Thalassaemia

Thalassaemias are classified into α and β types based on the affected globin chain. α-thalassaemia is caused by deletions in the four α-globin genes (chromosome 16), while β-thalassaemia is usually due to point mutations in the two β-globin genes (chromosome 11). Clinically, β-thalassaemia is divided into: 1) Trait (minor) - asymptomatic microcytosis; 2) Intermedia - varying severity; 3) Major - transfusion-dependency starting in infancy. In β-thalassaemia major, the lack of β-chains leads to an excess of α-chains, which precipitate and damage red cell precursors in the marrow (ineffective erythropoiesis) and mature RBCs in the spleen (haemolysis). This results in massive bone marrow expansion ('chipmunk facies') and extramedullary haematopoiesis. Chronic management involves lifelong blood transfusions, which inevitably cause iron overload (haemosiderosis); therefore, iron chelation therapy is crucial.

Haemoglobin A (HbA) consists of two α and two β chains. α-thalassaemia: There are four α-globin genes. One/two-gene deletion causes a mild trait. Three-gene deletion leads to HbH disease (β4 tetramers). Four-gene deletion causes Hb Barts (γ4 tetramers), which has massive oxygen affinity and leads to fatal hydrops fetalis. β-thalassaemia: Two β-globin genes. β0 indicates no production; β+ indicates reduced production. In β-thalassaemia major (homozygous), the lack of β-chains leads to an excess of α-chains. These α-chains are insoluble and precipitate, causing membrane damage and premature destruction of RBC precursors. The resulting anaemia triggers high levels of erythropoietin, leading to massive marrow expansion and cortical thinning of bones.

β-thalassaemia major presents at 3–6 months with pallor, failure to thrive, and hepatosplenomegaly. Bony changes (bossing of the forehead, prominent maxilla) occur due to marrow hyperplasia. Iron overload from transfusions affects the heart (cardiomyopathy/arrhythmias), liver (cirrhosis), and endocrine glands (diabetes, hypothyroidism, delayed puberty). α-thalassaemia trait is common and often misdiagnosed as iron deficiency; it should be suspected in patients of Southeast Asian or African descent with a very low MCV but normal ferritin. HbH disease presents as a chronic thalassaemia intermedia requiring occasional transfusions.

Bloods: FBC (Profound microcytic anaemia in Major; mild in Trait), Reticulocytes (high), Blood film (Target cells, nucleated RBCs, basophilic stippling). Diagnostic: Hb electrophoresis or HPLC (β-Major: HbA absent, HbF >90%, HbA2 variable; β-Trait: HbA decreased, HbA2 >3.5%). Iron studies: Normal or high ferritin (distinguishes from IDA). DNA analysis: Required for α-thalassaemia diagnosis. Imaging: X-ray skull (hair-on-end appearance), T2* MRI (to quantify cardiac and liver iron).

β-Thalassaemia Major: 1) Lifelong regular blood transfusions (usually every 3-4 weeks) to maintain Hb >95g/L and suppress ineffective erythropoiesis. 2) Iron Chelation: Essential to prevent organ damage. Agents include subcutaneous Desferrioxamine or oral Deferasirox/Deferiprone. 3) Splenectomy: If hypersplenism increases transfusion requirements (requires vaccinations and penicillin prophylaxis). 4) Folic acid. 5) Curative: Allogeneic Bone Marrow Transplant is the only cure. β-Thalassaemia Trait: No treatment required; avoid iron supplementation unless IDA is proven; provide genetic counselling.