Thalassaemia

Question 1

Define Thalassaemia

Answer 1

A group of genetic disorders characterised by reduced/no globin chain synthesis.

Question 2

Explain the aetiology / risk factors of thalassaemia

Answer 2

RISK FACTORS

• Positive FHx
• Mediterranean, SE Asia, Middle Eastern, African origin

BETA-THALASSAEMIA:

• The beta-globin gene is on Chromosome eleven so each beta-globin protein in Hb comes from one parent
• In β-thalassaemia, there is a mutation in the regulatory regions of the beta-globin gene affecting its expression leading to a reduced/complete lack of beta-globin
• This can range from β-thalassaemia minor/TRAIT, intermediate and MAJOR –> major means TRANSFUSION DEPENDENT

ALPHA THALASSAEMIA

• There are 2 alpha-globin genes (α1 + α2) on each Chromosome 16 so 4 alleles in total
• In alpha thalassaemia, there is a deletion of 1 (α+) or both (α0) of the alpha genes on a single chromosome (no alpha globin from affected parent)
• In α0 there is no alpha-globin protein so the non-alpha globins (beta & gamma) can aggregate forming
  
  • Hb H (4x β) - 3 x deleted alpha, leads to acute severe haemolysis
  • Hb Barts (4x 𝛄) - 4 deleted alpha, this is fatal in utero as HbF cannot be made

Unmatched globins precipitate, damaging RBC membranes causing their haemolysis whilst still in the marrow, however, there is also splenic haemolysis

Question 3

Summarise the epidemiology of thalassaemia

Answer 3

Mutations in the beta-globin gene cluster occur at high frequencies in the Mediterranean, Middle East, northern Africa, India, and SE Asia.

The worldwide distribution of inherited alpha-thalassaemia corresponds to areas of malaria exposure

Question 4

Recognise the presenting symptoms of thalassaemia

Answer 4

Beta-thalassaemia MAJOR usually present 3-6 months after birth (after gamma to beta switch)

Alpha & Beta Thalassaemia trait are often ASYMPTOMATIC

• Fatigue
• Dyspnoea
• Dizziness
• Failure to thrive (lack of height and weight)

Question 5

Recognise the signs of thalassaemia on physical examination

Answer 5

• Jaundice (scleral icterus, yellow mucus membranes)
• Gallstone symptoms (cholecystitis/cholangitis)
• Conjunctival Pallor
• Abdominal distension without lymphadenopathy
  
  • Hepatomegaly (due to EMH ± iron overload from repeated transfusions)
  • Splenomegaly (due to EMH, hypersplenism due to increased defective RBC removal)
• Intramedullary haematopoiesis:
  
  • Chipmunk facies (maxillary prominence, misaligned teeth)
  • Large head (frontal bossing)

Question 6

Identify appropriate investigations for thalassaemia and interpret the results

Answer 6

In all pt’s with microcytic hypochromic anaemia, you want to exclude IDA and do Hb electrophoresis to diff between beta and alpha

• FBC
  
  • Low Hb
  • Low MCV (microcytic)
  • Low MCH (hypochromic)
  • Increased reticulocyte percentage
• Peripheral blood smear
  
  • Target cells
  • Pokilocytosis
  • Pappenheimer bodies (coarse iron deposits due to iron overload from transfusion)
• Haemoglobin electrophoresis/HLPC
  
  • Beta thalassaemia MAJOR: NO HbA, increased HbF and HbA2
  • Alpha thalassaemia MAJOR: No HbA, HbF or HbA2 but Hb H and Hb Barts
  • Intermediate forms may have some HbA
• Serum Iron levels to exclude IDA
• Plain skull x-ray will show widening of diplopeic space and ‘hair on end’ appearance due to marrow expansion

Question 7

Compare Iron deficiency Anaemia to Thalassaemia trait (MCH, MCV, Hb, RCC)

Answer 7

Hb (g/L of blood):
- IDA: low
- Th trait: normal (rarely low)

MCV:
- BOTH low

RCC:
- IDA:Low/normal
- Th trait: Increased (increased EPO drive)

MCH (g of Hb in each cell):
- IDA: Low (less Hb is made)
- Th trait: Low