Haemoglobin structure

Alpha-type

Alpha-type

Beta-type

Beta-type

Haem

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

• 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 thalassaemiaUsually due to point mutation

Effect on Betachain productionvariable

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– 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