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The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
Habib, HM, Ibrahim, S, Zaim, A, Ibrahim, WH
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111228
Abstract
Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.
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A Systematic Review and Meta-Analysis of Stature Growth Complications in β-thalassemia Major Patients.
Arab-Zozani, M, Kheyrandish, S, Rastgar, A, Miri-Moghaddam, E
Annals of global health. 2021;(1):48
Abstract
BACKGROUND Blood transfusion is a traditional treatment for β-thalassemia (β-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream. OBJECTIVE To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in β-thalassemia major (βTM) patients. METHODS We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in β-thalassemia major (βTM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses. FINDINGS Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8). CONCLUSION Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.
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Too much iron: A masked foe for leukemias.
Brissot, E, Bernard, DG, Loréal, O, Brissot, P, Troadec, MB
Blood reviews. 2020;:100617
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Abstract
The role of iron in non-erythroid hematopoietic lineages and its implication in hemato-oncogenesis are still debated. Iron exerts an important role on hematopoietic stem cell transformation and on mature white blood cell differentiation. Iron acts experimentally as an oncogenic cofactor but its exact role in the transformation of the myelodysplastic syndrome into leukemia continues to be discussed. Body iron overload frequently develops mainly as the result of multiple erythrocyte transfusions in patients with leukemia or myelodysplastic syndrome, and, in the latter, as a result of increased ineffective erythropoiesis. Iron overload, especially through the deleterious effects of reactive oxygen species, leads to organ damage that likely impacts the global outcome of patients, especially after hematopoietic stem cell transplantation (HSCT). In these pathological settings (before and after HSCT), oral iron chelation should be considered whenever body iron overload has been firmly established, ideally by magnetic resonance imaging.
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Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis?
Edeas, M, Saleh, J, Peyssonnaux, C
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2020;:303-305
Abstract
The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on the premise that respiratory failure is the leading cause of mortality. However, mounting evidence links accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyper-ferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.
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The role of iron in viral infections.
Schmidt, SM
Frontiers in bioscience (Landmark edition). 2020;(5):893-911
Abstract
Crucial cellular processes such as DNA synthesis and the generation of ATP require iron. Viruses depend on iron in order to efficiently replicate within living host cells. Some viruses selectively infect iron - acquiring cells or influence the cellular iron metabolism via Human hemochromatosis protein (HFE) or hepcidin. During infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) iron overload is associated with poor prognosis for the patient and enhanced progression of the disease. Recent findings still lack to fully describe the viral interaction with the host iron metabolism during infection. This review summarizes the current knowledge of the viral regulation on the host cell iron metabolism in order to discuss the therapeutic option of iron chelation as a potential and beneficial adjuvant in antiviral therapy.
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Recovery Of Bone And Muscle Mass In Patients With Chronic Kidney Disease And Iron Overload On Hemodialysis And Taking Combined Supplementation With Curcumin And Resveratrol.
Murillo Ortiz, BO, Fuentes Preciado, AR, Ramírez Emiliano, J, Martínez Garza, S, Ramos Rodríguez, E, de Alba Macías, LA
Clinical interventions in aging. 2019;:2055-2062
Abstract
INTRODUCTION Malnutrition is common in haemodialysis patients and closely related to morbidity and mortality. We evaluated the effect of twelve weeks of supplementation with resveratrol and curcumin on recovery of bone and muscle mass and protein oxidation, lipid peroxidation on patients with chronic kidney disease and iron overload undergoing hemodialysis, we performed a randomized, double-blind, placebo-controlled trial. METHODS We included a total of 40 patients, were randomly assigned to two groups, 20 to the group with antioxidant supplementation (Resveratrol + Curcumin) (Group A), treated with a daily oral dose of 500 mg of Resveratrol and 500 mg of Curcumin, and 20 to the control group treated with placebo (Group B). RESULTS Significant differences were found in the body composition of the patients between both groups. There was a significant difference in Body Mass Index (BMI) values (p = 0.002), fat percentage (p = 0.007), muscle mass (p = 0.01) bone mass (p = 0.01), as well as in the score of the subjective global evaluation (p = 0.03). Also differences were found between the basal and final serum levels of Triglycerides (TG) (p = 0.01), VLDL (p = 0.003). A significant decrease in the levels of serum ferritin (2003.69 ± 518.73 vs 1795.65 ± 519.00 ng/mL; p = 0.04). Nor were significant differences observed between the baseline and the final Thiobarbituric Acid Reactive Substances (TBARS) values (70.45 ± 69.21 vs 50.19 ± 32.62, p = 0.24). The same results was obtained for carbonyl values (2.67 ± 0.75 vs 2.50 ± 0.85; p = 0.50). DISCUSSION The present study is the first assay on patients with chronic kidney disease and iron overload that demonstrates the beneficial effects of combined supplementation with Curcumin and Resveratrol on muscle and bone mass. There was a significant decrease in circulating levels of ferritin, to finding that remarkably novel.
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Liver R2* is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease.
Karlsson, M, Ekstedt, M, Dahlström, N, Forsgren, MF, Ignatova, S, Norén, B, Dahlqvist Leinhard, O, Kechagias, S, Lundberg, P
Journal of magnetic resonance imaging : JMRI. 2019;(1):325-333
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Abstract
BACKGROUND Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. PURPOSE To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. STUDY TYPE Prospective. POPULATION Eighty-one patients with suspected CLD. FIELD STRENGTH/SEQUENCE 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. ASSESSMENT Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. STATISTICAL TESTS Pearson correlation, linear regression, and area under the receiver operating curve. RESULTS There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. DATA CONCLUSION PDFF increases R2*. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.
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Deferasirox in the management of iron-overload in patients with myelofibrosis: a multicentre study from the Rete Ematologica Lombarda (IRON-M study).
Elli, EM, Iurlo, A, Aroldi, A, Caramella, M, Malato, S, Casartelli, E, Maffioli, M, Gardellini, A, Carraro, MC, D'Adda, M, et al
British journal of haematology. 2019;(5):e123-e126
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A randomized controlled trial evaluating the effects of amlodipine on myocardial iron deposition in pediatric patients with thalassemia major.
Khaled, A, Salem, HA, Ezzat, DA, Seif, HM, Rabee, H
Drug design, development and therapy. 2019;:2427-2436
Abstract
BACKGROUND Mortality rates increase due to iron deposition in the cardiac muscles of thalassemia major (TM) patients. Iron overload cardiomyopathy could be treated with a combination therapy of an iron chelator and an L-type calcium channel blocker. We designed a randomized controlled study to assess the potential of amlodipine, alongside chelation, in reducing myocardial iron concentration in TM patients compared with a placebo. OBJECTIVES This study aims to estimate the change in myocardial iron concentration (MIC) determined by magnetic resonance imaging after 6 months of treatment with amlodipine, as well as measuring the changes in the secondary outcomes (liver iron concentration (LIC), serum ferritin level (SF), and left ventricle ejection fraction (LVEF)) of study participants. METHODS A single, randomized, placebo-controlled trial was performed in 40 β-Thalassemia major patients aged between 6 and 20 years old, who received either oral amlodipine 2.5-5 mg/day or a placebo, in addition to a Deferasirox chelation regimen in a 1:1 allocation ratio. RESULTS After 6 months, a significant reduction was noted in the MIC of patients receiving amlodipine (n=20), compared with the patients receiving the placebo (n=20). At baseline, the mean was 0.76±0.11 mg/g dry weight, while at 6 months, the mean was 0.51±0.07 mg/g dry weight (p<0.001). Also, there was a significant change in the myocardial T2* after 6 months; the amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p<0.001). However, amlodipine did not significantly affect the secondary outcomes by the end of the study. CONCLUSION The addition of amlodipine to the standard chelation therapy in transfusion-dependent thalassemia major patients improves myocardial iron overload without increasing the adverse effects.
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Computer and mobile technology interventions to promote medication adherence and disease management in people with thalassemia.
Badawy, SM, Morrone, K, Thompson, A, Palermo, TM
The Cochrane database of systematic reviews. 2019;(6):CD012900
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Abstract
BACKGROUND Thalassemia syndromes are inherited hemoglobin disorders that result when the synthesis of normal hemoglobin is lacking or significantly reduced. For people with thalassemia, long-term red blood cell transfusion remains the mainstay of therapy, which may lead to iron overload causing severe complications and damage in different body organs. Long-term iron chelation therapy is essential for people with thalassemia to minimize the ongoing iron-loading process. In addition, suboptimal adherence can increase adverse events associated with iron overload and result in increased morbidity, mortality, healthcare utilization and cost of care. OBJECTIVES To identify and assess the effects of computer and mobile technology interventions designed to facilitate medication adherence and disease management in individuals with thalassemia, including:- evaluating the effects of using computer and mobile technology interventions for medication adherence and disease management on health and behavioral outcomes;- identifying and assessing the effects of computer and mobile technology interventions specific to different age groups (children, adolescents and adults) and type of modality (e.g. cell phone, the Internet). SEARCH METHODS We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Theses Global, Psychology and Behavioral Sciences Collection, Web of Science Science & Social Sciences Conference Proceedings Indexes, IEEE Xplore and ongoing trial databases (22 February 2018). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (20 June 2019). We also searched for unpublished work in the abstract book of nine major conferences in the related field. SELECTION CRITERIA Randomized controlled trials (RCT) and quasi-RCTs comparing single- or multi-component interventions versus no intervention, placebo or standard care, with adherence to iron chelation as the primary outcome were eligible for inclusion. Non-randomized studies of interventions, controlled before-after studies, and interrupted-time-series studies were also eligible for inclusion. DATA COLLECTION AND ANALYSIS Three authors independently assessed study eligibility. If we had included any studies, we would have independently assessed risk of bias and extracted data; we planned to assess the quality of the evidence using GRADE. MAIN RESULTS We did not identify any eligible studies for inclusion in the review. AUTHORS' CONCLUSIONS Due to lack of evidence, we cannot comment on the efficacy or effectiveness of computer and mobile technology intervention strategies to promote disease management and adherence to iron chelation therapy in people with thalassemia.We concluded that RCTs are needed to examine a variety of computer and mobile technology intervention strategies that may be useful for promoting disease management and increasing adherence to iron chelation therapy in individuals with thalassemia.