Thalassaemia is a group of hereditary haemoglobin disorders, caused by autosomal recessive mutations in the alpha or beta globin chains:
- Mutation in alpha globin chain → alpha thalassaemia
- Mutation in beta globin chain → beta thalassaemia
Quick comparison:
- Alpha thalassaemia is more common, and typically has a lower disease burden
- Beta thalassaemia is less common, and typically has a higher disease burden (severe and transfusion-dependent disease)
Alpha Thalassaemia
Aetiology
Autosomal recessive condition [Ref]
- Most common: deletion of one or more of the 4 alpha globin genes, on chromosome 16
- Less common: non-deletional mutation (less common but associated with more severe disease)
In contrast, point mutation is more common in beta thalassaemia (than deletional mutation).
Epidemiology
Alpha thalassaemia is more prevalent than beta thalassaemia (5% vs 1.5%) [Ref]
Thalassaemia is more prevalent in: [Ref]
- Mediterranean
- Southeast Asia
- Middle East
- Indian subcontinent and sub-Saharan Africa
There is a documented evolutionary association between the thalassaemia carrier state and resistance to malaria, which explains why the disease is highly prevalent in regions where malaria was or remains common. [Ref]
Classic textbook epidemiological associations:
- Thalassaemia → Mediterranean / Middle Eastern / Asian
- Sickle cell → African / Afro-Caribbean
Types and Clinical Manifestation
Based on the number of defective alpha globin alleles, there are 4 forms of alpha thalassaemia: [Ref1][Ref2][Ref3]
| Form | Genetic | Clinical manifestation |
|---|---|---|
| Minima (silent carrier) | 1 defect (-α/αα) |
|
| Minor (trait) | 2 defects (-α/-α or –/αα) |
|
| Intermediate (Hb H disease) | 3 defects (–/-α) | Variable clinical presentation (more severe in non-deletional variants):
|
| Major (Bart’s hydrops fetalis) | 4 defects (–/–) | Incompatible with life
Maternal complications:
|
Investigation and Diagnosis
Laboratory Tests
Thalassaemia causes a microcytic, hypochromic anaemia [Ref1][Ref2]
- ↓↓ Mean corpuscular volume (microcytic)
- ↓↓ Mean corpuscular haemoglobin (hypochromic)
- Anaemia is typically mild to moderate (only seen in trait and HbH disease)
Mean corpuscular volume and mean corpuscular haemoglobin are often significantly reduced in alpha-thalassaemia.
This reduction is typically disproportionate to the level of anaemia (i.e. the haemoglobin level is typically normal or mildly reduced). [Ref1][Ref2]
Electrophoresis findings: [Ref1][Ref2]
- Normal HbA2
- Normal HbF
- HbH – only present in HbH disease
Normal HbA2 Levels is a critical finding for alpha-thalassaemia, as it helps distinguish it from beta-thalassaemia, where HbA2 is typically elevated.
Confirmatory Test
Gold standard: genetic testing [Ref1][Ref2]
- Typically PCR to detect the mutation
- Venous blood can be used for testing
Note that haemoglobin electrophoresis is only used to diagnose beta thalassaemia, it cannot reliably diagnose alpha thalassemia (as it is typically normal)
Gold standard diagnosis of thalassaemia:
- Alpha → genetic testing
- Beta → haemoglobin electrophoresis
Bone marrow analysis is not routinely indicated in thalassaemia and is used only to exclude other haematological diseases.
Management
Form Specific Management
| Alpha thalassaemia form | Management approach |
|---|---|
| Minima (silent carrier) | No treatment is typically required |
| Minor (trait) | |
| Intermediate (Hb H disease) | Largely depends on disease severity:
|
| Major (Bart’s hydrops fetalis) |
|
Genetic counselling, including testing of partners is recommended for all patients due to the autosomal recessive inheritance pattern.
It plays a key role in identifying at-risk couples, assessing the risk of severe disease in offspring (including HbH disease and hydrops fetalis), and facilitating informed reproductive decision-making.
Conditional Management
| Management | Description / notes |
|---|---|
| Splenectomy | Primary indication: symptomatic splenomegaly |
| Curative treatment |
|
Beta Thalassaemia
Aetiology
Autosomal recessive condition [Ref]
- Most common: point mutation of one or more of the 2 beta globin genes, on chromosome 11
- Less common: insertion, deletional mutations
In contrast, deletional mutation is more common in alpha thalassaemia (than point mutation).
Thalassaemia is more prevalent in: [Ref]
- Mediterranean
- Southeast Asia
- Middle East
- Indian subcontinent and sub-Saharan Africa
There is a documented evolutionary association between the thalassaemia carrier state and resistance to malaria, which explains why the disease is highly prevalent in regions where malaria was or remains common. [Ref]
Classic textbook epidemiological associations:
- Thalassaemia → Mediterranean / Middle Eastern / Asian
- Sickle cell → African / Afro-Caribbean
Clinical Manifestation
| Form | Genetics | Clinical manifestation |
|---|---|---|
| Minor (trait) | 1 defective allele (heterozygous) | Typically asymptomatic |
| Major | 2 defective alleles (homozygous) | Considered as transfusion-dependent thalassaemia
Another major complication is chronic iron overload (see separate section below) |
Investigation and Diagnosis
Laboratory Tests
Confirmatory Test
Primary confirmatory test: haemoglobin analysis (by haemoglobin electrophoresis or liquid chromatography) [Ref1][Ref2]
- ↑ HbA2 (>3.5%)
- ↑ HbF
- No HbH
Genetic testing is typically used in those who are <12 m/o where haemoglobin analysis may be inconclusive due to physiological haemoglobin switching. [Ref]
Bone marrow analysis is not routinely indicated in thalassaemia and is used only to exclude other haematological diseases.
Management
Form Specific Management
| Form | Management approach |
|---|---|
| Minor (trait) |
|
| Major |
|
Conditional Management
| Management | Description / notes |
|---|---|
| Splenectomy | Primary indication: symptomatic splenomegaly |
| Curative treatment |
|
Iron Overload
Aetiology
Iron overload is a major complication of symptomatic alpha thalassaemia (esp. HbH disease), it can occur from 2 mechanisms:
- Regular red cell transfusions (not typically needed in alpha thalassaemia)
- Increased GI iron absorption (due to ineffective erythropoiesis) – main mechanism in non-transfusion dependent thalassaemia (esp. HbH disease)
Iron overload is an important and problematic complication as iron homeostasis is regulated by absorption, not excretion. The body has no active mechanism to remove excess iron.
The body stores excess iron as ferritin / haemosiderin. Iron loss only occurs passively (without regulation) via shedding of skin cells, sloughing of gut mucosa, menstruation and minor blood loss.
Clinical Manifestation
| Affected organ(s) | Clinical manifestation |
|---|---|
| Systemic / general |
|
| Joints |
|
| Skin |
|
| Liver |
|
| Heart |
|
| Endocrine organs |
|
Detection and Diagnosis
- Gold standard: MRI (measures liver and cardiac iron levels)
- Serum ferritin level (less precise than MRI, used for routine serial monitoring to track trends)
Management
Management is with iron chelation therapy (agents that bind to excess iron and allow active excretion in urine and/or faeces).
General indications: [Ref]
- Transfusion-dependent thalassaemias
- Hb Bart’s hydrops fetalis
- Beta thalassaemia major
- Non-transfusion-dependent thalassaemias with
- ↑ Serum ferritin (>800 μ/L)
- ↑ Liver iron concentration (>5 mg/g dry weight)
Key iron chelating agents: [Ref]
- Deferoxamine (subcutaneous / IV)
- Deferasirox (oral)
- Deferiprone (oral) – often used as 2nd line
Note that the management of secondary iron overload (i.e. secondary haemochromatosis) is different to that of primary (genetic) iron overload (i.e, primary haemochromatosis) where 1st line is regular venesection and 2nd line is iron chelation therapy.