Thalassemia (Literature Review)
1. Dr. Samatbek Turdaliev
2. Muruganandam Devabalan
Nagalingame Periane Eashwarnath
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
2. Students, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
ABSTRACT
Chronic anaemia is the result of thalassaemia, an inherited blood condition marked by decreased or nonexistent synthesis of one or more globin chains of haemoglobin. Depending on which globin chain is impacted, it is most frequently divided into alpha- and beta-thalassemia. From asymptomatic carrier states to potentially fatal anaemia necessitating frequent transfusions, the severity varies. The disorder is caused by mutations in the globin genes, which result in haemolysis, inadequate erythropoiesis, and a number of clinical consequences, including growth delay, bone abnormalities, and iron overload from recurrent transfusions. Haemoglobin electrophoresis, peripheral smears, complete blood counts, and genetic tests are all used in the diagnosis process. Regular transfusions, iron chelation therapy, folic acid supplementation, and in certain situations, curative bone marrow transplants are also part of the management. Early screening, premarital testing, and genetic counseling play an essential role in prevention, especially in high-prevalence regions. Advances in gene therapy offer promising future treatment options.
Keywords: Thalassemia, Genetic mutation, Anemia, Iron overload
INTRODUCTION
The globin chain subunits of haemoglobin are mutated in thalassaemia, a diverse group of inherited anaemias. This results in haemolytic anaemia and inefficient erythropoiesis due to insufficient haemoglobin synthesis and the buildup of insoluble unpaired chains that harm red blood cells. Mutations in the β-globin gene produce β-thalassemia, a frequent kind of thalassaemia, which interferes with the production of β-globin through a number of processes, including transcription and translation interference. Patients with thalassaemia frequently need blood transfusions for the rest of their lives, which can result in iron overload and possible organ damage, especially to the liver. Millions of people worldwide suffer from this condition, which is classified as a hemoglobinopathy, and its clinical symptoms are influenced by both genetic and molecular differences.
In order to prevent iron overload, management usually entails frequent transfusions and iron chelation therapy; new treatments such as gene therapy and bone marrow transplantation are being considered. Beyond its original geographic association, thalassemia's global significance is shown by its prevalence in areas including South Asia, the Middle East, Africa, and the Mediterranean Sea. The goal of this study is to present a thorough overview of thalassaemia, including its clinical symptoms, pathophysiology, epidemiology, diagnostic techniques, and available treatments. It will also go over current research developments and new treatments that could lead to better patient outcomes.
EPIDEMIOLOGY OF THALASSEMIA
The frequency of thalassaemia varies greatly among various populations and locations, making it a major worldwide health burden. Although historically more common in regions around the Mediterranean Sea, thalassaemia is today acknowledged as a worldwide health concern that affects millions of people. It is crucial to comprehend the epidemiology of thalassaemia in order to allocate resources and manage the disease effectively. The prevalence of thalassaemia varies throughout the world; it is more common in the Middle East, Asia, and the Mediterranean than in Europe and North America. The need for accurate information and patient registries, especially in poor nations, is highlighted by the importance of epidemiological statistics on thalassaemia for resource allocation and policy planning. 1,310,407 cases of thalassaemia were reported worldwide in 2021.
The frequency of thalassaemia varies widely, with the highest rates found in areas like sections of South Asia, the Middle East, and Africa where consanguineous marriages are prevalent. Thalassaemia is also growing increasingly common in other regions of the world, such as Europe, North America, and Australia, due to migratory trends. According to research, 19.48% of people in Southern China have thalassaemia. According to a study, 9.8% of Thai hill tribe youngsters had thalassaemia. The α-thalassemia 1 characteristic is one of the several types of thalassaemia that have been identified. Thalassaemia prevalence in Gulf Cooperation Council nations ranged from 0.25% to 43.3% across age categories, according to epidemiological profiles.
People of different ages, races, and ethnicities are affected by thalassaemia. However, thalassaemia gene mutations are more common in other demographic groups, such as individuals with Mediterranean, South Asian, or African ancestry. There are demographic differences in thalassaemia among various ethnic groups and geographical areas. The Mediterranean, the Middle East, the Arabian Peninsula, Turkey, Iran, India, Burma, and Southeast Asia all have significant incidence, according to research. The majority of people with homozygous β-thalassemia in North America are of Greek and Italian ancestry, and their mean age is rising as a result of better therapies and immigration from non-Mediterranean ethnic groups. Transfusion-dependent thalassaemia has a large financial burden in India, with treatment expenses taking up a sizable amount of family income, underscoring the difficulties afflicted people confront.
GENETIC ASPECT AND INHERITANCE PATTERNS
Thalassemia is inherited in an autosomal recessive way, meaning that individuals must inherit two defective copies of the gene (one from each parent) to acquire the condition. Heterozygotes, or carriers of a single aberrant gene copy, are typically asymptomatic but can transmit the faulty gene on to their offspring. A class of inherited anaemias known as thalassaemia is inherited in an autosomal recessive manner. People must inherit two faulty gene copies, one from each parent, in order for the illness to emerge. Although heterozygotes, who have a single faulty gene copy, are usually asymptomatic, they may pass on the defective gene to their progeny, which could result in thalassaemia in the following generation. Thalassaemia is caused by mutations that impact globin gene expression, specifically the β-globin gene, which results in decreased or nonexistent β-globin chain synthesis . Thalassaemia has a major therapeutic impact; severe patients necessitate iron chelation therapy and lifetime transfusion assistance. Significant obstacles are also faced by family members and carers of people with thalassaemia, including the psychological, social, financial, and physical strains of the illness and its treatment.
PATHOPHYSIOLOGY
Mutations in the genes that produce the alpha- or beta-globin chains of haemoglobin cause problems in the production of haemoglobin, the oxygen-carrying protein present in red blood cells. The pathophysiology of thalassaemia entails a disturbance in the equilibrium of globin chain synthesis, which results in an imbalance between the alpha and beta globin chains and consequent anomalies in the production and operation of red blood cells. A class of hereditary blood illnesses known as thalassaemia is typified by decreased production of normal haemoglobin chains, which results in hypochromic microcytic anaemias. Excess alpha chains build up in homozygous thalassaemia, such as beta-thalassemia, creating intracytoplasmic erythrocytic inclusions that cause anaemia, osteoporosis, hemosiderosis, bone marrow hyperplasia, and organ failure. Unmatched globin chains, such as alpha-globin in beta-thalassemia, accumulate during the pathogenesis, leading to haemolysis and inefficient erythropoiesis. This may be because alpha-globin deposition in erythroid precursors accelerates apoptosis. Iron overload is a key cause of tissue damage and mortality in beta-thalassemia, which results in erythroid maturation problems, red cell destruction, and a heterogeneous cell population in the blood due to an imbalance in globin chain synthesis. Reduced globin chain synthesis is a hallmark of thalassaemia, which causes haemolysis, inefficient erythropoiesis, early cell death, and variable degrees of anaemia.
TYPES
1.Alpha thalassemia
Mutations or deletions in the genes encoding alpha-globin chains, mainly HBA1 and HBA2 on chromosome 16, cause alpha-thalassemia. The amount of alpha-globin genes impacted determines how severe the illness is. Alpha-thalassemia trait and alpha-thalassemia minor are caused by the loss of one or two alpha-globin genes, respectively; more severe forms, such as Hb H disease and hydrops fetalis, are caused by the loss of three or four genes. Genetic mutations in the HBA1 and/or HBA2 genes cause alpha-thalassemia, an inherited blood condition. Alpha-thalassemia patients have mild to severe anaemia because they produce less haemoglobin than usual. Alpha-thalassemia comes in four different forms, from a trait (one or two alpha-globin genes deleted) to alpha-thalassemia major (all four alpha genes deleted), which causes severe transfusion-dependent anaemia. Accurate diagnosis and possible treatment strategies depend on an understanding of these genetic differences.
2.Beta thalassemia
Mutations or deletions in the beta-globin gene (HBB) on chromosome 11 result in beta-thalassemia. These mutations reduce the synthesis of normal haemoglobin (HbA) by impairing the formation of beta-globin chains. Beta-thalassemia can be categorised as beta-thalassemia mild (trait), beta-thalassemia intermedia, or beta-thalassemia major, depending on how severe the mutation is. Mutations in the β-globin gene cause beta-thalassemia by reducing or eliminating the synthesis of the β-globin chain. These mutations can include nucleotide substitutions, frameshift insertions/deletions, or extensive deletions within the β-globin gene, causing an imbalance in the α/β-globin chain ratio. As a result, iron overload, persistent anaemia, and inefficient erythropoiesis may develop. There are more than 200 known mutations that impact the expression of the β-globin gene, and the severity varies according to residual globin production. Accurate diagnosis and efficient treatment depend on an understanding of these molecular alterations. Innovative cell and gene therapy approaches are being investigated in an effort to potentially treat this monogenic illness.
SIGNS & SYMPTOMS
1.Thalassemia minor
Reduced haemoglobin levels and fewer red blood cells than normal are the hallmarks of thalassaemia minor, also known as the thalassaemia trait, which causes moderate anaemia. Fatigue, weakness, and paleness are common symptoms; physical abnormalities affecting the eyes, skin, ears, mental faculties, and bones/joints may also be present. Haemoglobin levels are often lower in people with thalassaemia minor, averaging 9.45 g/dL in younger age groups and 11.58 g/dL in older age groups. They may also be more vulnerable to infections of the eyes, gastrointestinal tract, lungs, skin, urinary tract, and ears. It is essential to spread knowledge about the dangers of consanguineous marriages in order to stop thalassaemia from spreading within families.
2.Intermedia
A wide range of clinical signs, including as prolonged anaemia, spleen enlargement, lumps outside the bone marrow, excess iron accumulation, jaundice, and abnormal growth, are present in halassemia intermedia. Short stature, microcytic hypochromic anaemia, high unconjugated bilirubin levels, and spleen enlargement are some of the symptoms that patients may exhibit. Additionally, those with thalassaemia intermedia may experience joint pain, noticeable paleness, cheekbone and forehead protrusion, and the development of tophaceous deposits. Additionally, they could experience issues like skeletal abnormalities, blood clotting difficulties, and leg ulcers.
3.Thalassemia major
A variety of signs and symptoms are present in thalassaemia major, a hereditary disorder characterised by aberrant haemoglobin synthesis. Affected children and babies usually have severe anaemia, stunted growth, and swollen abdomens. Additionally common are musculoskeletal abnormalities, such as lengthy bone thinning that gives the impression of a "sun-ray," changes to the skull that provide the appearance of a "hair-on-end," and enlarged maxillary sinuses that frequently result in a maxillary overbite. Additionally, because thalassaemia major is a lifelong condition, people with it may face psychosocial challenges that impact their social connections and mental health. Haematologic assessments, haemoglobin electrophoresis, and DNA analysis are used for diagnosis; iron chelation therapy, blood transfusions, and, in extreme cases, bone marrow transplants are often used for treatment.
SCREENING AND DIAGNOSTIC CARE
In order to confirm the existence of the condition and assess its severity, thalassaemia is diagnosed using a mix of laboratory testing, clinical evaluation, and genetic analysis. An accurate diagnosis is crucial for proper management and treatment planning because thalassaemia phenotypes vary widely and share symptoms with other forms of anaemia. Protocols for thalassaemia screening and diagnosis include a variety of techniques and rules. Prenatal and newborn screening is encouraged by initiatives like the NHS Sickle Cell and Thalassaemia Screening Program, especially in regions where the condition is highly prevalent. Because thalassemia's signs and symptoms might overlap with those of other haematologic illnesses, evaluating it can be difficult. A thorough method is needed to distinguish thalassaemia from other disorders, including genetic testing, haemoglobin electrophoresis, and evaluations of particular haematologic parameters such the MCV/RBC ratio and HbA2 levels. Additionally, research has demonstrated that erythropoiesis markers like GDF-15 and EPO are markedly enhanced in thalassaemia patients, indicating their potential as therapeutic targets and diagnostic indicators. For thalassaemia to be accurately diagnosed and treated, a multidisciplinary strategy combining clinical evaluation with cutting-edge diagnostic techniques is necessary.
1.Laboratory test
A crucial screening method for thalassaemia and other blood disorders is a complete blood count (CBC), which can identify microcytic hypochromic anaemia. To differentiate thalassaemia from other forms of anaemia, parameters like mean corpuscular volume (MCV) and red blood cell distribution width (RDW) are essential. With crucial details on cell components like white blood cells, red blood cells, and platelets, the CBC offers insightful information about the quantitative and qualitative makeup of the blood. The accuracy and efficiency of CBC results have greatly increased thanks to automated haematology analysers, however issues like inconsistent results brought on by interfering chemicals or aberrant cells still need to be carefully considered. The CBC is still essential for identifying and tracking a number of illnesses, underscoring its significance in clinical practice.
2.Hemoglobin electrophoresis
Haemoglobin electrophoresis is an essential diagnostic technique that helps identify aberrant patterns linked to diseases like thalassaemia by separating various haemoglobin types according to their charge. On haemoglobin electrophoresis, thalassaemia usually manifests as decreased adult haemoglobin (HbA) levels and increased foetal haemoglobin (HbF) levels. The accuracy of glycosylated haemoglobin (A1C) tests can also be impacted by aberrant haemoglobin variations, such as haemoglobin C (Hb C), which emphasises the necessity of taking these variants into account in diagnostic assessments. For the separation and characterisation of charged molecules like haemoglobin, electrophoresis is essential. It offers important insights into a variety of haematological illnesses and directs clinical decision-making.
3.Genetic testing
According to several studies, molecular genetic testing is essential for verifying thalassaemia diagnoses and detecting certain gene mutations, especially in the alpha- and beta-globin genes. These mutations can be found using methods like DNA sequencing and the polymerase chain reaction (PCR), which provide crucial details on the severity of the disease and inheritance patterns. The sensitivity and specificity of genetic testing have been greatly improved by these sophisticated molecular diagnostic methods, making it possible to precisely identify mutation carriers, which is essential for precise diagnoses and genetic counselling. Healthcare practitioners can verify the existence of thalassaemia, forecast the possibility of the disease, track its progression, and tailor treatment plans based on genetic variants by utilising nucleic acid-based techniques.
TREATMENT AND MANAGEMENT
The management of thalassemia aims to alleviate symptoms, prevent complications, and improve the quality of life for affected individuals. Treatment strategies vary depending on the type and severity of thalassemia and may include supportive measures, pharmacological interventions, and, in severe cases, bone marrow transplantation or gene therapy.
1.Blood Transfusion therapy
To maintain appropriate haemoglobin levels and avoid issues related to chronic anaemia, people with thalassaemia major or severe thalassaemia intermedia frequently need frequent blood transfusions. To properly manage their illness, thalassaemia patients—particularly those with transfusion-dependent β-thalassemia (TDT)—need frequent blood transfusions. These transfusions are intended to maintain or raise haematocrit levels, treat consequences from inadequate erythropoiesis, and lessen anaemia symptoms. To manage iron overload, a common side effect of thalassaemia treatment, continuous transfusions are frequently combined with iron chelation therapy for TDT patients. Leucodepleted packed red blood cells (P-RBCs) must be prepared using particular techniques in order to maximise transfusion therapy, lower transfusion-related problems, and improve patients' quality of life.
Despite being life-saving, blood transfusion therapy for thalassaemia has a number of drawbacks and debates. One significant issue that causes difficulty in clinical decision-making is the absence of clear guidelines for starting transfusions or establishing haemoglobin objectives for patients with E thalassaemia. Furthermore, individuals with thalassaemia intermedia who start receiving transfusions as adults run a significant risk of developing haemolytic transfusion responses and red cell alloimmunisation. Furthermore, because of things like poor adherence, inconsistent pharmacokinetics, and challenges in tracking treatment response, insufficient iron chelation therapy greatly increases avoidable morbidity and mortality in transfusion-dependent thalassaemia. Regular evaluation of adherence, side effects, and iron burden with suitable treatment modifications is essential to maximise patient results.
2. Use of Luspatercept in Thalassemic Patients in TDT and NTDT
By lowering the need for transfusions and increasing erythropoiesis, luspatercept has demonstrated encouraging outcomes in thalassemic patients with TDT. According to studies, luspatercept dramatically raises HbF levels; responders experience a higher rise in HbF than non-responders. Furthermore, luspatercept has been shown to be effective in increasing haemoglobin levels and alleviating NTDT-related symptoms in NTDT patients, offering a new method of treating anaemia in this group. By encouraging the differentiation and maturation of late-stage erythroid precursors, the medication functions as an erythroid maturation agent, which eventually assists patients who are unable to obtain enough blood transfusions. These results demonstrate the potential of luspatercept as a useful treatment option that can enhance haemoglobin levels, transfusion load, and general quality of life for both TDT and NTDT patients.
3.Pharmacological treatment
Hydroxyurea's therapeutic effects include its ability to lessen the clinical severity of hemoglobinopathies by lowering phosphatidylserine expression on erythrocytes. Hydroxyurea has the potential to be an alternative to blood transfusions and iron chelation therapies because research shows that patients with transfusion-dependent major β-thalassemia who received it had longer intervals between transfusions, increased haemoglobin levels, and decreased ferritin levels. Research on patients with β-thalassemia showed that hydroxyurea decreased the need for blood transfusions; 65.5% and 11.5% of patients responded well to the medication, respectively. Furthermore, compared to normal therapies, hydroxyurea dramatically decreased the requirement for packed RBC transfusions, increased haemoglobin levels, and decreased serum ferritin levels in paediatric patients with transfusion-dependent β-thalassemia major.
4.Bone marroe and stem cell transplantation
Transplanting bone marrow and stem cells is essential for treating thalassaemia, particularly beta-thalassemia major, which may be cured. The only effective treatment for transfusion-dependent thalassaemia major is allogeneic haematopoietic stem cell transplantation (allo-HSCT), and improvements in donor sources and conditioning regimens improve patient outcomes and quality of life. According to research, adding haploidentical related donors to the donor pool and using cutting-edge pharmacologic techniques have greatly increased the safety and effectiveness of HSCT in thalassaemia patients, resulting in excellent survival rates and a decrease in graft failures. Furthermore, research on the co-transplantation of mesenchymal stem cells (MSCs) and haematopoietic stem cells (HSCs) in patients with thalassaemia major shows that although MSC co-transplantation did not significantly alter transplantation results, it also does not significantly improve the alleviation of liver fibrosis.
5.Gene therapy
By fixing the genetic flaw in haematopoietic stem cells, gene therapy has become a viable thalassaemia treatment that may lead to transfusion independence. Promising outcomes have been observed in clinical trials employing editing technologies such as CRISPR/Cas9 to increase foetal haemoglobin synthesis and lentiviral vectors to add functional beta-globin genes. Following gene therapy, some patients have improved their quality of life and become transfusion independent. However, there are still issues with maximising safety and effectiveness, such as the high expense of this novel therapeutic strategy and the possibility of subsequent haematological cancers. Using autologous CD34+ cells transduced with the LentiGlobin BB305 vector, which encodes a modified β-globin gene (HbAT87Q), a study evaluated the safety and effectiveness of gene therapy for 22 patients with transfusion-dependent β-thalassemia.
SUPPORTIVE CARE
Numerous studies have shown that proper diet is essential for thalassaemia patients to ensure healthy growth and development. Bone abnormalities, endocrine problems, and psychological difficulties are common complications for patients with thalassaemia, underscoring the need for comprehensive care involving experts in haematology, endocrinology, cardiology, and psychology. The pathophysiology of thalassaemia is greatly influenced by nutritional deficiencies, especially iron and folate, which have an impact on vitamin levels, body composition, and general health. The quality of life for people with thalassaemia can be improved by reducing development delays and comorbidities through the early diagnosis of dietary abnormalities and multidisciplinary care.
CONCLUSION
A complicated and multidimensional hereditary condition, thalassaemia has a big impact on people, families, and healthcare systems all over the world. Thalassaemia still poses difficulties that call for a coordinated effort by medical professionals, legislators, researchers, and advocacy groups to successfully address, despite improvements in our knowledge of its pathophysiology, diagnosis, and therapy. The management of thalassaemia includes a range of interventions intended to improve patient outcomes, improve quality of life, and eventually find a cure for this chronic condition. These interventions range from early detection through universal screening programs to comprehensive multidisciplinary care and creative therapeutic approaches. There is still much to be done to guarantee fair access to healthcare services, lessen the burden of disease, and promote the psychosocial well-being of people with thalassaemia and their families, despite advancements in fields like gene therapy, iron chelation therapy, and supportive care.
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