Biomarkers Of Iron Metabolism Research Articles

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<0.05). Transferrin saturation of the first group was significantly (p<0.05) higher compared to the non-diabetic fatty liver disease group. Ferritin correlated well with Fibrosis-4 index level (τ= 0.193, p<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.

A Novel Serum Biomarker Model to Discriminate Aortic Dissection from Coronary Artery Disease.

Background The misdiagnosis of aortic dissection (AD) can lead to a catastrophic prognosis. There is currently a lack of stable serological indicators with excellent efficacy for the differential diagnosis of AD and coronary artery disease (CAD). A recent study has shown an association between AD and iron metabolism. Thus, we investigated whether iron metabolism could discriminate AD from CAD. Methods This retrospective and multicenter cross-sectional study investigated the efficacy of biomarkers of iron metabolism for the differential diagnosis of AD. We collected biomarkers of iron metabolism, liver function, kidney function, and other biochemistry test, and further, logistic regression analysis was applied. Results Between Oct. 8, 2020, and Mar. 1, 2021, we recruited 521 patients diagnosed with AD, CAD, and other cardiovascular diseases (OCDs) with the main symptoms of chest and back pain and assigned them to discovery set (n = 330) or validation set (n = 191). We found that six serum biomarkers, including serum iron, low-density lipoprotein, uric acid, transferrin, high-density lipoprotein, and estimated glomerular filtration rate, can serve as a novel comprehensive indicator (named FLUTHE) for the differential diagnosis of AD and CAD with a sensitivity of 0.954 and specificity of 0.905 to differentially diagnose AD and CAD more than 72 h past symptom onset. Conclusion Our findings provide insight into the role of iron metabolism in diagnosing and distinguishing AD, which might in the future be a key component in AD diagnosis. Furthermore, we establish a novel model named “FLUTHE” with higher efficiency, safety, and economy, especially for patients with chest pain for more than 72 h.

Antenatal Iron-Rich Food Intervention Prevents Iron-Deficiency Anemia but Does Not Affect Serum Hepcidin in Pregnant Women

BackgroundLimited evidence supports the efficacy of iron-rich foods (IRFs) in improving iron status during pregnancy. ObjectivesThe study aims to evaluate the effect of IRFs on iron status and biomarkers of iron metabolism in the third trimester of pregnancy. MethodsA total of 240 pregnant women at 11–13 wk of gestation without iron-deficiency anemia (IDA) in South China were recruited to this single-blind clinical trial [non-IDA referred to both hemoglobin (Hb) ≥110g/L and serum ferritin (SF) ≥15ng/mL], randomly assigned to 1) control, 2) IRFs containing 20 mg iron/d (IRF-20), or 3) IRFs containing 40 mg iron/d (IRF-40). The IRFs were consumed 3 days a week, including pork liver, chicken/duck blood, soybean, and agaric. The IRFs started at recruitment and ended in the predelivery room. Primary outcome included anemia (Hb <110 g/L), iron deficiency (ID, definition 1: SF <15 ng/mL; definition 2: SF <12 ng/mL), and IDA (ID and Hb <110 g/L). Secondary outcome was plasma Hb and iron indices, including SF, serum hepcidin, and iron. ResultsAll participants who completed the trial with full data (n = 170) were included in the analysis. At the endline, both intervention groups showed lower ID and IDA rates than control. Specifically, IRF-40 showed a lower ID (SF <12 ng/mL) rate than control (9.0% compared with 22.8%, P = 0.022). For IDA by definition 1, the incidence in IRF-40 was lower than that in control (1.9% compared with 8.9%, P = 0.045). For IDA by definition 2, the incidence in IRF-20 was lower than that in control (3.9% compared with 17.9%, P = 0.049). Moreover, IRF-20 showed higher SF concentrations than control (P = 0.039). No effects of IRFs on anemia (P = 0.856), plasma Hb (P = 0.697), serum hepcidin (P = 0.311), and iron (P = 0.253) concentrations were observed. The assessed iron intakes were 22.2 mg/d in IRF-20 and 25.0 mg/d in IRF-40, respectively. ConclusionsAntenatal IRFs reduce the risk of ID and IDA in late pregnancy, although the present results are inadequate to confirm an ideal dosage (No. ChiCTR1800017574).

SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study

▪BackgroundHepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers.ObjectivesThe primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated.MethodsEach subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo.ResultsThree cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed.Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively.Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57.The mean (±SD) percent transferrin saturation (TSAT) was reduced from baseline levels in all single dose administration groups with maximum decreases observed at day 29 but reductions still observed at day 57. (Table 1).The observed PK is consistent with the PK model based on preclinical data.Thus, whereas the effects of SLN124 on plasma hepcidin show clear increments across the dose range tested, the effect on lowering serum iron and transferrin saturation shows something of a plateau effect at the highest dose. In future studies in patients with raised baseline transferrin saturations, it will be of note to determine whether transferrin saturation continues to decrease at the highest SLN124 doses.Conclusion/summaryIn summary, SLN124, a GalNAc conjugated siRNA targeting TMPRSS6, effectively reduces serum iron levels and has the potential as a therapeutic for patients with alpha and beta-thalassemia, myelodysplastic syndromes, hereditary hemochromatosis and other related disorders. The effect on hepcidin levels at the end of study, day 57, suggest a prolonged duration of action. The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial (NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients withthalassemia and myelodysplastic syndromes. [Display omitted] DisclosuresPorter: bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scrimgeour: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Martinez: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. James: Silence Therapeutics: Consultancy. Aleku: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wilson: Silence Therapeutics: Consultancy. Muckenthaler: Silence Therapeutics: Research Funding. Schaeper: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Silence Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

Iron Replacement and Redox Balance in Non-Anemic and Mildly Anemic Iron Deficiency COPD Patients: Insights from a Clinical Trial.

In COPD patients, non-anemic iron deficiency (NAID) is a common systemic manifestation. We hypothesized that in COPD patients with NAID, iron therapy may improve systemic oxidative stress. The FACE (Ferinject assessment in patients with COPD and iron deficiency to improve exercise tolerance) study was a single-blind, unicentric, parallel-group, placebo-controlled clinical trial (trial registry: 2016-001238-89). Sixty-six patients were enrolled (randomization 2:1): iron arm, n = 44 and placebo arm, n = 22, with similar clinical characteristics. Serum levels of 3-nitrotyrosine, MDA-protein adducts, and reactive carbonyls, catalase, superoxide dismutase (SOD), glutathione, Trolox equivalent antioxidant capacity (TEAC), and iron metabolism biomarkers were quantified in both groups. In the iron-treated patients compared to placebo, MDA-protein adducts and 3-nitrotyrosine serum levels significantly declined, while those of GSH increased and iron metabolism parameters significantly improved. Hepcidin was associated with iron status parameters. This randomized clinical trial evidenced that iron replacement elicited a decline in serum oxidative stress markers along with an improvement in GSH levels in patients with stable severe COPD. Hepcidin may be a surrogate biomarker of iron status and metabolism in patients with chronic respiratory diseases. These findings have potential clinical implications in the management of patients with severe COPD.

Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.

BackgroundErythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early‐onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited.MethodsTo investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment‐naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25‐hydroxyvitamin D, and liver enzyme levels.ResultsMedian FEP concentration at the time of phototesting was 57.50 (IQR: 34.58‐102.70) μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest–positive patients than in those negative (64.37 [IQR: 57.45‐121.82] vs 45.35 [IQR: 24.53‐74.61] μg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5‐84] μg/dL vs 109 [IQR: 63.25‐154] μg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775‐18.41] % vs 29.645 [IQR: 17.8225‐34.3575] %; P = .0109) than those negative.ConclusionsOur study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.