Thalassaemia

Thalassaemias are a group of inherited microcytic, haemolytic anaemias caused by defective haemoglobin synthesis.

Normal adult haemoglobin (HbA) is 2 alpha + 2 beta chains; normal blood also contains ≤2.5% HbA2 (alpha + delta) and <1.4% HbF (alpha + gamma).

Thalassaemia results from unbalanced haemoglobin synthesis caused by decreased production of at least one globin chain (alpha, beta, gamma or delta).

Alpha-thalassaemia is common in people of African, Mediterranean or Southeast Asian ancestry; beta-thalassaemia in people of Mediterranean, Middle Eastern, Southeast Asian or Indian ancestry.

Unpaired globin chains from the under-produced partner aggregate and precipitate, damaging the red cell membrane. This causes haemolysis, death of erythroid precursors in the marrow (ineffective erythropoiesis) and, in severe disease, extramedullary haematopoiesis.

Symptoms arise from anaemia, haemolysis, splenomegaly, marrow hyperplasia and — after repeated transfusions — iron overload.

Alpha thalassaemia

People normally have 4 alpha genes (2 on each chromosome 16). Alpha thalassaemia results from deletion of one or more:

• Alpha+ thalassaemia: loss of a single gene on one chromosome.
• Alpha0 thalassaemia: loss of both genes on the same chromosome.
• Single alpha+ allele → clinically asymptomatic “silent carrier.”
• Alpha thalassaemia trait (2 of 4 genes affected — two alpha+ alleles, or one alpha0 allele; also called alpha-thalassaemia minor): mild-to-moderate microcytic anaemia, no symptoms.
• HbH disease (3 of 4 genes affected, coinheritance of alpha+ and alpha0): alpha-chain production is severely impaired, and excess beta chains form tetramers (Hb H) or, in infancy, gamma-chain tetramers (Bart’s haemoglobin). Often symptomatic haemolytic anaemia and splenomegaly. Diagnosed by demonstrating the fast-migrating Hb H or Bart’s fractions on electrophoresis.
• All 4 genes affected (two alpha0 alleles): lethal in utero (hydrops fetalis) — haemoglobin without alpha chains cannot transport oxygen.

Beta thalassaemia

Decreased beta-chain production from mutations or deletions in the beta globin gene (partial loss = beta+ allele, complete loss = beta0 allele); there are 2 beta genes, one on each chromosome 11.

• Beta-thalassaemia minor (trait): heterozygotes (beta/beta+ or beta/beta0), or mild beta+/beta+ — usually asymptomatic, mild microcytic anaemia.
• Beta-thalassaemia intermedia: two beta thalassaemia alleles (beta+/beta0, or severe beta+/beta+); a variable picture between major and minor.
• Beta-thalassaemia major (Cooley anaemia): homozygotes (beta0/beta0) or severe compound heterozygotes (beta0/beta+). Manifests at age 1–2 years with severe anaemia and marrow hyperactivity — thickening of the cranial bones and malar eminences, long-bone involvement (pathological fractures, impaired growth, possibly delayed or absent puberty), transfusional and absorptive iron overload, splenomegaly (often massive) with hypersplenism accelerating destruction of transfused cells, jaundice, leg ulcers and cholelithiasis.
• Beta-delta-thalassaemia: a less common form impairing both delta and beta chains.

Modern practice increasingly classifies beta thalassaemia as transfusion-dependent or non-transfusion-dependent rather than by the older major, intermedia and minor labels.

With iron overload, cardiac iron deposition can cause heart failure, hepatic siderosis leads to functional impairment and cirrhosis, and endocrine deposition can cause diabetes, hypothyroidism and hypoparathyroidism.

Diagnosis

FBC, peripheral smear, haemoglobin electrophoresis (or HPLC), and DNA testing where there is diagnostic uncertainty or for prenatal diagnosis. Serum bilirubin, iron and ferritin are typically raised.

• Trait: microcytic anaemia with a raised RBC count and normal ferritin. The Mentzer index (MCV ÷ red cell count) is useful — below 13 suggests thalassaemia, above 13 suggests iron deficiency.
• Alpha: HbF and HbA2 percentages are generally normal, so the diagnosis needs genetic testing and is often one of exclusion of other causes of microcytic anaemia.
• Beta major: severe microcytic anaemia (haemoglobin often ≤60 g/L) with an RBC count high relative to haemoglobin; the smear is virtually diagnostic — nucleated erythroblasts, target cells, small pale red cells, and punctate and diffuse basophilic stippling.
• Quantitative Hb studies: a mild HbA2 elevation (>3.5–4%) alone is diagnostic for beta-thalassaemia minor; in beta-thalassaemia major HbF is usually raised (sometimes to 90%) and HbA2 is usually >3%.
• Imaging may show the skeletal changes of chronic marrow hyperactivity (skull “sun-ray” trabeculation, widened diploic space, cortical thinning of long bones).

Haemoglobin electrophoresis is essential for diagnosing beta thalassaemia minor and clinically significant haemoglobin variants; red cell indices alone are inadequate for screening.

All antenatal patients should have a full blood examination and haemoglobin electrophoresis (or HPLC), plus ferritin if microcytic, as early in pregnancy as possible — ideally before conception.

Management

• Trait: no treatment needed.
• HbH disease: splenectomy may help if anaemia is severe or splenomegaly is present.
• Intermedia / non-transfusion-dependent: as few transfusions as possible to avoid iron overload.
• Major / transfusion-dependent: transfuse to keep haemoglobin around 90–100 g/L and suppress abnormal marrow expansion.
• Iron chelation to remove transfusional iron, generally started when serum ferritin exceeds ~1000 ng/mL or after about 1–2 years of scheduled transfusions.
• Splenectomy if significant splenomegaly — can reduce transfusion requirements (with pre-/post-splenectomy vaccination and, in children, prophylactic penicillin; usually deferred to age 6–7).
• Luspatercept, a TGF-β pathway inhibitor, is an option for transfusion-dependent beta-thalassaemia and reduced transfusion needs in a phase 3 trial.
• Allogeneic stem cell transplant and gene therapy (betibeglogene autotemcel, exagamglogene autotemcel) are potentially curative and should be considered in all patients with transfusion-dependent beta-thalassaemia where available.

Prognosis

Life expectancy is normal for beta- or alpha-thalassaemia minor.

In beta-thalassaemia major, life expectancy is decreased — mostly from chronic transfusion complications — but is substantially improved with regular transfusion and appropriate chelation (>90% survival at 30 years), and further improved by stem cell transplantation.