Biomarkers Of Iron Metabolism Research Articles

The contribution of iron metabolism to heart failure: a haematological and biochemical perspective

Abstract Introduction Heart failure (HF) can be influenced by diverse modulators, such as genes involved in iron metabolism - HFE, SLC40A1 and TMPRSS6, and haematological and biochemical parameters - serum iron, ferritin, transferrin saturation, mean corpuscular volume (MCV) and Red Cell Distribution Width (RDW). Objectives To investigate the association of genetic variants in the HFE gene [C282Y (rs1800562) and H63D (rs1799945)], SLC40A1 (rs1439816 and rs2304704) and TMPRSS6 (rs855791) with haematological parameters and biochemical biomarkers of iron metabolism in HF and in its various forms of presentation [preserved Ejection Fraction-HFpEF and non-preserved Ejection Fraction-HFnpEF (middly reduced + reduced)], in each sex. Methods 301 individuals with HF were studied (141 men and 160 women), with a median age of 80 years (min=31 and max=99) and a median body mass index (BMI) of 25.90 kg/m2 (min=16.50 and max=47.30). Multiplex PCR-ARMS technique was used to analyze the HFE gene variants (C282Y and H63D) and Endpoint Genotyping was used for the remaining variants. Statistical analysis was carried out using SPSS software, version 28.0, with a statistical significance level of p<0.05. Results The presence of indicators of iron deficiency anaemia was verified in the haematological and biochemical parameters in our population of HF. Significant differences were found in serum iron values in the presence of the mutant allele for the three genes studied: 1)in the H63D (p=0.006) for females, and more particularly in females with HFnpEF (p=0.020); 2) in the rs1439816 for males (p=0.035) and more particularly in males with HFpEF (p=0.036); and 3) in the rs855791 for males (p=0.018). As for ferritin, significant differences were found in the presence of the mutant allele for the rs2304704 (p=0.001) in females. For transferrin saturation, significant differences were found in the presence of the mutant allele for the three genes studied: 1) in the H63D (p=0.013) for females, more specifically in females with HFpEF (p=0.043); 2) in the rs1439816 in males (p=0.037); and 3) in the rs855791 in females (p=0.034), particularly in females with HFpEF (p=0.023), and in males (p=0.032), particularly in males with HFpEF (p=0.037). Analyzing the MCV, there were statistically significant differences in the presence of the mutant allele for the rs2304704 (p=0.012) in females, particularly in those with HFpEF (p<0.001). Regarding RDW, significant differences were found in the presence of the mutant allele of the C282Y polymorphism in females with HFpEF (p=0.048). Conclusion Ferropenic anaemia highly prevalent in this population with HF. All the genes analyzed contribute to the modulation of the analyzed parameters/biomarkers, however, the SLC40A1 gene showed greater modulating capacity. Genetic modulation was more relevant in HFpEF women, suggesting that this sex is the most susceptible to genetic modulation.

Iron metabolism biomarkers and nutritional assessments in subjects living with or without obesity and iron deficiency without anaemia

Iron metabolism biomarkers and nutritional assessments in subjects living with or without obesity and iron deficiency without anaemia

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.

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

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. 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. 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. 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. 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.

Iron metabolism biomarkers and mortality risk in U.S. patients with congestive heart failure: NHANES 1999–2018 analysis

Background and aimsIron deficiency is a major public health concern. We aimed to assess the predictive capability of 4 iron metabolism biomarkers for all-cause and cardiovascular disease-specific mortality in U.S. patients with congestive heart failure (CHF). Methods and results1904 CHF patients aged ≥20 years were enrolled from NHANES, 1999–2000 to 2017–2018. All analyses were weighted to provide nationally representative estimates. Among 1905 CHF patients, mean age was 71 years, and 1024 (53.8%), 459 (24.1%), 206 (10.8%), and 216 (11.3%) were Non-Hispanic Black, Non-Hispanic White, Hispanic-Mexican American, and Hispanic-Other Hispanic, respectively. During follow-ups, 1080 deaths occurred. Median follow-up time was 5.08 years. Per-unit increase in natural-logarithmic-transformed iron and transferrin saturation decreased all-cause mortality risk separately by 33.0% (adjusted hazard ratio: 0.670, 95% confidence interval: 0.563 to 0.797, P < 0.001) and 32.6% (0.674, 0.495 to 0.917, 0.013), and per-unit increase in transferrin receptor increased mortality risk by 33.7% (1.337, 1.104 to 1.618, 0.004). Two derivates from 3 significant iron biomarkers were generated - transferrin receptor to natural-logarithmic-transformed iron ratio (TRI) and transferrin receptor to natural-logarithmic-transformed transferrin saturation ratio (TRTS), which were significantly associated with all-cause mortality, with per-unit increase corresponding to 2.692- and 1.655-fold increased all-cause mortality risk (P: 0.003 and 0.023). Only iron and TRTS were associated with the significant risk of cardiovascular disease-specific mortality (P: 0.004 and 0.017). ConclusionsOur findings identified 3 iron metabolism biomarkers that were individually, significantly, and independently associated with all-cause mortality in patients with CHF, and importantly 2 derivates generated exhibited stronger predictive capability.

Serum NOXs and Iron Metabolism Biomarkers in RRMS Patients

Serum NOXs and Iron Metabolism Biomarkers in RRMS Patients

Ferroptosis is involved in focal segmental glomerulosclerosis in rats

To explore whether ferroptosis is involved in focal segmental glomerulosclerosis (FSGS) and its mechanism. The FSGS rat model was constructed by single nephrectomy combined with fractional tail vein injection of doxorubicin. 24-hour urine protein, serum biochemistry, HE, PAS and Masson pathological staining were measured to assess renal injury. Glomerular and morphological changes of ferroptosis were observed by transmission electron microscopy. Iron content in renal tissue was assessed by Prussian blue staining and iron detection. GSH/GSSG kit was used to detect the content and proportion of reduced/oxidized glutathione. Lipid peroxidation related proteins including MDA expression was assessed by colorimetry. The iron metabolism biomarkers such as hepcidin, ferroportin and TFR, ferroptosis biomarkers such as GPX4, ACSL4, and ferritinophagy biomarkers such as LC3II/LC3I, NCOA4, and FTH1 were detected by Western blot. Significant urinary protein, hyperlipidemia, azotemia, increased serum creatinine and hypoproteinemia were observed in FSGS rats. Histology and electron microscopy showed segmental sclerosis of glomeruli, compensatory enlargement of some glomeruli, occlusion of capillary lumen, balloon adhesion, increased mesangial matrix, atrophy of some tubules, and renal interstitial fibrosis in renal tissue of FSGS rats. The morphology of glomerular foot processes disappeared; the foot processes were extensively fused and some foot processes detached. Mitochondria became smaller, membrane density increased, and mitochondrial cristae decreased or disappeared. In addition, iron deposition was observed in renal tissue of FSGS rats. Compared with the control group, the levels of GSH, GSH/GSSG, GPX4, and ferroportin were reduced and the expression of GSSG, MDA, ACSL4, hepcidin, and TFR was increased in the renal tissue of FSGS rats; meanwhile, the expression of LC3II/LC3I and NCOA4 was increased and the expression of FTH1 was decreased. Ferroptosis is involved in the pathological progression of FSGS, which is probably associated with activation of ferritinophagy. This represents a potential therapeutic target for FSGS.

Association between biomarkers of iron status and cardiometabolic risk in Spanish children aged 9–10 years. The ELOIN study

The relationship between iron metabolism and cardiometabolic risk factors has been scarcely studied in children, and the results are controversial. The objective of this study was to evaluate the association between iron parameters and lipid, glycemic and blood pressure alterations in the pediatric population. This was a cross-sectional study of 1954 children between 9 and 10 years of age in Madrid (Spain), participants in a longitudinal study of childhood obesity. Iron metabolism parameters, i.e., serum iron (Is), ferritin (Fs), transferrin (Tf) and transferrin saturation (STf) and lipid, glycemic and blood pressure profiles were evaluated. Odds ratios (ORs) were estimated using logistic regression models adjusted for sociodemographic characteristics, diet, physical activity, C-reactive protein and body mass index. Compared with the participants in the low Is and STf tertiles, those in the upper tertiles had a lower risk of low HDL-Chol (OR: 0.34; 95%CI: 0.17; 0.67) and OR: 0.44 (95%CI: 0.23; 0.84), respectively, and children in the upper Fs tertile had an OR of 2.07 (95%CI: 1.16; 3.68) for low HDL-Chol. Children in the highest Is and STf tertiles had a lower risk of prediabetes [OR: 0.63 (95%CI: 0.41; 0.97) and OR: 0.53 (95%CI: 0.34; 0.82)] and insulin resistance (IR) (OR: 0.37; 95%CI: 0.22; 0.64), and those in the upper Tf tertile had a higher risk of IR (OR: 1.90; 95%CI: 1.16; 3.12). An increased risk of hypertension was found only in children in the upper Fs tertile (OR: 1.46; 95%CI: 1.01; 2.13). Conclusions: Biomarkers of iron metabolism are associated with cardiometabolic alterations in the pediatric population, with a variable direction and magnitude depending on the indicators used.What is Known:• Iron metabolism is related to important cardiometabolic alterations such as metabolic syndrome and its components.• Association between biomarkers of iron status and cardiometabolic risk have been less explored in children.What is New:• Biomarkers of iron metabolism are associated with cardiometabolic alterations in the pediatric population.• Iron parameters in the pediatric population could be of great help to detect and prevent cardiometabolic abnormalities early.

Iron metabolism and metabolic dysfunction-associated fatty liver disease

Abstract Objective: The primary objective of this study was to investigate the association between biomarkers of iron metabolism and metabolic dysfunction-associated fatty liver disease in individuals with type 2 diabetes and non-diabetic individuals compared to a control group. We also examined the possible association between estimated liver fibrosis and serum ferritin levels in all three groups. Methods: We conducted a descriptive, cross-sectional, comparative study involving subjects diagnosed with diabetes and/or metabolic dysfunction-associated fatty liver disease from an outpatient diabetology clinic and two general practices in Târgu Mureș. The patient population was divided into 3 groups: first group including diabetic patients suffering from fatty liver disease, second group including patients without fatty liver disease and third group with non-diabetic patients suffering from fatty liver disease. We compared the three groups based on specific laboratory tests. Results: Patients with fatty liver disease had significantly higher ferritin and transferrin saturation levels than non-fatty liver disease sufferers (p&lt;0.05). Transferrin saturation of the first group was significantly (p&lt;0.05) higher compared to the non-diabetic fatty liver disease group. Ferritin correlated well with Fibrosis-4 index level (τ= 0.193, p&lt;0.01) considering the whole sample and especially in the first group. Conclusions: In our study, there was a clear association between higher ferritin levels and the presence of metabolic dysfunction-associated fatty liver disease. The higher transferrin saturation observed in diabetic patients suffering from metabolic dysfunction-associated fatty liver disease may indicate the possible etiological significance of iron overload. Higher ferritin levels in diabetes increase the risk of liver fibrosis.

Association of Body Iron Metabolism with Type 2 Diabetes Mellitus in Chinese Women of Childbearing Age: Results from the China Adult Chronic Disease and Nutrition Surveillance (2015).

High iron stores have been reported to be associated with type 2 diabetes mellitus (T2DM). However, evidence for the associations of iron metabolism with T2DM is inconsistent, and whether there is a threshold effect remains controversial. In the present study, we aimed to examine the associations between various iron biomarkers and the risk of T2DM as well as impaired glucose metabolism (IGM) and hyperglycemia in Chinese women of childbearing age. A total of 1145 women were divided into three groups (normal blood glucose metabolism group; IGM group; T2DM group). Biomarkers of iron metabolism (serum ferritin (SF), transferrin, soluble transferrin receptor (sTfR), transferrin saturation, serum iron, total body iron, and sTfR-to-lgferritin index) were measured. After adjusting for various confounding risk factors, SF and sTfR were positively associated with the risk of IGM (fourth vs. first quartile: SF odds ratio (OR) = 1.93 (95% CI 1.17-3.20) and sTfR OR = 3.08 (95% CI 1.84-5.14)) and T2DM (SF OR = 2.39 (95% CI 1.40-4.06) and sTfR OR = 3.84 (95% CI 2.53-5.83)). There was a nonlinear relationship between SF and risk of T2DM and hyperglycemia (p for nonlinearity < 0.01). Our findings suggested that SF and sTfR could be independent predictors of T2DM risk.

Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes.

Abnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM. A total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity. Compared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity. Elevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM.

Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review

Iron deficiency (ID) in conjunction with heart failure (HF) poses a challenge for clinicians and is associated with worse HF outcomes. Treatment of ID with IV iron supplementation for patients with HF has demonstrated benefits in quality of life (QoL) and HF-related hospitalizations. The aim of this systematic review was to summarize the evidence linking iron metabolism biomarkers with outcomes in patients with HF to assist in the optimal use of these biomarkers for patient selection. A systematic review of observational studies in English from 2010 to 2022 was conducted using PubMed, with keywords of "Heart Failure" and respective iron metabolism biomarkers ("Ferritin", "Hepcidin", "TSAT", "Serum Iron", and "Soluble Transferrin Receptor"). Studies pertaining to HF patients, with available quantitative data on serum iron metabolism biomarkers, and report of specific outcomes (mortality, hospitalization rates, functional capacity, QoL, and cardiovascular events) were included, irrespective of left ventricular ejection fraction (LVEF) or other HF characteristics. Clinical trials of iron supplementation and anemia treatment were removed. This systematic review was conducive to formal assessment of risk of bias via Newcastle-Ottawa Scale. Results were synthesized based on their respective adverse outcomes and iron metabolism biomarker(s). Initial and updated searches identified 508 unique titles once duplicates were removed. The final analysis included 26 studies: 58% focused on reduced LVEF; age range was 53-79 years; males composed 41-100% of the reported population. Statistically significant associations of ID were observed with all-cause mortality, HF hospitalization rates, functional capacity, and QoL. Increased risk for cerebrovascular events and acute renal injury have also been reported, but these findings were not consistent. Varying definitions of ID were utilized among the studies; however, most studies employed the current European Society of Cardiology criteria: serum ferritin < 100 ng/mL or the combination of ferritin between 100-299 ng/mL and transferrin saturation (TSAT) < 20%. Despite several iron metabolism biomarkers demonstrating strong association with several outcomes, TSAT better predicted all-cause mortality, as well as long-term risk for HF hospitalizations. Low ferritin was associated with short-term risk for HF hospitalizations, worsening functional capacity, poor QoL, and development of acute renal injury in acute HF. Elevated soluble transferrin receptor (sTfR) levels were associated with worse functional capacity and QoL. Finally, low serum iron was significantly associated with increased risk for cardiovascular events. Considering the lack of consistency among the iron metabolism biomarkers for association with adverse outcomes, it is important to incorporate additional biomarker data, beyond ferritin and TSAT, when assessing for ID in HF patients. These inconsistent associations question how best to define ID to ensure proper treatment. Further research, potentially tailored to specific HF phenotypes, is required to optimize patient selection for iron supplementation therapy and appropriate targets for iron stores replenishment.

Ferritin as proinflamatory biomarker of iron metabolism in tuberculosis patients (review)

Traditional methods of tuberculosis (TB) diagnosis, including sputum microscopy and culture for Mycobacterium tuberculosis detection, are time-consuming or have unsatisfactory sensitivity. However, early diagnosis of TB with high accuracy and sensitivity is very important for disease outcomes and prevention. Therefore, there is an urgent need for new TB diagnostic methods based on TB-associated biomarkers, with rapid availability of results that do not require sputum analysis, are inexpensive, and have high sensitivity and specificity. Objective — to study the mechanisms of ferritin participation in the pathogenesis of tuberculosis basing on the literature data. Materials and methods. 242 literature sources were found in the PubMed system by the query «Ferritin AND Tuberculosis» and 40 of them were selected for further detailed study. Results and discussion. Studies have shown that serum iron and transferrin concentrations are lower and ferritin levels are higher in patients with TB compared to those without TB. These deviations in the concentration of ferritin and transferrin usually normalize after treatment. Lower transferrin levels are associated with both early and late TB progression, and higher ferritin and hepcidin levels are associated with a higher risk of early TB progression in TB contacts. In addition, the status of biomarkers of iron metabolism can be used as an indicator of treatment failure (low ferritin) and mortality (high ferritin). Finally, low levels of transferrin and serum iron, as well as high ferritin concentrations in HIV-infected patients predict an increased risk of TB disease and relapse. Conclusions. Iron metabolism between M. tuberculosis and the host organism is closely related and plays an important role in the pathogenesis of tuberculosis. Parameters of iron metabolism are promising markers of both the course and effectiveness of tuberculosis treatment. In particular, changes in the level of ferritin can be predictors of both the ineffectiveness of tuberculosis treatment and mortality from this disease, so the prognostic value of this marker requires further detailed study.

PM2.5 caused ferroptosis in spermatocyte via overloading iron and disrupting redox homeostasis

Fine particulate matter (PM2.5) has been reported to cause various types of damage to male reproductive system, but the research on the underlying mechanisms is still insufficient. This study attempted to explore the underlying mechanisms of this widely concerning environmental health problem through in vivo and in vitro exposure models. Significant pathological damage and abnormal mitochondria in spermatocytes were observed in the real-time PM2.5 exposure animal model. In addition, significant alterations in key biomarkers of iron metabolism and ferroptosis were found in testis tissues. Notably decreased cell viability was found in vitro. Moreover, the ferroptosis pathway was significantly enriched in the transcriptome enrichment analysis. Subsequent experiments showed that the two core events of ferroptosis, iron overload and lipid peroxidation, occurred in spermatocytes after PM2.5 treatment. Moreover, lipid metabolic genes (Acsl4 and Aloxe3) and the antioxidant gene Gpx4 were found to be key target genes of ferroptosis caused by PM2.5 in spermatocytes. Importantly, further studies showed that the damaging effect could be reversed by the iron chelator deferoxamine mesylate (DFOM) and the lipid peroxidation inhibitor ferrostatin-1 (Fer-1), which further confirmed the role of ferroptosis in PM2.5 toxicity. Our study revealed the vital role of ferroptosis in PM2.5-induced male reproductive damage, providing novel insights into the air pollution-induced decrease in male fertility.

Soluble Hemojuvelin and Ferritin: Potential Prognostic Markers in Pediatric Hematopoietic Cell Transplantation.

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. 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. 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). 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. 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.

Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients.

Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group. Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance. Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.

Iron Status of a People Living with HIV in Sub-Saharan Africa Using a Multi-Criteria Approach Based on the Determination of Blood Ferritin, sTfR, CRP and sTfR-F Index

Background: The assessment of iron status using a single biomarker of iron metabolism is not enough sensitive and specific to reliably diagnose iron deficiency associated with multiple comorbidities. The objective of this study was to describe the iron status of people living with HIV in sub-Saharan Africa using a multi-criteria approach based on the determination of blood ferritin, sTfR, CRP and the calculation of sTfR-F index. Methods: This study was conducted using a retrospective panel of 933 sera/plasmas. We determined serum ferritin concentration, serum sTfR concentration, and C-reactive protein (CRP) by immunoturbidimetry for each subject. The sTfR-F index was determined by calculating the sTfR/log ferritin ratio. The statistical test used was Chi2. Results: Regardless of the inflammatory syndrome, we determined 3.80%, 30.29%, and 42.70% iron deficiency based on the separate interpretation of ferritin concentration, sTfR, and sTfR-F calculation, respectively. We used those biomarkers in addition to CRP in an algorithm for the diagnosis of iron deficiency. Subjects without inflammatory syndrome, had iron deficiency of 2.89% (n = 26). Taking into account the presence of an inflammatory syndrome, the frequency obtained was n = 88 (9.78%). Overall, iron deficiency was diagnosed in 114 (12.67%) patients when we used the diagnostic algorithm. Conclusion: The use of diagnostic algorithms combining several biomarkers of iron metabolism and taking into account the presence or absence of an inflammatory syndrome is a good approach to detect a large number of iron deficiencies in a population. Therefore, an assessment of the effectiveness of different diagnostic algorithms is necessary.

Association between iron metabolism and non-alcoholic fatty liver disease: results from the National Health and Nutrition Examination Survey (NHANES 2017–2018) and a controlled animal study

BackgroundIron metabolism may be involved in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). The relationship between iron metabolism and NAFLD has not been clearly established. This study aimed to clarify the relationship between biomarkers of iron metabolism and NAFLD.MethodsBased on the National Health and Nutrition Examination Survey (NHANES), restricted cubic spline models and multivariable logistic regression were used to examine the association between iron metabolism [serum iron (SI), serum ferritin (SF), transferrin saturation (TSAT), and soluble transferrin receptor (sTfR)] and the risk for NAFLD. In addition, stratified subgroup analysis was performed for the association between TSAT and NAFLD. Moreover, serum TSAT levels were determined in male mice with NAFLD. The expression of hepcidin and ferroportin, vital regulators of iron metabolism, were analyzed in the livers of mice by quantitative real-time PCR (qRT-PCR) and patients with NAFLD by microarray collected from the GEO data repository.ResultsPatients with NAFLD showed decreased SI, SF, and TSAT levels and increased STfR levels based on the NHANES. After adjusting for confounding factors, TSAT was significantly negatively correlated with NAFLD. Of note, the relationship between TSAT and NAFLD differed in the four subgroups of age, sex, race, and BMI (P for interaction < 0.05). Consistently, mice with NAFLD exhibited decreased serum TSAT levels. Decreased hepcidin and increased ferroportin gene expression were observed in the livers of patients and mice with NAFLD.ConclusionSerum TSAT levels and hepatic hepcidin expression were decreased in both patients and mice with NAFLD. Among multiple biomarkers of iron metabolism, lower TSAT levels were significantly associated with a higher risk of NAFLD in the U.S. general population. These findings might provide new ideas for the prediction, diagnosis, and mechanistic exploration of NAFLD.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA-HF.

Background:Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline.Methods:Iron deficiency was defined as a ferritin level <100 ng/mL or a transferrin saturation <20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.Results:Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P<0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron-replete patients (hazard ratio, 0.74 [95% CI, 0.58–0.92] versus 0.81 [95% CI, 0.63–1.03]; P-interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo.Conclusions:Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.