Haemoglobin structure by MalsD5xC


									Haemoglobin structure



 Beta-            Alpha-
 type              type
        Normal Haemoglobin
• Always 2 Beta-type and 2 Alpha-type
  globin chains carrying haem molecule
• Beta-type
  – epsilon, gamma, beta, theta
• Alpha-type
  – zeta, alpha
       Haemoglobin structure
• So functional Hb is always a heterotetramer
• there must be 2 Beta and 2 Alpha for
  oxygen carrying function
• different types at different stages of fetal
  and early neonatal life
• by 6 months we have adult proportions
           Hb development
• Up to 8/40
  – zeta2/epsilon2, alpha2/epsilon2, zeta2/gamma2
• From 8/40 to birth
  – 85% alpha2/gamma2 (HbF)
  – 5-10% alpha2/beta2 (HbA)
  – remainder alpha2/theta2 (HbA2) + others
• By 6/12, adult proportions of A, A2, F
            Normal adult Hb
• HbA (alpha2/beta2)
  – 97% +
• HbA2 (alpha2/theta2)
  – 2-3%
• HbF (alpha2/gamma2)
  – 0.5% or less
   Haemoglobin abnormalities
• Haemoglobinopathies
  – normal amounts of abnormal beta chains
  – crystalline disorders (S, C, D, E)
  – familial polycythaemia, M Hb, unstable Hb,
• Thalassaemias
  – reduced amounts of normal alpha or beta chains
• Can be BOTH!
    Thalassaemias (simplistic)
• Reduced production of BETA chains
  – BETA thalassaemias
• Reduced production of ALPHA chains
  – ALPHA thalassaemias
  – more severe clinical disease
         Beta thalassaemias
• Beta chain deficiency
• So reduced HbA
• BUT retained production of other beta-type
  chains, so increased
  – theta production (HbA2)
  – gamma production (HbF)
            Beta thalassaemias
•   Encoded by a single gene pair
•   Autosomal recessive (but not totally)
•   heterozygotes have beta thalassaemia trait
•   homozygotes have beta thalassaemia
    (thalassaemia MAJOR)
    – but they are ALIVE at birth
    – variable clinical severity - why?
Inheritance of beta thalassaemia
   Usually due to point mutation

                                   Effect on Beta
                                   chain production
   Beta plus thalassaemia genes
• If the mutation causes total shutdown of the
  beta chain gene
  – no beta chain produced
  – Beta nought thalassaemia
• If the mutation reduces beta chain
  production (but does not shut it down)
  – some beta chain produced
  – Beta plus thalassaemia
• Beta/beta plus heterozygote
  – microcytosis, Hb normal
  – raised A2 and F
• Beta/beta nought heterozygote
  – more severe microcytosis, Hb normal
  – raised A2 and F
• Beta plus/beta plus
  – microcytosis, +/- anaemia
• Beta nought/beta nought
  – microcytosis, red cell changes, transfusion
• Beta plus/beta nought
  – microcytosis, variably anaemic
Inheritance of alpha thalassaemia
• More complex as encoded by 2 gene pairs
  (so four genes per person, not two)
• However, usually due to whole gene
  deletions, so total gene loss/shutdown
• haematology and clinical presentation
  depends on how many genes are lost
Gene deletions in alpha

          One gene deletion
          (alpha/alpha +)
Gene deletions in alpha
          Two gene deletion
          (alpha +/alpha +)

          Two gene deletion
          (alpha/alpha 0)
Gene deletions in alpha
         Three gene deletion
         (alpha +/alpha 0)

          Four gene deletion
           Clinical disorders
• Alpha/alpha +
  – alpha thalassaemia trait, normal Hb, normal or
    slightly reduced MCV
• Alpha +/Alpha + or alpha/alpha 0
  – normal Hb, microcytic
           Clinical disorders
• Alpha +/alpha 0
  – HbH disease, reduced Hb, splenomegaly, may
    or may not be transfusion dependent
  – presence of beta tetramers (HbH) on film (“golf
    ball” cells)
  – unlike in beta thalassaemia, there is no
    substitute for alpha
              Hydrops fetalis
• Four gene deletion
  –   no alpha chain production
  –   incompatible with life
  –   fetus dies in utero
  –   gamma tetramers instead - Hb Barts
HbH and Hb Barts

 HbA         HbF

  HbH        HbBarts
        Laboratory diagnosis
• Beta thalassaemia
  – relies on raised F and A2
• Alpha thalassaemia
  – F and A2 normal
  – may see “golf balls” on HbH prep
  – gene analysis

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