Thalassemia

 

• Background

  Pathophysiology

  • Autosomal recessive mutation leading to absence or dysfunction of the α or β globin chains on the haemoglobin A (HbA) molecule.
  • α-thalassaemia leads to impaired oxygen transport and extravascular haemolysis (via splenic clearance).
  • β-thalassaemia leads to failed erythropoiesis, with the build up of α chains causing cell destruction. Compensatory erythroid hyperplasia (↑immature RBCs) causes bone growth.
  • Severity of disease reflects how many alleles are affected: out of 4 for α (which has 2 genes), and out of 2 for β (just 1 gene).

  Symptomatic and asymptomatic states

  Asymptomatic carrier states:

  • β-thalassaemia trait (aka minor): 1 β allele affected.
  • α-thalassaemia silent carrier (aka minima), with 1 allele affected, or α-thalassaemia trait (aka minor), with 2 alleles affected.
  • In α or β thalassaemia minor/trait, microcytic anaemia may be the only sign.

  Symptomatic disease:

  • β-thalassaemia: homozygous for partly functioning alleles (thalassaemia intermedia) or non-functioning alleles (thalassaemia major). The latter presents earlier and more severely.
  • α-thalassaemia: 3 affected alleles (HbH disease) or 4 affected alleles (Hb Bart). The latter causes intrauterine haemolytic anaemia and hydrops fetalis, and is usually fatal.

  Epidemiology

  • β-thalassaemia: common in Mediterranean, Middle East, Central and South Asia, China.
  • α-thalassaemia: common in Southeast Asia, Africa, India.

• Presentation

  Presents anytime from neonate to adult, but later onset tends to be milder.

  In general symptoms are worse in β-thalassaemia patients, as the most severe α-thalassaemia doesn't survive pregnancy or early life.

  Signs and symptoms:

  • Haemolytic anaemia: fatigue, SOB, pallor, jaundice (commoner in β). Cardiac flow murmur from high output.
  • Splenomegaly (α) or hepatosplenomegaly with abdominal distention (β).
  • Failure to thrive, growth restriction.
  • Facial dysmorphia: fontal bossing, maxillary hypertrophy, large head. Commoner and more prominent in β-thalassaemia.
  • Osteopenia (β).

• Investigations

  Preconception screening (questionnaire ± DNA testing) of both parents in at risk populations.

  Bloods:

  • FBC: ↓Hb, ↓MCV, ↓MCH. Unlike iron deficiency, RBC may be normal or high.
  • ↑Reticulocytes
  • Blood film.
  • ↑Iron and ↑ferritin in severe disease. Due to disease itself or frequent transfusions.
  • LFT: ↑unconjugated BR (β). ↑Liver enzymes if there is iron overload.

  Diagnosis:

  • Hb electrophoresis.
  • Gap-PCR detects common deletions to confirm diagnosis. Other mutations may require DNA sequencing.

  Imaging:

  • Skull XR: bony abnormalities.
  • Chest XR: rib deformities, cardiomegaly.
  • Abdo US for organomegaly.
  • ECG and echo for cardiac function.

  Liver biopsy and/or MRI if there is iron overload.

• Management

  Asymptomatic carriers require no specific treatment. Just avoid iron supplements.

  Transfusion indications:

  • Symptomatic anaemia, or aplastic or hyperhaemolytic crisis.
  • Regular transfusion for thalassaemia major, or if there is growth impairment.

  Iron chelation if there is overload:

  • Parenteral desferrioxamine.
  • May cause hearing loss and visual impairment so check both regularly.

  Splenectomy:

  • Indication: hypersplenism with increasing transfusion requirements.
  • Avoid if possible.

  Bone marrow transplantation:

  • Used in severe, transfusion-dependant disease.
  • Curative

• Complications and prognosis

  Complications:

  • Iron overload affecting liver, heart, pancreas, and pituitary gland.
  • High-output heart failure.
  • Gallstones
  • Hypersplenism
  • Aplastic crisis due to parvovirus B19 infection.

  Prognosis:

  • HbH: generally good.
  • β-thalassaemia major: without treatment, death <5 years old from heart failure or anaemia. Regular transfusions and iron chelation allow near-normal life expectancy.