thalassaemia

Question 1

definition of thalassaemia

Answer 1

group of genetic disorders characterised by reduced globin chain synthesis

unmatched globins precipitate, damaging RBC membranes = haemolysis while still in the marrow

Question 2

aetiology of thalassaemia

Answer 2

autosomal recessive genetic defects

= imbalance of globin chain production and deposition in erythroblasts and erythrocytes

= ineffective erythropoiesis, haemolysis, anaemia, extramedullary haemopoiesis

Question 3

aetiology of a-thalassaemia

Answer 3

reduced synthesis of a-globin chains

chromosome has 4 a-globin genes (aa/aa)

4 gene deletion: Hb Barts (y4 - physiologically useless) and intrauterine death (hydrops fetalis). (–/–)

3 gene deletion: Microcytic hypochromic anaemia, hepatosplenomegaly, leg ulcers, jaundice. HbH (–/-a)

1-2 gene deletion: Microcytic hypochromic red cells; no anaemia. asymptomatic carrier state

Question 4

aetiology of B thalassaemia major (homozygous B-thalassaemia)

Answer 4

B-globin gene point mutations on chr 11 = no or minimal B-chain synthesis (B0 or B+)

Various combinations of mutations are possible (eg B0 /B0 , B+ /B+ , or B+ /B0 ).

Question 5

aetiology of B thalassaemia intermedia

Answer 5

mild defect in B-chain synthesis = microcytic anaemia, reduced a chain synthesis or increased Y chains

Question 6

B thalassaemia trait - heterozygous carrier

Answer 6

B/B+

asymptomatic

mild microcytic anaemia, may worsen in pregnancy

Hb >90, MCV <75fL, HbA2 >3.5%, slightly high HbF

increased red cell count

Question 7

epidemiology of thalassaemia

Answer 7

Worldwide, but more common in the Mediterranean and areas of theMiddle East.

Question 8

sx of thalassaemia

Answer 8

b-Thalassaemia major: Anaemia presenting at 3–6 months (when y-chain synthesis switches to b-chain synthesis). Failure to thrive, prone to infections

a-or b-Thalassaemia trait: May be asymptomatic. Detected on routine blood tests or from a family history.

Question 9

signs of B thalassaemia intermedia/major

Answer 9

pallor

malaise

dyspnoea

mild jaundice

frontal bossing and thalassaemic facies - marrow hyperplasia

hepatosplenomegaly - erythrocyte pooling, extramedullary haemopoiesis

Question 10

ix for thalassaemia

Answer 10

blood - FBC - low Hb, MCV and MCH

iron

blood film

Hb electrophoresis - absent or low HbA and high levels of HbF (fetal Hb, a2 y2)

bone marrow - hypercellular and erythroid hyperplasia

genetic testing - rarely necessary, for specific mutations

skull XR - hair on end appearance - caused by expansion of the marrow into the cortex in B-thalassaemia major

MRI when suspect myocardial siderosis from iron overload

Question 11

thalassaemia blood film

Answer 11

hypochromic,

microcytic anaemia

target cells

nucleated red cells

increased reticulocyte count

Question 13

B thalassaemia intermedia

Answer 13

moderate anaemia, not needing transfusions

may be splenomegaly

causes:

• mild homozygous B thalassaemia mutationes eg B+/B+
• co-inheritance of B thalassaemia trait with another haemoglobinopathy ehg HbC thalassaemia - one parent has HbC trait, other B+
• sickle cell B+ thalassaemia = similar picture to sickle cell anaemia

Question 14

B thalassaemia major

Answer 14

significant abnormalities in both B globin genes

presents in 1st year - severe anaemia and failure to thrive

= extramedullary haematopoiesis = skull bossing and hepatosplenomegaly

haemolysis = hepatosplenomegaly

osteopenia

life long blood transfusions needed = iron overload/desposition seen after 10yrs = endocrine failure (pit, thyroid, pancreas -> dm), liver disease, cardiac toxicity

Question 15

blood film for HbH disease

Answer 15

ie (–/-a)

formation of B4 tetramers (=HbH) due to excess B chains, HbBarts, HbA and HbA2

Hypochromia, microcytosis, target cells, increased polychromasia; red cell fragments may be seen

Question 16

normal Hb

Answer 16

adult Hb (HbA) is a tetramer of 2a and 2B globin chains, each containing a haem group

in 1st yr - adult Hb replace HbF

same mutation can = different disease

perhaps because of co-inheritance, or efficiency of production of HbF, or rate of proteolysis of excess a-globin chains