained significantly higher in patients with high compared to low pretransplant ferritin. After allogeneic HCT with or without EPO therapy, significant alterations of hepcidin occur between pretransplant and day 180, in correlation with iron status and inversely with erythroid ERFE.

Effect of increased blood flow rate on renal anemia and hepcidin concentration in hemodialysis patients.

BACKGROUND: Increasing the blood flow rate (BFR) is a useful method for increasing Kt/V and the clearance for low molecular solutes. Hemodialysis patients are often anemic due to hypoerythropoiesis and their chronic inflammatory state. Hepcidin, a hormone that regulates iron homeostasis, is considered as an indicator of iron deficiency in patients with end-stage renal disease. This study aimed to investigate the effects of an increased BFR during hemodialysis on serum hepcidin levels and anemia. METHODS: Between April 2014 and March 2016, 22 chronic dialysis patients (11 men [50.0 %]; mean [± standard deviation] age, 72 ± 12 years) undergoing maintenance hemodialysis treatment, thrice weekly, were enrolled and followed prospectively for 24 months. In April 2014, the BFR was 200 mL/min; in April 2015 this was increased to 400 mL/min, which was within acceptable limits. The dialysate flow rate remained stable at; 500mlL/min. Blood samples were collected in March 2015 and 2016. The primary endpoint was the comparison of the amounts of erythropoiesis-stimulating agent (ESA) required. RESULTS: The increased BFR increased the Kt/V and contributed to significantly decreased urea nitrogen (UN) (p = 0.015) and creatinine (Cr) (p = 0.005) levels. The dialysis efficiency was improved by increasing the BFR. Ferritin (p = 0.038), hepcidin (p = 0.041) and high-sensitivity interleukin-6 (p = 0.038) levels were also significantly reduced. The ESA administered was significantly reduced (p = 0.004) and the Erythropoietin Resistant Index (ERI) significantly improved (p = 0.031). The reduction rates in UN (p < 0.001), Cr (p < 0.001), and beta-2 microglobulin (p = 0.017) levels were significantly greater post the BFR increase compared to those prior to the BFR increase. However, hepcidin was not affected by the BFR change. CONCLUSIONS: Increasing BFR was associated with hemodialysis efficiency, and led to reduce inflammatory cytokine interleukin-6, but did not contribute to reduce C-reactive protein. This reduced hepcidin levels, ESA dosage and ERI. Hepcidin levels were significantly correlated with ferritin levels, and it remains to be seen whether reducing hepcidin leads to improve ESA and iron availability during anemia management.

Risk of Iron Overload in Obesity and Implications in Metabolic Health.

Excessive adiposity is associated with several metabolic perturbations including disturbances in iron homeostasis. Increased systemic inflammation in obesity stimulates expression of the iron regulatory hormone hepcidin, which can result in a maldistribution of bodily iron, which may be implicated in metabolic dysfunction. This study aimed to investigate the effect of adiposity and any associated inflammation on iron homeostasis and the potential implications of dysregulated iron metabolism on metabolic health. Analyses are based on a subsample from the cross-sectional Irish National Adult Nutrition Survey (2008-2010) (n = 1120). Ferritin status and risk of iron overload were determined based on established WHO ferritin ranges. Participants were classed as having a healthy % body fat or as having overfat or obesity based on age- and gender-specific % body fat ranges as determined by bioelectrical impedance. Biomarkers of iron status were examined in association with measures of body composition, serum adipocytokines and markers of metabolic health. Excessive % body fat was significantly associated with increased serum hepcidin and ferritin and an increased prevalence of severe risk of iron overload amongst males independent of dietary iron intake. Elevated serum ferritin displayed significant positive associations with serum triglycerides and markers of glucose metabolism, with an increased but non-significant presentation of metabolic risk factors amongst participants with overfat and obesity at severe risk of iron overload. Increased adiposity is associated with dysregulations in iron homeostasis, presenting as increased serum hepcidin, elevated serum ferritin and an increased risk of iron overload, with potential implications in impairments in metabolic health.

Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.

Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.