Insights into Iron Metabolism Parameters in Ischemic Stroke: A Single-Center Prospective Cohort Study.

The hemojuvelin-hepcidin regulatory axis may play a key role in the iron metabolism both systemically and locally. There is a pressing need to evaluate this tightly regulated network of iron parameters and their potential impact on the development of ischemic stroke (IS). We aimed to assess iron metabolism biomarkers in patients after IS, evaluating changes over time and considering their clinical features. We studied 45 patients diagnosed with IS. We assessed major iron metabolism parameters, such as hepcidin, soluble hemojuvelin (sHJV), soluble transferrin receptor (sTfR), and ferritin, using immunoenzymathic methods at two time points: on admission and on the 7th day post IS. We found increased ferritin levels on the 7th day post IS compared to admission, and this was observed in the entire study group (p = 0.03) and in the subgroup treated with thrombolysis (p = 0.02). The hepcidin levels, on the other hand, showed a significant decrease on the 7th day, though this difference was only evident in the entire study group (p = 0.04). We also discovered significantly elevated sHJV levels in patients with PACI stroke compared to other stroke locations, both on admission and on the 7th day post IS (p < 0.05). Significantly higher sHJV levels were observed in patients treated with thrombolysis compared to those receiving conventional treatment, regardless of the time point (p < 0.0001 and p = 0.0002, respectively). Our study revealed changes in the iron metabolism parameters during stroke. The patients with anterior cerebral infarction and those treated with thrombolysis presented significantly elevated sHJV levels.

Association between overweight/obesity and iron deficiency anaemia among women of reproductive age: a systematic review.

OBJECTIVE: Numerous studies have examined the relationship between overweight/obesity and iron deficiency anaemia (IDA) across diverse population groups, but a definitive link has not been clearly determined. This systematic review examined the association between overweight/obesity and IDA in women of reproductive age (WRA). DESIGN: The initial search was performed in the CINAHL, Embase, MEDLINE, SCOPUS and Web of Science databases. The studies included should report at least one Fe status with/without an inflammatory marker, using the BMI to define overweight/obesity. Only baseline data were extracted for longitudinal studies. SETTING: Global. PARTICIPANT: Pregnant or non-pregnant women aged 18-50 years. RESULTS: In total, twenty-seven papers were included (twelve addressing pregnant women and fifteen addressing non-pregnant women). Overall, most of the studies reported no association between overweight/obesity and Hb concentration. However, a positive association was reported more frequently in pregnant women. The association between overweight/obesity and serum ferritin concentrations was mixed. Most of the studies on non-pregnant women reported a positive association. Only a few studies measured hepcidin and inflammatory markers, and the majority revealed an increased level among overweight/obese WRA. Among pregnant women, overweight/obesity was positively associated with anaemia and IDA but negatively associated with iron deficiency (ID). Meanwhile, overweight/obese non-pregnant women were positively associated with anaemia, ID and IDA. CONCLUSIONS: Overweight/obesity was associated with a decreased prevalence of anaemia and IDA but an increased prevalence of ID, while its association with several Fe markers was inconclusive. Further studies integrating the assessment of various Fe markers, inflammatory markers and hepcidin are needed.

Intact FGF23 and Markers of Iron Homeostasis, Inflammation, and Bone Mineral Metabolism in Acute Pediatric Infections.

We intend to evaluate the association of intact Fibroblast Growth Factor 23 (i-FGF23), a phosphaturic hormone that contributes to anemia of inflammation, with markers of iron homeostasis, inflammation, and bone mineral metabolism in acute pediatric infections. Seventy-nine children, aged 1 month-13 years, out of which forty-two were males and thirty-seven females, participated in this study. Children with diseases and nutrient deficiencies causing anemia were excluded. Twenty-six patients had bacterial infections, twenty-six had viral infections, and twenty-seven children served as healthy controls. Complete blood count, markers of inflammation, iron and mineral metabolism, serum hepcidin, and i-FGF23 were compared between the groups. Thirty-nine percent of patients with bacterial infection and twelve percent of patients with viral infection presented characteristics of anemia of inflammation (p < 0.001). Ninety-two percent of patients with bacterial infection and eighty-one percent of patients with viral infection had functional iron deficiency (p < 0.001). Hepcidin was significantly positively correlated with the duration of fever, markers of inflammation, and negatively with iron, mineral metabolism parameters, and i-FGF23. i-FGF23 was positively correlated with iron metabolism parameters and negatively with the duration of fever, markers of inflammation, and hepcidin. Hepcidin levels increase, whereas i-FGF23 levels decrease in acute pediatric infections. Further research is required to understand the role of FGF23 in the hepcidin-ferroportin axis and for hepcidin in the diagnosis of bacterial infections and mineral metabolism.

Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis.

Leukemia inhibitory factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in ferroptosis in osteoblasts. We observed that the Lif-deficient (Lif-/-) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from Lif-/- mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of Lif-/- mice. Besides, Lif-/- mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of Lif-/- mice. It also holds true in the AML-12 hepatocyte cell line after Lif-knockdown. Immunohistochemistry and RT-PCR revealed elevated ferroportin (FPN) in duodenal cells of Lif-/- mice. Lif-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in ferroptosis of osteoblasts in Lif-/- mice. Whole-transcriptome sequencing showed gene expression changes after Lif-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that Lif-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to ferroptosis.

Iron Homeostasis-Related Parameters and Hepcidin/Ferritin Ratio: Emerging Sex-Specific Predictive Markers for Metabolic Syndrome.

Metabolic syndrome (MetS) is a worldwide public health challenge. Accumulating evidence implicates elevated serum ferritin and disruptions in iron metabolism as potential elements linked to an increased risk of MetS. This study investigates the relationship between iron homeostasis-including hepcidin levels, serum iron concentration, unsaturated iron-binding capacity (UIBC), and the hepcidin/ferritin (H/F) ratio-and MetS. In this descriptive cross-sectional study, 209 participants aged 24-70 were categorized into two groups: 103 with MetS and 106 without MetS. All participants underwent medical assessment, including anthropometric measures, indices of glycemic control, lipid profiles, and iron-related parameters. Participants were further stratified by the Homeostasis Model Assessment-Insulin Resistance index into three subgroups: insulin-sensitive (IS) (<1.9), early insulin resistance (EIR) (>1.9 to <2.9), and significant insulin resistance (SIR) (>2.9). Notable increments in serum ferritin and hepcidin were observed in the SIR group relative to the IS and EIR groups, with a significant association between metabolic parameters. The UIBC and serum ferritin emerged as significant predictors of MetS, particularly in men, with an area under the curve (AUC) of 0.753 and 0.792, respectively (p ≤ 0.001). In contrast, hepcidin was notably correlated with MetS in women, with an AUC of 0.655 (p = 0.007). The H/F ratio showed superior predictive capability for MetS across both sexes (at cutoff level = 0.67). Among women, this ratio had an AUC of 0.639 (p = 0.015), and for men, it had an AUC of 0.792 (p < 0.001). Hypertension proved an independent risk factor for MetS, affirming its role in metabolic dysregulation. The findings highlight a significant interconnection between iron homeostasis parameters and MetS, with sex-specific variations underscoring the importance of personalized diagnostic criteria. The crucial role of the H/F ratio and the UIBC as emerging predictive markers for MetS indicates their potential utility in identifying at-risk individuals. Further longitudinal research is essential to establish causality and explore the interplay between these biomarkers and MetS.

Vamifeport: Monography of the First Oral Ferroportin Inhibitor.

Over the last few years, several mechanisms that are involved in congenital diseases characterized by ineffective erythropoiesis have been described. Therefore, multiple new target drugs are being developed in preclinical models against the main regulators of normal erythropoiesis. Above all, the key mechanism that regulates systemic iron homeostasis, represented by the hepcidin-ferroportin axis, is considered to be the target for new therapies. The main hypothesis is that iron restriction, through blocking ferroportin (the unique iron transporter in mammals) in such diseases, ameliorates erythropoiesis. The action of vamifeport is different from the currently approved drugs in this setting since it acts straight on the ferroportin-hepcidin axis. The data presented in the sickle cell disease (SCD) Townes mouse model showed a preclinical proof-of-concept for the efficacy of oral ferroportin inhibitor. Vamifeport reduced hemoglobin concentration in red blood cells (RBCs) and diminished intravascular hemolysis and inflammation, improving hemodynamics and preventing vascular occlusive crises. On this basis, clinical trials were commenced in patients with SCD, non-transfusion-dependent (NTD) thalassemia and transfusion-dependent (TD) thalassemia. Preliminary data in NTD thalassemic patients also confirm the safety and efficacy in decreasing iron level. In conclusion, vamifeport represents a new option in the panorama of drugs targeting the hepcidin-ferroportin axis, but its efficacy is still under investigation as a single agent.

Anemia of inflammation and iron metabolism in chronic diseases.

Anemia of Inflammation begins with the activation of the immune system and the subsequent release of cytokines that lead to an elevation of hepcidin, responsible for hypoferremia, and a suppression of erythropoiesis due to lack of iron. The anemia is usually mild/moderate, normocytic/normochromic and is the most prevalent, after iron deficiency anemia, and is the most common in patients with chronic diseases, in the elderly and in hospitalized patients. Anemia can influence the patient's quality of life and have a negative impact on survival. Treatment should be aimed at improving the underlying disease and correcting the anemia. Intravenous iron, erythropoietin and prolyl hydroxylase inhibitors are the current basis of treatment, but future therapy is directed against hepcidin, which is ultimately responsible for anemia.

P. Gingivalis induce macrophage polarization by regulating hepcidin expression in chronic apical periodontitis.

INTRODUCTION: Hepcidin, a central regulatory molecule of iron metabolism, is upregulated through the IL-6/STAT3 signaling pathway in inflammatory and infectious states, contributing to the pathogenesis of various diseases. In chronic apical periodontitis (CAP), Porphyromonas gingivalis (P. gingivalis) and its lipopolysaccharides (LPS) activate various immune responses in vivo, contributing to disease progression. This study evaluated the role and mechanism of hepcidin in P. gingivalis-induced bone tissue damage in CAP, focusing on its promotion of macrophage M1 polarization via the IL-6/STAT3 signaling pathway. METHODS: We analyzed a GSE77459 dataset from the GEO database, containing data from inflammatory and normal dental pulp tissues. RT-qPCR and immunofluorescence staining were used to detect the expression of hepcidin in human CAP tissues and its relationship with macrophages. Mouse bone marrow derived macrophages (BMDMs) were cultured in vitro and stimulated with P. gingivalis LPS. The effects of Stattic on macrophage hepcidin expression, IL-6 expression, STAT3 phosphorylation, and macrophage polarization were detected by ELISA, western blotting, RT-qPCR, and flow cytometry, respectively. RESULTS: Hepcidin expression in human inflammatory dental pulp tissues was upregulated via the IL-6/STAT3 pathway and correlated with macrophage polarization. Hepcidin-encoding genes were found to be highly expressed and primarily associated with M1 macrophages in CAP tissues. In vitro experiments revealed that P. gingivalis LPS stimulation induced macrophages to express hepcidin through the IL-6/STAT3 pathway and polarize to M1. Additionally, the IL-6/STAT3 pathway inhibitor Stattic suppressed these changes. CONCLUSIONS: Our study demonstrates that in CAP, macrophages highly express hepcidin, which subsequently alters macrophage metabolism, regulates M1 polarization, and leads to bone tissue destruction.

Vitamin C-Dependent Uptake of Non-Heme Iron by Enterocytes, Its Impact on Erythropoiesis and Redox Capacity of Human Erythrocytes.

In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H+ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H+-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H+-coupled uptake of non-heme Fe2+-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis.

Evaluation of hepcidin-25/erythroferrone ratio as a potential biomarker for iron utility and erythropoiesis responsiveness to erythropoiesis-stimulating therapy in comparison to immature erythrocyte/reticulocyte parameters in hemodialysis patients.

BACKGROUND: Anemia-associated chronic kidney disease increases in more advanced stages with a subsequent acceleration in renal impairment progressing to end-stage renal disease. Although hepcidin and erythroferrone have been described as novel biomarkers of iron metabolism, there is still an area of ambiguity regarding iron utility in anemia-associated end-stage renal disease. OBJECTIVES: This study aims to determine the correlations between erythropoietin, erythroferrone, and hepcidin-25 in hemodialysis, and to evaluate the clinical utility of the hepcidin-25/erythroferrone ratio as a biomarker of erythropoiesis-stimulating agent effectiveness compared to reticulocyte maturation parameters. METHODS: Serum erythropoietin, erythroferrone, and hepcidin-25 levels in 35 dialysis-dependent patients on a maintenance dose of a short-acting erythropoiesis-stimulating agent were consequently assessed on Days 0, 5, and 7. The erythropoiesis activity was monitored by measuring the increment in reticulocyte maturation parameters. RESULTS: Though the effectiveness of erythropoiesis in these patients was not associated with the hepcidin-25/erythroferrone ratio, it was lower among those with effective erythropoiesis than those with ineffective erythropoiesis. The effective group showed a statistically significant increase in reticulocyte maturation parameters compared to the ineffective group. CONCLUSIONS: The findings show the pathogenesis of iron homeostasis in hemodialysis, the validity of hepcidin-25/erythroferrone ratio as a biomarker of erythropoiesis-stimulating agent effectiveness, and the advantageous monitoring of reticulocyte maturation measures to improve management of anemia-associated chronic kidney disease.

The evolving landscape of polycythemia vera therapies.

INTRODUCTION: The treatment landscape of polycythemia vera (PV) has seen major advancements within the last decade including approval of ruxolitinib in the second line setting after hydroxyurea, ropegylated interferon-α2b, and advanced clinical development of a novel class of agents called hepcidin mimetics. AREAS COVERED: We provide a comprehensive review of the evidence discussing the risk stratification, treatment indications, role and limitations of phlebotomy only approach and pivotal trials covering nuances related to the use of interferon-α (IFN-α), ruxolitinib, hepcidin mimetics, and upcoming investigational agents including HDAC and LSD1 inhibitors. EXPERT OPINION: The research paradigm in PV is slowly shifting from the sole focus on hematocrit control and moving toward disease modification. The discovery of hepcidin mimetics has come as a breakthrough in restoring iron homeostasis, achieving phlebotomy-independence and may lead to improved thrombosis-free survival with stricter hematocrit control. On the other hand, emerging data with IFN- α and ruxolitinib as well as combination of the two agents suggests the potential for achieving molecular remission in a subset of PV patients and long-term follow-up is awaited to validate the correlation of molecular responses with clinically relevant outcomes of progression-free and thrombosis-free survival.

Diagnostic Value of Hepcidin in Sepsis: A Systematic Review and Meta-Analysis.

Objectives: To investigate the diagnostic value of hepcidin for sepsis diagnosis. Methods: The relevant literature on hepcidin for sepsis diagnosis published up to October 20, 2023, was systematically searched in the Web of Science, PubMed, Embase, and China Knowledge Network databases. Two researchers screened the literature and extracted relevant data according to the inclusion and exclusion criteria. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis and calculation of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were performed using State16 and Review Manager 5.3 software. Furthermore, receiver operating characteristic curve (ROC) was plotted, and the respective area under the curve (AUC) was calculated to assess the accuracy of hepcidin. Publication bias was evaluated using Deeks' funnel plot asymmetry test. Results: Overall, 1047 patients from 8 studies were included (625 patients with sepsis and 422 controls). The quality of the literature was relatively moderate. Meta-analysis demonstrated the presence of heterogeneity in the data (I2 > 50%, P < .05), and a randomized model was employed to combine the diagnostic indicators. Regarding its accuracy for sepsis diagnosis, hepcidin demonstrated a pooled sensitivity of 0.88 (95% confidence interval [CI]: 0.76-0.94) and specificity of 0.91 (95% CI: 0.76-0.97). The diagnostic odds ratio was 69.00 (95% CI: 19.00-253.00), and the ROC curve revealed an AUC of 0.95. Additionally, Deeks' funnel plot asymmetry test demonstrated absence of publication bias. Conclusions: Our meta-analysis suggested that hepcidin has a high diagnostic value in sepsis and may be a valuable diagnostic tool.

Visceral adiposity is associated with iron deposition and myelin loss in the brains of aged mice.

Iron deposition and myelin loss are observed in the brain with aging, and iron accumulation is suggested to be involved in myelin damage. However, the exact mechanism of iron deposition with aging remains unclear. This study was aimed to determine whether expanded visceral adipose tissue contributes to iron deposition and myelin loss by inducing hepcidin in the brains of aged male mice. Compared with young adult mice, levels of hepcidin in the brain, epididymal adipose tissue, and circulation were increased in aged mice, which had expanded visceral adipose tissue with inflammation. An increase in expressions of ferritin, an indicator of intracellular iron status, was accompanied by decreased levels of proteins related to myelin sheath in the brains of aged mice. These age-related changes in the brain were improved by visceral fat removal. In addition, IL-6 level, activation of microglia/macrophages, and nuclear translocation of phosphorylated Smad1/5 (pSmad1/5) inducing hepcidin expression were reduced in the brains of aged mice after visceral fat removal, accompanied by decreases of pSmad1/5- and ferritin-positive microglia/macrophages and mature oligodendrocytes. These findings indicate that visceral adiposity contributes to hepcidin-mediated iron deposition and myelin loss with inflammation in the aged brain. Our results support the importance of preventing visceral adiposity for maintaining brain health in older individuals.

Social defeat stress impairs systemic iron metabolism by activating the hepcidin-ferroportin axis.

Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin-ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron-refractory anemia.

Investigating the Hepcidin Gene Polymorphisms in COVID-19-Associated Mucormycosis Susceptibility: A Clinical-Laboratory Study.

Background: Following the coronavirus disease 2019 outbreak (COVID-19), it became a worrisome health burden worldwide. COVID-19-associated mucormycosis emergence, characterized by dysregulated inflammation and iron metabolism, exacerbated the prognosis of affected patients. Given the significance of hepcidin in regulating inflammation and iron metabolism, this study investigated the significance of hepcidin single nucleotide polymorphisms (SNP) in COVID-19-associated mucormycosis development, along with the association between the clinical and laboratory factors and COVID-19-associated mucormycosis. Methods: From September 2021 to November 2021, COVID-19 patients with and without mucormycosis were enrolled in this cross-sectional study. Their medical records and laboratory results were investigated. SNP genotyping was performed using Sanger sequencing. Hardy-Weinberg Equilibrium, Pearson's Chi square, and student t test were used for analyzing the data using SPSS software version 25. P<0.05 was regarded as statistically significant. Results: Here, 110 COVID-19 patients with and without mucormycosis were investigated. Elevated levels of urea, aspartate aminotransferase, lactate dehydrogenase, and increased ratio of polymorphonuclear neutrophil to lymphocytes were associated with decreased risk of COVID-19-associated mucormycosis in patients (all P<0.05). Moreover, diabetes mellitus increased the risk of mucormycosis (P=0.028). In contrast to patients without mucormycosis, patients with mucormycosis did not display 442 GA and SNP335 GT genotypes. Unlike patients without mucormycosis, none of the patients with mucormycosis had SNP442 GA and SNP335 GT genotypes. Regarding SNP 443 C>T, and the combination of SNPs 582 A>G and 443 C>T, CC genotype and AA+CC genotypes were associated with increased lactate dehydrogenase levels in COVID-19 patients, respectively. Conclusion: Regarding SNP 443 C>T, the CC genotype was associated with increased lactate dehydrogenase levels in COVID-19 patients. In terms of SNP 582 A>G and SNP 443 C>T, COVID-19 patients with AA+CC genotypes had higher levels of LDH. None of the patients with mucormycosis had SNP442 GA and SNP335 GT genotypes.

Functional iron deficiency anemia in patients with cancer.

Anemia is frequently observed in patients with cancer owing to anticancer chemotherapy, radiation therapy, and inflammatory responses. This often leads to functional iron deficiency, characterized by adequate iron stores but impaired use of iron for red blood cell production. This condition, termed functional iron deficiency anemia (IDA), is identified by a ferritin level of 30-500 µg/dL and a transferrin saturation < 50%. Functional iron deficiency often develops with the prolonged use of erythropoiesis-stimulating agents, leading to a diminished response to anemia treatment. Although oral iron supplementation is common, intravenous iron is more effective and recommended in such cases. Recent studies have shown that ferric carboxymaltose (FCM) is effective in treating functional IDA in patients with cancer. However, because of its potential to induce asymptomatic severe phosphate deficiency, it is important to closely monitor phosphate levels in patients receiving FCM.

Elevated plasma hepcidin concentrations are associated with an increased risk of mortality and nonfatal cardiovascular events in patients with type 2 diabetes: a prospective study.

BACKGROUND: The effect of plasma hepcidin concentrations on the long-term risk of developing adverse cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) is unclear. METHODS: We followed for a median of 55.6 months 213 outpatients with established T2DM (45.5% women, mean age 69 ± 10 years; BMI 28.7 ± 4.7 kg/m2; median diabetes duration 11 years). Baseline plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. The primary study outcome was a composite of all-cause mortality or incident nonfatal cardiovascular events (inclusive of myocardial infarction, permanent atrial fibrillation, ischemic stroke, or new hospitalization for heart failure). RESULTS: 42 patients developed the primary composite outcome over a median follow-up of 55.6 months. After stratifying patients by baseline hepcidin tertiles [1st tertile: median hepcidin 1.04 (IQR 0.50-1.95) nmol/L, 2nd tertile: 3.81 (IQR 3.01-4-42) nmol/L and 3rd tertile: 7.72 (IQR 6.37-10.4) nmol/L], the risk of developing the primary composite outcome in patients in the 3rd tertile was double that of patients in the 1st and 2nd tertile combined (unadjusted hazard ratio [HR] 2.32, 95%CI 1.27-4.26; p = 0.007). This risk was not attenuated after adjustment for age, sex, adiposity measures, smoking, hypertension, statin use, antiplatelet medication use, plasma hs-C-reactive protein and ferritin concentrations (adjusted HR 2.53, 95%CI 1.27-5.03; p = 0.008). CONCLUSIONS: In outpatients with T2DM, higher baseline hepcidin concentrations were strongly associated with an increased long-term risk of overall mortality or nonfatal cardiovascular events, even after adjustment for established cardiovascular risk factors, plasma ferritin concentrations, medication use, and other potential confounders.

The effect of iron supplementation in preterm infants at different gestational ages.

BACKGROUND: Iron deficiency (ID) is the most prevalent nutritional deficiency disease in preterm infants, significantly affecting their growth and development. For preterm infants to flourish physically and neurologically, timely iron supplementation is essential. The main goals of this study were to determine whether the present iron supplementation regimen results in iron overload in late preterm infants and whether it can meet the growth requirements of early preterm infants for catch-up. METHODS: We conducted a prospective follow-up study on preterm infants at the Department of Child Health, West China Second University Hospital, Sichuan University, from January 1, 2020, to August 31, 2020. In this study, 177 preterm infants were divided into two groups based on gestational age-early preterm infants (gestational age < 34 weeks) and late preterm infants (gestational age ≥ 34 weeks and < 37 weeks)-to compare the incidence of iron deficiency, iron status, and physical growth of preterm infants receiving iron supplements (2-4 mg/kg/d). RESULTS: Iron supplementation considerably reduced the incidence of iron deficiency in preterm infants. The prevalence of iron deficiency in early preterm infants and late preterm infants was 11.3% and 5.1%, respectively, at the corrected gestational age of 3 months; at the corrected gestational age of 6 months, the prevalence was 5.3% and 6.3%, respectively. No preterm infants with iron deficiency were detected in either group at the corrected gestational age of 12 months. Ferritin was substantially lower in early preterm infants (36.87 ± 31.57 ng/ml) than in late preterm infants (65.78 ± 75.76 ng/ml) at the corrected gestational age of 3 months (p < 0.05). A multifactorial regression analysis of factors influencing iron metabolism levels in preterm infants revealed a positive relationship between log10hepcidin, birth weight, and ferritin, with higher birth weights resulting in higher ferritin levels. CONCLUSIONS: Postnatal iron supplementation at 2-4 mg/kg/d in preterm infants significantly decreases the incidence of ID. There were substantial differences in iron levels across preterm infants of varying gestational ages. A tailored iron supplementation plan based on growth, birth weight, and gestational age may be a more suitable route for iron supplementation. Although the current study found that the postnatal iron status of early preterm infants differed from that of late preterm infants, the actual mechanism of action remains unknown, and large-sample, multicenter clinical studies are required to investigate this further.

Absolute and functional iron deficiency: Biomarkers, impact on immune system, and therapy.

Iron is essential for numerous physiological processes and its deficiency often leads to anemia. Iron deficiency (ID) is a global problem, primarily affecting reproductive-age women and children, especially in developing countries. Diagnosis uses classical biomarkers like ferritin or transferrin saturation. Recent advancements include using soluble transferrin receptor (sTfR) or hepcidin for improved detection and classification of absolute and functional iron deficiencies, though mostly used in research. ID without anemia may present symptoms like asthenia and fatigue, even without relevant clinical consequences. ID impacts not only red-blood cells but also immune system cells, highlighting its importance in global health and immune-related comorbidities. Managing ID, requires addressing its cause and selecting appropriate iron supplementation. Various improved oral and intravenous products are available, but further research is needed to refine treatment strategies. This review updates on absolute and functional iron deficiencies, their relationships with the immune system and advancements in diagnosis and therapies.