Thalassaemia

Inherited disorders of globin chain synthesis in which reduced or absent production of alpha or beta globin chains causes imbalanced haemoglobin assembly, ineffective erythropoiesis and haemolysis. Severity ranges from asymptomatic carrier states to transfusion-dependent disease.

Beta thalassaemia: caused by mutations reducing (beta+) or abolishing (beta0) beta globin production.

• Thalassaemia minor (trait): heterozygous, asymptomatic carrier state with mild microcytic anaemia, important to recognise to avoid misdiagnosis as iron deficiency and inappropriate iron supplementation.
• Thalassaemia intermedia: moderate disease, variable transfusion requirement.
• Thalassaemia major (Cooley anaemia): homozygous or compound heterozygous, severe transfusion-dependent anaemia presenting in infancy as fetal haemoglobin production declines.

Alpha thalassaemia: caused by deletion (usually) of one to four of the four alpha globin genes.

• Silent carrier (1 gene deleted): asymptomatic.
• Alpha thalassaemia trait (2 genes deleted): mild microcytic anaemia.
• HbH disease (3 genes deleted): moderate to severe haemolytic anaemia with splenomegaly.
• Hb Bart hydrops fetalis (all 4 genes deleted): incompatible with extrauterine life, causes severe fetal anaemia, hydrops and stillbirth or neonatal death.

Pathophysiology: unpaired excess globin chains (alpha chains in beta thalassaemia, beta/gamma chains forming HbH in alpha thalassaemia) precipitate within red cell precursors, causing membrane damage, ineffective erythropoiesis with destruction in the marrow, and peripheral haemolysis. Chronic anaemia drives compensatory marrow expansion (skeletal deformity) and extramedullary haematopoiesis.

• Thalassaemia trait: usually asymptomatic, mild anaemia found incidentally, normal or mildly reduced MCV disproportionately low relative to the degree of anaemia (a useful discriminator from iron deficiency, where MCV falls roughly proportionately).
• Thalassaemia major: presents at 6-24 months as fetal haemoglobin falls, with severe pallor, failure to thrive, hepatosplenomegaly, and if untreated, skeletal changes from marrow expansion --- frontal bossing, maxillary hypertrophy ("chipmunk facies"), and pathological fractures.
• Growth retardation and delayed puberty from chronic anaemia and, later, iron overload affecting the pituitary.
• Complications of chronic transfusion and iron overload: cardiomyopathy (leading cause of death if untreated), hepatic fibrosis/cirrhosis, endocrinopathy (diabetes, hypothyroidism, hypogonadism, hypoparathyroidism), skin bronzing.
• HbH disease: chronic haemolytic anaemia, splenomegaly, gallstones, leg ulcers in some, exacerbated by oxidant stress or infection.
• Extramedullary haematopoietic masses (paraspinal, hepatic) in undertreated thalassaemia intermedia.

• Full blood count: microcytic, hypochromic anaemia with a markedly low MCV disproportionate to the haemoglobin level, and typically a normal or elevated red cell count (helps distinguish from iron deficiency where red cell count tends to be low).
• Blood film: target cells, poikilocytosis, basophilic stippling, nucleated red cells (in major/intermedia).
• Haemoglobin electrophoresis or HPLC: elevated HbA2 and often HbF in beta thalassaemia trait; absent or reduced HbA with elevated HbF in beta thalassaemia major; HbH visible on electrophoresis in HbH disease. Alpha thalassaemia trait/carrier states typically show normal electrophoresis, requiring genetic testing for confirmation.
• Iron studies to exclude coexisting or confounding iron deficiency, and critically to avoid misdiagnosing thalassaemia trait as iron deficiency and prescribing unnecessary iron.
• Genetic testing (globin gene analysis) for definitive diagnosis, particularly for alpha thalassaemia and for genetic counselling/prenatal diagnosis.
• Prenatal screening and counselling for couples where both partners carry trait, given the risk of thalassaemia major or hydrops fetalis in offspring.

• Thalassaemia trait: no treatment required; genetic counselling regarding reproductive risk; explicit advice against inappropriate iron supplementation.
• Thalassaemia major: regular transfusion programme (every 2-4 weeks) to maintain pre-transfusion haemoglobin above 90-100 g/L, suppressing ineffective erythropoiesis and supporting growth.
• Iron chelation therapy is mandatory once significant transfusion burden accumulates (typically after 10-20 transfusions or ferritin above 1000 μg/L): deferasirox (oral, first line in many settings), deferiprone (oral, particularly effective for cardiac iron), or deferoxamine (subcutaneous/intravenous infusion). Monitor iron burden with serum ferritin and, more accurately, cardiac and hepatic MRI T2* measurement.
• Splenectomy for hypersplenism with increasing transfusion requirement, balanced against increased infection risk (particularly encapsulated organisms) --- vaccinate (pneumococcal, meningococcal, Haemophilus influenzae type b) and give penicillin prophylaxis before and after splenectomy.
• Curative options: allogeneic haematopoietic stem cell transplantation, most successful in younger patients without significant iron overload; gene therapy (increasingly available) offers a curative alternative avoiding donor requirements.
• Monitor and treat endocrine, cardiac and hepatic complications of iron overload with regular screening (echocardiography, endocrine panel, liver assessment).
• Folic acid supplementation given increased erythropoietic demand.
• HbH disease: monitor for anaemia exacerbation with infection/oxidant stress, avoid oxidant drugs, transfusion during crises, splenectomy in selected severe cases.
• Multidisciplinary care (haematology, cardiology, endocrinology, genetics) for major and intermedia disease.