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Thalassemias

1. THALASSEMIAS

  • Quantitative abnormality of globin chain synthesis
  • Genetic mutation in thalassemia results in
    • Absence of mRNA production from the involved gene
    • Production of non-functional mRNA
    • Production of an unstable mRNA that is prematurely degraded
  • The above results in decreased synthesis of the involved globin chain. This has 2 consequences
    • Decreased Hb synth – resulting in anaemia and microcytosis
    • Aggregation of excess free globin chains – produced by the non-thalassemic gene. These aggregates of unpaired globin chains attach to and damage er cell membrane, causing hemolysis
  • In severe cases, many erythroid precursors are destroyed in the BM, those that escape are prematurely destroyed by macrophages in spleen and liver
  • Extremely heterogeneous
  • High prevalence of thalassemia in areas with endemic malaria – Africa, Mediterranean, Middle East, India

Complications

  • Chronic anaemia – leads to growth retardation, delayed sexual maturation, cardiac dilation, CHF
  • Expansion of BM – Due to erythroid hyperplasia
    • ‘Hair on end’ appearance on radiograph due to widening of diploic spaces in skull – EMH
    • Frontal bossing of forehead. Prominent cheeks due to hypertrophy of maxillae (chipmunk appearance).
    • Extramedullary haematopoiesis causes enlargement of spleen and liver.
  • Iron overload – chronic hyper-absorption of iron by GIT, due to chronic erythropoiesis
    • Fe deposition in the heart causes cardiomyopathy and arrhythmias
    • Deposition in liver causes portal fibrosis and cirrhosis (↑risk of HCC)
  • Chronic hemolysis – causes splenomegaly, hepatomegaly, bilirubin gallstones

α-Thalassemia

Epidemiology

  • Mediterranean, Middle East, China, SE Asia, Africa
  • Single gene mutation MC in Africa

Pathophysiology

  • Deletion of α globin chains
  • There are 2 genes for the α globin chain on chromosome 16
Single-gene mutation

Silent

(-a/aa) Asymptomatic, without microcytosis or anemia
2 gene mutation

a-thal minor or trait

 (-a/-a)

(–/aa)

 Mild microcytic anemia, serious complications are rare
3-gene mutation

HbH disease(β4)

 (–/-a) Moderately severe, microcytic anemia. Excess β chains precipitate as β4 tetramers (HbH). Pts may/may not have splenomegaly, Fe overload, skeletal complications
4-gene mutations

Hb Barts (γ4)

 (–/–) Hydrops fetalis. Incompatible with life. Pregnancies terminate spontaneously. Infants who survive have severe anasarca and die of CHF.

β-Thalassemia

Epidemiology

  • Mediterranean – esp Greece and Italy (βo). Africa (β+)

Pathophysiology

  • There is a single gene for β globin chain on chromosome 11
  • Mutations can result in either
    • A complete lack of β chain synthesis (βo-thalassemia)
    • A decrease in β chain synthesis (β+-thalassemia)
Β- Thalassemia minor (β/β+) Heterozygosity results in mild clinical syndrome. Mild decrease in Hb and MCV. Few sx
B-Thalassemia major

Cooley’s Anemia

(β0/β0) Severe anemia and v.low MCV. Near total absence of HbA. Ineffective erythropoiesis, expansion of BM with skeletal complications. Splenomegaly, Fe overload due to hyperabsorption of iron
B-Thalassemia intermedia (β+/β+) or (β+/β0) Some HbA is produced

Diagnosis

HbA – α2β2

HbA2 – α2δ2

HbF – α2γ2

HbS – sickle

  • A microcytic anemia that is not due to iron deficiency is most likely thalassemia
  • Blood smear – microcytosis, hypochromia
    • Severe cases – anisocytosis, bizarre poikilocytes, polychromasia, nucleated er
  • B-Thal diagnosed by Hb electrophoresis
    • Shows increased HbA2
    • Also slight increase in HbF
  • A-Thal diagnosed By exclusion
    • A microcytic anaemia not due to IDA and has a normal level of HbA2 is most likely A-Thal
    • HbH disease can be diagnosed by presence of HbH on electrophoresis (it is the fastest migrating Hb)

Treatment

  • RBC transfusion – 1-3 units every 3 weeks
    • Complications – alloimmunisation, Fe overlaod, infections (esp viral hepatitis)
  • In pts with severe thalassemia, aim to keep Hb>12g/dL to prevent skeletal complications by shutting of erythropoein-driven erythroid hyperplasia
  • Iron chelation – to treat iron overload
    • Deferoxamine (Desferal) – subcutaneous infusions. Deferasirax (oral)
    • Mobilises Fe so it’s excreted in urine
    • Complications – cataracts, hearing loss
  • Splenectomy
    • Patients should be immunised against S.pneumoniae, H.influenza, N.meningitidis prior

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