Overview
Thalassaemias are a group of genetically inherited autosomal recessive conditions leading to abnormal haemoglobin production. Like sickle-cell anaemia, they are a type of haemoglobinopathy.
Most adult haemoglobin (HbA) is made of four proteins:
- Two α-globin chains
- Encoded by 2 genes on chromosome 16, therefore 4 alleles are present
- Two β-globin chains
- Encoded by 1 gene on chromosome 11, therefore 2 alleles present
It may be helpful to look at the chapter on Anaemia: Data Interpretation alongside reading this section to help wrap your head around when to suspect what type of anaemia.
Epidemiology
- β-thalassaemia is more common
- β-thalassaemia is more common in the Mediterranean, Middle East, Central and South Asia, and Southern China
- α-thalassaemia is more common in Southeast Asia, Africa, and India
α-thalassaemia
Mutated α-globin alleles lead to reduced α-globin production. Fewer α-globin chains result in excess β chains which form unstable haemoglobin H (HbH) with abnormal oxygen dissociation curves.
The severity correlates with the number of affected α-globin alleles:
- 1 affected allele – silent carrier
- 2 affected alleles – α-thalassaemia trait
- Minor anaemia
- 3 affected alleles – haemoglobin H disease
- Mild-moderate anaemia
- 4 affected alleles – hydrops fetalis
- Usually fatal, leading to death in utero
β-thalassaemia
Mutations in β-globin alleles can lead to:
- β+ – some function is preserved
- β0 – no function preserved
Different genotypes:
- β-thalassaemia major (β0/β0):
- No HbA production
- β-thalassaemia intermedia (β+/βo or β+/β+):
- Some HbA production
- β-thalassaemia minor (β/β0 or β/β+):
- Relatively asymptomatic
Presentation
If a patient presents with microcytic, hypochromic anaemia that fails to respond to iron treatment. Haemoglobinopathies should be considered.
General features of anaemia include:
- Fatigue
- Pallor
- Shortness of breath on exertion
- Palpitations
- Children with impaired growth
Features of thalassaemia include:
- Splenomegaly:
- Red blood cells are destroyed more easily in the spleen and recycled more quickly
- Bone problems:
- Pronounced forehead and cheekbones
- The bone marrow expands to try and make more red blood cells to compensate
- Poor growth and development:
- Due to anaemia and endocrinopathy
- Recurrent infection:
- The spleen is ‘not as good at its job’
- Iron overload may occur leading to iron deposition in different organs:
- Increased skin pigmentation due to skin deposition
- Endocrinopathy due to deposition in hormone glands
- This can cause sexual dysfunction, poor growth etc.
- Arrhythmia due to deposition in the heart
- Heart failure due to deposition in the heart
- Liver cirrhosis due to deposition in the liver
People with thalassaemia are prone to iron overload. This is because the body tries to absorb as much iron as possible due to chronic anaemia. It is important to consider this when treating thalassaemia with blood transfusions and iron.
Differential Diagnoses
Anaemia of chronic disease
- There may be signs of an underlying chronic illness (e.g. chronic kidney disease or autoimmune diseases)
- Ferritin may be normal or high
- Total-iron binding capacity may be low
Iron-deficiency anaemia
- Depending on the severity, thalassaemias can range from mild to profound anaemia. In general, the MCV is disproportionately low compared to the level of anaemia seen in iron-deficiency anaemia.
Sickle-cell anaemia
- In sickle-cell anaemia, the anaemia is normocytic
- Splenomegaly is not seen in sickle-cell anaemia except in splenic sequestration crises
- The thalassaemias do not have crises, unlike sickle-cell anaemia
Investigations
All patients
- Full blood count (FBC):
- Shows anaemia with disproportionately low MCV
- The blood count generally drops with increased severities of splenomegaly
- Reticulocyte count:
- May be elevated – the bone marrow responds by trying to create new, immature red cells
- Peripheral smear:
- Microcytic red cells are seen
- Tear-drop cells and target cells seen
- Serum ferritin:
- May be elevated in iron overload
- Mentzer index:
- <13 in thalassaemia
- Markers of haemolysis:
- Bilirubin – may be elevated
- Lactate dehydrogenase (LDH) – may be elevated
- Haptoglobins – may be reduced
- Abdominal ultrasound:
- May show hepato- and/or splenomegaly
- X-ray of skull and long bones:
- May show ‘hair-on-end’ appearance
- Haemoglobin electrophoresis:
- Identifies globin chain abnormalities
- DNA testing
Pregnant people in the UK are offered screening for thalassemia.
Management
Overview
General management measures depend on severity:
- Genetic counselling and avoiding excess iron
- Intermedia – blood transfusions when needed, monitoring, and iron chelation
- Major – regular blood transfusions, monitoring, and iron chelation
- Haematopoietic stem cell transplant
- Splenectomy for hypersplenism
- Desferrioxamine is an iron-chelating agent
Iron overload
Patients are susceptible to iron overload due to haemolysis and continuous blood transfusions, leading to symptoms similar to haemochromatosis and organ failure.
Patients must have regular iron monitoring and are given iron-chelating agents such as desferrioxamine.
Complications
- Iron overload – deposits of iron can lead to organ damage and failure:
- Endocrine dysfunction
- Hypogonadism
- Slowed growth
- Diabetes if the pancreas is affected
- Arthritis
- Skin hyperpigmentation
- Liver fibrosis
- Arrhythmia
- Endocrine dysfunction
- Incorrect HbA1c readings:
- The red blood cells have a shortened lifespan, giving a falsely lowered HbA1c result when monitoring diabetic control
- Jaundice and gallstones
- This is due to increased cell turnover and hyperbilirubinaemia
- Hypersplenism
- Slowed growth
Prognosis
- α-thalassaemia:
- Silent carrier – prognosis excellent
- Trait and HbH disease – moderate anaemia, the prognosis varies
- Many survive into adulthood but can have complications
- Hydrops fetalis – incompatible with life
- β-thalassaemia:
- Trait – mild and asymptomatic
- Major – prognosis has improved due to iron chelation
