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Transfusion dependent thalassemia (TDT) patients require a regular blood transfusion to survive. Without adequate transfusion support, they suffer many complications, and have a short life span. Near about 200 milligrams of iron remains within a single Red cell concentrate (RCC) unit. So, blood transfusion acts as a double-edged sword, prolonging life while eventually leading to iron overload. For patients who are receiving transfusions for several years, iron accumulation causes different types of morbidity including thyroid failure. Though serum ferritin is a simple tool for measuring the iron load of the body, it is often misleading. Because, in first 100 unit of blood transfusion serum ferritin levels increase steadily. After that, this relation is not simple. Serum ferritin may increase in chronic inflammation or decrease in vitamin C deficiency, which may be misleading. The study aimed to identify a simple predictor of hypothyroidism in TDT patients. This cross-sectional study conducted from April 2018 to September 2019 includes 64 TDT patients according to selection criteria. Among them 43 were male and 21 were female TDT patients, with a mean age of 25.5 years. Body iron load was estimated by serum ferritin level. Pearson correlation test was done to measure the correlation of serum TSH level with serum ferritin, unit of blood transfused so far and duration of receiving transfusion therapy. All of these three variables had positive correlation with serum TSH level (r value 0.241, 0.319 and 0.332 respectively). Level of correlation of serum TSH was statistically significant with unit of blood transfused (p=0.010) and with duration of transfusion therapy taken (p=0.007) but not with serum ferritin level (p=0.055). Meticulous transfusion history taking is more important than investigation reports like serum ferritin level to predict hypothyroidism in TDT patients.

With the aging of the global population and the increase in the number of people with conditions such as obesity, the incidence of osteoarthritis (OA) is increasing annually. Clinical studies have shown that excessive accumulation of iron in joints is associated with age-related OA. However, there have been no reports on the relationship between iron metabolism and osteoarthritis. A STROBE-compliant cross-sectional observational study, was carried out and analyzed from the National Health and Nutrition Examination Survey from 2001 to 2020, including data on serum iron, transferrin saturation, serum ferritin, total iron-binding capacity, and transferrin receptors, as well as data on osteoarthritis. This cross-sectional study was conducted to explore the relationship between serum iron levels, osteoarthritis, and related metabolic factors. By adjusting the model and using quantile logistic regression models, the interaction between human body iron content and the aforementioned variables was analyzed. A total of 56,323 participants over 5 cycles were assessed for iron levels. After adjusting the model for age, sex, race, education level, marital status, total energy intake, physical activity, drinking, BMI, smoking, hypertension, and diabetes, we found that in different quantile regression results, serum iron was associated with OA, Q4: OR = 1.231 (95%CI: 1.009-1.501, P < .05). Ferritin is associated with OA, Q2: OR = 1.309 (95%CI: 1.012-1.692, P < .05); Q3: OR = 1.424 (95%CI: 1.129-1.797, P < .01); Q4: OR = 1.280 (95%CI: 1.013-1.616, P < .05). This cross-sectional study found that serum iron and transferrin saturation levels were positively correlated with OA incidence, suggesting that iron overload is a risk factor for OA. Large-sample prospective cohort studies are needed to confirm the correlation between iron overload and OA., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Transfusion dependent β-thalassemia is a genetic blood disorder characterized by chronic anaemia. Blood transfusion is lifesaving but comes at a cost. Iron overload emerges as a prime culprit as a free radicals damage endothelial cells. Chronic anaemia further disrupts oxygen delivery, exacerbating the oxidative stress. Increased levels of met-haemoglobin and malondialdehyde compromise endothelial function. This research sheds light on the impact of met-haemoglobin and oxidative stress on endothelial function in 50 patients with transfusion dependent β-thalassemia major compared to 50 healthy individuals as control. Blood samples were collected & subjected to CBC, biochemical analysis including creatinine, ferritin, CRP, LDH, and HCV antibodies. Oxidative stress was assessed using met-haemoglobin & malondialdehyde. Endothelial dysfunction was evaluated by endothelial activation and stress index (EASIX). EASIX, met-haemoglobin and malondialdehyde were significantly increased in patients (1.44 ± 0.75, 2.07 ± 0.2, 4.8 ± 0.63; respectively) compared to the control (0.52 ± 0.24,0.88 ± 0.34,0.8 ± 0.34; respectively). Significant strong positive correlation was found between EASIX and met-haemoglobin, malondialdehyde, serum ferritin and CRP (P = 0.00, r = 0.904, P = 0.00, r = 0.948, P = 0.00, r = 0.772, P = 0.00, r = 0.971; respectively. Met-haemoglobin as well as EASIX should be routinely estimated to assess endothelial function especially before the decision of splenectomy. Antioxidant drugs should be supplemented., (© 2024. The Author(s).)

Ferritin is one of the most requested blood tests in both primary and inpatient care, and high values occur frequently. One of the greatest challenges in the investigation of hyperferritinemia is to determine if there is a presence of iron overload. Patient history (chronic liver disease, excessive alcohol consumption, hereditary factors), clinical features (metabolic syndrome, acute or chronic inflammation, infection, malignancy) and biochemical tests (ferritin, transferrin saturation, hemoglobin, liver enzymes, CRP/SR, phosphatidyl ethanol, lipid profile, glucose) facilitate the determination of the cause of hyperferritinemia. High transferrin saturation indicates iron overload, which is usually linked to hereditary hemochromatosis. In the case of homozygosity of the HFE mutation p.C282Y in the presence of hyperferritinemia, venesection can be started without further investigations, while in the absence of HFE mutations a possible iron excess must be validated with magnetic resonance imaging (MRI) for iron determination before venesection is started. Dysmetabolic iron overload syndrome (DIOS) or alcohol-related hemosiderosis can be treated with venesection in selected cases if there is a significant deposition of iron in the liver on MRI. An individual with ferritin below 1000 µg/L, a normal transferrin saturation, and normal liver tests does not need further investigations and can be followed in primary care. We propose an algorithm for the investigation of hyperferritinemia that facilitates the investigation both in primary and inpatient care.

Most of the thalassemic children of Bangladesh are receiving repeated blood transfusion. But they do not receive chelation therapy due to financial constraints. As a result, iron overload occurs in various organs of these children. Extra iron that is loaded in thyroid gland causes thyroid dysfunction. This study was undertaken to evaluate thyroid status in children with transfusion dependent Thalassemia patient. This cross-sectional analytical study was conducted in the Department of Pediatrics, Mymensingh Medical College Hospital, Bangladesh from September 2016 to April 2018. Children having thalassemia diagnosed by Hb electrophoresis, aged 3-12 years of both sexes were included as study group. Children of same age and sex admitted in indoor of Mymensingh Medical College Hospital with minor illness and without thalassemia were taken as comparison group. Purposive Sampling technique was applied. Serum FT₄, TSH and ferritin level were estimated in all children. Data analysis was done with Statistical Package for Social Science (SPSS) version 21.0. A total of 60 patients were enrolled as study group and another 60 patients were compared as comparison group. Mean ages of study group was 7.88±2.55 years and comparison group were 7.22±2.48 years. The mean pre-transfusion hemoglobin, serum ferritin, serum FT₄ and serum TSH level were found 6.23±0.60 gm/dl, 2658.33±879.39 ng/ml, 15.14±4.40 fmol/mL, 4.29±4.60 μIU/mL respectively in study group. The mean serum FT₄ was found significantly lower and mean serum TSH was significantly higher in thalassemic children in comparison to non-thalassemic children (p= <0.05). Frequency of subclinical hypothyroidism was found significantly higher in study group (25.0%) compared to comparison group (3.3%) (p=0.001). Mean serum ferritin level was found significantly higher in hypothyroid cases. Mean FT₄ level was significantly lower and mean TSH level was significantly higher in hypothyroid thalassemic patients (p= <0.001). Significant positive correlation between serum ferritin level and serum TSH level was found. Higher serum ferritin level was found significantly associated with the development of hypothyroidism in thalassemic patients.

Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron-related outcomes in 101 patients on chronic RCE with a post-procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre-procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post-procedure Ht targeted at 34% is not iron-neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Sickle cell disease (SCD) is a prevalent inherited blood disorder arising from a single point mutation that results in substitution of valine with glutamic acid in the Beta hemoglobin chain, making red blood cells assume a banana shape under low oxygen state. It is most prevalent in sub-Saharan Africa, affecting approximately 2% of the population in Mali. This study aimed to evaluate the iron status and associated hematological parameters in SCD patients at steady state in an environment with a high prevalence of iron deficiency. A cross-sectional study was conducted at the Center de Recherche et de Lutte contre la Drépanocytose (CRLD) in Bamako, Mali, involving 757 SCD patients aged 10 to 29 years. Iron deficiency was defined as serum ferritin < 20 ng/mL, while iron overload was associated with serum ferritin > 500 ng/mL. The study population consisted of 171 (22.6%) hemolytic phenotypes (SS and Sβ 0 ) and 586 (77.4%) viscous phenotypes (SC and Sβ + ). Iron deficiency was found in 19 SCD patients (2.5%), with a higher prevalence in the SC phenotype (68.4%). All iron-deficient subjects exhibited microcytosis (MCV < 80 fL) and hypochromia (MCH < 26 pg). Hemoglobin levels < 12 g/dL were observed only in homozygous SCD patients. Low reticulocyte counts were noted in iron-deficient subjects with SC and Sβ+ phenotypes, but not in iron-deficient SS subjects. Serum C-reactive protein (CRP) was normal (< 10 mg/L) in all iron-deficient subjects, excluding iron deficiency due to chronic inflammation. Iron deficiency was observed among 2.5% of the study population, with a predominant occurrence among those with SC phenotype. All iron deficient subjects had microcytosis and hypochromia. Hemoglobin levels below 12 g/dL were only found in homozygous SCD patients. Additionally, low reticulocyte counts were noted in iron deficient patients with SC and Sβ+ phenotypes, though not in those with the SS phenotype. These findings contribute to the understanding of iron status in SCD patients in an African context and highlights the importance of monitoring iron levels in these population to prevent complications associated with iron deficiency or overload.

Background/objectives: Sickle cell anemia (SCA) is marked by hypoxia, inflammation, and secondary iron overload (IO), which potentially modulate hepcidin, the pivotal hormone governing iron homeostasis. The aim was to evaluate the iron incorporation in red blood cells (RBC) in SCA pediatric patients, considering the presence or absence of IO., Subjects/methods: SCA children (n = 12; SCA total ) ingested an oral stable iron isotope ( 57 Fe) and iron incorporation in RBC was measured after 14 days. Patients with ≥1000 ng/mL serum ferritin were considered to present IO (SCAio+; n = 4) while the others were classified as being without IO (SCAio-; n = 8). Liver iron concentration (LIC) was determined by Magnetic Resonance Imaging (MRI) T2* method., Results: The SCAio+ group had lower iron incorporation (mean ± SD: 0.166 ± 0.04 mg; 3.33 ± 0.757%) than SCAio- patients (0.746 ± 0.303 mg; 14.9 ± 6.05%) (p = 0.024). Hepcidin was not different between groups. Iron incorporation was inversely associated with serum ferritin level (SCA total group: r = -0.775, p = 0.041; SCAio- group: r = -0.982; p = 0.018) and sickle hemoglobin (HbS) presented positive correlation with iron incorporation (r = 0.991; p = 0.009) in SCAio- group. LIC was positively associated with ferritin (SCA total : r = 0.921; p = 0.026) and C reactive protein (SCAio+: r = 0.999; p = 0.020)., Conclusion: SCAio+ group had lower iron incorporation in RBC than SCAio- group, suggesting that they may not need to reduce their intake of iron-rich food, as usually recommended. Conversely, a high percentage of HbS may indirectly exacerbate hypoxia and seems to increase iron incorporation in RBC., Trial Registration: This trial was registered at www.ensaiosclinicos.gov.br . Identifier RBR-4b7v8pt., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to explore the correlation between serum ferritin and additional biomarkers associated with iron metabolism, as well as their connection to muscle atrophy and frailty in the community-dwelling middle-aged and elderly population. The study included 110 middle-aged and elderly participants. Participants were categorized into an iron accumulation group (31 cases) and a normal iron group (79 cases) based on the standard ferritin values for men and women. Based on the criteria of the Asian Working Group on Muscular Dystrophy, participants were classified into a sarcopenia group (31 cases) and a non-sarcopenia group (79 cases). Using the Fried frailty syndrome criteria, participants were categorized into non-frailty (7 cases), pre-frailty (50 cases), and frailty (53 cases) groups. We employed multiple linear regression, binary logistic regression, partial correlation analysis, and ordinal logistic regression to assess the associations between iron metabolism indices and the presence of muscle atrophy and frailty. Compared with the normal iron group, the iron overload group had significantly higher ferritin, weight loss, fatigue, slow gait, and frailty scores (P < .05). Among the 3 models we set, ferritin was not significantly correlated with muscle mass in models 1 and 3 (P > .05), ferritin was positively correlated with muscle mass in model 2 (Pmodel2 = .048), but Transferrin saturation was positively correlated with muscle mass in all 3 models (Pmodel1 = .047, Pmodel2 = .026, Pmodel3 = .024). Ferritin, body mass index and iron overload were the influencing factors of sarcopenia (Pferritin = .027, PBMI < .001, Piron overload = .028). Ferritin was positively correlated with weight loss, fatigue, slow gait, frailty score, and frailty grade (P < .05). Age, gender and ferritin were the influencing factors of frailty classification (P < .05). Disrupted iron metabolism can lead to decreased muscle mass and function among the middle-aged and elderly, increasing frailty risk. It's crucial to prioritize community-based frailty screening and prevention, focusing on iron utilization as well as storage, since accelerating the body's iron metabolism cycle might influence muscle health more significantly than iron reserves., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the iron overload among individuals with acute myeloid leukemia (AML) who have not received red blood cell transfusions., Methods: A comprehensive search was conducted in Embase, PubMed, PubMed Central, Web of Science, NIH, and Blood Library databases up to September 2023. The search strategy included keywords related to AML, iron overload, serum ferritin, survival, outcomes, and inflammation. Manual searches through included articles and relevant references were also performed. From 1650 initial articles, 16 studies involving 8752 patients met the inclusion criteria for systematic review. Statistical analysis used hazard ratios (HR) and confidence intervals (CI).  Results: The systematic review and meta-analysis revealed a statistically significant association between high serum ferritin (SF) levels and poor outcomes in AML patients before starting chemotherapy. Elevated SF levels (>1000 mg/L) were associated with lower overall survival (OS) and event-free survival (EFS) (HR for OS: 1.99, 95% CI: 1.48-2.66; HR for EFS: 2.29, 95% CI: 1.73-3.05). Elevated SF levels were inversely correlated with the gradual onset of infections, indicating an increased risk of early mortality (p<0.05)., Conclusion: Elevated serum ferritin levels are significantly associated with poor outcomes in AML patients before treatment initiation. These findings highlight the importance of monitoring iron levels in these patients to improve prognostic assessments and treatment strategies.

Background and Aims: Both iron overload and iron deficiency have been associated with cardiovascular diseases in observational studies. Previous Mendelian Randomization (MR) studies discovered a protective effect of higher iron status on coronary atrial disease, while a neutral effect on all-cause heart failure. Using two-sample MR, we evaluated how genetically predicted systemic iron status affects the risk of non-ischemic cardiomyopathy and different phenotypes., Methods and Results: Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. An increase in genetically determined serum iron (odds ratio [OR] per standard deviation [SD], 1.25; 95% confidence interval [CI], 1.13-1.38) and ferritin (OR, 1.49; 95% CI, 1.02-2.18) were associated with an increased risk of cardiomyopathy. Total iron binding capacity, a marker of reduced iron status, was inversely linked with cardiomyopathy (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure., Conclusions: These analyses support the causal effect of increased systemic iron status on a higher risk of non-ischemic cardiomyopathy. A screening test for cardiomyopathy should be considered in patients with evidence of iron overload. Future study is needed for exploring the mechanism of these causal variants on cardiomyopathy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

We compared serum anti-Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80-2.76 vs. 4.12, 95% CI 3.11-5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43-76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Very preterm infants often need red blood cell transfusions (RBCT) during intensive care and are at risk of iron overload. This study reviewed the records of 65 very preterm neonates who required at least one RBCT to ascertain the iron status using serum ferritin levels at 4-6 weeks age before oral iron was commenced. High serum ferritin level was found in 52.3% (n = 34) neonates. Need for > 1RBCT was significantly and independently associated with iron excess (P < 0.001). Increased ferritin noted following transfusions in neonatal period can have implications for determining the appropriate time for starting iron supplementation in this subgroup of neonates.

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard., Material and Method: MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations., Result: Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* ( p -value = .015), and no significant association was observed with cardiac siderosis ( p -value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level ( p -value = -.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) ( p -value = .001), aspartate aminotransferase (AST (( p -value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level ( p -value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload ( p value = .36)., Conclusion: An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

Objective: This study was performed to examine the possible association of iron overload with infectious complications and survival among liver transplant recipients., Methods: We conducted a systematic review and meta-analysis of studies published in the PubMed, Embase, Web of Science, and Cochrane Library databases up to September 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted to estimate the association of iron overload with infectious outcomes and overall survival after liver transplantation., Results: Eight studies involving 2817 recipients met the inclusion criteria. Iron overload was strongly associated with an increased risk of infection after liver transplantation (HR, 1.66; 95% CI, 1.03-2.68). An increase in the serum ferritin level was associated with an increased risk of infection after liver transplantation (HR, 1.44; 95% CI, 1.09-1.91). Iron overload was a significant predictor of worse overall survival (HR, 1.35; 95% CI, 1.11-1.64). In addition, a high serum ferritin level was significantly associated with an increased risk of death (HR, 1.34; 95% CI, 1.10-1.64)., Conclusion: Iron overload may be associated with a higher risk of infectious complications and a worse prognosis among liver transplant recipients., Competing Interests: Declaration of conflicting interestThe authors disclose no potential conflicts of interest. All authors have agreed to publish this manuscript.

Introduction: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients., Methods: An LC-MS/MS-based method was performed to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 h after an iron-rich meal in HH patients., Results: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal., Discussion: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal, but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Excess iron deriving from a chronic transfusion and dietary intake increases the risk for cardiac complications in β-thalassemia major patients. Deferiprone and deferasirox are commonly prescribed to thalassemic patients who are at risk of iron overload. This study aimed to compare the performance and toxicity of deferiprone and deferasirox in β-thalassemia major patients., Methods: A cross-sectional observation was performed on 102 patients with β-thalassemia major. Serum ferritin along with total, indirect, and direct bilirubin levels were measured. Levels of liver enzymes, transaminase (ALT), and aspartate transaminase (AST), were also determined. Ferritin correlations with serum ALT, AST, and total bilirubin were constructed based on Spearman's rank correlation. Statistical differences based on the serum parameters were analyzed between deferiprone and deferasirox groups. The differences of iron chelators' effects between those receiving short-term (≤7 years) and long-term (>7 years) blood transfusion were also analyzed., Results: The averaged levels of bilirubin, ALT, AST, and ferritin were found to be high. Ferritin was positively correlated with ALT (r=0.508 and p <0.001) and AST ((r=0.569; p<0.001). There was no statistical difference in ferritin levels between the deferiprone and deferasirox groups ( p =0.776). However, higher total bilirubin and ALT were observed in the deferasirox group than in the deferiprone group ( p =0.001 and 0.022, respectively). Total ( p <0.001), indirect ( p <0.001), and direct bilirubin levels ( p =0.015) were significantly higher in patients with long-term transfusions than those receiving short-term transfusions. Higher ferritin was found with a statistical significance of p =0.008 in the long-term transfusions group., Conclusions: Ferritin is high in people with transfusion-dependent β-thalassemia major and positively correlated with ALT and AST. Deferasirox might pose a higher risk of developing hepatic injury as compared with deferiprone. Yet, no significant change of deferasirox efficacy (based on ferritin level) was found between those receiving short-term and long-term transfusions., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Yusuf S et al.)

Background & Aims: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening., Methods: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation., Results: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 μg/L, and liver iron concentration (LIC) 166±77 μmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37)., Conclusion: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice., Lay Summary: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing., Competing Interests: Conflict of interest Dr. LOUSTAUD-RATTI reports personal fees from Abbvie, personal fees from Gilead, personal fees from IPSEN, outside the submitted work. Dr. Causse reports personal fees from Abbvie, personal fees from Gilead Sciences, personal fees from MSD, outside the submitted work. Dr. SI AHMED reports grants and non-financial support from Abbvie, grants and non-financial support from Gilead, grants from MSD, outside the submitted work. Dr. Ganne-Carrié reports personal fees and non-financial support from GILEAD, personal fees and non-financial support from BAYER, personal fees from IPSEN, outside the submitted work. Dr. Loréal reports personal fees and other from Diafir, outside the submitted work. Other authors have no conflict of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy., Patients and Methods: This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019., Results: Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity., Conclusions: Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most important iron storage protein. It is composed of variable proportions of two peptides, the L- and H-ferritins (FTL and FTH). We previously showed that macrophages increase their expression of FTH1 when they are infected in vitro with Mycobacterium avium , without a significant increase in FTL. In this work, we investigated the role of macrophage FTH1 in M. avium infection in vivo. We found that mice deficient in FTH1 in myeloid cells are more resistant to M. avium infection, presenting lower bacterial loads and lower levels of proinflammatory cytokines than wild-type littermates, due to the lower levels of available iron in the tissues. Importantly, we also found that FTH1 produced by myeloid cells in response to infection may be found in circulation and that it plays a key role in iron redistribution. Specifically, in the absence of FTH1 in myeloid cells, increased expression of ferroportin is observed in liver granulomas and increased iron accumulation occurs in hepatocytes. These results highlight the importance of FTH1 expression in myeloid cells for iron redistribution during infection.

Abnormally high serum ferritin levels have been reported during pediatric ECMO, attributed to frequent red blood cell transfusion and suggestive of iron overload. However, the utility of ferritin for diagnosing iron overload is complicated by its response as an acute-phase reactant. In this study, we aimed to assess the utility of ferritin for diagnosing ECMO-related iron overload, with secondary aims of understanding its relationship with inflammation and erythropoiesis. Ferritin was elevated in all pediatric ECMO runs (median 459 ng/ml, IQR = 327.3-694.4). While intermittent elevations in serum iron were observed, all normalized prior to decannulation. Unreported previously, erythropoietin (EPO) remained well above normative values prior to and throughout ECMO runs, despite frequent transfusion and exposure to hyperoxia. Ferritin correlated poorly with serum iron [r(80) = 0.05, p = 0.65], but correlated well with IL-6 [r(76) = 0.48, p < 0.001] and EPO [r(81) = 0.55, p < 0.001]. We suggest that serum ferritin is a poor biomarker of iron overload in ECMO patients, and that future investigation into its relationship with EPO is warranted., (Published by Elsevier Inc.)

Objectives: To evaluate any association between pre-transfusion hemoglobin (Hb) levels and thalassemia complications and to identify the Hb cutoff values to predict thalassemia complications., Methods: We performed a cross-sectional study in thalassemia patients who attended the Adult Hematology Clinic of the tertiary care University Hospital from October 2017 to October 2018. A point-biserial correlation was used to identify any association between Hb levels and thalassemia complications. A receiver operating characteristic (ROC) curve was used to identify the diagnostic ability of Hb levels to predict thalassemia complications and identify Hb cutoff values., Results: Out of the 102 patients, there were 53 transfusion dependent thalassemia (TDT) patients and 49 non-transfusion dependent thalassemia (NTDT) patients. In theTDT group, Hb levels showed a negative correlation with severe hepatic iron overload and hypogonadism. The cutoff Hb levels to predict severe hepatic iron overload and hypogonadism were ≤7.01 and 6.81 g/dL, respectively, at which points the area under the ROC curve (AUC) were 0.721 and 0.708, respectively. In the NTDTgroup, Hb levels were negatively correlated with hepatic iron overload, osteoporosis, and pulmonary hypertension. The cutoff values of Hb levels to predict hepatic iron overload, osteoporosis, and pulmonary hypertension were ≤8.24, 7.16, and 7.16 g/dL, respectively, at which points the AUC were 0.923, 0.715, and 0.725, respectively., Conclusions: Lower Hb level was associated with more frequent complications in both TDT and NTDT patients. The Hb cutoff levels to predict these complications were identified.

Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs "miR-let-7d, miR-122, and miR-200b" and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased-iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Iron overload is tightly connected with metabolic disorders. Excess iron in the adipose and its roles in dyslipidemia are of interest to be identified. In acute iron overload mice receiving intraperitoneal injection of 100 mg/kg/day dextran-iron for 5 days, the epididymis adipose showed a remarkable increase in iron. Serum triglyceride and low-density lipoprotein cholesterol (LDL-C) levels were increased and high-density lipoprotein cholesterol (HDL-C) level was decreased, while serum alkaline phosphatase, aspartate aminotransferase, glucose, and insulin were not affected. The serum-cytokine-microarray showed that adipocytokines, including adiponectin, leptin, and resistin were significantly decreased. Other serum cytokines, including pro-insulin cytokines, inflammatory cytokines, chemokines, and growth factors were not changed, except that ghrelin and chemokine RANTES were increased. Iron overload decreased expressions of adiponectin and leptin both in vivo and in vitro. Intraperitoneal injection of recombinant leptin at 1 μg/g in acute iron overload mice had no significant effects on serum levels of TC, TG, HDL-C, and LDL-C, while intraperitoneal injection of recombinant adiponectin at 3 μg/g partially restored serum TG level through improving activities of lipoprotein lipase and hepatic lipase, but abnormal serum LDL-C and HDL-C were not redressed, suggesting other mechanisms also existed. In conclusion, the adipose responds to iron overload at an early stage to interfere with lipid metabolism by secreting adipocytokines, which may further affect glucose metabolism, inflammation, and other iron overload-induced effects on the body., (© 2021 Wiley Periodicals LLC.)

Aims: Iron released from lysed red blood cells within the hematoma plays a role in intracerebral hemorrhage (ICH)-related neurotoxicity. This study utilizes magnetic resonance imaging (MRI) to examine the time course, extent of erythrolysis, and its correlation with perihematomal iron accumulation and white matter loss., Methods: The feasibility of assessing proportional erythrolysis using T2* MRI was examined using pig blood phantoms with specified degrees of erythrolysis. Fifteen prospectively enrolled ICH patients had MRIs (3-Tesla) at days 1-3, 14, and 30 (termed early, subacute, and late periods, respectively). Measurement was performed on T2*, 1/T2*, and fractional anisotropy (FA) maps., Results: Pig blood phantoms showed a linear relationship between 1/T2* signal and percent erythrolysis. MRI on patients showed an increase in erythrolysis within the hematoma between the early and subacute phases after ICH, almost completing by day 14. Although perihematomal iron overload (IO) correlated with the erythrolysis extent and hematoma volume at days 14 and 30, perihematomal white matter (WM) loss significantly correlated with both, only at day 14., Conclusion: MRI may reliably assess the portion of the hematoma that lyses over time after ICH. Perihematomal IO and WM loss correlate with both the erythrolysis extent and hematoma volume in the early and subacute periods following ICH., (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

The atherosclerosis "iron hypothesis" generates a fair amount of debate since it has been proposed. Here, we revisited the "iron hypothesis" by examining whether dietary iron overload would intensify iron deposition in plaques and thus lead to further exacerbation of atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were fed either a normal chow diet (ND) or a high fat diet (HFD) supplemented with or without 2% carbonyl iron (Fe) for 16 weeks. However, contrary to our assumption, dietary iron overloading did not intensify, but rather diminished the atherosclerotic lesion area by 65.3%, which was accompanied by significantly decreased serum total cholesterol, triglyceride and low-density lipoprotein cholesterol contents, together with hepatic lipid accumulation decline, despite the evident existence of aortic iron accumulation and the typical signs of iron overload in ApoE KO mice. Using isobaric tag for absolute quantification (iTRAQ) proteomics approach, hepatic CD36 and fatty acid binding proteins-mediated fatty acid (FA) uptake and trafficking impairment were identified as the key potential pathomechanisms by which iron overload diminishes atherosclerotic lesions. Furthermore, downstream hepatic FA de novo biosynthesis was enhanced and FA oxidation was inhibited to compensate for the FA deficiency triggered by iron overload-impaired fatty acid uptake and trafficking. Our findings suggested that dietary iron overload is not atherogenic in ApoE KO mice, and more research efforts are warranted to revisit the "iron hypothesis" of atherosclerosis., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress, and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of patients with T2DM show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear whether hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we generated and characterized a mouse model of T2DM with IR, steatosis, and iron overload., Methods: Lepr db/db mice hallmarked by T2DM, IR and steatosis were crossed with Fpn wt/C326S mice with systemic iron overload to generate Lepr db/db /Fpn wt/C326S mice. The resulting progeny was characterized for major diabetic and iron-related parameters., Results: We demonstrated that features associated with T2DM in Lepr db/db mice, such as obesity, steatosis, or IR, reduce the degree of tissue iron overload in Fpn wt/C326S mice, suggesting an 'iron resistance' phenotype. Conversely, we observed increased serum iron levels that strongly exceeded those in the iron-overloaded Fpn wt/C326S mice. Increased hepatic iron levels induced oxidative stress and lipid peroxidation and aggravated IR, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver, we observed gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we showed that iron overload in Lepr db/db /Fpn wt/C326S mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye., Conclusion: Taken together, our data show that iron causes the worsening of symptoms associated with the MetS and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate IR and diabetic late complications., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

This study proposed to investigate the effect of Ilex paraguariensis infusion on the absorption of non-heme iron in hereditary hemochromatosis (HH) patients with the HFE genotype. A two-way randomized, controlled, crossover trial was conducted on patients, aged 29-69 years, undergoing maintenance therapy. Fourteen HFE-HH patients ingested a meal containing 11.4 mg iron and 200 mL either of water (control) or of Ilex paraguariensis leaf infusion. The beverages were offered in random order, at intervals separated by a washout period of 7 days. Active surveillance showed no adverse effects. Blood samples were drawn shortly before and 1, 2, 3, and 4 h after the meal for serum iron measurement. A significant reduction in the postprandial serum iron was observed for HH patients after intake of the Ilex paraguariensis infusion (area under the curve (AUC) expressed as mean ± SEM: 173.3 ± 44.7 μmol h -1 L -1 ) compared to water (1449.4 ± 241.5 μmol h -1 L -1 ) (p < 0.001). In summary, intake of Ilex paraguariensis leaf infusion significantly inhibited the absorption of iron in patients with HH and, therefore, should be considered as a potential adjuvant for iron overload control.

Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [C max : 99.5 (FCT) and 69.7 (DT) μMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose-response correlation [Spearman r (dose-serum ferritin variation): - 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.

Background: Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice., Objectives: To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes., Search Methods: We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies., Selection Criteria: We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country., Data Collection and Analysis: We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions., Main Results: Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8., Authors' Conclusions: At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Red blood cell (RBC) transfusion is an effective therapy for anemia, but repeated transfusions may cause iron overload-related damage to various organs. Iron chelation therapy, now widely available for patients who have received transfusions, is expected to reduce organ damage even in patients who received many transfusions. Therefore, determining when to start iron chelation therapy is important. In guidelines for iron chelation therapy, the serum ferritin level has been widely accepted as a practical marker for estimating iron overload. However, guidelines recommend multiple measurements of serum ferritin, because levels often fluctuate. Here, we investigated the usefulness of glycosylated ferritin as a marker of iron overload using a cohort consisted of 103 patients who had a total ferritin value over 1000 ng/mL. We found that the volume of RBCs transfused was clearly associated with the glycosylated ferritin level. We also found that acute inflammation, as represented by C-reactive protein values, was associated with increased non-glycosylated ferritin and that patients with hematopoietic diseases had higher glycosylated ferritin levels, possibly because of repeated RBC transfusions. We thus conclude that glycosylated ferritin may be an improved marker for predicting iron overload status.

Context: Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states., Objectives: (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention., Design: Randomized, parallel, open-label, clinical trial., Setting: Academic hospital., Patients: Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism., Intervention: After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months., Main Outcome Measures: Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36., Results: From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34., Conclusions: Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The mutation of the homeostatic iron regulatory genes (HFE) impaired the hepatic hepcidin transcription leading to the chronic excess of the iron pool, with the adverse consequences of free radical oxidative damages. We herein reported the findings of Thai family members who had the compound of uncommon HFE rs2794719, together with transferrin (TF) rs1867504, transferrin receptor 2 (TfR2) rs7385804, and hemojuvelin (HJV) rs16827043 genetic variants involved in the hepcidin transcriptional pathway. These compounded genetic variants could produce the spectrum of clinical phenotypes that spanned from mild to moderate symptoms of chronic anemia to an established motor neuron disorder. The feasible pathophysiologies were the impairment of the transferrin receptor functions, which affected the endocytic uptake of halo-transferrin into the erythroblast precursors. Such a defect left the erythropoiesis depleted of their iron supply. These alterations also promoted the TfR-independent uptake of iron into other target tissues and left the TrF2/BMP-dependent-hepcidin activation pathway unattended. We used the predicted molecular interactive proteomes to support our speculated dysregulated iron metabolism. During the early stage of an elevated ferritin level, there was no inhibition of ferroportin activities from hepcidin. These pathophysiological processes went on to the point of an iron overload threshold. After that, the hepcidin transcription started to kick in with the resulting decreased serum iron levels and deterioration of clinical symptoms.

Myelodysplasticsyndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs. Here, we provide an overview of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weber, Parmon, Kurrle, Schnütgen and Serve.)

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the "iron paradox" in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aims: Exposure to fine particulate matter (PM2.5) is correlated to atherosclerosis, but the mechanism remains largely undefined. Iron overload is a significant contributor to atherosclerosis, and iron homeostasis is highly regulated by the hepcidin-ferroportin (FPN) axis. Here we aimed to investigate the association between iron overload and PM2.5-induced atherosclerotic mice., Main Methods: Apolipoprotein E knockout (ApoE -/- ) mice were randomly assigned to filtered air (FA group) or PM2.5 (PM2.5 group) for 3-month inhalation. Daily PM2.5 mass concentrations, serum levels of ferritin, iron, pro-atherosclerotic cytokines and lipid profiles, atherosclerotic lesion areas, hepcidin, FPN and iron depositions in atherosclerotic lesions, hepcidin, FPN mRNA and protein expressions in the aorta were detected, respectively., Key Findings: The daily average concentration of atmospheric PM2.5 was 68.2 ± 21.8 μg/m 3 . Serum levels of ferritin, iron, VEGF, MCP-1, IL-6, TNF-α, TC and LDL-C, atherosclerotic lesion areas, hepcidin and iron depositions in atherosclerotic lesions, hepcidin mRNA and protein expressions in the PM2.5 group were observably higher than those in the FA group. Nevertheless, FPN deposition in atherosclerotic lesions, FPN mRNA and protein expressions in the aorta of the PM2.5 group were markedly lower than those of the FA group., Significance: PM2.5 inhalation could exacerbate the formation and development of atherosclerosis in ApoE -/- mice, the potential mechanisms may be partly associated with iron overload via the hepcidin-FPN axis, as well as iron-triggered systemic inflammation and hyperlipidemia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: This study was performed on patients with transfusion-dependent beta-thalassemia (TDT) to investigate the effect of HFE gene mutations of iron overload in a large group of patients with TDT major and its relationship with heart and liver T2* magnetic resonance imaging (MRI) level., Materials and Methods: In a cross-sectional study, a total of 253 patients with TDT who had regular blood transfusion were included in this study. HFE gene mutations including H63D and C282Y were evaluated in all patients through molecular assay. Heart and liver T2* MRI results, types, duration of iron therapy, and the demographic data including age, gender, serum ferritin level, blood transfusion, and splenectomy history of the included participants were also collected, using a questionnaire., Results: Homozygous and heterozygous H63D mutation was found in 39.5% of the patients and C282Y mutation was found only in 1 patient. Ferritin level was significantly higher in patients with H63D mutation in comparison with patients without this mutation (P=0.036). Although heart T2* MRI and also the liver T2* MRI in the patients with H63D was slightly higher, the difference was not statistically significant. No significant correlation was observed between serum ferritin level and heart and liver T2* MRI, and iron chelation regimen., Discussion: Heart and liver iron overload was not significantly different between patients with and without H63D mutation. As for serum ferritin, it was significantly higher among patients with H63D mutation compared with patients without this mutation. Hence, it is recommended to consider HFE gene mutations among patients with thalassemia to reach a better iron overload evaluation and management.

Ethnopharmacological Relevance: Gundelia tournefortii is a member of the Asteraceae (Compositae) family which is widely consumed as edible plant in the Eastern Mediterranean. In folkloric medicine, it is used for the treatment of various diseases and conditions, including pain, liver diseases, kidney stones and inflammations., Aim of the Study: Recently, many commoners use this plant as adjuvant therapy for treating symptoms associated with liver diseases and thalassemia. Thus, the present study was conducted to evaluate, biochemically, the iron chelating activity of G. tournefortii methanolic extract in iron overloaded rats., Materials and Methods: Fifty Wister male rats were divided into five groups: one group was a healthy control, while iron overload was induced in the other four groups by 100 mg/kg iron-dextran. Of these, one group was left untreated as a control, while the other three groups were treated with 50 mg/kg deferoxamine, 100 mg/kg and 200 mg/kg of G. tournefortii methanolic extract, respectively. The total flavonoid and phenolic contents of the methanolic extract were estimated. The biochemical assessment was performed by measuring blood levels of iron, ferritin, liver biomarkers (ALT, ALP and AST), cardiac biomarkers (CPK and LDH) and lipid profile., Results: Not only the blood levels of iron, ferritin, liver biomarkers and cardiac biomarkers were reduced significantly by G. tournefortii methanolic extract, but also the lipid profile was improved. This clearly supports the chelating activity of G. tournefortii and its hepatoprotective and cardioprotective effects in iron overloaded rats., Conclusions: This highlights the value of medicinal plants as alternative therapies for iron overload conditions such as thalassemia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Iron overload is the main cause of morbidity and mortality in β-thalassemia major patients, and cardiac iron overload is the most common reason for death in these transfusion-dependent patients. Hepcidin, a liver-derived peptide hormone, plays a key role in plasma iron levels regulation by controlling two main stages, digestive iron absorption in enterocytes, and iron recycling in macrophages. Although hepcidin is mainly secreted from hepatocytes in the liver, it is also synthesized from mononuclear cells consisting of monocytes and lymphocytes. Binding of this molecule to ferroportin, a specific cellular exporter of iron, leads to degradation of the ligand-receptor complex, which reduces the iron overload by lowering the amounts of iron released into the plasma. Likewise, the same mechanism has been proved to be true for lymphocyte-drived hepcidin. The expression levels of hepcidin mRNA were evaluated using quantitative real time PCR (qRT-PCR) in 50 β-thalassemia major patients, as well as 25 healthy volunteers as the group of control. There was a significantly positive correlation between the cardiac iron concentration, showed by higher T2 values, and hepcidin levels in the patients (p = 0.028; r = 0.311). However, hepcidin expression levels did not significantly correlate with ferritin and liver iron concentrations. Hepcidin can act as a beneficial marker to determine iron overload degrees, particularly in the heart, in β-thalassemia major patients and be used as a logical therapeutic agent for treatment of β-thalassemia disorders.

Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.