Beta-thalassemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

The Thalassemia term was invented by a hematologist, Dr. Thomas Cooley, in 1925. It has a Greek origin and consists of Thalassa and Emia which mean sea and blood, respectively. The diagnostic certainty was ultimately established with hemoglobin electrophoresis in the 20th century.

Beta-Thalassemia is classified based on the severity and the type of responsible mutation. It mainly has 3 types: β thalassemia minor, β thalassemia major, Thalassemia intermedia. There are less common types such as E/Beta-thalassemia, autosomal dominant Beta-thalassemia and atypical Beta-Thalassemia.

Beta-Thalassemia is an inherited disorder in hemoglobulin production due to a variety of genetic mutations in the gene responsible for Beta-globin production (HBB gene, on chromosome 11). The effects of beta-thalassemia on red blood cell morphology and function are significantly detrimental. Beta-Thalassemia contributes to abnormal hemoglobin and red blood cells (RBCs) that have impaired function in efficient oxygen delivery to different body tissues, which is called the state of anemia. As mutated genes are passed down, the shortage of functional red blood cells begins affecting the body from early infancy, and the lifelong persistence of insufficiency in beta-globin production results in chronic anemia. Hepatosplenomegaly, delayed developmental milestones, jaundice, bone problems, and different infections might happen in early infancy.

Beta-thalassemia may have similar features of other conditions such as iron deficiency anemia, sideroblastic anemia, Alpha-thalassemia, other hemolytic anemia and other hemoglobinopathies including sickle cell anemia. To differentiate these conditions, history and physical examination, electrophoresis of hemoglobin, DNA analysis and iron level assessments would be useful.

The prevalence of beta-thalassemia carrier is 1.5% of the world population which is mainly in regions with a historical association with malaria, including the Mediterranean, Middle East, Central Asia, Indian subcontinent, and parts of Southeast Asia and Africa. The incidence of beta-thalassemia is 42,000 per year. It affects both males and females in a similar demographic manner.

In general, positive family history and specific ethnicities are the major risk factors for beta-thalassemia. On the other hand, lack of awareness and education about the screening for beta-thalassemia, limited resources for screening programs and consanguineous marriages are contributing factors for increasing the risk of beta-thalassemia.

Without regular blood transfusions, affected individuals by major beta-thalassemia typically develop severe anemia and other complications such as pulmonary hypertension, right heart failure, iron overload, infections early in life, while beta-thalassemia intermedia patients would have a variable clinical course, complications, and prognosis. Beta-thalassemia minor subjects would not have significant symptoms, while in some cases might have an increased risk for iron deficiency anemia. Iron overload complications happen in transfusion-dependent thalassemia. The prognosis of beta-thalassemia depends on the severity of the disease and the presence of complications such as iron overload-related complications and cardiovascular disorders.

Patients with beta-thalassemia major may manifest with severe anemia, failure to thrive, pallor, jaundice, abdominal enlargement, fatigue, recurrent fever attacks, growth retardation and poor muscle tone early in childhood. Multiple transfusions can cause arthritis, abdominal pain, bronzed or grayish skin, loss of libido, hormonal imbalances, and cognitive problems. Intermedia variant patients might experience moderate anemia, splenomegaly, bone changes, and intermittent need for blood transfusions at different ages. Patients with beta-thalassemia minor are basically asymptomatic or have minor anemic symptoms.

In physical examination of patients with beta-thalassemia major, pallor, jaundice, hepatosplenomegaly, frontal bossing, long bone abnormalities, skull expansion with frontal, malar, and nasal bridge prominences, maxillary hypertrophy, malocclusion of jaw, short trunk, genu valgum, delayed sexual development, low blood pressure and irregular pulse may be noticeable. Beta-thalassemia minor does not have significant signs and manifestations.

The initial work-up for diagnosis of beta-thalassemia includes complete blood count and hemoglobin electrophoresis which may indicate low hemoglobin level, MCV, MCH and high hemoglobin F and A2. For advanced assessment, there are other methods such as: high-performance liquid chromatography (HPLC), capillary zone electrophoresis (CE) systems, chorionic villus sample, amniotic fluid evaluation, DNA analysis, PCR and genome sequencing.

In X-ray evaluation, thinning of bones and expanded bone marrow spaces can be observed.

CT scan is not a routine work-up in beta-thalassemia. However, the abdominal CT scan may reveal Hepatosplenomegaly due to Extramedullary hematopoiesis.

Abdominopelvic MRI can suggest hepatosplenomegaly. MRI with T2 star sequence is a particular sequence of MRI that specifically assesses for iron overload states. MRI with T2 star of the heart or liver can help determine the degree of iron overload.

Ultrasound is not a routine work-up in beta-thalassemia. However, the abdominal ultrasound may reveal Hepatosplenomegaly due to Extramedullary hematopoiesis.

There are no other imaging findings for beta-thalassemia.

Serum ferritin levels, liver function tests, and genetic testing to identify specific beta-thalassemia mutations are other diagnostic studies which may help to confirm the diagnosis.

The mainstay of treatment for beta-thalassemia major is blood transfusion. Chelation therapy is also required to manage iron overload resulting from repeated transfusions. In less severe cases, folic acid supplementation may be recommended to support red blood cell production. Bone marrow transplantation is the only cure for thalassemia, and is indicated for patients with severe thalassemia major. Untreated thalassemia major eventually leads to death, usually by heart failure; therefore, birth screening is very important.

In beta-thalassemia minor, a serum ferritin test can determine what their iron levels are and guide them to further treatment if necessary.

Surgical intervention is frequently required to guarantee optimum management of the accompanying morbidity in beta-thalassemia cases. The most prevalent types of surgical interventions associated with beta-thalassemia include splenectomy, cholecystectomy, leg ulcers, fractures, and extramedullary pseudotumor.

Primary prevention strategies are carrier screening, genetic counseling, and prenatal testing to identify at-risk couples and provide appropriate guidance regarding family planning options.

Secondary prevention measures would be needed after the initiation of blood transfusions with regular monitoring of iron overload, maintaining appropriate transfusion and chelation therapy regimens, and managing potential complications such as infections or organ dysfunction.

The long-term cost-effectiveness of therapy for beta-thalassemia major depends on factors such as access to healthcare resources, availability of blood products, affordability of chelation therapy, and overall disease management.

Promising future therapies for beta-thalassemia major include gene therapy, stem cell transplantation, and novel approaches targeting gene editing or gene regulation to enhance the production of functional beta-globin chains.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

The Thalassemia term was invented by a hematologist, Dr. Thomas Cooley, in 1925. It has a Greek origin and consists of Thalassa and Emia which mean sea and blood, respectively. The diagnostic certainty was ultimately established with hemoglobin electrophoresis in the 20th century.

The Thalassemia term was coined by Dr. Thomas Cooley (1871-1945), an American hematologist, in 1925, when he first described the disease in the Mediterranean Sea descent. Thalassemia is a Greek word derived from Thalassa meaning sea and Emia meaning blood ^[1]. The pattern of the disease was also observed and recorded in the Middle East and Southeast Asia frequently. Later, Dr. James V. Neel distinguished thalassemia from sickle cell anemia. VALENTINE, W. N., and J. V. NEEL, Hematologic and genetic study of the transmission of thalassemia. Arch. Intern. Med. 1944, 74: 185-196. The diagnostic certainty was ultimately established with hemoglobin electrophoresis in the 20th century.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

Beta-Thalassemia is classified based on the severity and the type of responsible mutation. It mainly has 3 types: β thalassemia minor, β thalassemia major, Thalassemia intermedia. There are less common types such as E/Beta-thalassemia, autosomal dominant Beta-thalassemia and atypical Beta-Thalassemia.

Beta-Thalassemia is classified based on the severity, dependency on blood transfusions, and the mutation responsible for the disease. Any given individual has two β globin alleles ^[1]:

Name	Description	Alleles
β thalassemia minor (sometimes called β thalassemia trait)	If only one β globin allele bears a mutation. This is a mild microcytic anemia. Detection usually involves measuring the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume than normal. The patient will have an increased fraction of Hemoglobin A2 (>2.5%) and a decreased fraction of Hemoglobin A (<97.5%).	β+/β or βo/β
β thalassemia major or Cooley’s anemia	If both alleles have thalassemia mutations. This is a severe microcytic, hypochromic anemia. Untreated, this progresses to death before age twenty. Treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.	β+/β+ or βo/βo
Thalassemia intermedia	A condition intermediate between the major and minor forms. Affected individuals can often manage a normal life but may need occasional transfusions e.g. at times of illness or pregnancy, depending on the severity of their anemia.	β+/β+ or βo/β

Note that β⁺/β⁺ can be associated with β thalassemia minor or β thalassemia intermedia.

There are other types of beta-thalassemia which are not as common as the above:

• E/Beta-thalassemia: It is another term in which a special mutation in Beta-globin is combined with Beta-thalassemia. Its symptoms and clinical severity can range from mild to severe ^[2].
• Autosomal dominant Beta-thalassemia: Beta-thalassemia is an inherited autosomal recessive disease, while one variant might happen with a mutation that causes autosomal dominant disease.
• Atypical Beta-Thalassemia: It might happen due to rare mutations that do not match with previously mentioned classifications. When having no symptoms and being detected through genetic testing, the state would be named a silent carrier ^[3].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

Beta-Thalassemia is an inherited disorder in hemoglobulin production due to a variety of genetic mutations in the gene responsible for Beta-globin production (HBB gene, on chromosome 11). The effects of beta-thalassemia on red blood cell morphology and function are significantly detrimental. Beta-Thalassemia contributes to abnormal hemoglobin and red blood cells (RBCs) that have impaired function in efficient oxygen delivery to different body tissues, which is called the state of anemia. As mutated genes are passed down, the shortage of functional red blood cells begins affecting the body from early infancy, and the lifelong persistence of insufficiency in beta-globin production results in chronic anemia. Hepatosplenomegaly, delayed developmental milestones, jaundice, bone problems, and different infections might happen in early infancy.

Beta thalassemia is a hereditary disease affecting hemoglobin. As with about half of all hereditary diseases, an inherited mutation damages the assembly of the messenger-type RNA (mRNA) that is transcribed from a chromosome. DNA contains both the instructions (genes) for stringing amino acids together into proteins, as well as stretches of DNA that play important roles in regulating produced protein levels. In thalassemia, an additional, contiguous length or a discontinuous fragment of non-coding instructions is included in the mRNA. This happens because the mutation obliterates the boundary between the intronic and exonic portions of the DNA template. Because all the coding sections may still be present, normal hemoglobin may be produced and the added genetic material, if it produces pathology, instead disrupts regulatory functions enough to produce anemia. Hemoglobin’s normal alpha and beta subunits each have an iron-containing central portion (heme) that allows the protein chain of a subunit to fold around it. Normal adult hemoglobin contains 2 alpha and 2 beta subunits. Thalassemia typically affects only the mRNAs for production of the beta chains (hence the name). Since the mutation may be a change in only a single base (single-nucleotide polymorphism), ongoing efforts seek gene therapies to make that single correction^[1][2].

Beta-globin is an indispensable component of hemoglobin that is functioning alongside the alpha chain. In normal individuals, hemoglobin has two alpha-globin chains and two beta-globin chains (α2β2). In beta-thalassemia, the mutated gene of HBB is affecting the encoded beta-globin chains^[3]. The pattern of these impaired genes can cause different pathologic conditions as shown in the table below^[4][5]:

Type of Beta Thalassemia	Hemoglobin Chain Composition (genotype)	Severity
β thalassemia minor	α2β+/α2β+ or α2β+/α2β0	Mild
β thalassemia major	α2β0/α2β0	Sever
Thalassemia intermedia	Variable (can be similar to Major variant or may have some residual beta globin production)	Variable (milder than the Major variant but more severe than Beta Thalassemia Minor)

Then a cascade of events would contribute to ineffective erythropoiesis and reduced hemoglobin production or impaired hemoglobin stability, hemolysis, and increased erythropoietin production (the hormone secreted by the kidney in response to low oxygen levels). Most other pathologic manifestations happen due to iron overload following the transfusions needed for the treatment ^[6].

• Hemolysis may happen due to the destruction of ineffective RBCs in the bone marrow, spleen, and blood, causing various consequences as well as hepatosplenomegaly^[7].
• Extramedullary hematopoiesis might happen following the expansion of the bone marrow due to an increased need for erythropoiesis and increased erythropoietin production^[6].
• Biliary lithiasis or gallstones would frequently happen due to products of hemolysis, excess iron, and liver damage^[8].
• Endocrine disturbances might happen due to chronic anemia and low oxygen levels in the blood and iron overload^[9]; followed by changes in the normal pattern of secretion of various hormones as well as^[9]:
  • Growth hormone: It causes delayed growth and development.
  • Hypothalamic-pituitary-gonadal axis hormones: It causes hypogonadism.
  • Thyroid stimulating hormone: It causes hypothyroidism.
  • Parathyroid hormone (PTH): It causes parathyroid dysfunction.
  • Adrenal hormones dysfunction.

The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished^[10][11][1]:

• Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
• Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (β^o) or hereditary persistence of fetal hemoglobin syndromes.

The severity of the disease depends on the nature of the mutation^[12].

• Mutations are characterized as (β^o) if they prevent any formation of β chains.
• Mutations are characterized as (β⁺) if they allow some β chain formation to occur.
• Alleles without a mutation that reduces function is characterized as (β). (Note that the “+” in β⁺ is relative to β^o, not β.)

In either case, there is a relative excess of α chains, but these do not form tetramers; rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

Beta-thalassemia may have similar features of other conditions such as iron deficiency anemia, sideroblastic anemia, Alpha-thalassemia, other hemolytic anemia and other hemoglobinopathies including sickle cell anemia. To differentiate these conditions, history and physical examination, electrophoresis of hemoglobin, DNA analysis and iron level assessments would be useful.

Beta-thalassemia disease symptoms are having a wide range and can be similar to various other diseases such as^[1][2]:

• Iron deficiency anemia
• Sideroblastic anemia
• Alpha-thalassemia
• Sickle cell anemia
• Hemolytic anemia
• Other hemoglobinopathies and other causes of chronic anemia

However, the diagnosis and differentiation would be properly performed thorough history and physical examination, electrophoresis of hemoglobin, DNA analysis and iron level assessments.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

The prevalence of beta-thalassemia carrier is 1.5% of the world population which is mainly in regions with a historical association with malaria, including the Mediterranean, Middle East, Central Asia, Indian subcontinent, and parts of Southeast Asia and Africa. The incidence of beta-thalassemia is 42,000 per year. It affects both males and females in a similar demographic manner.

There are insufficient data about the exact prevalence of beta-thalassemia.

• The prevalence of beta-thalassemia carrier is 1.5% of the world population.^[1]
• More than 90% of the cases live in a geographic “belt” extending from the Mediterranean basin and parts of Africa, throughout the Middle East, the Indian subcontinent, Southeast Asia, and Melanesia into the Pacific Islands (regions with a historical association with malaria).^[2][3]
• There are increases in the number of cases through North America and Europe, which reflects the increased rates of migrations, refugees and adaptation of children.^[4]
• Gender distribution: It affects both males and females in a similar demographic manner. Lahiry P, Al-Attar SA, Hegele RA. Understanding beta-thalassemia with a focus on the Indian subcontinent and the Middle East. The open hematology journal. 2008 Jan 22;2(1).

• The incidence of beta-thalassemia is 42,000 per year.^[5]
• Recent studies suggest that around 23000 infants with beta-thalassemia major are born every year and up to 90% of these infants are in low- or middle-income countries.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

In General, Positive family history and specific ethnicities are the major risk factors for beta-thalassemia. On the other hand, Lack of awareness and education about the screening for beta-thalassemia, limited resources for screening programs and the consanguineous marriages are contributing factors for increasing the risk of beta-thalassemia.

Positive family history and certain ethnicities are factors that increase the risk of beta thalassemia. Depending on family history, if a person’s parents or grandparents had beta thalassemia major or intermedia, there is a 75% (3 out of 4) probability of the mutated gene being inherited by an offspring. Even if a child does not have beta thalassemia major or intermedia, they can still be a carrier, possibly resulting in future generations of their offspring having beta thalassemia. Another risk factor is ethnicity. Beta thalassemia occurs most often in people of Italian, Greek, Middle Eastern, Southern Asian, and African ancestry^[1].

Risk Factors in areas with high beta-thalassemia prevalence:

• Lack of awareness and education about the screening for beta-thalassemia^[2].
• Limited resources for screening programs^[2].
• Cultural and societal norms encouraging consanguineous marriage^[3].
• Consanguineous marriage in areas with a high prevalence of the disease^[3].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]

Without regular blood transfusions, affected individuals by major beta-thalassemia typically develop severe anemia and other complications such as pulmonary hypertension, right heart failure, iron overload, infections early in life, while beta-thalassemia intermedia patients would have a variable clinical course, complications, and prognosis. Beta-thalassemia minor subjects would not have significant symptoms, while in some cases might have an increased risk for iron deficiency anemia. Iron overload complications happen in transfusion-dependent thalassemia. The prognosis of beta-thalassemia depends on the severity of the disease and the presence of complications such as iron overload-related complications and cardiovascular disorders.

• Untreated beta-thalassemia can result in significant morbidity, mortality, and diminished quality of life. Patients with non-transfusion-dependent beta-thalassemia (NTD) can develop a wide range of complications in critical organ systems due to ineffective erythropoiesis, hemolysis, and primary iron overload. NTD patients can progress to transfusion-dependent beta-thalassemia (TD) later in life, which further exacerbates the risk of complications and iron overload^[1].
• Untreated thalassemia major patients are at a high risk of developing pulmonary hypertension and right heart failure. The prevalence of these conditions in beta-thalassemia patients depends on the severity of the disease and the adequacy of treatment. Thalassemia major patients who do not receive treatment almost universally develop pulmonary hypertension. On the other hand, thalassemia intermedia patients are more likely to develop pulmonary hypertension compared to treated thalassemia major patients^[2].
• Untreated beta-thalassemia major patients may also experience irreversible bone and organ damage due to iron overload^[3].

Beta-thalassemia is associated with complications such as:

• Hemolytic anemia, chronic microcytic hypochromic anemia
• Iron overload due to chronic hemolysis and transfusion
• Irreversible bone and organ damage secondary to iron overload^[3].
• Oxidative stress, which is mainly caused by tissue injury due to the overproduction of free radicals resulting from secondary iron overload^[4].
• Infections (hepatitis B, hepatitis C, HIV) due to contaminated blood transfusion^[5].

The prognosis of beta-thalassemia depends on the severity of the disease and the presence of complications.

• Beta-thalassemia major: Without treatment, individuals with thalassemia major may experience growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, and skeletal changes. Regular transfusion therapy can lead to iron overload-related complications, including endocrine complications, dilated cardiomyopathy, liver fibrosis, and cirrhosis. Cardiac disease caused by myocardial injury is the most important life-limiting complication of iron overload in beta-thalassemia.
• Beta-thalassemia intermedia: present later in life with moderate anemia and do not require regular transfusions. However, they may experience complications such as hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis, gallstones, painful leg ulcers, and increased predisposition to thrombosis.
• Beta-thalassemia minor: clinically asymptomatic, but some individuals may have moderate anemia^[6].

The prognosis of beta-thalassemia can also be influenced by cardiovascular involvement.

• Parenchymal injury secondary to myocardial iron deposition and immune-inflammatory processes are known to be primary reasons for cardiovascular disorders in patients with thalassemia.
• Early abnormalities in ventricular myocardium can occur in patients with beta-thalassemia, even in those receiving effective chelation therapies.
• Aortic elasticity indices are impaired in patients with beta-thalassemia major, and these parameters may be used to predict cardiovascular complications in asymptomatic patients^[7].

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