Transcript Normal Haemoglobin

Haemoglobin structure
Betatype
Alphatype
Haem
Betatype
Alphatype
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
• NOTE ALL NEED ALPHA!
Haemoglobin abnormalities
• Haemoglobinopathies
– normal amounts of abnormal beta chains
– crystalline disorders (S, C, D, E)
– familial polycythaemia, M Hb, unstable Hb,
HPFH
• 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
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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
variable
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
Combinations
• Beta/beta plus heterozygote
– microcytosis, Hb normal
– raised A2 and F
• Beta/beta nought heterozygote
– more severe microcytosis, Hb normal
– raised A2 and F
Combinations
• Beta plus/beta plus
– microcytosis, +/- anaemia
• Beta nought/beta nought
– microcytosis, red cell changes, transfusion
dependent
• 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
thalassaemia
Normal
One gene deletion
(alpha/alpha +)
Gene deletions in alpha
thalassaemia
Two gene deletion
(alpha +/alpha +)
Two gene deletion
(alpha/alpha 0)
Gene deletions in alpha
thalassaemia
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
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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