Thalassaemia

Thalassaemias are a group of inherited (autosomal recessive) microcytic hypochromic anaemias caused by reduced or absent synthesis of one or more globin chains of haemoglobin. The defect is quantitative (chain production is decreased), in contrast to sickle cell disease where the defect is qualitative (an abnormal chain is made). They are the commonest monogenic disorders worldwide and are highly prevalent across the "thalassaemia belt" — the Mediterranean, Middle East, the Indian subcontinent and South-East Asia.

Normal haemoglobin background — the foundation

To make sense of every electrophoresis pattern, anchor the normal adult globin composition:

Haemoglobin	Chains	Normal adult level
HbA	α₂β₂	96–98%
HbA₂	α₂δ₂	2.0–3.5%
HbF	α₂γ₂	< 1% (<2%)

• α-globin is coded by 4 genes (two on each chromosome 16 → αα/αα).
• β-globin is coded by 2 genes (one on each chromosome 11 → β/β).
• α-chains are needed for every post-embryonic haemoglobin (HbA, HbA₂, HbF), which is why severe α-thalassaemia is incompatible with life, whereas β-thalassaemia spares foetal life (HbF, α₂γ₂, does not need β-chains).

High-yield: The clinical severity of thalassaemia is driven by the imbalance of globin chains. The chain produced in excess precipitates inside the red cell or its precursor, causing membrane damage → ineffective erythropoiesis (intramedullary death) and haemolysis (peripheral destruction).

Classification

Alpha thalassaemia — a question of how many of the 4 genes are deleted

α-thalassaemia is usually due to gene deletions on chromosome 16. Severity tracks the number of functional α-genes lost.

Genotype	Functional α-genes	Name	Phenotype
αα/αα	4	Normal	Normal
-α/αα	3	Silent carrier	Asymptomatic, normal/near-normal indices
--/αα or -α/-α	2	α-thalassaemia trait (minor)	Mild microcytic anaemia, asymptomatic
--/-α	1	HbH disease	Moderate–severe haemolytic anaemia
--/--	0	Hb Bart hydrops fetalis	Incompatible with life (intrauterine/neonatal death)

• HbH = β₄ (a tetramer of four β-chains) — forms because there is a relative excess of β-chains. HbH is detected on electrophoresis and as golf-ball inclusions on supravital staining (brilliant cresyl blue).
• Hb Bart's = γ₄ (four γ-chains) — has extremely high oxygen affinity, delivers no oxygen to tissues → severe hypoxia, high-output failure, generalised oedema, hepatosplenomegaly → hydrops fetalis, classically seen in South-East Asia (cis deletion --SEA).

High-yield: The cis deletion (--/, both genes on the same chromosome lost) is common in South-East Asians and is what allows Hb Bart's hydrops fetalis to occur in their offspring. The trans arrangement (-α/-α) predominates in Africans, so Hb Bart's is rare in that population even though the trait is common.

Beta thalassaemia — usually point mutations, graded by transfusion need

β-thalassaemia is mostly due to point mutations (not deletions) that reduce (β⁺) or abolish (β⁰) β-chain synthesis.

Type	Genotype	Clinical label	Key feature
β-thalassaemia minor (trait)	β/β⁰ or β/β⁺ (heterozygous)	Carrier	Asymptomatic, raised HbA₂ (>3.5%)
β-thalassaemia intermedia	variable	Non-transfusion-dependent	Symptomatic anaemia, transfusion only intermittently
β-thalassaemia major (Cooley anaemia)	β⁰/β⁰ or β⁺/β⁺ (homozygous)	Transfusion-dependent	Severe anaemia from 3–6 months of age

High-yield: β-thalassaemia major presents at 3–6 months of age — not at birth. This is because of the physiological switch from γ-chain (HbF) to β-chain (HbA) synthesis after birth. Before this switch, HbF protects the baby.

Etiology & pathophysiology

The unifying mechanism is unbalanced globin chain synthesis:

β-thalassaemia major: Reduced β-chain → excess free α-chains → α-chains are highly unstable, precipitate in red cell precursors → membrane damage → apoptosis of erythroblasts in the marrow (ineffective erythropoiesis) and haemolysis of the cells that escape into circulation.

The downstream cascade: ↓β-chains → excess α-chains precipitate → ineffective erythropoiesis + haemolysis → severe anaemia → ↑erythropoietin → massive marrow hyperplasia → skeletal deformity + extramedullary haemopoiesis → hepatosplenomegaly.

Two further consequences are heavily tested:

1. Iron overload. Chronic anaemia and ineffective erythropoiesis suppress hepcidin, increasing gut iron absorption. Add lifelong transfusions and the result is massive iron loading of heart, liver, and endocrine glands — the major cause of death in transfused patients.
2. Bone changes. Marrow expansion thins the cortex and widens the diploic space of the skull → "hair-on-end" / "crew-cut" appearance on skull X-ray; "chipmunk facies" from maxillary overgrowth; thinned cortices prone to fracture.

High-yield: In β-thalassaemia major, death is most commonly due to iron-overload cardiomyopathy/cardiac failure, not the anaemia itself once a transfusion programme is established.

Clinical features

β-thalassaemia major (Cooley anaemia):

• Onset 3–6 months: pallor, failure to thrive, feeding difficulty, irritability.
• Hepatosplenomegaly (extramedullary haemopoiesis + iron + haemolysis).
• Skeletal changes: frontal bossing, prominent maxilla with malocclusion ("chipmunk/rodent facies"), hair-on-end skull.
• Iron overload (if under-chelated): bronze/slate-grey skin, diabetes ("bronze diabetes" picture), hypothyroidism, hypogonadism and delayed puberty, hypoparathyroidism, growth retardation, cardiomyopathy and arrhythmia.
• Increased infection risk (especially post-splenectomy — encapsulated organisms; Yersinia enterocolitica is classically associated with iron overload and desferrioxamine therapy).
• Gallstones (pigment) from chronic haemolysis.

β-thalassaemia minor / α-trait: usually asymptomatic; mild microcytic anaemia often discovered incidentally and frequently misdiagnosed and over-treated as iron deficiency.

HbH disease: moderate haemolytic anaemia, splenomegaly, jaundice; may worsen with oxidant stress, infection or pregnancy.

Diagnosis & investigation of choice

Step 1 — Complete blood count and film

• Microcytic hypochromic picture: low MCV, low MCH.
• RBC count is normal or HIGH despite anaemia (a key discriminator from iron deficiency).
• Film: target cells, basophilic stippling, nucleated red cells, anisopoikilocytosis; in major, marked changes.
• Reticulocytosis with raised indirect bilirubin and LDH (haemolysis).

Step 2 — Discriminant indices to separate thalassaemia trait from iron deficiency

Parameter	Thalassaemia trait	Iron deficiency anaemia
RBC count	Normal/high	Low
RDW	Usually normal	High (anisocytosis)
Serum ferritin	Normal/high	Low
Mentzer index (MCV ÷ RBC)	< 13	> 13
HbA₂	Raised (β-trait)	Normal/low

High-yield: Mentzer index = MCV / RBC count. A value < 13 suggests thalassaemia trait; > 13 suggests iron deficiency. This single calculation is a recurring NEET PG MCQ.

Step 3 — Haemoglobin analysis (investigation of choice)

Hb electrophoresis / HPLC is the diagnostic investigation of choice.

Condition	HbA	HbA₂	HbF	Other
Normal	96–98%	2–3.5%	<1%	—
β-thal minor	Slightly ↓	↑ (>3.5%)	Slightly ↑	—
β-thal major (β⁰/β⁰)	Absent	Variable ↑	Markedly ↑ (90%+)	—
β-thal major (β⁺/β⁺)	↓	↑	Markedly ↑	—
HbH disease	↓	↓	normal	HbH (β₄) present
Hb Bart hydrops	absent	absent	absent	Hb Bart's (γ₄)

High-yield: A raised HbA₂ (>3.5%) is the single most useful lab marker of β-thalassaemia trait. Note that co-existing iron deficiency can lower (mask) HbA₂, so confirm iron status before excluding β-trait.

Step 4 — Confirmatory / supportive

• DNA analysis (PCR/gene studies): definitive; needed for α-thalassaemia trait (which electrophoresis cannot reliably detect because indices may be near-normal and HbA₂ is normal or low) and for prenatal diagnosis.
• Skull X-ray: hair-on-end appearance.
• Cardiac & hepatic iron: serum ferritin for monitoring, and T2 MRI* (cardiac and liver) as the modern gold standard for tissue iron quantification.

High-yield: In α-thalassaemia trait, HbA₂ is normal or low (because α-chains are needed to make HbA₂ as well) — so a microcytic anaemia with normal HbA₂ and normal iron studies should raise suspicion of α-thalassaemia trait, confirmed by DNA studies.

Management / drug of choice

β-thalassaemia major

Approach: Transfuse → Chelate → consider definitive cure.

1. Regular (hypertransfusion) programme — keep pre-transfusion Hb around 9–10.5 g/dL to suppress endogenous ineffective erythropoiesis, prevent bony deformity and allow normal growth. Use leucodepleted, phenotype-matched packed cells.
2. Iron chelation (started after ~10–20 transfusions or ferritin >1000 ng/mL):

Chelator	Route	Notable points
Deferoxamine (desferrioxamine)	SC/IV infusion	Classic agent; ototoxicity, retinopathy, growth/bone effects; Yersinia risk
Deferiprone	Oral	Good for cardiac iron; risk of agranulocytosis (monitor counts)
Deferasirox	Oral, once daily	Convenient first-line oral agent; GI upset, renal/hepatic monitoring

3. Folic acid supplementation (high turnover).
4. Splenectomy if hypersplenism increases transfusion requirements — give pneumococcal, meningococcal and Hib vaccines beforehand and penicillin prophylaxis after.
5. Allogeneic haematopoietic stem cell transplantation (HSCT) — the only established curative option, best results with an HLA-matched sibling done early before iron damage.
6. Gene therapy (e.g., lentiviral β-globin addition; and luspatercept, an erythroid maturation agent that reduces transfusion burden) — modern, increasingly examined options.

High-yield: HSCT from an HLA-matched sibling is the only curative therapy for β-thalassaemia major; outcomes are best in young, well-chelated children with minimal liver iron/fibrosis (low Pesaro risk class).

High-yield: Iron should NOT be given to thalassaemia trait patients — their microcytosis is not due to iron deficiency, and supplementation risks iron overload. Confirm with iron studies first.

HbH disease

Folic acid, avoid oxidant drugs, occasional transfusion; splenectomy in selected cases; chelation if iron-loaded.

Prevention — arguably the most important "management"

• Carrier (premarital/antenatal) screening using CBC + HbA₂.
• Genetic counselling: two carriers have a 1 in 4 risk of an affected child each pregnancy.
• Prenatal diagnosis: chorionic villus sampling (10–12 weeks) with DNA analysis, or amniocentesis; permits informed reproductive choice. Pre-implantation genetic diagnosis is also used.

High-yield: Because there is no easy cure and treatment is lifelong, prevention through carrier screening and prenatal diagnosis is the cornerstone public-health strategy — a frequently tested concept in community medicine cross-over questions.

Complications

• Iron overload: cardiomyopathy/heart failure (leading cause of death), liver cirrhosis, diabetes, hypothyroidism, hypoparathyroidism, hypogonadism, short stature.
• Transfusion-related: alloimmunisation, transfusion-transmitted infection (HBV, HCV, HIV), febrile/allergic reactions.
• Skeletal: osteoporosis, pathological fractures, facial deformity.
• Extramedullary haemopoiesis: paraspinal masses (can cause cord compression).
• Pigment gallstones, leg ulcers, thrombotic tendency (especially non-transfused intermedia and post-splenectomy).
• Post-splenectomy sepsis with encapsulated organisms.

Key differentials

The core differential for a microcytic hypochromic anaemia — remember "TICS / SITA":

Cause	RBC count	RDW	Ferritin	HbA₂	Clue
Iron deficiency	Low	High	Low	Normal/low	Low iron, high TIBC
Thalassaemia trait	Normal/high	Normal	Normal/high	High (β)	Mentzer <13
Anaemia of chronic disease	Low/normal	Normal	Normal/high	Normal	Low TIBC, raised inflammatory markers
Sideroblastic anaemia	Low	High	High	Normal	Ring sideroblasts in marrow; dimorphic film

• Sickle cell disease/trait is the qualitative cousin — combinations such as HbS/β-thalassaemia and HbE/β-thalassaemia (very important in India and South-East Asia) produce intermediate phenotypes and appear on electrophoresis.

High-yield: HbE-β-thalassaemia is one of the commonest severe thalassaemia syndromes in eastern India and South-East Asia and can mimic thalassaemia major; HbE migrates with HbA₂ on standard electrophoresis.

Eponyms, criteria & cut-offs to memorise

• Cooley anaemia = β-thalassaemia major.
• Mentzer index = MCV/RBC; <13 → thalassaemia, >13 → iron deficiency.
• HbA₂ cut-off for β-trait = >3.5%.
• Hair-on-end / crew-cut skull, chipmunk/rodent facies — marrow expansion.
• HbH = β₄ (golf-ball inclusions); Hb Bart's = γ₄ (hydrops fetalis).
• Pesaro classification — risk-stratifies children for HSCT (based on hepatomegaly, portal fibrosis, quality of prior chelation).
• Pre-transfusion Hb target ≈ 9–10.5 g/dL.

Recently asked / exam angle

• Electrophoresis interpretation: "Child, 8 months, severe anaemia, HbF 90%, HbA absent" → β-thalassaemia major (β⁰/β⁰).
• Mentzer index calculation from given MCV and RBC to choose between thalassaemia and iron deficiency — a recurring numerical MCQ.
• HbA₂ raised → β-thalassaemia trait; remember concurrent iron deficiency can falsely lower it.
• Number of α-genes vs phenotype matching (silent carrier → trait → HbH → Bart's).
• Hb Bart's hydrops fetalis = 0 functional α-genes (γ₄), high O₂ affinity, South-East Asian cis deletion.
• Commonest cause of death in transfused thalassaemia major = cardiac (iron-overload) failure.
• Drug of choice questions: oral chelator first-line = deferasirox; deferiprone preferred for cardiac iron; agranulocytosis with deferiprone.
• Only curative therapy = HSCT (matched sibling).
• Skull X-ray "hair-on-end" image-based identification.
• Yersinia enterocolitica infection link with iron overload + desferrioxamine.
• Cross-over with community medicine: premarital screening and prenatal diagnosis as prevention.

Rapid revision

1. Thalassaemia = quantitative globin defect; severity = degree of chain imbalance.
2. α-gene = 4 copies (chr 16); β-gene = 2 copies (chr 11).
3. α-thal: 3 genes = silent carrier, 2 = trait, 1 = HbH (β₄), 0 = Hb Bart's (γ₄) hydrops fetalis.
4. β-thalassaemia major presents at 3–6 months as HbF→HbA switch fails; HbA absent, HbF markedly raised.
5. β-thalassaemia minor: asymptomatic, HbA₂ >3.5% is the marker.
6. **Mentzer index <13 → thalassaemia**; >13 → iron deficiency; RBC count high/normal in trait.
7. Investigation of choice = Hb electrophoresis/HPLC; DNA analysis for α-trait and prenatal diagnosis.
8. α-thalassaemia trait: HbA₂ normal/low with normal iron studies — confirm by DNA.
9. Manage major by regular transfusion (keep Hb 9–10.5) + iron chelation + folate; HSCT is curative.
10. Chelators: deferasirox (oral first-line), deferiprone (cardiac iron, agranulocytosis), desferrioxamine (infusion, Yersinia risk).
11. Iron-overload cardiomyopathy is the leading cause of death; never give iron to trait patients.
12. Prevention = carrier screening + genetic counselling (1-in-4 risk) + prenatal diagnosis; bone clue = hair-on-end skull / chipmunk facies.