Serum Transferrin Saturation Research Articles

The Genetic Diagnostics of Hemochromatosis: Disparities in Low- Versus High-Income Countries.

This study provides a comprehensive overview of hereditary hemochromatosis (HH), a genetic condition characterized by iron overload due to excessive iron absorption. It elucidates diverse inheritance patterns and clinical manifestations by exploring mutations in critical genes such as HFE (hemochromatosis), HJV (hemojuvelin), HAMP (hepcidin antimicrobial peptide), TfR2 (transferrin receptor 2), and FP (ferroportin). The significance of early screening, diagnosis, and personalized management strategies based on genetic classification is emphasized, particularly in terms of high-income vs. low-income countries. Addressing challenges in diagnosis, genetic testing accessibility, and healthcare disparities, the study highlights the importance of early detection, cost-effective screening strategies, and enhancing healthcare outcomes globally. Advanced genetic testing in high-income countries facilitates early diagnosis and management, reducing complications such as liver disease and cardiomyopathy. In contrast, low-income populations face several barriers, including limited access to genetic testing, high costs, and inadequate healthcare infrastructure. Cost-effective serum ferritin (SF) and transferrin saturation (TS) tests and emerging point-of-care (POC) tests offer affordable diagnostic options for low-resource settings. Additionally, the ongoing development of hepcidin measurement methods holds promise for enhancing diagnostic capabilities. Implementing these strategies can aid healthcare providers in improving global HH management and reducing the burden of iron overload complications. Furthermore, the study underscores the need for public health initiatives to raise awareness about HH, promote routine screenings, and advocate for equitable healthcare policies. Collaborative efforts between governments, healthcare organizations, and research institutions are crucial in addressing the global burden of HH. By fostering international cooperation and resource-sharing, it is possible to bridge the gap between high-income and low-income countries, ensuring all individuals have access to the necessary diagnostic and treatment options. This holistic approach can ultimately lead to better health outcomes and improved quality of life for individuals affected by HH worldwide. This comprehensive examination of HH not only illuminates the genetic and clinical aspects of the condition but also provides a roadmap for addressing the multifaceted challenges associated with its diagnosis and management.

Prevalence of C282Y, H63D and S65C gene mutations in patients with hyperferritinemia undergoing therapeutic phlebotomy suspected of having hereditary hemochromatosis

Background: Hemochromatosis is an autosomal recessive disorder caused by excessive iron overload in parenchymal organs. In Brazil, the prevalence of hereditary hemochromatosis (HH) may vary compared to other countries due to different ethnical backgrounds according to the geographic region studied. The prevalence of C282Y mutation of the HFE gene ranges from three to eight times lower in Brazilians than in Caucasians of Northern European origin. Methods: A retrospective cross-sectional study was carried out in 222 patients submitted to therapeutic phlebotomy between March 2011 and July 2014 in a tertiary hospital blood center. The prevalence of HH was determined in 89 (47.3%) out of 188 (84.6%) patients presenting hyperferritinemia, and divided in two genotype groups: C282Y mutation and other mutations. The HH patients’ geographical and clinical characteristics, serum ferritin rate (SF) and transferrin saturation (TS) were analyzed. Results: The HH group consisted of 71 males (79.7%) and 18 (20.3%) females, with a median age of 51.5 ± 10.6 years. There were 36 (40.0%) symptomatic patients and 65 (73.0%) tested positive for the HFE mutation. The initial baseline TS values were significantly higher in primary HH patients (48.6%, IC 95% 43.2% - 55.7%) compared to those with secondary HH (35.0%, IC 95% 27.5% 41.8%, p=0.001). Conclusion: The prevalence of C282Y mutation was higher in this population from the South region compared to previous reports in the Brazilian population, yet inferior to that of Northern Europeans.

Anemia and Iron Profile in Hemodialysis and Nonhemodialysis Patients with Chronic Kidney Disease

Abstract BACKGROUND: Chronic kidney disease (CKD) is a global health concern, with anemia being a significant complication. Anemia in CKD patients is multifactorial and often leads to poorer outcomes. Assessing the iron profile, including serum ferritin, iron, and transferrin saturation, is crucial for identifying absolute or functional iron deficiency anemia (IDA). An objective evaluation of the iron profile is essential for effective and comprehensive management of anemia. MATERIALS AND METHODS: The study involved 100 adult patients with CKD and anemia, who were divided into two groups based on age and sex. The patients were divided into two groups: one received regular hemodialysis (HD) 2–3 times per week, whereas the other received no dialysis or dialysis infrequently. Exclusion criteria included infections, inflammation, renal injury, neoplasms, acute hemolysis, and thalassemia. RESULTS: Anemia is a common complication in patients with CKD, both those on HD and non-HD. Among the types of anemia observed, 50% of HD patients and 72% of non-HD CKD patients have normochromic anemia. In addition, 46% of HD patients and 24% of non-HD patients have IDA. Specifically, 24% of HD patients have absolute IDA and 22% have functional IDA, compared to 12% of both absolute and functional IDA in non-HD CKD patients, with a significant statistical difference between the two groups. Furthermore, serum iron and transferrin saturation levels show significant differences between HD and non-HD CKD patients. CONCLUSION: Anemia, especially IDA in CKD patients undergoing HD, requires accurate diagnosis through transferrin saturation and serum iron levels, and customized treatment based on dialysis status and anemia type is crucial.

Mendelian Randomization Analysis of Systemic Iron Status and Risk of Different Types of Kidney Disease.

With rapid increases in incidence, diverse subtypes, and complicated etiologies, kidney disease remains a global public health problem. Iron, as an essential trace element, has pleiotropic effects on renal function and the progression of kidney diseases. A two-sample Mendelian randomization (MR) analysis was implemented to determine the potential causal effects between systemic iron status on different kidney diseases. Systemic iron status was represented by four iron-related biomarkers: serum iron, ferritin, transferrin saturation (TfSat), and total iron binding capacity (TIBC). For systemic iron status, 163,511, 246,139, 131,471, and 135,430 individuals were included in the genome-wide association study (GWAS) of serum iron, ferritin, TfSat, and TIBC, respectively. For kidney diseases, 653,143 individuals (15,658 cases and 637,485 controls), 657,076 individuals (8160 cases and 648,916 controls), and 659,320 individuals (10,404 cases and 648,916 controls) were included for immunoglobulin A nephropathy (IgAN), acute kidney disease (AKD), and chronic kidney disease (CKD), respectively. Our MR results showed that increased serum iron [odds ratio (OR): 1.10; 95% confidence interval (95% CI): 1.04, 1.16; p < 0.0042], ferritin (OR: 1.30; 95% CI: 1.14, 1.48; p < 0.0042), and TfSat (OR: 1.07; 95% CI: 1.04, 1.11; p < 0.0042)] and decreased TIBC (OR: 0.92; 95% CI: 0.88, 0.97; p < 0.0042) were associated with elevated IgAN risk. However, no significant associations were found between systemic iron status and AKD or CKD. In our MR study, the genetic evidence supports elevated systemic iron status as a causal effect on IgAN, which suggests a potential protective effect of iron chelation on IgAN patients.

Iron Status in Male Type 2 Diabetic Patients and Its Association with Their Glycemic Status

Background &amp; objective: Alteration in iron metabolism may occur in diabetic patients especially those who have poor glycemic control. Serum iron is involved in free radical formation associated with hyperglycemia and causes diabetic complications. The present study was undertaken to observe the iron status and its relation with glycemic control in male type 2 diabetic patients. Methods: This cross-sectional analytical study was carried out in the Department of Physiology, Sir Salimullah Medical College (SSMC), Dhaka from July 2017 to June 2018. A total of 48 diagnosed male type 2 diabetic patients (cases) were recruited from the Out-patient Department (OPD) of Endocrinology based on predefined eligibility criteria. Of them, 24 had good glycemic control (HbA1c level &lt; 7%) (Group B1) and 24 had poor glycemic control (HbA1c level ≥ 7%) (Group B2). To compare the outcome (serum iron status) of these diabetic patients, another 48 age- and BMI-matched healthy non-diabetic male subjects were selected from personal contact as control. While diabetes and glycemic status (fasting blood glucose level, and HbA1c) of the diabetic patients were exposure variables, serum iron, serum total iron binding capacity (TIBC), transferrin saturation, and serum ferritin were the outcome variables. Results: The mean age of the subjects of either study group was around 43 and there was no significant difference between the groups concerning age (p = 0.610). The distribution of BMI and serum creatinine between groups was also similar (p = 0.135 and p = 0.134 respectively). The cases had a significantly higher level of serum iron, transferrin saturation, and an insignificantly lower total iron binding capacity (TIBC) than their non-diabetic peers (p = 0.045, p = 0.036, and p = 0.061 respectively). A comparison of outcome variables among the three groups shows that the groups were significantly heterogeneous in terms of serum iron, TIBC, transferrin saturation, haemoglobin level (p = 0.032, p = 0.012, p = 0.008 and p = 0.018 respectively). The associations were more conspicuous in patients with poor glycemic status. Correlation analyses revealed that while there was a significant linear correlation between serum iron and HbA1c (r = + 0.376, p &lt; 0.01), it was negatively correlated with serum TIBC (r = -0.478, p &lt; 0.001). The glycemic status (HbA1c) was also found to be linearly correlated with serum ferritin and transferrin saturation (r = + 0.354, p = 0.013 and r = + 0.462, p &lt; 0.001 respectively). Conclusion: The study concluded that type 2 diabetic patients have a significantly higher level of serum iron, transferrin saturation, and a lower total iron binding capacity (TIBC) than the non-diabetic healthy subjects, all of which may lead to reduced synthesis of hemoglobin. The compromised iron metabolism is even more evident as the hyperglycemia aggravates. Ibrahim Card Med J 2023; 13 (1&amp;2): 32-39

SLC40A1-related hemochromatosis associated with a p.Y333H mutation in mainland China: a pedigree report and literature review

BackgroundHaemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete.Case presentationWe report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin.ConclusionsThis study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

Analysis of erythrocyte and iron study data among plateletpheresis donors in Hangzhou, China

BackgroundThe purpose of this study is to obtain the iron parameters level of blood donors and the population who need to pay attention to iron parameters level in this area. MethodsA total of 993 plateletpheresis donors were included in this study, including 798 males and 195 females. The results of erythrocyte and iron parameters of blood donors were compared and analyzed in different groups according to the gender, age and number of blood donations. ResultThe proportion of men and women with low serum ferritin (SF) levels was 10.8 % and 27.7 %, respectively. The mean levels of serum iron (SI), SF, transferrin saturation (Tfs), hemoglobin (Hb) and hematocrit (HCT) of male blood donors decreased with the increase of age groups, but there was no significant statistical difference between the results of female blood donors. The level of SI, SF, Tfs, Hb and HCT of male donors decreased with the increase of blood donations in the past year, while TRF and TIBC increased. The level of Hb, HCT and SF of female donors showed no significant downward trend, while the levels of TRF increased with increasing donations in the past year, excluding first-time donors. The SI of female donors trended down, and TIBC trended up with increasing donations. ConclusionBlood collection institutions need to focus on iron parameters levels in older and frequent male donors, and young fertile female donors.

Hematological parameters of healthy pregnant women in three trimesters compared with parameters of non-pregnant women

Anemia is a public health problem, especially in developing countries. All over the world iron deficiency is the main cause of anemia, especially during pregnancy. Pregnant women belong to the most vulnerable population group in Iraq.The objective: to determine the impact of pregnancy on hematological parameters and to compare the hematological indicators in different periods of gestation with the indicators of non-pregnant women.Materials and methods. The study was conducted over a three-month period at Baghdad hospitals and medical centers, including Baghdad Teaching Hospital, Al-Karam Hospital, and a health center in Al-Dorrah and Al-Shaab, Baghdad province, from September 1 to December 1, 2022. 60 pregnant women, 20 persons in each trimester, and 25 non-pregnant women (control) aged 18–35 years were included in the study. All participants were examined for hematological parameters: hemoglobin, erythrocytes, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), measured of the concentration of hemoglobin in red blood cells (MCHC) and determined the level of iron in the blood (serum iron – SI, total iron binding capacity – TIBC, transferrin saturation – TS and serum ferritin – SF).Results. A significant decrease in the hematological indicators of pregnant women in the first trimester of pregnancy compared to non-pregnant women was established – hemoglobin, erythrocytes, PCV, MCH, MCHC. The dynamics of the decrease in the level of these parameters increases in the second trimester, and also progressively decreases in the third trimester, which leads to anemia.Starting from the first trimester and during the second and third trimesters, a decrease in the level of serum iron, transferrin saturation and serum ferritin was found in pregnant women compared to non-pregnant women, but the level of TIBC increased. During the second trimester, the need for iron begins to increase and continues to growth until the end of pregnancy. In addition, these research results indicate the importance of iron deficiency in the development of iron deficiency anemia.Conclusions. During pregnancy, anemia and a decrease in the level of some hematological parameters were determined, which progresses with increasing gestational age and is less compared to that in non-pregnant women. A decrease in the level of iron in the blood serum was established from the first to the third trimester of pregnancy. The severity of anemia is related to many factors, especially age, education level, low income, type of diet and parity.

Clinical management of iron deficiency anemia in Japan: iron prescription patterns, treatment effectiveness, and assessments

Iron deficiency anemia is one of the most common types of anemia, but real-world clinical management practices in Japan are unclear. This study retrospectively explored iron prescription patterns, treatment effectiveness, and assessments. Patients with at least one treatment period between September 2020 and September 2022 were included and classified into three groups (ferric carboxymaltose [FCM]: 7437 patients, saccharated ferric oxide [SFO]: 98,648 patients, and oral iron: 359,547 patients). Iron-related laboratory values over time and testing proportions were evaluated. Median baseline hemoglobin levels were lowest with FCM (FCM: 8.10 g/dL, SFO: 8.70 g/dL, oral iron: 9.70 g/dL), but changes in hemoglobin levels by 12 weeks were greatest with FCM (FCM: 3.20 g/dL, SFO: 2.60 g/dL, oral iron: 1.70 g/dL). The median serum ferritin level at 8 weeks after FCM treatment was 43.70 ng/mL for ≤500 mg, versus 123.30 ng/mL for >500 to ≤1500 mg. All groups had a low proportion of serum ferritin and transferrin saturation (TSAT) testing at diagnosis (<38%), which decreased further for post-treatment assessment (<24%). This study suggests the importance of prescribing an appropriate total iron cumulative dose per the package insert, along with diagnosis and assessments based on serum ferritin/TSAT.

#2938 The association between serum iron biomarkers and health-related quality of life in patients undergoing dialysis

Abstract Background and Aims Anemia is a very common complication of chronic kidney disease, affecting most patients undergoing dialysis. Iron deficiency, one of the causes of anemia, is generally a second consideration in the management of anemia. Nephrologists mainly focus on the correction of hemoglobin, often prescribing iron therapy for this indication only. However, iron has important physiological functions besides erythropoiesis. Conversely, iron overload can lead to oxidative stress and cellular damage. Therefore, nephrologists have been cautious to prescribe iron therapy to patients with already high serum iron levels. This caution has been underscored by studies linking higher levels of iron to increased mortality. Unfortunately, evidence is lacking regarding the impact of iron on important patient-reported outcomes like health-related quality of life (HRQoL). Therefore, the aim of this study is to explore the association between serum iron biomarkers, health-related quality of life (HRQoL) and the presence of anemia-related symptoms over a one-year period in patients undergoing dialysis. Method Data were obtained from the multicenter, prospective, observational Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes (DOMESTICO). Adult patients new to dialysis were included, and had a baseline and follow-up assessments at 3, 6 and 12 months, with measurements of serum iron biomarkers ferritin and transferrin saturation (TSAT). HRQoL, encompassing physical and mental HRQoL, was measured using the validated 12-item Short Form Health Survey (SF12, summary scores ranging from 0 to 100). The presence of anemia-related symptoms: fatigue, shortness of breath, restless legs and muscle cramps were assessed using the Dialysis Symptom Index. Patients were categorized into 4 groups depending on their ferritin levels (μg/L): &amp;lt;200, 200–500 (reference), &amp;gt;500–700 and &amp;gt;700, and into 3 groups depending on their TSAT levels (%) at baseline: &amp;lt;20, 20–39 (reference), and ≥40. Longitudinal analyses were conducted using sequential conditional mean models to adjust for time-independent and time-varying confounding. All analyses captured the overall association over a one-year follow-up. Results We included 1069 patients, of whom 76% started hemodialysis, the median age was 68, 66% were male, and 32% were receiving iron therapy. Over a one-year follow-up, patients with ferritin &amp;lt;200 μg/L had similar physical HRQoL (MD=0.5 ; 95% CI –2.4 to 3.3 ) and mental HRQoL (MD=0.04 ; 95% CI -2.0 - 2.0) compared to the reference group with ferritin between 200–500 μg/L. Patients with ferritin between 501–700 μg/L also had a similar physical and mental HRQoL mental HRQoL compared to those with ferritin between 200-500 μg/L. This was also found for patients with ferritin above 700 μg/L (Fig. 1). Similarly, patients with TSAT levels below 20% and patients with TSAT levels ≥40% had comparable physical and mental HRQoL compared the reference group of patients with a TSAT between 20-39% (Fig. 2). For the secondary objectives, we found no significant differences in the anemia-related symptoms fatigue, shortness of breath, restless legs, or muscle cramps between patients with various levels of ferritin nor between the various TSAT groups. Conclusion We found that dialysis patients with higher or lower levels of ferritin or TSAT did not have a significantly different physical or mental HRQoL over a one year-follow up after starting dialysis. Similarly, no significant differences were found in the presence of fatigue, shortness of breath, restless legs, and muscle cramps between patients with these higher or lower levels of serum iron markers. And although iron levels do have impact on clinical outcomes such as mortality, these results suggest that they do not influence patient reported outcomes such as physical and mental HRQoL.

Ferritin Levels on Hospital Admission Predict Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest: A Prospective Observational Single-Center Study.

Out-of-hospital cardiac arrest (OHCA) is a major health concern in Western societies. Poor outcome after OHCA is determined by the extent of hypoxic-ischemic encephalopathy (HIE). Dysregulation of iron metabolism has prognostic relevance in patients with ischemic stroke and sepsis. The aim of this study was to determine whether serum iron parameters help to estimate outcomes after OHCA. In this prospective single-center study, 70 adult OHCA patients were analyzed. Serum ferritin, iron, transferrin (TRF), and TRF saturation (TRFS) were measured in blood samples drawn on day 0 (admission), day 2, day 4, and 6 months after the return of spontaneous circulation (ROSC). The association of 4 iron parameters with in-hospital mortality, neurological outcome (cerebral performance category [CPC]), and HIE was investigated by receiver operating characteristics and multivariate regression analyses. OHCA subjects displayed significantly increased serum ferritin levels on day 0 and lowered iron, TRF, and TRFS on days 2 and 4 after ROSC, as compared to concentrations measured at a 6-month follow-up. Iron parameters were not associated with in-hospital mortality or neurological outcomes according to the CPC. Ferritin on admission was an independent predictor of features of HIE on cranial computed tomography and death due to HIE. OHCA is associated with alterations in iron metabolism that persist for several days after ROSC. Ferritin on admission can help to predict HIE.

Association among attention-deficit hyperactivity disorder, restless legs syndrome, and peripheral iron status: a two-sample Mendelian randomization study.

Epidemiological evidence indicates a high correlation and comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and Restless Legs Syndrome (RLS). We aimed to investigate the causal relationship and shared genetic architecture between ADHD and RLS, as well as explore potential causal associations between both disorders and peripheral iron status. We performed two-sample Mendelian randomization (MR) analyses using summary statistics from genome-wide meta-analyses of ADHD, RLS, and peripheral iron status (serum iron, ferritin, transferrin saturation, and total iron binding capacity). Additionally, we employed linkage disequilibrium score regression (LDSC) to assess genetic correlations between ADHD and RLS using genetic data. Our MR results supports a causal effect from ADHD (as exposure) to RLS (as outcome) (inverse variance weighted OR = 1.20, 95% CI: 1.08-1.34, p = 0.001). Conversely, we found no a causal association from RLS to ADHD (inverse variance weighted OR = 1.04, 95% CI: 0.99-1.09, p = 0.11). LDSC analysis did not detect a significant genetic correlation between RLS and ADHD (Rg = 0.3, SE = 0.16, p = 0.068). Furthermore, no evidence supported a causal relationship between peripheral iron deficiency and the RLS or ADHD onset. However, RLS may have been associated with a genetic predisposition to reduced serum ferritin levels (OR = 1.20, 95% CI: 1.00-1.04, p = 0.047). This study suggests that ADHD is an independent risk factor for RLS, while RLS may confer a genetic predisposition to reduced serum ferritin levels. The GWAS summary data utilized originated from populations of European ancestry, limiting the generalizability of conclusions to other populations. The potential co-occurrence of RLS in individuals with ADHD should be considered during diagnosis and treatment. Moreover, iron supplementation may be beneficial for alleviating RLS symptoms.

IMPACT OF IRON DEFICIENCY ON CLINICAL,BIOCHEMICAL AND ECHOCARDIOGRAPHIC PARAMETERS IN HEART FAILURE PATIENTS

Objective: Iron deficiency (ID) is prevalent in HF irrespective of the presence of anemia. Objective was to study the impact of iron deficiency on clinico- biochemical and echocardiographic parameters of heart failure patients. Design and method: Sixty adult heart failure patients were included in observational study with consent. Excluded were anemia not attributed to ID,IV iron or blood transfusion administered in last 3 months,Oral iron supplements in previous 4 weeks, dyspnea of non cardiac origin,clinical evidence of ACS, TIA or stroke within the last 30 days,CABG, PTCA, cardiac device implant/resynchronisation therapy or any other cause leading to significant blood loss within the last 30 days. Demographic information and medical history including NYHA grade of Dyspnea at presentation were noted. Iron studies,Nt proBNP levels and echocardiography were performed and appropriate statistical tests were applied. Results: Mean Age of cases was 57 (+/-5) years. Most common presenting symptom was breathlessness in 49(81.7%)patients followed by leg swelling in 46 (76.7%) and chest pain in 34 (56.7%)where as among the signs on examination; raised JVP was recorded in 18 (30%),hepatomegaly in 30(50%), splenomegaly in 17(28.3%),ascites in 19(31.7%),S3 gallop rhythm and basal lung crepitations in 10(16.6%) and 47(78.3%)patients respectively. Majority of patients were in grade2 NYHA. Iron Deficiency as determined by serum ferritin of &lt;100 μg/mL or ferritin 100-300 μg/ml but transferrin saturation less than 20% was present in 43(71.7%)patients whereas in 17 patients(28.3%) it was not observed. Mean serum Iron was 36.417μg/dl,mean serum ferritin was 242.89 μg/ml and mean transferrin saturation was 17.25%. Mean Hb was 10 gm% and mean NTProBNP was 11,324.65 picogm/ml.Mean Ejection fraction was 38%(+/- 12.75%).NtProBNP levels did not show any correlation with iron profile whereas LVEF showed a significant correlation with serum Iron as well as transferrin saturation (p &lt;0.001). Serum iron and Transferrin saturation were significantly reduced with the progression of severity grade (p&lt;0.006&amp;0.001 respectively). Conclusions: Targeting iron deficiency in HF can improve outcomes as it targets mitochondrial dysfunction. This makes ID stand out as a therapeutic target in HF since it is relatively easy to diagnose and treat.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia.

Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intravenous iron supplementation improves energy metabolism of exercising skeletal muscles without effect on either oxidative stress or inflammation in male patients with heart failure with reduced ejection fraction.

Skeletal muscle dysfunction is a feature of heart failure (HF). Iron deficiency (ID) is prevalent in patients with HF associated with exercise intolerance and poor quality of life. Intravenous iron in iron deficient patients with HF has attenuated HF symptoms, however the pathomechanisms remain unclear. The aim of study was to assess whether intravenous iron supplementation as compared to placebo improves energy metabolism of skeletal muscles in patients with HF. Men with heart failure with reduced ejection fraction (HFrEF) and ID were randomised in 1:1 ratio to either intravenous ferric carboxymaltose (IV FCM) or placebo. In vivo reduction of lactates by exercising skeletal muscles of forearm was analyzed. A change in lactate production between week 0 and 24 was considered as a primary endpoint of the study. There were two study arms: the placebo and the IV FCM (12 and 11 male patients with HFrEF). At baseline, there were no differences between these two study arms. IV FCM therapy as compared to placebo reduced the exertional production of lactates in exercising skeletal muscles. These effects were accompanied by a significant increase in both serum ferritin and transferrin saturation in the IV FCM arm which was not demonstrated in the placebo arm. Intravenous iron supplementation in iron deficient men with HFrEF improves the functioning of skeletal muscles via an improvement in energy metabolism in exercising skeletal muscles, limiting the contribution of anaerobic reactions generating ATP as reflected by a lower in vivo lactate production in exercising muscles in patients with repleted iron stores.

Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

Rocaglamide regulates iron homeostasis by suppressing hepcidin expression

The anemia of inflammation (AI) is characterized by the presence of inflammation and abnormal elevation of hepcidin. Accumulating evidence has proved that Rocaglamide (RocA) was involved in inflammation regulation. Nevertheless, the role of RocA in AI, especially in iron metabolism, has not been investigated, and its underlying mechanism remains elusive. Here, we demonstrated that RocA dramatically suppressed the elevation of hepcidin and ferritin in LPS-treated mice cell line RAW264.7 and peritoneal macrophages. In vivo study showed that RocA can restrain the depletion of serum iron (SI) and transferrin (Tf) saturation caused by LPS. Further investigation showed that RocA suppressed the upregulation of hepcidin mRNA and downregulation of Fpn1 protein expression in the spleen and liver of LPS-treated mice. Mechanistically, this effect was attributed to RocA's ability to inhibit the IL-6/STAT3 pathway, resulting in the suppression of hepcidin mRNA and subsequent increase in Fpn1 and TfR1 expression in LPS-treated macrophages. Moreover, RocA inhibited the elevation of the cellular labile iron pool (LIP) and reactive oxygen species (ROS) induced by LPS in RAW264.7 cells. These findings reveal a pivotal mechanism underlying the roles of RocA in modulating iron homeostasis and also provide a candidate natural product on alleviating AI.

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.

No genetic causal association between iron status and pulmonary artery hypertension: Insights from a two‐sample Mendelian randomization

AbstractTo explore the genetic causal association between pulmonary artery hypertension (PAH) and iron status through Mendelian randomization (MR), we conducted MR analysis using publicly available genome‐wide association study (GWAS) summary data. Five indicators related to iron status (serum iron, ferritin, total iron binding capacity (TIBC), soluble transferrin receptor (sTfR), and transferrin saturation) served as exposures, while PAH was the outcome. The genetic causal association between these iron status indicators and PAH was assessed using the inverse variance weighted (IVW) method. Cochran's Q statistic was employed to evaluate heterogeneity. We assessed pleiotropy using MR‐Egger regression and MR‐Presso test. Additionally, we validated our results using the Weighted median, Simple mode, and Weighted mode methods. Based on the IVW method, we found no causal association between iron status (serum iron, ferritin, TIBC, sTfR, and transferrin saturation) and PAH (pβ &gt; 0.05). The Weighted median, Simple mode, and Weighted mode methods showed no potential genetic causal association (pβ &gt; 0.05 in the three analyses). Additionally, no heterogeneity or horizontal pleiotropy was detected in any of the analyses. Our results show that there are no genetic causal association between iron status and PAH.

Serum iron Profile of Patients with Sickle Cell Disease and its Association with Socio-demographic Characteristics and Duration of Diagnosis.

Sickle cell anemia is the most common hemoglobinopathy in the world. The study aimed to evaluate the iron profile and its association with socio-demographic characteristics in patients with sickle cell disease. A hospital-based descriptive cross-sectional study was conducted to know the iron profile and its socio-demographic association in patients with sickle cell disease. The average serum iron, TIBC, and transferrin saturation were 16.75 ± 6.40 mcgMole/L, 69.46 ± 16.94 mcg/dl and 25.15 ± 12.51% respectively. The serum ferritin ranged from 10.00 to 3000.00 ng/ml. The proportion of participants with normal serum iron, TIBC, serum ferritin, and transferrin saturation were 86.10%, 0.00%, 33.90% and 36.40% respectively. All of the participants of this study had low TIBC (1005), and more than half of the participants had elevated serum ferritin (56.40%). Iron overload is a common complication of sickle cell disease. There was no association of age and sex with iron profile. The TIBC variation between the Chaudhary ethnic group compared to other ethnic groups signifies the ethnic role in the iron profile.