23rd May 2023

Thalassaemia

Overview of thalassaemia

Haemoglobin consists of four polypeptide subunits that contain two alpha chains and two beta chains. Thalassaemias are inherited autosomal recessive genetic disorders that cause reduced synthesis of alpha or beta chains in haemoglobin. This impairs formation of red blood cells, reducing their oxygen-carrying capacity, resulting in microcytic hypochromic anaemia. The defects are caused by genetic point mutations or deletions of key gene fragments. There are two main groups of thalassaemia based on the polypeptide chain that is affected: alpha and beta thalassaemia.

The haemoglobin alpha chain is coded by 4 alleles, leading to a range of severity of alpha thalassaemia, depending on the number of alleles affected. The beta chain is coded by 2 alleles, resulting in only two possible variants of beta thalassaemia.

Alpha thalassaemia predominantly affects those of Asian or African descent, while beta thalassaemia is prevalent in the Mediterranean and Southeast Asian population.

Patients present with a range of phenotypes depending on their inherited thalassaemia trait. These include symptoms of anaemia i.e. fatigue and pallor, slow growth rates in children, jaundice, hepatosplenomegaly, or death in-utero.

Treatment is mainly supportive and includes blood transfusion, oral iron chelating agents to prevent overload, and patient education.

Alpha thalassaemia

Alpha thalassaemia is due to reduced or absent alpha chain production and accumulation of beta-like chains. There are two alpha chain genes (HBA1 and HBA2) on each copy of chromosome 16, thus four alleles exist. The number of deleted alpha-globin alleles determines which of the four different traits seen in alpha thalassaemia results.

Alpha thalassaemia minima (silent carrier)

• One affected alpha chain
• Asymptomatic
• No anaemia
• Normal haemoglobin analysis

Alpha thalassaemia minor (alpha thalassaemia trait)

• Loss of two alpha chains
• Homozygous if one alpha chain on each chromosome affected
• Heterozygous if both alpha chains on one chromosome affected
• Mild asymptomatic microcytic hypochromic anaemia
• Homozygous patients are more affected – mild anaemia, low MCV, splenomegaly

Haemoglobin H disease

• Three alpha chains affected
• Variable clinical severity
• Symptomatic from birth but typically do not require regular blood transfusion
• Periods of increased haemolysis and aplastic crises e.g. during infection, may require blood transfusion
• Risk of iron overload even in absence of regular blood transfusion

Haemoglobin Bart’s Hydrops Foetalis (Homozygous alpha thalassaemia)

• Deletion of all alpha chains
• Severe anaemia during foetal development causing foetal hydrops
• Often in-utero death occurs

Management of alpha thalassaemia

• Patient education and counselling, particularly around family planning is important.
• Avoid iron supplementation unless proven to be iron deficient, due to risk of iron overload.
• Blood transfusion, depending on the clinical severity and symptoms of anaemia.
• Iron chelating therapy, as these patients are at risk of iron overload from repeated blood transfusions or from increased absorption from the gastrointestinal tract. Careful monitoring of cardiac, endocrine, and hepatic function is required.
• Splenectomy may be considered in patients with painful splenomegaly, hypersplenism with pancytopenia, increased transfusion requirement, and worsening anaemia.
• Haematopoietic stem cell transplant is the only curative treatment and should be considered in severe transfusion dependent patients.

Beta thalassaemia

Beta thalassaemia is a result of defective beta chain synthesis due to point mutation in the HBB gene on chromosome 11. Two alleles may therefore be affected; the mutated alleles can create either partially functioning, non-functioning, or reduced quantities of beta-globin, resulting in the variations of beta thalassaemia.

Beta thalassaemia can be classified as major, intermedia or minor. However, there has been a shift recently to classify beta thalassaemia as transfusion dependent or non-transfusion dependent.

Beta thalassaemia major (Cooley’s anaemia, transfusion dependent)

• Both beta chain alleles affected resulting in no functional beta chain production.
• Severe haemolytic anaemia requiring regular blood transfusions.
• Symptoms manifest between 6 to 12 months of life during the transition from foetal to adult haemoglobin production, when gamma-chain production ceases and beta-chains fail to form.
• Present with pallor, abdominal distension secondary to hepatosplenomegaly, fatigue, and poor feeding.
• Bony abnormalities may also be present such as frontal and parietal bossing and chipmunk facies due to increased extramedullary haematopoiesis.

Beta thalassaemia intermedia

• Both beta chains affected but variable quantity and function of beta chains.
• Range of signs e.g. pallor, jaundice, splenomegaly. Can present as a less severe phenotype, as some adult haemoglobin (HbA – α2β2) is produced.
• For some, blood transfusions are only required later in life in 30s or 40s, however, each case is unique.

Beta thalassaemia minor (beta thalassaemia trait)

• Only one beta chain affected
• Heterozygous carrier
• Asymptomatic or mild anaemia that is often mistaken as iron deficiency due to microcytosis.