Write a short note on thalassaemia.

Definition

The thalassaemias are inherited disorders of haemoglobin synthesis characterised by reduced or absent production of one or more globin chains, leading to imbalanced globin chain synthesis, precipitation of the excess chain, ineffective erythropoiesis and haemolysis.

They are quantitative defects (too little of a normal chain) — in contrast to sickle cell disease, which is a qualitative defect (a structurally abnormal chain).

India has a very high burden: an estimated carrier rate of 3–4% for beta-thalassaemia nationally, higher in certain communities (Sindhi, Punjabi, Gujarati, Bengali, and several tribal populations), with tens of thousands of transfusion-dependent patients.

Classification

Pathophysiology of Beta-thalassaemia Major

Absent beta chain synthesis leaves excess alpha chains, which precipitate within red cell precursors, causing:

1. Ineffective erythropoiesis — destruction of precursors within the marrow.

2. Haemolysis of those cells that reach the circulation.

3. Severe anaemia → erythropoietin drive → massive marrow expansion → skeletal deformity and fragility.

4. Extramedullary haemopoiesis → hepatosplenomegaly, paraspinal masses.

5. Increased intestinal iron absorption (suppressed hepcidin) plus transfusional iron loading → iron overload, the principal cause of death.

Symptoms begin at 3–6 months of age, as the switch from fetal (HbF, α2γ2) to adult haemoglobin (HbA, α2β2) occurs.

Clinical Features

Beta-thalassaemia major:

• Severe anaemia from 6 months — pallor, failure to thrive, poor feeding, irritability.
• Skeletal changes from marrow expansion: frontal bossing, maxillary hypertrophy with prominent cheekbones and malocclusion ("chipmunk" or thalassaemic facies), and the "hair-on-end" appearance of the skull on X-ray; thinned cortices with pathological fractures.
• Hepatosplenomegaly from extramedullary haemopoiesis and haemolysis; hypersplenism increases transfusion requirement.
• Growth retardation and delayed puberty.
• Complications of iron overload — the dominant long-term problem: cardiac (cardiomyopathy, heart failure, arrhythmia — the commonest cause of death), endocrine (diabetes mellitus, hypothyroidism, hypoparathyroidism, hypogonadism, growth failure), hepatic (fibrosis, cirrhosis), and skin bronzing.
• Transfusion-transmitted infection — hepatitis B, hepatitis C and HIV; a substantial issue in India before universal screening.
• Gallstones, leg ulcers, thrombotic tendency.

Beta-thalassaemia trait: asymptomatic, with a mild microcytic anaemia frequently misdiagnosed and inappropriately treated as iron deficiency — an important and common error, since iron therapy is useless and iron loading is harmful.

Investigations

• CBC: markedly low MCV and MCH with only mild anaemia in trait; severe anaemia in major; normal or raised red cell count.
• Peripheral smear: microcytic hypochromic cells with marked anisopoikilocytosis, target cells, basophilic stippling, nucleated red cells and, in major, tear-drop cells.
• Iron studies — normal or raised ferritin, which distinguishes it from iron deficiency (see the table in the iron deficiency answer).
• HPLC or haemoglobin electrophoresis — the diagnostic test:
• Beta-thalassaemia trait: raised HbA2 (> 3.5%), with slightly raised HbF
• Beta-thalassaemia major: HbF markedly raised (often > 90%), HbA absent or markedly reduced
• Alpha-thalassaemia: electrophoresis is often normal — requires DNA analysis; HbH inclusions on supravital staining in HbH disease
• DNA studies for mutation identification, prenatal diagnosis and confirmation of alpha-thalassaemia.
• Monitoring in major: serum ferritin, cardiac and hepatic T2* MRI (the standard for tissue iron quantification), liver function, endocrine screen (glucose, thyroid, calcium, growth and pubertal assessment), viral serology, and echocardiography.

Management

1. Regular transfusion (beta-thalassaemia major)

Lifelong regular packed red cell transfusion, aiming to maintain a pre-transfusion haemoglobin sufficient to suppress ineffective erythropoiesis and permit normal growth (conventionally around 9–10 g/dL). Use leucodepleted, phenotype-matched blood to reduce febrile reactions and alloimmunisation.

2. Iron chelation — as important as the transfusion itself

Started after a defined transfusion burden or once ferritin is persistently raised. Agents: deferasirox and deferiprone (oral) and desferrioxamine (parenteral), used alone or in combination. Adherence to chelation is the single strongest determinant of survival — and it is where most patients struggle, because the regimens are burdensome.

3. Other supportive measures

• Folic acid supplementation; avoid iron supplements and iron-rich fortified foods.
• Splenectomy for hypersplenism with escalating transfusion requirement — with vaccination beforehand and lifelong penicillin prophylaxis.
• Vaccination against hepatitis B; screening and treatment of transfusion-transmitted infection.
• Management of endocrine complications — growth hormone, sex steroid replacement, treatment of diabetes and thyroid disease.
• Psychosocial support and schooling — the burden on families is enormous.

4. Curative and emerging therapy

• Allogeneic haematopoietic stem cell transplantation — the only established cure, best performed young with a matched sibling donor.
• Gene therapy — betibeglogene autotemcel (Zynteglo), a lentiviral gene addition therapy, and exagamglogene autotemcel (Casgevy), a CRISPR-based therapy that reactivates fetal haemoglobin, are approved for transfusion-dependent beta-thalassaemia; cost and availability severely limit access in India.
• Luspatercept — reduces transfusion burden in selected patients.

5. Prevention — the highest-impact intervention in India

Carrier screening (premarital, antenatal and extended family), genetic counselling for at-risk couples, and prenatal diagnosis by chorionic villus sampling with DNA analysis. Several Indian states run screening programmes; prevention is far more achievable than treatment at population scale.