Haemoglobinopathies Flashcards
What are the functions of the globin chains in Hb?
keep haem soluble and protect from oxidation
Which chromosome are alpha globin chains found on?
16
How many alpha genes are there per chromosome?
2
Which chromosome are beta like genes found on?
11
How many beta genes per chromosome?
1
How are genes on the chromsomes coding for globin arrranged?
in order of expression (eg, from 5 to 3 fetal to adult)
By what age have adult levels of Hb been reached?
6-12 months of age
What are haemoglobinopathies?
hereditary conditions affecting globin chain synthesis
How are haemogloinopatheis generally inherited?
autosomal recessive
What are the 2 main groups of haemoglobinopathy?
thalassaemias; structual haemoglobin variants
What happens in thalassaemias?
decreased rate of globin chain synthesis restuling in impaired Hb production
What are the two groups of thalassaemia?
alpha and beta
What type of anaemia is seen with thalassamia?
microcytic hypochromic anaemia (inadequate Hb production)
Why is there haemolysis in thalassaemia?
unbalanced accumulation of globin chains is toxic resulting in ineffective erythropoiesis
What has allowed thalassaemia to flourish?
malaria
What is a+?
deletion of one alpha gene from chromsome 16
Waht is a0?
both alpha genes have been lost from chromsome 16
what types of Hb are affected in alpha thalassaemia?
all forms- HbA; HbA2 and HbF as all contain alpha chains
What is the alpha thal trait?
one or two genes missing out of 4
What is HbH disease?
only one alpha gene left (a0/a+)
What is Hb Barts hydrops fetalis?
no functional a genes
What is seen with alpha thal trait?
asymptomatic and no rx needed- mild anaemia
What is seen with HbH disease?
anaemia with very low MCV and MCH
What is HbH?
excess beta chains forming a tetramer called HbH- cant carry oxygen
What are the clinical features of HbH?
mod anaemia to transfusion dependent; splenomegaly; jaundice
Where is HbH commonest globally?
SE Asia; middle east and mediterranean
What is the majority of Hb seen at birth with Hb Barts hydrops fetalis syndrome?
Hb Barts (gamma tetramer) and HbH
What are the clinical features of Hb Barts hydrops fetalis syndrome?
almost all die in utero- severe anaemia; cardiac failure; growth retardation; severe hepatosplenomegaly; SK and CVS abnormalities
What is the difference between the mutations causing beta and alpha thalassaemias?
alpha is caused by deletions whereas beta are usually point mutations
What type of Hb is affected in beta thalassaemia?
HbA
What is seen with beta thalassaemia trait?
(b+/b or b0/b) asymptomatic- low MCV/MCH; raised HbA2
What is beta thalassaemia intermedia?
b+/b+ or b0/b+
moderate requiring occasional tranfusion
What is beta thalassaemia major?
b0/b0 - svere, lifelong transfusion dependency
When does beta thalassaemia major present?
6-24 months
What does extramedullary haematompoisis cause?
hepatosplenomegaly; thickening of skull; organ damage; cord compression
Why is regular transfusion required in beta thal major?
suppress ineffective erythropoiesis and inhibit over-absoprtion of iron
Waht is the main cause of mrotality with treated beta thal major?
iron overload from transufion
What are the consequences of iron overload?
impaired grwoth and puberty; DM; OP; cardiomyopathy; arrhythmias; cirrhosis; hepatocellular cancer; increased risk of sepsis
How is iron overload managed?
iron chelation- desferrioxamine
what is the mutation in sickling disorders?
point mutation in the beta globin gene substituting glutamine to valine producing bS
What is the problem with HbS?
polymerises if exposed to low oxygen for a prolonged period which distorts the red cell damaging the RBC membraen
Waht is the sickle trait?
one normal, one abnormal beta geen
Why is there few clinical features of sickle trait?
HbS level too low to polymerise but may in severe hypoxia eg high altitude or under anaesthesia
What is the inheritance of sickle cell anaemia?
autosomal recessive
What is a sickle crisis?
episode of tissue infarction due to vascular occlusion
Why do patients with sickle cell anaemia have chronic haemolysis?
shortened RBC lifespan
Why do patients with HbSS have hyposplenism?
repeated splenic infarcts
What is sickle cell disease?
compound heterozygosity for HbS and another beta chain mutation
What is HbSC disease?
milder but increased risk of thrombosis
What are the precipitatns of sickle crisis?
hypoxia; dehydration; infection; cold exposure; stress/fatigue
What is the treatment of sickle crisis?
opiate; hydration; rest; oxygen; abx if infection; red cell exchange transfusion if severe
What are the longterm effects of sickle cell anaemia?
impaired grwoth; pulmonary hypertension; renal disease; avascular necrosis; leg ulcers; stroke
What is the long term mx of sickle cell anaemia?
hyposplenism so need to reduce infection risk; folic acid supplementation; hydroxycarbamide
what is the function of hydroxycarbamide?
reduce severity of disease by inducing HbF production
How can you quantify haemoglobins present?
high performance liquid chromatography or gel electrophoresis
What does raised HbA2 on HPLC suggest?
beta thal trait
What is the problem with HPLC in alpha thal trait?
is normal so DNA testing needed
