High Transferrin Saturation Research Articles

Alterations of Hepcidin and Iron Markers Associated with Obesity and Obesity-related Diabetes in Gambian Women

Aims Obesity, type 2 diabetes (T2D), and chronic inflammation are associated with disturbances in iron metabolism. Hepcidin is hypothesized to play a role in these alterations owing to its strong association with inflammation via the JAK-STAT3 pathway. The current study investigated the differences between inflammatory markers and iron indices and their association with hepcidin in lean women, women with obesity, and women with obesity and T2D (obesity-T2D) in The Gambia. Materials and methods In a cross-sectional study design, fasted blood samples were collected from three groups of women: lean women (n=42, body mass index (BMI)=20.9 kg/m2), women with obesity (n=48, BMI=33.1 kg/m2) and women with obesity-T2D (n=30, BMI=34.5 kg/m2). Markers of inflammation (IL-6 and CRP) and iron metabolism [hepcidin, iron, ferritin, soluble transferrin receptor (sTfR), transferrin, transferrin saturation, and unsaturated iron-binding capacity (UIBC)] were compared using linear regression models. Simple regression analyses were performed to assess the association between hepcidin levels and respective markers. Results Women with obesity and obesity-T2D showed elevated levels of inflammatory markers. There was no evidence that markers of iron metabolism differed between lean women and obese women, but women with obesity-T2D had higher transferrin saturation, higher serum iron concentration, and lower UIBC. Serum hepcidin concentrations were similar in all the groups. Hepcidin was not associated with markers of inflammation but was strongly associated with all other iron indices (all P<0.002). Conclusion Contrary to our original hypothesis, hepcidin was not associated with markers of inflammation in the three groups of Gambian women, despite the presence of chronic inflammation in women with obesity and obesity-T2D.

Serum iron status is associated with all-cause mortality in metabolic dysfunction-associated steatotic liver disease: a prospective, observational study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD. A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age. During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (P overall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD. This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status.

#1650 Synergistic effects of mineral bone disorder (MBD) markers and iron metabolism markers on QT prolongation in maintenance haemodialysis patients

Abstract Background and Aims Prolonged QT interval is known to be common in maintenance haemodialysis (HD) patients, and QT prolongation is a risk for the development of fatal arrhythmias and cardiovascular complications. Previously, we showed that low Ca and low or high P before dialysis were associated with QT prolongation in HD patients. In this study, we aimed to investigate the effect of abnormalities in MBD markers such as Ca and P on QT time when added to abnormalities in markers of iron metabolism, a known cardiac prognostic factor due to abnormal energy metabolism in the myocardium. Method A cross-sectional study was conducted on adult maintenance HD patients enrolled in the 2020 Japanese Society for Dialysis Therapy Annual Survey. Patients with dialysis frequency less than 3 times per week and patients with absent serum Ca, serum P, transferrin saturation (TSAT), serum ferritin, and QTc were excluded. After describing patient characteristics, an analytical-epidemiological study was conducted with serum Ca, P, TSAT, and serum ferritin as exposure and QTc &amp;gt;500 msec as outcome. Exposure was defined as cut off values for Ca, P, TSAT, and serum ferritin of 8.4/10, 3.5/6, 20/40, and 100/300, respectively according to JSDT guideline. Adjusted variables in the multivariate analysis were age, gender, history of dialysis, BMI, and presence or absence of diabetes, previous cardiovascular disease, P adsorption medication, vitamin D analogue use, calcimimetics use. Missing values were addressed using Multiple Imputation by Chained Equations. All analyses were performed using STATA 18.0. The significance level was set at 5%. Results 169 705 patients were analysed. Among all subjects, 65.6% were male, mean age was 69.7 years (standard deviation (SD) 12.4), 50.6% had comorbid diabetes, 24.1% had previous cardiovascular disease, and mean serum Ca and P levels were 8.6 mg/dL (SD 0.7) and 5.2 mg/dL (SD 35.8), respectively. The mean QTc was 452 msec (SD 37.9). In multivariate analysis, the increased risk of QT prolongation in the low Ca, low P, and high P categories was further increased with low TSAT and cancelled with high TSAT (Table). In contrast, no such effect was appeared for ferritin. Conclusion The present study suggests that the association between lower serum Ca and lower and higher serum P levels and QTc prolongation in maintenance haemodialysis patients may be enhanced at low TSAT levels and weakened at normal and high TSAT levels.

Iron, hemochromatosis genotypes, and risk of infections: a cohort study of 142 188 general population individuals

AbstractIt is unclear whether risk of infection is increased in individuals with hereditary hemochromatosis and in individuals with low or high plasma iron, transferrin saturation, or ferritin. Therefore, we tested whether high and low iron, transferrin saturation, and ferritin are associated with risk of infections observationally and genetically through HFE genotypes. We studied 142 188 Danish general population individuals. Iron, transferrin saturation, and ferritin were measured in 136 656, 136 599, and 38 020 individuals, respectively. HFE was genotyped for C282Y and H63D in 132 542 individuals. Median follow-up after study enrollment was 8 years (range, 0-38) for hospital and emergency room admissions with infections (n = 20 394) using the National Patient Register, covering all Danish hospitals. Hazard ratios for any infection were 1.20 (95% confidence interval [CI], 1.12-1.28) and 1.14 (95% CI, 1.07-1.22) in individuals with plasma iron ≤5th or ≥95th percentile compared with individuals with iron from 26th to 74th percentiles. Findings for transferrin saturation were similar, whereas infection risk was not increased in individuals with ferritin ≤5th or ≥95th percentile. Hazard ratios in C282Y homozygotes vs noncarriers were 1.40 (95% CI, 1.16-1.68) for any infection, 1.69 (95% CI, 1.05-2.73) for sepsis, and 2.34 (95% CI, 1.41-3.90) for death from infectious disease. Risk of infection was increased in C282Y homozygotes with normal plasma iron, transferrin saturation, or ferritin, and in C282Y homozygotes without liver disease, diabetes, and/or heart failure. In summary, low and high plasma iron and transferrin saturation were independently associated with increased infection risk. C282Y homozygotes had increased risk of any infection, sepsis, and death from infections. Even C282Y homozygotes with normal iron, transferrin saturation, or ferritin, not currently recommended for genotyping, had increased infection risk.

Hemojuvelin-mediated hepcidin induction requires both bone morphogenetic protein type I receptors ALK2 and ALK3

AbstractHemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) levels, soluble HJV (sHJV), splenic iron content (SIC), as well as phosphorylated small mothers against decapentaplegic protein (pSMAD1/5/8) levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice after HJV overexpression. In phosphate-buffered saline–injected Alk3fl/fl;Alb-Cre mice, serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1% to 5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

Hemoglobin variability in patients receiving EPO and roxadustat during maintenance hemodialysis: a self-control study.

The aim of this study was to investigate the hemoglobin variability in patients undergoing maintenance hemodialysis during the application of erythropoietin (EPO) and roxadustat. For this retrospective study, we analyzed the clinical records of 80 patients with renal anemia on maintenance hemodialysis (MHD) admitted to our hospital between January 2017 and December 2022. We adopted a self-control design comparing the hemoglobin variability of the values before and after roxadustat administration in each patient. The patients received EPO from January 2017 to December 2019 and roxadustat from January 2020 to December 2022. We compared the levels of serum ferritin, transferrin saturation, and hemoglobin and calculated the hemoglobin variabilities by comparing values before and after roxadustat treatments. We found higher transferrin saturation levels at different time points after the roxadustat treatments (p<0.01); meanwhile, the serum ferritin and hemoglobin levels were significantly higher after the roxadustat treatment (p<0.001). During the treatments with EPO and roxadustat, the transferrin saturation, serum ferritin, and hemoglobin levels differed significantly at different time points for each patient (p<0.05). After roxadustat administration, the hemoglobin levels were significantly higher than after EPO administration (p<0.001) and changed more rapidly after roxadustat administration than after EPO administration (p<0.05). The hemoglobin variability after roxadustat administration was significantly lower than that after EPO administration (p<0.05). Treatment with roxadustat led to higher hemoglobin levels and less hemoglobin variability than the treatment with EPO, with high transferrin saturation and higher ferritin levels in patients with renal anemia on MHD.

Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study

ObjectivesThe aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis. MethodsWe applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism. ResultsThe risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66–0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96–2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63–1.29) and ferritin (OR, 1.33; 95% CI, 0.54–3.30). ConclusionsMR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis.

Maternal hemoglobin and iron status in early pregnancy and risk of respiratory tract infections in childhood: A population-based prospective cohort study.

Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age. In a population-based cohort study among 5134 mother-child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied. After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects. High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections.

Iron overload leading to cirrhosis in a patient with hereditary spherocytosis and heterozygosity for H63D mutation in the HFE gene

Hereditary spherocytosis (HS) refers to a group of autosomal dominantly inherited heterogeneous hereditary haemolytic anaemias (HHA). Significant iron overload in HS is uncommon. Iron overload has been described as a complication of HS when there is co-inheritance of hereditary haemochromatosis (HH). H63D mutation accounts for a minority of hereditary hemochromatosis cases and does not cause iron overload in an otherwise healthy heterozygous carrier state. We present a 64-year-old man , diagnosed with HS presenting with cirrhosis without significant on-going haemolysis. He had a markedly high serum ferritin and transferrin saturation. Magnetic Resonance Imaging for liver iron concentration revealed haemochromatosis of the liver. HFE genotyping showed heterozygosity for the H63D mutant allele. Haemolysis in HS does not usually result in clinically significant iron excess leading to haemochromatosis and the presence of H63D heterozygous mutation will increase the risk of clinically significant iron overload which can lead to hepatic iron deposition and fibrosis. Therefore, if a patient with H63D mutation demonstrates clinically significant iron overload, clinicians should search for other factors that increase iron excess such as on-going haemolysis, alcohol abuse and presence of metabolic syndrome.

A Case of Autoimmune Hepatitis Chronic Liver Disease with Iron Overload

Autoimmune hepatitis (AIH) is a rare autoimmune disorder causing chronic inflammation in liver which affects all ages, both genders, and all ethnicities. It has a heterogenous presentation in which patients may either be asymptomatic, chronically ill or may present with acute liver failure [1]. The diagnosis should be considered in patients with acute or chronic liver dysfunction including patients with graft dysfunction after Liver Transplantation [1]. AIH does not have a signature diagnostic feature, and the diagnosis requires the presence of a constellation of typical features which can vary between patients with the same disease and can occur in other liver diseases. AIH like other inflammatory conditions is associated with increased ferritin levels (acute phase reactant) but normal transferrin saturation level. The presence of excessive ferritin in absence of high transferrin saturation helps differentiate secondary iron overload from hemochromatosis where transferrin saturation is high [2]. There are case reports of chronic liver disease and secondary iron overload. We report a rare case of chronic liver disease due to AIH and secondary iron overload leading to diagnostic dilemma encountered during our clinical practice.

#6917 IMPACT OF FUNCTIONAL IRON DEFICIENCY IN NON-ANEMIC HEMODIALYSIS PATIENT ON NEUROCOGNITIVE AND QUALITY OF LIFE: A SINGLE CENTER CROSS-SECTION STUDY

Abstract Background and Aims The clinical paradox of high ferritin levels and low TSAT is a condition known as "functional iron deficiency." This occurs when the body has adequate iron stores, as indicated by high ferritin levels, but the iron is not available for use in the body, as indicated by low TSAT levels. This can be caused by inflammation, chronic disease, or other conditions that interfere with the body's ability to absorb and utilize iron. Hemodialysis patients may suffer from both absolute and functional iron deficiency. Most studies was directed to study effect of absolute iron deficiency even without anemia, and the important of supplementing with oral or intravenous iron ; however, impact of functional iron deficiency without anemia and subsequently decision of iron supplementation especially in presence of high ferritin is still undetermined. Our aim is to assess the impact of functional iron deficiency without anemia in neurocognitive function and quality of life among hemodialysis patients in dialysis unit in urology and nephrology center Mansoura University. Method Patients on regular haemodialysis were screened using complete blood picture, transferrin saturation (TSAT) and serum ferritin to determine iron status. The Saint Louis University Mental Status assessed cognitive function. (SLUMS) Examination used for detecting mild cognitive impairment and dementia. Quality of life was assessed by 36-item short-form (SF-36). The SF-36 measures eight scales: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Results Among 70 patients maintained on regular hemodialysis, A 42 patients have normal hemoglobin level (above 12 mg/dl with high serum ferritin &amp;gt;300 ng/mL). They classified into two group: A 26 patients with high ferritin, high TSAT &amp;gt;20%, and normochromic red blood cells, A 16 patients with high ferritin level,low TSAT&amp;lt;20% and hypochromic red blood cells. Among the 26 patients, 17 male and 9 female, and among the 16 patients, 11 male and 5 female. The 26 patients have mean age of (41 +/- 13) and the 16 patients have mean age of (39 +/- 10). No significant difference between the two groups regarding sex and age with p value (0.5 and 0.1 respectively). Assessment of cognitive function by SLUM score revealed regarding normal group (4 have normal score, 18 have mild impairment of cognitive function and 4 have dementia score) and the iron deficient group (4 have normal score, 9 have mild impairment of cognitive function and 3 have dementia score) with no statistically different between the two group (P = .6).requarding quality of life, no statistically difference was fond between the two group regarding : physical functioning (p= 0.18), role physical (P = .11), bodily pain (p = 0.33), general health (p= 0.5), vitality (P = .41), social functioning (P = .2), role emotional (P = .4), and mental health (P = .21 ). Conclusion Non-anemic hemodialysis Patients with Functional iron deficiency has no statistically difference regarding neurocognitive function and quality of life from normal iron non-anemic patients.

Juvenile Hemochromatosis With Non-transfused Hemolytic Anemia Caused by a De Novo PIEZO1 Gene Mutation.

Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-transfused hemolytic anemia in children and young adults.

Impact of iron status on kidney outcomes in kidney transplant recipients

Iron plays an important role in hemodynamics and the immunity, independent of anemia. Since dynamic changes occur in iron storage after kidney transplantation (KT), we investigated the association between iron status and kidney outcomes in KT patients. We analyzed data from the KoreaN cohort study for Outcome in patients With KT (KNOW-KT). The iron status was classified into three groups based on ferritin or transferrin saturation (TSAT) levels one year after KT, with reference ranges of 20‒35% and 100‒300 ng/mL for TSAT and ferritin, respectively. The primary outcome was the composite outcome, which consisted of death, graft failure, and an estimated glomerular filtration rate decline ≥ 50%. In total, 895 patients were included in the final analysis. During a median follow-up of 5.8 years, the primary outcome occurred in 94 patients (19.8/1000 person-years). TSAT levels decreased one year after KT and thereafter gradually increased, whereas ferritin levels were maintained at decreased levels. The adjusted hazard ratios (95% confidence intervals) for the composite outcome were 1.67 (1.00–2.77) and 1.20 (0.60–2.40) in the TSAT > 35% and ferritin > 300 ng/mL groups, respectively. High iron status with high TSAT levels increases the risk of graft failure or kidney functional deterioration after KT.

Hereditary hemochromatosis beyond hyperferritinemia: Clinical and laboratory investigation of the patient's profile submitted to phlebotomy in two reference centers in southern Brazil.

Hereditary Hemochromatosis is a disorder characterized by iron deposition in several organs and hyperferritinemia. The most studied variants are linked to the HFE gene. In Brazil, surveys that characterize this population are scarce, with no sampling in the state of Rio Grande do Sul. Our objective is to carry out a data collection focusing on the profile of this population and the influence of the most frequently HFE variants. Two centers were enrolled: Hospital de Clínicas de Porto Alegre and Hospital São Vicente de Paulo. Patients with hyperferritinemia and undergoing phlebotomy were invited. Clinical data were collected, including HFE investigation. Among the descriptive data, the allele frequency of the C282Y variant (0.252) stands out, which differs from the national scenario. Systemic arterial hypertension was the most cited comorbidity. Differences between centers were observed, highlighting higher frequency of H63D cases in HSVP (p<0.01). Genotypes were stratified according to deleterious effect of C282Y variant. Higher transferrin saturation and number of phlebotomies were observed in the C282Y/C282Y cases (p<0.001). Positive family history for hyperferritinemia was more prevalent in compound heterozygotes (p<0.01). The results presented confirm the importance of encouraging such studies and reiterate the need for greater attention to this population.

Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis

Hepcidin deficiency in hereditary hemochromatosis (HH) leads to hyperabsorption of dietary iron and primary iron overload (Nemeth E., Science 2004). Therapeutic phlebotomy is used to reduce organ iron-overload in HH patients. However, persistent high transferrin-saturation (TSAT%) may result in toxic labile iron that can deposit in organs, leading to tissue damage and subsequent organ dysfunction. Additionally, newly diagnosed patients with severe iron overload require frequent phlebotomies during the induction phase of therapy that can last for many months, during which TSAT% levels may continue to be high even when serum ferritin levels are reduced. Rusfertide is a hepcidin mimetic peptide that has demonstrated potential benefit in reducing the need for therapeutic maintenance phlebotomy in a Phase 2 trial with hemochromatosis subjects who have previously required chronic phlebotomies to reduce and maintain ferritin and liver iron values within normal range (Kowdley KV, AASLD Hepatology 2021). To evaluate the potential benefits of co-treatment of hepcidin mimetic during induction phase of clinical management, we evaluated additive effects of PN23114 in combination with phlebotomy in HJV-/- mouse model for HH (129S-Hjvtm1Nca/J; Andrews NC, J Clin Invest. 2005). PN23114 is an analog of rusfertide with a single amino acid change and with similar pharmacokinetic and pharmacodynamic characteristics. Male HJV-/- mice at 8-12 weeks of age were treated with either PN23114 (7.5 mg/kg, TIW), phlebotomy (~0.3mL blood drawn, QW), or combination of both for a total of 46 days. We found that all three treatment strategies reduced iron concentrations in both heart and kidney, as compared to a baseline group that was terminated at start of study. None of the treatments were able to reduce liver iron but all three prevented further iron deposition in the liver as compared to baseline. It's possible that the length of phlebotomy treatment is not sufficient to result in iron removal from liver. Treatment with PN23114 redistributed the excess iron into spleen and duodenum, thereby significantly elevating spleen iron concentration, while co-treatment of PN23114 and phlebotomy did not result in marked iron sequestration in spleen. Serum ferritin was reduced in all three treatment groups, the group that received the PN23114 and phlebotomy co-treatment showed the largest reduction. Serum iron was normalized with PN23114 treatment and with co-treatment with PN23114 and phlebotomy. Phlebotomy treatment was not able to lower serum iron to normal levels. Our data overall indicate that combining hepcidin mimetic treatment along with phlebotomy may be more effective in quickly lowering TSAT% and labile iron, and thereby quickly reversing tissue iron deposition in specific organs. Titration of rusfertide to the desired clinical effect may be effective in combination with phlebotomy during the induction phase of clinical management to reduce the frequency and duration of phlebotomy treatment as well as lower the lingering high TSAT% levels.

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (β = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (β = -0.37; 95%CI = -0.39, -0.35), hepcidin (β = -0.22, 95%CI = -0.24, -0.20), and TSAT (β = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (β = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (β = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (β = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

Impact of Transferrin Saturation and Anemia on Radial Artery Calcification in Patients with End-Stage Kidney Disease.

Background: Arterial calcification is an important factor in determining the prognosis of patients with chronic kidney disease (CKD). Few studies on aortic calcification have involved radial artery calcification (RAC). This study aimed to analyze risk factors for RAC in patients with end-stage kidney disease (ESKD) and investigate the relationship between subsequent cardiovascular events (CVE) and vascular access trouble (VAT). Methods: This cohort study included 64 consecutive patients with ESKD who initiated hemodialysis and underwent a procedure for the creation of a primary radiocephalic arteriovenous fistula (RCAVF). Small arterial specimens were obtained from patients during RCAVF surgery. Tissue samples were stained with von Kossa, and arterial microcalcification was evaluated. We analyzed the association between preexisting arterial microcalcifications, clinical characteristics, CVE, and VAT. Results: In the univariate analysis, RAC patients demonstrated high systolic blood pressure (sBP), low hemoglobin (Hb), and low transferrin saturation (TSAT) (<0.05, <0.05, and <0.05, respectively). In the multivariate analysis, Hb (HR–0.516 (0.278–0.959), p < 0.05), TSAT (HR–0.0012 (0.00000248–0.597), p < 0.05), and sBP (HR–1.037 (1.001–1.073), p < 0.05) were independent risk factors for RAC. The cumulative incidence rate of CVE/VAT was not associated with RAC for one year. Conclusion: RAC was associated with sBP, TSAT, and anemia; however, no association with CVE/VAT was observed.

Iron Chelation with Deferasirox Suppresses the Appearance of Labile Plasma Iron During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation

During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favor infection and mediate transplantation-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peritransplantation period are sparse. In this study, we investigated the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities, and the tolerability of this treatment in the peritransplantation period. We conducted this single-center prospective observational study in 25 adults with iron overload (serum ferritin >1000 µg/L) undergoing allogeneic HSCT after myeloablative busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 post-transplantation. Iron parameters, including LPI, were obtained at the chelator's trough level daily until day 0 and then on days 4, 7, and 14. Data on infection (bacteremia or invasive fungal disease) and toxicity, as well as the tolerability of deferasirox, were collected until the end of the follow-up period on day 28. Data were analyzed descriptively. TfS levels exceeded 70% in median on 6 days (range, 4 to 10days) and in 63.6% (range, 36.4% to 90.9%) of the samples per patient, although in 19 of 25 patients (76%), no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only 6 patients (24%) showed mildly increased LPI values (≤0.5units) during the intake of deferasirox, 3 of whom had presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated, and no aggravation of toxicities was observed. Infection occurred in 5 patients (20%), including 3 of the 6 patients with elevated LPI values despite chelation therapy. In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, whereas the impact on transplantation-associated toxicities remains to be elucidated.

Association of ferritin and transferrin saturation with all-cause mortality, and the effect of concurrent inflammation: a danish cohort study

The association between ferritin and transferrin saturation (TS), respectively, and all-cause mortality is unclear. Furthermore, the influence of concurrent inflammation has not been sufficiently elucidated. We investigated these associations and the effect of concurrently elevated C-reactive protein (CRP), and accordingly report the levels associated with lowest all-cause mortality for females and males with and without inflammation. Blood test results from 161,921 individuals were included. Statistical analyses were performed in sex-stratified subpopulations, with ferritin or TS level as continuous exposure variables, and were adjusted for age, co-morbidity and inflammation status using CRP. An interaction was used to investigate whether the effect of ferritin or TS on all-cause mortality was modified by inflammation status (CRP ≥ 10 mg/L or CRP < 10 mg/L). Low and high ferritin and TS levels were respectively associated with increased all-cause mortality in females and in males. These associations persisted with concurrent CRP ≥ 10 mg/L. The ferritin level associated with lowest mortality was 60 µg/L for females and 125 µg/L for males with CRP < 10 mg/L. It was 52 µg/L for females and 118 µg/L for males with CRP ≥ 10 mg/L. The TS level associated with lowest mortality was 33.9% for females and 32.3% for males with CRP < 10 mg/L. It was 28.7% for females and 30.6% for males with CRP ≥ 10 mg/L. Our findings can nuance clinical interpretation and further aid in defining recommended ranges for ferritin and TS.

Iron-dependent BMP6 Regulation in Liver Sinusoidal Endothelial Cells Is Instructed by Hepatocyte-derived Secretory Signals.

Iron-dependent BMP6 Regulation in Liver Sinusoidal Endothelial Cells Is Instructed by Hepatocyte-derived Secretory Signals.