Beta-thalassemia is a hereditary hemoglobin disorder due to reduced or absence of beta-globin chain production leading to ineffective erythropoiesis and anemia. It is predominantly an autosomal recessive gene disorder.

Epidemiology

Approximately 1.5% of the global population are beta thalassemia carriers. High prevalence in the Mediterranean, Southeast Asia, Africa, Middle East, India, Pakistan and Southern China.

Genetics of beta thalassemia

More than 400 beta thalassemia mutations have been recorded and they are mainly single nucleotide polymorphisms (SNPs), insertions or small deletions. Mutations cause impairments in transcription, RNA splicing and modifications, translations due to frame shift mutations and nonsense codons among others.

Classifications

	β-Thalassemia minor	β-Thalassemia intermedia	β-Thalassemia major
Pathogenesis	E.g.: single β⁺⁺ or β⁺or β⁰ mutation	E.g.: β⁺/ β⁺or β⁺/ β⁰	E.g.: β⁰/ β⁰
Signs and Symptoms	Mainly asymptomatic	Pallor, splenomegaly, moderate anemia presenting after the age of 1 – 2 years old	Noticeable anemia around 3 – 6 months of age, failure to thrive, intercurrent infections, mild jaundice, hepatosplenomegaly, frontal bossing, thal facies, features of iron overload
Pathophysiology	α/β chain ratio is almost balanced thus minimal hematologic abnormalities	Low β chain production → excess unpaired α chains → membrane damage in erythroblasts → ineffective erythropoiesis → moderate anemia and extramedullary hemopoiesis. Signs and symptoms depends on impact of various genetic modifiers involved	No β chain production → excess unpaired α chains → membrane damage in erythroblasts→ ineffective erythropoiesis and extravascular hemolysis in RE → severe anemia → medullary and extramedullary hemopoiesis
Laboratory investigations	FBC: Slight reduction or normal Hb level with reduced MCV and MCH. Hb A₂ 3.5 – 7.0%. Hb F 1.0 – 5.0% PBF: Hypochromic microcytic red cells. Presence of some target cells.	FBC: Moderate anemia (Hb 7 – 9 g/dL), variable reticulocytes count (5 – 10%). PBF: Moderate microcytic hypochromic RBCS with marked poikilocytosis including target cells. Bone marrow: erythroid hyperplasia. Splenomegaly	FBC: Severe anemia (Hb 3 – 7 g/dL), low MCV and MCH. PBF: Severe microcytic hypochromic anemia with numerous nucleated RBCs. Bone marrow: marked erythroid hyperplasia. Splenomegaly. Growth retardation, bony abnormalities if untreated. DNA mutation analysis: positive HPLC and Hb electrophoresis: No Hb A and predominantly Hb F (30 – 90%) Other investigations: ↑ bilirubin, ↑ urine urobilinogen, ↓ serum haptoglobin, markedly ↑ serum iron, serum ferritin and transferrin saturation, ↓TIBC
Treatment	None required	Intermittent transfusions dependent on severity	Transfusion dependent. Iron chelation therapy. Splenectomy if recommended due to splenomegaly, trapping of transfused red cells and increased transfusion requirements. Oral penicillin therapy for life following splenectomy. Cure: HLA-matched hemopoietic stem cell transplantation.
Management	Genetic counselling and prenatal diagnosis recommended

What is beta thalassemia?

Beta thalassemia is a genetic blood disorder that reduces the production of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Thalassemia is defined as the quantitative reduction of globin chains production leading to anemia.

Thalassemia can be loosely classified into alpha thalassemia and beta thalassemia depending on the affected globin gene. Beta-thalassemia occurs due to a mutation found in the beta globin gene or the promoter region which leads to a quantitative reduction or absence of the beta globin chain production depending on the severity that the mutation has caused.

Even though the production of the beta globin chain has decreased, the production of alpha globin chains is not affected and produces normally. These will lead to a lack of Hb A formation as well as an excess of free alpha globin chains. Free alpha globin chains precipitate as monomers and cause membrane damage leading to anemia as well as an increase in oxidative reactive oxygen species and thus oxidative stress in the cell.

What is the function of the beta-globin gene in hemoglobin?

The beta-globin gene is a gene that provides instructions for making a protein called beta-globin. Beta-globin is a component (subunit) of a larger protein called hemoglobin, which is located inside red blood cells. Hemoglobin is responsible for carrying oxygen from the lungs to the body’s tissues and carbon dioxide from the tissues back to the lungs.

Image depicting a schematic diagram illustrating the normal beta globin cluster on chromosome 11, highlighting the developmental switch of globin chain expression from embryonic to adult stages. — A schematic diagram of the normal beta globin cluster found on chromosome 11. The globin chain produced switches according to the different developmental stages.

The beta-globin gene is located on chromosome 11. Humans have two copies of the beta-globin gene, one on each chromosome 11. In adults, hemoglobin consists of four protein subunits: usually two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA.

The beta-globin gene is responsible for producing the beta-globin subunit of hemoglobin. Beta-globin is a globular protein, meaning that it folds into a three-dimensional structure. The beta-globin subunit has a pocket that can bind to an iron-containing molecule called heme. Hemoglobin can bind up to four oxygen molecules, one to each heme molecule.

When red blood cells reach the lungs, oxygen binds to the beta-globin subunits of hemoglobin. The red blood cells then travel throughout the body, delivering oxygen to the tissues. When the red blood cells reach the tissues, oxygen is released from the beta-globin subunits of hemoglobin and diffuses into the tissues.

Carbon dioxide is a waste product of metabolism. It is produced in the tissues and diffuses into the red blood cells. In the red blood cells, carbon dioxide binds to the beta-globin subunits of hemoglobin. The red blood cells then travel back to the lungs, where the carbon dioxide is released and exhaled.

The beta-globin gene is essential for life. Without the beta-globin gene, humans would not be able to produce hemoglobin and would not be able to carry oxygen to the tissues. Mutations in the beta-globin gene can lead to a variety of blood disorders, including beta thalassemia and sickle cell anemia.

How does beta thalassemia occur?

Beta thalassemia occurs when there is a mutation in the beta-globin gene. The beta-globin gene is responsible for producing the beta-globin protein, which is one of the two proteins that make up hemoglobin, the protein in red blood cells that carries oxygen.

Mutations in the beta-globin gene can reduce or eliminate the production of beta-globin. This can lead to a deficiency of hemoglobin causing anemia. The severity of beta thalassemia depends on the severity of the mutation in the beta-globin gene.

Beta thalassemia is an inherited disorder, meaning that it is passed down from parents to children. The beta thalassemia mutation can be inherited autosomal recessively from one parent (carrier) or from both parents (carriers).

If one parent is a carrier (beta thalassemia minor) of the beta-globin gene mutation, there is a 50% probability that the offspring will inherit the mutation (beta thalassemia minor). If both parents are carriers of the beta-globin gene mutation, there is a 25% probability that the offispring will have beta thalassemia major, a 50% probability that the offspring will have beta thalassemia minor, and a 25% probability that the offspring will not have beta thalassemia at all.

Beta thalassemia is most common in people of Mediterranean, Middle Eastern, and Southeast Asian descent. However, it can occur in people of any ethnicity.

Molecular classifications of beta thalassemia

The molecular classifications of beta thalassemia can be loosely classified into

Beta thalassemia minor (trait): Usually represents the inheritance of a single beta-thalassemia allele and the hemoglobin reduction is mild.
Beta thalassemia intermedia: Could involve homozygosity of compound heterozygosity for mild beta thalassemia mutations or homozygosity or compound heterozygosity for severe mutations with the co-inheritance of alpha thalassemia or heterocellular hereditary persistence of foetal hemoglobin (HPFH).
Beta thalassemia major: Usually represents the inheritance of homozygosity or compound heterozygosity for severe mutations.

Beta thalassemia signs & symptoms

The clinical features of beta thalassemia vary depending on the severity of the condition.

Beta thalassemia minor (trait)

Beta thalassemia minor (trait) individuals are typically asymptomatic with or without mild anemia. Clinically beta thalassemia minor (trait) individuals are asymptomatic and are only picked up through a routine blood test. The alpha/beta chain ratio is not affected much as there is minimal quantitative reduction in beta globin chains thus there are only slight hematologic abnormalities.

Beta thalassemia intermedia

Phenotypically, beta thalassemia intermedia falls in between relatively severe anemia to a clinically asymptomatic phenotype.

Beta thalassemia intermedia individuals are pale and have a slightly enlarged spleen as they grow older and typically present around 2 – 6 years of age. A lower beta globin chain production will lead to excess unpaired alpha globin chains which precipitate to cause membrane damage in the erythroblasts. This leads to ineffective erythropoiesis and moderate anemia.

Signs and symptoms of beta thalassemia intermedia are highly variable depending on the various genetic modifiers involved. Homozygosity or compound heterozygosity for severe beta thalassemia mutations usually presents a beta thalassemia major phenotype, however, co-inheritance of alpha thalassemia or HPFH ameliorates the severity to an intermediate phenotype.

Beta thalassemia intermedia individuals are able to survive without regular blood transfusions. Blood transfusions for beta thalassemia intermedia individuals may be required at longer intervals although growth and development may be retarded.

Beta thalassemia major

Beta thalassemia major refers to the severe end of the clinical spectrum and these patients are severely anemic and are dependent on regular blood transfusion for survival.

Beta thalassemia major individuals usually present with lethargy and anemia around 6 months of age. Beta thalassemia major individuals will fail to thrive with intercurrent infections, hepatosplenomegaly, frontal bossing, thal facies i.e. chipmunk face and features of iron overload if not treated quickly.

Without treatment, beta thalassemia major individuals usually die within the first decade of life. As quantitatively there is no beta globin chain production, the excess alpha globin chains will cause ineffective erythropoiesis and extravascular hemolysis in the reticuloendothelial system. Severe anemia will lead to increased medullary and extramedullary hematopoiesis.

Beta thalassemia complications

The hallmark of beta thalassemia is ineffective erythropoiesis where 10 -15% of the erythroblasts dies in the bone marrow prematurely. This leads to anemia, bone marrow expansion and extramedullary erythropoiesis.

Complications related to ineffective erythropoiesis include bone pain and fractures and hepatosplenomegaly. The high red cell turnover rate predisposes to gallstone formation. Iron overload due to increased GIT iron absorption for erythropoiesis and iron from transfused blood leads to iron deposition in visceral organs which causes heart failure, growth retardation and even delayed sexual maturity.

Clinically, the anemia caused by the premature destruction of the erythroid cells due to alpha globin chain excess induces a hyperproliferation of erythropoiesis leading to an expansion of the bone marrow. This contributes to serious deformities of the skull and long bones if untreated. A classic ‘hair-on end’ appearance on skull radiography is apparent due to marked erythroid hyperplasia. Splenomegaly results from a constant influx and destruction of abnormal red blood cells by the spleen.

Complications of severe beta thalassemia intermedia and beta thalassemia major include bone expansion, hypopituitarism, hypothyroidism and hypoparathyroidism, cardiomyopathy, pulmonary hypertension and embolism, hemosiderosis, liver cirrhosis and extramedullary hematopoiesis, splenomegaly, diabetes mellitus, delayed puberty and secondary sexual characteristics, osteoporosis and short stature.

Image depicting the organ damage caused by beta thalassemia major, highlighting the impact of iron overload on various organs — **The Silent Accumulation: Iron Overload Takes Center Stage**
Beta thalassemia major, a severe form of genetic anemia, results in the abnormal production of hemoglobin, leading to chronic anemia. The repeated blood transfusions required to manage anemia introduce excess iron into the body, gradually accumulating in various organs.

Laboratory investigations for beta thalassemia

Laboratory investigations play an important role in the diagnosis and management of beta thalassemia.

Complete blood count (CBC)

A CBC is a test that measures the number of different types of blood cells in the blood. A low red blood cell count and a low hemoglobin level are suggestive of anemia. Beta thalassemia is characterised by low hemoglobin level, low MCV and MCH and increased reticulocyte count.

Beta thalassemia minor (trait) has hypochromic microcytic red blood cells with or without a mild anemia, increased levels of Hb A2 and variable increases in Hb F levels.

Peripheral blood smear

A peripheral blood smear is a microscopic examination of blood cells. It can be used to look for signs of anemia, such as small, pale red blood cells.

In beta thalassemia minor (trait), the peripheral blood smear shows hypochromic microcytic red cells with presence of target cells.
Beta thalassemia intermedia will have moderate microcytic hypochromic anemia with reticulocytosis.
Beta thalassemia major will show marked anisopoikilocytosis with numerous target cells and nucleated red cells may be seen.

Unveiling the Hallmarks of Beta Thalassemia Major: A Microscopic Portrait of Anisocytosis, Target Cells, and Nucleated Red Blood Cells — Image depicting a peripheral blood smear of beta thalassemia major, showcasing the characteristic features of anisopoikilocytosis, target cells, and nucleated red blood cells

Hemoglobin electrophoresis

Hemoglobin electrophoresis is a test that is used to identify the different types of hemoglobin in the blood. In beta thalassemia, hemoglobin electrophoresis may show a decrease in the amount of normal hemoglobin (HbA) and an increase in the amount of abnormal hemoglobin (such as HbS, HbE, or HbF).

Gel electrophoresis results, illustrating the identification of abnormal hemoglobin variants — Gel eletrophoresis plays a crucial role in diagnosing beta thalassemia by allow us to identify abnormal hemoglobin variants. However, these days the automated methods like HPLC and capillary eletrophoresis is more common.

High performance liquid chromatography (HPLC)

Similar to hemoglobin electrophoresis, there will be a quantitative reduction or absence of Hb A with an increase of Hb A2 and Hb F.

HPLC chromatogram indicating elevated HbA2 levels, potentially suggesting homozygous Hb E. — This HPLC chromatogram depicts an individual with an elevated HbA2 level, a potential indication of homozygous Hb E. HbA2, a minor hemoglobin component, typically constitutes 1.5-3.5% of total hemoglobin in normal individuals. However, in individuals with homozygous Hb E, HbA2 levels can increase significantly, reaching up to 20% or more.

DNA testing

DNA testing is the most definitive test for the diagnosis of beta thalassemia. It can be used to identify the specific mutation in the beta-globin gene that is causing beta thalassemia. DNA testing for example PCR can also be used to identify carriers of beta thalassemia, which is important for genetic counseling and prenatal diagnosis.

Other laboratory tests

Other laboratory tests that may be used to investigate beta thalassemia include:

Iron studies: Iron studies are used to measure the amount of iron in the blood and body tissues. Beta thalassemia major individuals are at risk for iron overload due to the regular blood transfusions that they require. There will be a marked increase in serum iron, serum ferritin and transferrin saturation level while low TIBC.
Liver function tests: Liver function tests are used to assess the function of the liver. Beta thalassemia major individuals are at risk for liver damage due to iron overload.
Cardiac function tests: Cardiac function tests are used to assess the function of the heart. Beta thalassemia major individuals are at risk for heart problems due to iron overload, anemia, and other complications of the disorder.
Other investigations will show increased bilirubin and urobilinogen level with decreased serum haptoglobin.

How is beta thalassemia treated?

There is no treatment necessary for beta thalassemia minor (trait).

As for beta thalassemia intermedia, intermittent transfusions can be given to patients as and when needed. Iron chelation therapy can be used to prevent iron overload when the patient is older.

The first line treatment of beta thalassaemia major is packed red cell transfusion every 2 – 4 weeks and splenectomy is indicated if there is significant splenomegaly and excessive consumption of the red cells. However, splenectomy has a higher risk of thrombotic complications and post-splenectomy sepsis thus splenectomy is recommended only in children older than 6 years old or extremely necessary.

Apart from iron accumulation due to transfusion, iron loading and overloading are common complications in beta thalassaemia individuals due to excess intestinal iron absorption and accumulation in the tissues rising from ineffective erythropoiesis even without transfusion. Therefore, iron chelation therapy is recommended to prevent the deleterious effects of iron overload.

As thalassaemia intermedia and major can be a debilitating disorder, the only current cure is bone marrow transplantation and as scientists and medical doctors look for better treatment and cure for this disease, gene therapy has made remarkable progress in this area.

Many countries with high frequency of beta thalassemia run a prevention screening program while offering genetic counselling to those affected.

Frequently Asked Questions (FAQs)

What is the life expectancy of a person with beta thalassemia?

The life expectancy of a person with beta thalassemia significantly depends on the severity of the condition and the availability of proper medical care.

Types of Beta Thalassemia and Life Expectancy

Beat thalassemia minor (trait): People with this mild form typically have a normal life expectancy.
Beta thalassemia intermedia: Life expectancy can vary widely depending on the severity of symptoms. With proper medical management, many individuals can live relatively normal lives.
Beta thalassemia major: Historically, life expectancy was significantly shortened. However, with advancements in medical treatment, including regular blood transfusions and iron chelation therapy, many individuals with beta thalassemia major are now living into their 50s and 60s.

Does beta thalassemia get worse with age?

Beta thalassemia itself doesn’t necessarily worsen with age. However, the risk of complications associated with the condition does increase over time.

Common Complications

Iron overload: This is a major concern due to regular blood transfusions.
Bone problems: These can develop due to the body’s attempt to produce more red blood cells.
Liver and heart issues: These can be caused by iron overload.
Blood clots: Increased risk due to changes in blood composition.

Can people with thalassemia donate blood?

Generally, individuals with beta thalassemia intermedia or major cannot donate blood. Thalassemia is a blood disorder that affects the production of hemoglobin, the protein in red blood cells that carries oxygen. People with thalassemia intermedia and major often rely on regular blood transfusions to survive, making them ineligible to donate. Additionally, their blood may not meet the necessary health standards for donation.

Should I take iron if I have thalassemia?

Taking iron supplements if you have thalassemia is generally not recommended. People with thalassemia often have too much iron in their body, not too little. Excess iron can damage organs like the heart and liver. If you’re concerned about iron levels, it’s crucial to consult with your doctor to determine the best course of action based on your specific condition and medical history.

How to check for beta thalassemia?

To check for beta thalassemia, a blood test is typically performed. This involves a complete blood count (CBC) to examine red blood cells, and hemoglobin electrophoresis to analyze the types of hemoglobin present. In some cases, genetic testing may also be necessary to confirm the diagnosis.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

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