22nd July 2024

Thalassaemia

Thalassaemias are disorders of haemoglobin production with a reduced production of one type of globin chain (alpha or beta). This leads to an excess of the unaffected chain, which ultimately damages RBCs in the bone marrow and causes haemolysis. Thalassaemia is more common in patients from the Mediterranean, northern Africa and parts of the Middle and Far East.

FBC will show a microcytic anaemia, with blood film findings including tear drop cells, target cells and nucleated RBCs. Raised bilirubin, LDH and reticulocytes indicate haemolysis.

Beta thalassaemia

Mutations of the beta globin gene on chromosome 11 lead to β⁺ (reduced beta chain production) or β⁰ (absence of beta chain production). Various combinations of mutations are possible leading to different phenotypes.

Beta thalassaemia major (two defective genes)

This presents in early childhood with impaired growth, abdominal distention (hepatosplenomegaly), frontal bossing of the skull (extramedullary haematopoesis) and severe anaemia.

Hb electrophoresis shows significantly reduced or absent HbA (adult haemoglobin, the most common haemoglobin tetramer), with elevated HbF and HbA₂. X-rays of the skull can show the ‘hair-on-end’ sign due to bone marrow hyperplasia and widening of the medullary cavity in order to aid haematopoesis (this can also be seen, but generally to a lesser extent, in other causes of bone marrow hyperplasia, e.g. hereditary spherocytosis and sickle cell disease). Genetic testing is used to confirm the diagnosis and evaluate the nature of the mutation and can also be used to assess for carrier status in relatives.

Patients need lifelong RBC transfusions (2-4 weekly) to reduce extramedullary haematopoeisis and, therefore, need to be monitored for iron overload with 3-monthly ferritin levels. If iron chelation is indicated (criteria include ferritin >1000 ug/L, liver iron concentration >3 mg/g of dry weight on MRI, cardiac T2* <20 ms), subcutaneous (SC) desferrioxamine is first line, and patients should undergo 3-monthly monitoring of side effects including visual and auditory neurotoxicity, growth impairment, renal and liver failure and increased susceptibility to Yersinia infections.

Splenectomy is indicated if there are increasing transfusion requirements. Hydroxycarbamide can increase HbF and improve symptoms. Bone marrow transplantation offers a cure but is rarely done due to the associated risks.

Beta thalassaemia intermedia (mild homozygous mutations or heterozygotes with another haemoglobinopathy)

This causes moderate anaemia but patients are not usually transfusion dependent.

Beta thalassaemia minor or trait (heterozygous with one functioning gene)

Patients are usually asymptomatic, although Hb can drop in pregnancy. They are likely to have mild anaemia, with a similar picture to iron deficiency but with significantly low MCV (< 75). Electrophoresis shows HbA2 >3.5% with a mildly raised HbF.

Alpha thalassaemia

Alpha globin chains are coded for by two separate genes on each copy of chromosome 16 (normal alleles are designated αα/αα). There are 4 distinct phenotypes of alpha thalassaemia:

• Silent carrier (1 affected gene): asymptomatic with normal Hb
• Alpha thalassaemia trait (2 affected genes): asymptomatic with mild microcytic anaemia
• HbH disease (3 affected genes): moderate anaemia and haemolysis with jaundice and hepatosplenomegaly, and failure to thrive in infancy
• Hb Bart or hydrops fetalis syndrome (deletion of all 4 alpha globin genes): death in utero