Thalassaemias

Autosomal recessive inherited disorders of haemoglobin, causing reduced globin chain synthesis, resulting in impaired haemoglobin production

Aetiology

  • Genetic defect
    • Defects in alpha-globin chains leads to alpha thalassaemia
    • Defects in the beta-globin chains leads to beta thalassaemia
    • Both conditions are autosomal recessive

Pathophysiology

Alpha thalassaemia

  • Deletion of one ⍺+ (-⍺) or both ⍺0 (- -) alpha genes from chromosome 16 results in defects in alphaglobin chains
  • ⍺ chains present in HbA, HbA2 and HbF are all affected
Classification - based on genetics
  • Unaffected = 4 normal ⍺ genes (⍺⍺/⍺⍺)
  • ⍺ thalassaemia trait = one or two ⍺ genes missing
    • Asymptomatic carrier state, no Rx needed
    • Microcytic hypochromic red cells with mild anaemia
    • Important to distinguish from iron deficiency - ferritin will be normal
  • HbH disease = only one alpha gene left (- -/-⍺)
    • Moderate to severe anaemia with very low MCV and MCH
    • Excess β chains form tetrameres (β4) called HbH
    • Common in SE asia
  • Hb Barts hydrops fetalis = no functional ⍺ genes (- -/- -)
    • Minimal or no ⍺ chain production → HbF and HbA can’t be made
    • No alpha chains to bind to so tetramers of Hb Barts (𝛾4) and HbH (β4) produced
    • Incompatible with life - antenatal screening to avoid risk

Beta thalassaemia

  • Mutations affecting β globin chain synthesis, usually caused by point mutations on chromosome 11
  • Reduced (β+) or absent (β0) beta chain production depending on the mutation
  • Only β chains and hence only HbA (⍺2β2) affected
Classification - based on clinical severity
  • β thalassaemia trait/minor (β+/β or β0/β) = asymptomatic, no/mild anaemia, low MCV/MCH, raised HbA2 diagnostic
  • β thalassaemia intermedia (β+/β+ or β0/β+) = moderate severity requiring occasional transfusion
  • β thalasseamia major (β0/β0) = severe, lifelong transfusion dependency

Consequences

  • Results in inadequte Hb production → microcytic hypochromic anaemia
  • If severe:
    • Unbalanced accumulation of globin chains which are toxic to the cell
    • Ineffective erythropoiesis
    • Haemolysis

Clinical presentation

  • Minor forms are often asymptomatic and may never be detected, or may cause a microcytic anaemia in later childhood or adulthood
  • Major forms present early in life, e.g. β thalasseamia major:
    • Presents age 6-24 months (as HbF falls)
    • Pallor, failure to thrive
    • Extramedullary haematopoiesis causing:
      • Hepatosplenomagely
      • Skeletal changes
      • Organ damage
    • Hb analysis: mainly HbF, no HbA
  • Severe major forms are often incompatible with life, e.g. Hb Barts hydrops fetalis
    • Profound anaemia
    • Cardiac failure
    • Growth retardation
    • Severe hepatosplenomegaly
    • Skeletal and cardiovascular abnormalities
    • Almost all die in utero

Investigations

  • Bloods - FBC shows microcytic anaemia
  • High performance liquid chromatography (HPLC) or electophoresis to quantify haemoglobins present e.g. raised HbA2 diagnostic of β thal trait
  • DNA testing can be used to look for the genetic abnormality
  • Pregnant women in the UK are offered a screening test for thalassaemia at booking

Management

  • Many patients with ‘minor’ disease may not require any treatment at all
  • In patients with severe disease, the aim of treatment is to keep Hb at 95-105g/L - achieved through lifelong blood transfusions
    • Suppresses ineffective erythropoiesis
    • Inhibits over-absorption of iron
    • Allows for normal growth and development
  • Bone marrow transplant may be an option if carried out before complications develop

Complications

Iron overload

  • Iron overload from transfusion becomes the main cause of mortality
  • Consequences of iron overload include:
    • Hemosiderosis
    • Endocrine dysfunction - impaired growth and pubertal development, diabetes, osteoporosis
    • Cardiac disease - cardiomyopathy, arrhythmias
    • Liver disease - cirrhosis, hepatocellular carcinoma
  • Management of iron overload - iron chelating drugs e.g. desferrioxamine
    • Bind to iron which is then excreted

Other complications

  • Transfusion related - viral (HIV, hepatitis B and C), alloantibodies (hard to crossmatch), transfusion reactions
  • Increased risk of sepsis - bacteria like iron