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American Family Physician Mar 2022Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective...
Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia intermedia have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.
Topics: Child, Preschool; Hematologic Diseases; Humans; Infant, Newborn; Iron; Iron Overload; Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 35289581
DOI: No ID Found -
Science Bulletin Sep 2021The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can... (Review)
Review
The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy.
Topics: Humans; Homeostasis; Immunity; Iron; Iron Overload; Macrophages; Inflammation
PubMed: 36654387
DOI: 10.1016/j.scib.2021.02.010 -
Drugs Jul 2020Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation.... (Review)
Review
Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation. The thalassemias are characterized by autosomal recessive inherited defects in the production of hemoglobin. They are highly prevalent in the Mediterranean, Middle East, Indian subcontinent, and East and Southeast Asia. Due to recent migrations, however, the thalassemias are now becoming more common in Europe and North America, making this disease a global health concern. Currently available conventional therapies in thalassemia have many challenges and limitations. A better understanding of the pathophysiology of β-thalassemia in addition to key developments in optimizing transfusion programs and iron-chelation therapy has led to an increase in the life span of thalassemia patients and paved the way for new therapeutic strategies. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. In this review, we provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.
Topics: Blood Transfusion; Genetic Therapy; Humans; Iron Chelating Agents; Iron Overload; Molecular Targeted Therapy; beta-Thalassemia
PubMed: 32557398
DOI: 10.1007/s40265-020-01341-9 -
Cancer Medicine Aug 2018Macrophages play critical roles in inflammation and wound healing and can be divided into two subtypes: classically activated (M1) and alternatively activated (M2)...
PURPOSE
Macrophages play critical roles in inflammation and wound healing and can be divided into two subtypes: classically activated (M1) and alternatively activated (M2) macrophages. Macrophages also play important roles in regulating iron homeostasis, and intracellular iron accumulation induces M1-type macrophage polarization which provides a potential approach to tumor immunotherapy through M2 tumor-associated macrophage repolarization. However, the mechanisms underlying iron-induced M1 polarization remain unclear.
METHODS
Western blotting, qRT-PCR, and flow cytometry were used to detect the polarization indexes in RAW 264.7 murine macrophages treated with iron, and Western bloting and qRT-PCR were used to detect p21 expression. The compound 2,7-dichlorofluorescein diacetate was used to measure reactive oxygen species (ROS) levels in macrophages after iron or N-acetyl-l-cysteine (NAC) treatment. The p300/CREB-binding protein (CBP) inhibitor C646 was used to inhibit p53 acetylation, and Western bloting, qRT-PCR, and immunofluorescence were used to detect p53 expression and acetylation. BALB/c mice were subcutaneously injected with H22 hepatoma cells, and macrophage polarization status was investigated after tail intravenous injection of iron. Immunohistochemical staining was used to evaluate the protein expression of cluster of differentiation 86 (CD86) and EGF-like module-containing mucin-like hormone receptor-like 1 (F4/80) in the subcutaneous tumors.
RESULTS
Iron overload induced M1 polarization by increasing ROS production and inducing p53 acetylation in RAW cells, and reduction in ROS levels by NAC repressed M1 polarization and p53 acetylation. Inhibition of acetyl-p53 by a p300/CBP inhibitor prevented M1 polarization and inhibited p21 expression. These results showed that high ROS levels induced by iron overload polarized macrophages to the M1 subtype by enhancing p300/CBP acetyltransferase activity and promoting p53 acetylation.
Topics: Acetylation; Animals; Biomarkers; Female; Inflammation; Iron; Iron Overload; Macrophage Activation; Macrophages; Mice; Phenotype; Reactive Oxygen Species; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 29989329
DOI: 10.1002/cam4.1670 -
Blood Advances Jan 2020Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific...
BACKGROUND
Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes.
OBJECTIVE
Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications.
METHODS
The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment.
RESULTS
The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload.
CONCLUSIONS
The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.
Topics: Anemia, Sickle Cell; Blood Grouping and Crossmatching; Erythrocyte Transfusion; Evidence-Based Medicine; Humans; Iron Overload; Transfusion Reaction
PubMed: 31985807
DOI: 10.1182/bloodadvances.2019001143 -
Journal of Atherosclerosis and... Mar 2022Iron is an important element for life; however, intracellular labile iron overload can lead to the generation of reactive oxygen species and cellular damage. Although... (Review)
Review
Iron is an important element for life; however, intracellular labile iron overload can lead to the generation of reactive oxygen species and cellular damage. Although iron is mainly utilized for heme synthesis and is incorporated into hemoglobin, body iron status is often implicated in the pathogenesis of cardiovascular diseases. In a cell, iron is used for basic processes such as cell growth, maintenance, and repair. Thus, iron is considered to be involved in the pathogenesis of arteriosclerosis. In fact, clinical and experimental studies have shown an association between iron and arteriosclerosis. These data suggest the crosstalk between iron and arteriosclerosis. However, iron metabolism in arteriosclerosis is often complicated, and the systemic and cellular mechanisms of iron homeostasis in arteriosclerosis remain completely unsolved. Thus, in this review, we aimed to examine the role of iron in arteriosclerosis.
Topics: Animals; Arteriosclerosis; Homeostasis; Humans; Iron Overload; Oxidative Stress; Reactive Oxygen Species
PubMed: 34421089
DOI: 10.5551/jat.RV17060 -
Blood Reviews Mar 2024α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying... (Review)
Review
α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.
Topics: Humans; beta-Thalassemia; alpha-Thalassemia; Erythropoiesis; Hematologic Diseases; Erythrocyte Transfusion; Iron Overload
PubMed: 38182489
DOI: 10.1016/j.blre.2023.101165 -
British Journal of Clinical Pharmacology Jun 2022Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment,... (Review)
Review
Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment, β-thalassaemia major is lethal within the first decade of life due to the complex pathophysiology, which leads to wide clinical manifestations. Current clinical management for these patients depends on repeated transfusions followed by iron-chelating therapy. Several novel approaches to correct the resulting α/β-globin chain imbalance, treat ineffective erythropoiesis and improve iron overload are currently being developed. Up to now, the only curative treatment for β-thalassemia is haematopoietic stem-cell transplantation, but this is a risky and costly procedure. Gene therapy, gene editing and base editing are emerging as a powerful approach to treat this disease. In β-thalassaemia, gene therapy involves the insertion of a vector containing the normal β-globin or γ-globin gene into haematopoietic stem cells to permanently produce normal red blood cells. Gene editing and base editing involves the use of zinc finger nucleases, transcription activator-like nucleases and clustered regularly interspaced short palindromic repeats/Cas9 to either correct the causative mutation or else insert a single nucleotide variant that will increase foetal haemoglobin. In this review, we will examine the current management strategies used to treat β-thalassaemia and focus on the novel therapies targeting ineffective erythropoiesis, improving iron overload and correction of the globin chain imbalance.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Iron Overload; beta-Globins; beta-Thalassemia
PubMed: 34004015
DOI: 10.1111/bcp.14918 -
British Journal of Haematology Nov 2020Since the inception of the British Society for Haematology (BSH) 60 years ago, our increased scientific understanding of iron metabolism, together with clinical... (Review)
Review
Since the inception of the British Society for Haematology (BSH) 60 years ago, our increased scientific understanding of iron metabolism, together with clinical developments, have changed the way we diagnose and treat its disorders. In the UK, perhaps the most notable contributions relate to iron overload, some of which I will outline from personal experience. Diagnostically, this began with the identification of serum ferritin as a marker of iron overload and continued later with the application of MRI-based imaging techniques for iron and its distribution. Therapeutically, the first trials of both parenteral and oral chelation, which have radically changed the outcomes of transfusional iron-overloaded patients, took place in the UK and are now part of standard clinical practice. During this time, our scientific understanding of iron metabolism at a cellular and systemic level have advanced the diagnosis and treatment of inherited disorders of iron metabolism. There are potential novel applications related to our recent understanding of hepcidin metabolism and manipulation.
Topics: Biomarkers; Disease Management; Disease Susceptibility; Hematologic Diseases; Hemochromatosis; Humans; Iron; Iron Chelating Agents; Iron Overload
PubMed: 33190267
DOI: 10.1111/bjh.17164 -
Hematology/oncology Clinics of North... Apr 2018Stress erythropoiesis (SE) is characterized by an imbalance in erythroid proliferation and differentiation under increased demands of erythrocyte generation and tissue... (Review)
Review
Stress erythropoiesis (SE) is characterized by an imbalance in erythroid proliferation and differentiation under increased demands of erythrocyte generation and tissue oxygenation. β-thalassemia represents a chronic state of SE, called ineffective erythropoiesis (IE), exhibiting an expansion of erythroid-progenitor pool and deposition of alpha chains on erythrocyte membranes, causing cell death and anemia. Concurrently, there is a decrease in hepcidin expression and a subsequent state of iron overload. There are substantial investigative efforts to target increased iron absorption under IE. There are also avenues for targeting cell contact and signaling within erythroblastic islands under SE, for therapeutic benefits.
Topics: Anemia; Animals; Biomarkers; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Gene Expression Regulation; Humans; Iron Overload; Signal Transduction; Stress, Physiological
PubMed: 29458727
DOI: 10.1016/j.hoc.2017.11.009