Describe the pathogenesis, clinical features and laboratory diagnosis of thalassaemia.

Definition

• Contrast with the haemoglobinopathies such as sickle cell disease, where a structurally abnormal chain is made in normal amount
• Normal adult haemoglobin — HbA (α2β2) 97%, HbA2 (α2δ2) 2%, HbF (α2γ2) under 1%
• India has a heavy burden — beta thalassaemia trait affects 3–4% overall and much more in certain communities; about 10,000 affected children are born each year

Pathogenesis

Reduced synthesis of one globin chain (say beta) → The other chain (alpha) is produced in normal amount and is now in excess → Unpaired alpha chains precipitate within the red cell and its precursors → Membrane damage from oxidation → Two consequences follow: → ineffective erythropoiesis — precursors destroyed in the marrow → haemolysis — circulating cells destroyed in the spleen → Anaemia → erythropoietin → marrow expansion and increased iron absorption

• The damage is done by the chain in excess, not by the one that is missing — which is why co-inheriting alpha thalassaemia makes beta thalassaemia milder

Beta Thalassaemia

Clinical features of thalassaemia major

• Presents at 6 to 9 months, when the switch from gamma to beta chain synthesis is complete — not at birth
• Severe pallor, failure to thrive, hepatosplenomegaly from extramedullary haemopoiesis
• Skeletal changes from marrow expansion — "hair-ON-end" appearance of the skull, frontal bossing, prominent maxillae with malocclusion giving the "chipmunk facies", and pathological fractures
• Iron overload from repeated transfusion and increased absorption — causing cardiac failure and arrhythmia (the usual cause of death), cirrhosis, diabetes, hypogonadism and delayed puberty, and skin pigmentation

Alpha Thalassaemia

• Alpha thalassaemia is usually caused by deletions (there are four alpha genes), whereas beta thalassaemia is usually caused by point mutations affecting transcription or splicing
• Alpha thalassaemia can present at birth, since alpha chains are needed for fetal haemoglobin too — unlike beta thalassaemia

Laboratory Findings

• Severe microcytic hypochromic anaemia with a haemoglobin often below 6 g/dL in major
• Peripheral smear — marked anisopoikilocytosis, target cells, basophilic stippling, nucleated red cells, tear-drop cells, and a raised reticulocyte count
• The red cell count is normal or high despite the low haemoglobin, and the RDW is normal — both distinguishing it from iron deficiency
• Mentzer index (MCV divided by red cell count) — below 13 suggests thalassaemia, above 13 suggests iron deficiency
• Haemoglobin electrophoresis or HPLC — raised HbF and HbA2 in beta thalassaemia major; raised HbA2 alone in trait
• Serum ferritin is normal or high, and rises steeply with transfusion

Applied Aspects

• Regular transfusion to keep haemoglobin above about 9–10 g/dL suppresses ineffective erythropoiesis and prevents the skeletal changes, but causes iron overload
• Iron chelation is essential — desferrioxamine by infusion, or oral deferasirox and deferiprone; without it, death from cardiac iron overload occurs in the second or third decade
• Serum ferritin and cardiac and hepatic T2* MRI monitor the iron burden
• Allogeneic haemopoietic stem cell transplantation is curative, and gene therapy is now available in some centres
• Prevention is what matters at population level — carrier screening, premarital and antenatal counselling, and prenatal diagnosis by chorionic villus sampling. Cyprus and several Indian states have shown that the birth incidence can be reduced dramatically
• Never transfuse without confirming the diagnosis, and always vaccinate and screen donors — transfusion-transmitted hepatitis B, C and HIV remain real risks in a multiply transfused child
• Splenectomy may reduce transfusion requirement in hypersplenism, but carries the usual infective risk and is now performed less often
• Folic acid supplementation is given lifelong because of the greatly increased marrow turnover
• Alloimmunisation from repeated transfusion makes cross-matching progressively harder, which is an argument for extended red cell phenotyping before the first transfusion
• Thalassaemia intermedia may need chelation without transfusion, because ineffective erythropoiesis itself drives excessive iron absorption
• The economic burden on families is severe, and is a strong practical argument for a prevention programme over lifelong treatment
• HbE-beta thalassaemia is common in eastern India and Bengal, and its severity is highly variable — from a transfusion-independent state to a picture resembling thalassaemia major
• Co-inheritance of alpha thalassaemia mildens beta thalassaemia, because there is less excess alpha chain to precipitate — a direct consequence of the pathogenesis
• Hereditary persistence of fetal haemoglobin likewise reduces severity, which is the rationale for hydroxyurea and for the newer HbF-inducing agents
• Vitamin C should be given with caution during chelation, as it mobilises iron and may worsen cardiac toxicity if given without adequate chelation
• Growth and puberty must be monitored, since endocrine failure from iron deposition in the pituitary is common and treatable
• Splenomegaly increasing the transfusion requirement above about 200–220 mL/kg a year is the conventional indication for splenectomy
• Antenatal diagnosis by chorionic villus sampling at 10 to 12 weeks allows an informed choice, and is the practical basis of every successful prevention programme
• Both parents must be tested when a trait is found, since it is the combination that matters and the couple's risk is what counts
• HbA2 may be falsely normal in coexisting iron deficiency, so iron status should be corrected before electrophoresis is interpreted
• Bone marrow examination is not needed to diagnose thalassaemia; the blood count, smear and electrophoresis are sufficient, which matters where resources are limited