Overview
Thalassaemia
1. Clinical Overview
Summary
Thalassaemia is a group of Inherited Haemoglobinopathies characterised by Reduced or Absent Synthesis of One or More Globin Chains (Alpha or Beta) of the haemoglobin molecule. This imbalance leads to Ineffective Erythropoiesis, Haemolysis, and Varying Degrees of Anaemia. Thalassaemia is one of the most common genetic disorders worldwide, Particularly prevalent in Mediterranean, Middle Eastern, South Asian, Southeast Asian, and African Populations. The two main types are Alpha-Thalassaemia (Reduced alpha-chain production, Chromosome 16) and Beta-Thalassaemia (Reduced beta-chain production, Chromosome 11). Severity ranges from Asymptomatic Carriers (Trait/Minor) to Severe Transfusion-Dependent Anaemia (Major). Beta-Thalassaemia Major (Cooley's Anaemia) presents in infancy with severe anaemia, Hepatosplenomegaly, Growth retardation, And bone deformities if untreated. Management involves Regular Blood Transfusions and Iron Chelation Therapy to prevent iron overload complications. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative option, and Gene Therapy is emerging. [1,2,3]
Clinical Pearls
"Microcytic Anaemia with Low MCV, High RBC Count": Thalassaemia trait often has MCV/RBC ratio less than 13 (Mentzer Index).
"Mediterranean/Asian Ethnicity + Microcytic Anaemia ≠ Always Iron Deficiency": Consider Thalassaemia.
"HbA2 Raised in Beta-Thalassaemia Trait": Key diagnostic feature.
"Iron Overload is the Main Killer": Cardiac and hepatic iron toxicity. Chelation is life-saving.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Carrier Rate | ~1-5% worldwide are carriers of Thalassaemia. ~270 million carriers globally. |
| Prevalence | Highest in: Mediterranean (Greece, Italy, Cyprus), Middle East, South Asia (India, Pakistan), Southeast Asia (Thailand, Indonesia), Sub-Saharan Africa, China. |
| Births with Severe Thalassaemia | ~60,000-70,000 per year worldwide. |
Genetics
| Type | Gene | Chromosome | Normal Genes | Notes |
|---|---|---|---|---|
| Alpha-Thalassaemia | HBA1, HBA2 | Chromosome 16 | 4 alpha genes (2 on each Chrom 16). | Gene deletions most common. |
| Beta-Thalassaemia | HBB | Chromosome 11 | 2 beta genes (1 on each Chrom 11). | Point mutations most common. β⁰ (No production), β⁺ (Reduced). |
3. Classification
Alpha-Thalassaemia (Based on Number of Alpha Gene Deletions)
| Genotype | Genes Affected | Clinical Phenotype |
|---|---|---|
| Silent Carrier (αα/α-) | 1 gene deleted | Asymptomatic. Normal blood counts or minimal changes. |
| Alpha-Thalassaemia Trait (Minor) (αα/-- or α-/α-) | 2 genes deleted | Mild microcytic anaemia. Usually asymptomatic. |
| HbH Disease (-α/--) | 3 genes deleted | Moderate-severe haemolytic anaemia. Splenomegaly. May need transfusions. HbH (β₄ tetramers) on electrophoresis. |
| Haemoglobin Bart's Hydrops Fetalis (--/--) | 4 genes deleted | Incompatible with Life. Severe foetal anaemia. Hydrops fetalis. Stillbirth or neonatal death (Unless intrauterine transfusion). Hb Bart's (γ₄). |
Beta-Thalassaemia
| Genotype | Clinical Phenotype |
|---|---|
| Beta-Thalassaemia Minor (Trait) (β/β⁺ or β/β⁰) | Heterozygous. One normal gene. Mild microcytic anaemia. Asymptomatic or minimal symptoms. Raised HbA2. |
| Beta-Thalassaemia Intermedia | Variable severity (Between Trait and Major). May or may not be transfusion-dependent. Can be homozygous or compound heterozygous with milder alleles. |
| Beta-Thalassaemia Major (Cooley's Anaemia) (β⁰/β⁰ or β⁺/β⁺ severe or β⁰/β⁺) | Homozygous or compound heterozygous for severe alleles. Severe transfusion-dependent anaemia from infancy. Hepatosplenomegaly. Bone deformities. Iron overload. |
4. Pathophysiology
Mechanism (Beta-Thalassaemia Major as Example)
- Reduced/Absent Beta-Globin Synthesis: HBB gene mutations.
- Globin Chain Imbalance: Excess unpaired alpha-chains.
- Alpha-Chain Precipitation: Forms toxic precipitates in red cell precursors (Erythroblasts).
- Ineffective Erythropoiesis: Destruction of erythroblasts in bone marrow BEFORE they mature. Major pathological feature.
- Haemolysis: Shortened survival of abnormal RBCs.
- Anaemia: Severe.
- Compensatory Responses:
- Marrow Expansion: Bones enlarge (Skull, Face – "Chipmunk facies", "Hair-on-end" skull X-ray).
- Extramedullary Haemopoiesis: Liver, Spleen (Hepatosplenomegaly).
- Increased Iron Absorption: Hepcidin suppression due to ineffective erythropoiesis.
- Iron Overload: From transfusions AND increased absorption. Deposits in Heart, Liver, Endocrine glands → Organ failure.
Alpha-Thalassaemia (HbH Disease)
- Excess unpaired beta-chains form HbH (β₄ Tetramers).
- HbH is unstable, Precipitates → Inclusion bodies → Haemolysis.
5. Clinical Presentation
Beta-Thalassaemia Major (Presents ~6-12 Months of Age)
| Feature | Notes |
|---|---|
| Severe Anaemia | Pallor, Lethargy, Irritability, Failure to thrive. |
| Hepatosplenomegaly | Extramedullary haemopoiesis. |
| Skeletal Deformities (If Untreated/Undertreated) | Frontal bossing, Maxillary hyperplasia ("Chipmunk facies"), Dental malocclusion, Bone thinning (Prone to fractures). |
| Growth Retardation | Short stature. |
| Jaundice | Haemolysis. |
| Dark Urine | Haemolysis. |
Iron Overload Complications (Later – Transfused Patients Without Chelation)
| Complication | Notes |
|---|---|
| Cardiac | Cardiomyopathy, Heart failure, Arrhythmias. Leading cause of death. |
| Hepatic | Liver fibrosis, Cirrhosis. |
| Endocrine | Diabetes Mellitus, Hypothyroidism, Hypoparathyroidism, Delayed puberty, Hypogonadism, Short stature. |
| Skin | Bronze/Grey pigmentation. |
Beta-Thalassaemia Minor (Trait)
| Feature | Notes |
|---|---|
| Usually Asymptomatic | |
| Mild Microcytic Hypochromic Anaemia | Often incidental finding. |
| Diagnosis Important for Genetic Counselling |
HbH Disease (Alpha-Thalassaemia)
| Feature | Notes |
|---|---|
| Variable Anaemia (Moderate-Severe) | |
| Splenomegaly | |
| Jaundice | |
| May Need Intermittent Transfusions |
6. Investigations
Blood Counts
| Parameter | Findings |
|---|---|
| Hb | Low (Severity depends on type). |
| MCV | Low (Microcytic) – Often disproportionately low for Hb. |
| MCH | Low (Hypochromic). |
| RBC Count | Elevated or Normal (Despite anaemia). High turnover. |
| Reticulocyte Count | Variable. Can be paradoxically low (Ineffective erythropoiesis) or elevated (Haemolysis). |
Mentzer Index (MCV / RBC Count)
| Index | Interpretation |
|---|---|
| less than 13 | Suggests Thalassaemia. |
| >13 | Suggests Iron Deficiency Anaemia. |
| (Screening tool, Not diagnostic) |
Blood Film
| Finding | Notes |
|---|---|
| Microcytic Hypochromic RBCs | |
| Target Cells | |
| Basophilic Stippling | |
| Nucleated RBCs (Major) | |
| Heinz Bodies (HbH Disease – With supravital stain) | HbH precipitates. |
Haemoglobin Electrophoresis / HPLC
| Finding | Notes |
|---|---|
| Beta-Thalassaemia Trait | Raised HbA2 (>3.5%) ± Raised HbF. |
| Beta-Thalassaemia Major | HbF Markedly Elevated (>90%). HbA absent or reduced. HbA2 variable. |
| HbH Disease | HbH (β₄) Present (~5-30%). May have Hb Bart's at birth. |
Iron Studies
| Test | Finding |
|---|---|
| Serum Ferritin | Often normal or elevated (Iron loading). |
| Transferrin Saturation | Normal or elevated. |
| Key: Iron Studies Normal in Thalassaemia Trait – Helps differentiate from IDA (Where ferritin low). |
Genetic Testing (DNA Analysis)
- Confirms diagnosis.
- Identifies specific mutations.
- Essential for genetic counselling and prenatal diagnosis.
Iron Overload Assessment (Transfusion-Dependent Patients)
| Test | Notes |
|---|---|
| Serum Ferritin | Monitor (Target less than 1000 µg/L). |
| Cardiac MRI (T2*) | Gold standard for cardiac iron. Low T2* = High iron. |
| Liver MRI (T2* / R2*) | Liver Iron Concentration (LIC). |
7. Management
Management Algorithm
THALASSAEMIA DIAGNOSED
(Electrophoresis, Genetic testing)
↓
CLASSIFY SEVERITY
┌────────────────┬────────────────┐
TRAIT INTERMEDIA MAJOR
(Minor)
↓ ↓ ↓
Reassurance Variable Mx TRANSFUSION-DEPENDENT
Genetic │
Counselling │
↓
BETA-THALASSAEMIA MAJOR MANAGEMENT
┌──────────────────────────────────────────────────────────┐
│ **REGULAR BLOOD TRANSFUSIONS (Lifelong)** │
│ - Goal: Maintain Pre-Transfusion Hb 9-10.5 g/dL │
│ - Typically every 2-4 weeks │
│ - Leucodepleted, Phenotypically matched RBCs │
│ (Reduce alloimmunisation) │
└──────────────────────────────────────────────────────────┘
↓
IRON CHELATION THERAPY (Essential – Lifelong)
┌──────────────────────────────────────────────────────────┐
│ Start after 10-20 transfusions or Ferritin >1000 µg/L │
│ │
│ **CHELATORS** │
│ - **Deferoxamine (Desferal)** SC or IV infusion │
│ (6-7 days/week, 8-12 hours). Effective. Cumbersome. │
│ - **Deferasirox (Exjade)** Oral once daily. Most widely │
│ used. Monitor renal/Hepatic function. │
│ - **Deferiprone (Ferriprox)** Oral TDS. Good cardiac │
│ protection. Risk: Agranulocytosis (Monitor FBC). │
│ - **Combination Chelation** for severe iron overload. │
│ │
│ **TARGET**: Ferritin less than 1000 µg/L. Cardiac T2* >20ms. │
└──────────────────────────────────────────────────────────┘
↓
CURATIVE TREATMENT
┌──────────────────────────────────────────────────────────┐
│ **ALLOGENEIC HSCT (Bone Marrow Transplant)** │
│ - Only cure. Best results in young patients with │
│ HLA-matched sibling donor and minimal complications. │
│ - Thalassaemia-free survival >90% with optimal donor. │
│ - Risks: Graft failure, GVHD, Mortality (~5-10%). │
│ │
│ **GENE THERAPY (Emerging)** │
│ - Betibeglogene autotemcel (Zynteglo) – EMA/FDA │
│ approved for TDT. │
│ - Autologous gene-corrected stem cells. │
│ - Promising. Expensive. Limited availability. │
└──────────────────────────────────────────────────────────┘
↓
SUPPORTIVE CARE / MONITORING
┌──────────────────────────────────────────────────────────┐
│ **SPLENECTOMY** (If Hypersplenism – Increasing │
│ transfusion requirement). Vaccinations. Prophylactic │
│ penicillin post-splenectomy. │
│ **VACCINATIONS**: Hep B, Pneumococcal, Meningococcal, │
│ Influenza. │
│ **FOLIC ACID**: Supplementation (High turnover). │
│ **ENDOCRINE MONITORING**: Growth, Puberty, Thyroid, │
│ Glucose, Bone density. │
│ **CARDIAC MONITORING**: Regular Echo, Cardiac MRI T2*. │
│ **AVOID IRON SUPPLEMENTS**: Unless also iron deficient │
│ (Rare). │
│ **HEPATITIS SCREENING**: Transfusion-transmitted. │
│ **PSYCHOSOCIAL SUPPORT** │
└──────────────────────────────────────────────────────────┘
Beta-Thalassaemia Trait (Minor)
- Reassurance: Usually does not require treatment.
- Genetic Counselling: Crucial. Risk of Thal Major if partner also carrier.
- Avoid Unnecessary Iron: Unless proven iron deficient.
- Prenatal Diagnosis: If both parents carriers.
8. Complications
| Complication | Notes |
|---|---|
| Iron Overload | Cardiac (Heart failure), Hepatic (Cirrhosis), Endocrine. Main cause of morbidity/Mortality in well-transfused patients. |
| Cardiac Complications | Cardiomyopathy, Arrhythmias, Heart failure. |
| Endocrinopathies | Diabetes, Hypothyroidism, Hypoparathyroidism, Hypogonadism, Adrenal insufficiency, Short stature, Delayed puberty. |
| Osteoporosis | Iron overload, Endocrinopathy, Marrow expansion. |
| Splenomegaly / Hypersplenism | Increased transfusion requirement. May need splenectomy. |
| Infections | Transfusion-transmitted (Hep B, C, HIV – Now rare with screening). Post-splenectomy sepsis. |
| Alloimmunisation | Antibodies to transfused RBCs. |
| Gallstones | Pigment stones (Chronic haemolysis). |
| Leg Ulcers | Especially HbH, Thal Intermedia. |
9. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Thalassaemia Trait | Normal lifespan. No treatment needed. |
| Thalassaemia Major (Well-Managed) | Lifespan significantly improved (~50-60 years+) with optimal transfusion and chelation. Cardiac iron overload remains main cause of death. |
| HSCT | Curative. Excellent outcomes with matched sibling donor. |
| Gene Therapy | Promising. May eliminate transfusion dependence. |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Thalassaemia | TIF, BSH, AABB | Regular transfusions (Pre-Hb 9-10.5). Iron chelation (Ferritin less than 1000). Cardiac MRI T2*. HSCT if suitable donor. |
11. Patient and Layperson Explanation
What is Thalassaemia?
Thalassaemia is an inherited blood disorder where your body makes abnormal or insufficient haemoglobin (The protein in red blood cells that carries oxygen). This leads to anaemia.
What are the types?
- Thalassaemia Trait (Minor): You carry one faulty gene. Usually no symptoms. Important to know for family planning.
- Thalassaemia Major (Severe): You inherit faulty genes from both parents. Causes severe anaemia needing regular blood transfusions.
- Thalassaemia Intermedia: In between in severity.
What are the symptoms of Thalassaemia Major?
- Severe tiredness and paleness.
- Slow growth.
- Enlarged liver and spleen.
- Bone changes (Facial, Skull).
How is it treated?
- Thalassaemia Trait: Usually no treatment needed.
- Thalassaemia Major:
- Regular blood transfusions (Every 2-4 weeks).
- Iron-removal medication (Chelation): Transfusions cause iron buildup, Which damages the heart, Liver, And glands. Chelation drugs remove this excess iron.
- Bone marrow transplant: Can cure Thalassaemia, But needs a matching donor.
- Gene therapy: New treatment becoming available.
Is it inherited?
Yes. If both parents carry the Thalassaemia gene, There is a 25% chance with each pregnancy of having a child with Thalassaemia Major. Genetic counselling and prenatal testing are available.
12. References
Primary Sources
- Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-167. PMID: 28774421.
- Cappellini MD, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). Thalassaemia International Federation. 3rd Edition, 2014.
- Musallam KM, et al. Non-transfusion-dependent thalassemias. Haematologica. 2013;98(6):833-844.
13. Examination Focus
Common Exam Questions
- Raised HbA2: "In which condition is HbA2 characteristically raised?"
- Answer: Beta-Thalassaemia Trait (>3.5%).
- Mentzer Index: "What is the Mentzer Index and how is it used?"
- Answer: MCV / RBC Count. less than 13 suggests Thalassaemia. >13 suggests Iron Deficiency Anaemia.
- Main Cause of Death (Thal Major): "What is the leading cause of death in well-transfused Thalassaemia Major patients?"
- Answer: Cardiac Iron Overload (Cardiomyopathy, Heart failure, Arrhythmias).
- Curative Treatment: "What is the curative treatment for Beta-Thalassaemia Major?"
- Answer: Allogeneic Haematopoietic Stem Cell Transplantation (HSCT / Bone Marrow Transplant).
Viva Points
- "Chipmunk Facies" / "Hair-on-End Skull": Bone marrow expansion (Undertreated Major).
- Hb Bart's Hydrops Fetalis: 4 alpha gene deletions. Fatal in utero.
- Cardiac MRI T2*: Gold standard for cardiac iron. Low T2* = High iron.
- Deferasirox: Oral chelator. Most widely used. Monitor renal function.
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