haemoglobinopathies

Question 1

what are they?

Answer 1

Hereditary conditions affecting globin chain synthesis
o Hundreds of mutations
o Behave as autosomal recessive disorders

Question 2

what are the 2 main groups of them?

Answer 2

Thalassaemias, decreased rate of globin chain synthesis

Structural haemoglobin variants – normal production of abnormal globin chain – variant haemoglobin e.g. HbS

Question 3

what is a thalassaemia?

Answer 3

• Reduced globin chain synthesis resulting in impaired haemoglobin production
o Alpha thalassaemia – alpha chains affected
o Beta thalassaemia – beta chains affected

Question 4

how do thalassaemias present?

Answer 4

inadequate Hb production - microcytic hypchromic anaemia
if severe:
- unbalanced accumulation of globin chains which are toxic to the cell
- ineffective erythropoiesis
- haemolysis

Question 5

how are thalassaemias diagnosed?

Answer 5

Simple things first!
o FBC; Hb, red cell indices
o Blood film
o Ethnic origin
High performance liquid chromatography (HPLC) or electrophoresis to quantify haemoglobins present
o Identifies abnormal haemoglobins eg HbS
o Raised HbA2 diagnostic of beta thal trait

Question 6

antenatal screening for thalassaemias

Answer 6

antenatal screening to identify carrier parents - now standard
family origin questionnaire and FBC
further testing if high-risk area or abnormal RBC indices
couples at risk are counselled
prenatal diagnosis is offered where appropriate
newborn screening programme is also in place

Question 7

what is an alpha thalassaemia

Answer 7

• Mutations affecting the alpha globin chain synthesis
• Unaffected individuals have 4 normal alpha genes
• Occurs because of deletion in the alpha genes from chromosome 16. Results in reduced α+ or absent α0 alpha chain synthesis from that chromosome
• Alpha chains present in HbA, HbA2 and HbF therefore all are affected

Question 8

what are the classifications of alpha thalassemia?

Answer 8

unaffected = 4 normal α genes (αα/αα)
α thalassaemia trait
HbH disease
Hb Barts hydrops fetalis;

Question 9

what is α thalassaemia trait

Answer 9

1 or 2 alpha genes missing, asymptomatic carrier state, microcytic, hypochromic red cells but normal ferritin

Question 10

how does α thalassaemia trait present

Answer 10

o Asymptomatic carrier state, no Rx needed
o Microcytic, hypochromic red cells with mild anaemia
o Important to distinguish from iron deficiency (but ferritin will be normal)

Question 11

what is HbH disease

Answer 11

only one alpha gene left (–/-α ), moderate to severe anaemia – anaemia with very low MCV and MCH

Question 12

presentation of HbH disease

Answer 12

o Excess β chains form tetramers (β4) called HbH
o Red cell inclusions of HbH can be seen with special stains
o Common in SE Asia
o Jaundice, splenomegaly, may need transfusion

Question 13

what is Hb Barts hydrops fetalis

Answer 13

no functional α genes (–/–) , incompatible with life
most severe form of alpha thalassaemia
No alpha chains to bind to so tetramers of Hb Barts (γ4) and HbH (β4) produced

Question 14

who gets Hb Barts hydrops fetalis

Answer 14

o Possible risk if both parents from SE Asia where α0 (–) thal trait prevalent
o Antenatal screening to avoid risk

Question 15

clinical features of Hb Barts hydrops fetalis

Answer 15

o	Profound anaemia 
o	Cardiac failure 
o	Growth retardation 
o	Severe hepatosplenomegaly 
o	Skeletal and cardiovascular abnormalities 
o	Almost all die in utero

Question 16

what are beta thalassaemias

Answer 16

• Disorder of beta chain synthesis
• Usually caused by point mutations
• Reduced ( β+), or absent ( β0 ) beta chain production depending on the mutation
• Only β chains and hence only HbA (α2β2) affected

Question 17

what are the classifications of beta thalassaemias?

Answer 17

β thalassaemia trait (β+/β or β0/β)
β thalassaemia intermedia (β+/β+ or β0/β+)
β thalassaemia major (β0/β0)

Question 18

how does β thalassaemia trait (β+/β or β0/β) present?

Answer 18

asymptomatic
no/mid anaemia
low MCV/MCH
raised HbA2 diagnostic

Question 19

how does β thalassaemia intermedia (β+/β+ or β0/β+) present?

Answer 19

moderate severity requiring occasional transfusion (similar phenotype to HbH disease)

Question 20

how does β thalassaemia major (β0/β0) present?

Answer 20

o Severe, lifelong transfusion dependency
o Presents aged 6-24 months (as HbF falls)
o Pallor, failure to thrive
o Extramedullary haematopoiesis causing hepatosplenomegaly, skeletal changed, organ damage
o Haemoglobin analysis – mainly HbF, no HbA

Question 21

how is β thalassaemia major (β0/β0) managed?

Answer 21

regular transfusion programme to maintain Bh at 95-105g/l (suppresses ineffective erythropoiesis, inhibits over-absorption of iron)
allows for normal growth and development
iron overload from transfusion becomes main cause of mortality
bone marrow transplant may be an option if carried out before complications develop