Haemoglobinopathy Flashcards
Describe the structure of haemoglobin
2 alpha and 2 beta chains
One haem group attached to each
What are the 3 major forms of Hb?
HbA (2 alpha and 2 beta)
HbA2 (2 alpha ad 2 delta)
HbF (fetal haemoglobin)
Alpha and beta genes are on which chromosomes?
Alpha gene is on chromosome 16
Beta gene is on chromosome 11
How many alpha and beta genes are there per chromosome and cell?
2 alpha genes per chromosome - 4 per cell
1 beta gene per chromosome - 2 per cell
When are adult levels of haemoglobin reached in infancy?
At 6-12 months
Before this HbF predominates
Are hereditary conditions affecting globing chain synthesis usually autosomal recessive or autosomal dominant?
Usually autosomal recessive
What are the 2 main groups of haemoglobinopathy?
Thalassaemias
(Decreased rate of globin chain synthesis)
Structural haemoglobin variants
(normal production of structurally abnormal globin chains)
What investigations can be done for haemoglobinopathies?
Genetic screening
FBCs and Hb
HPLC (high performance liquid chromatography)
What is HPLC (high performance liquid chromatography)? What would it show in alpha vs beta that trait?
A test for haemoglobinopathies which involves identifying and quantifying haemoglobins that are present
HPLC is normal in alpha that trait so DNA testing is required
HPLC shows raised HbA2 in beta that trait
Thalassaemias cause what type of anaemia?
Microcytic hypochromic anaemia
What types of Hb are affected in patients with alpha thalassaemia?
Alpha chains are present in all forms of Hb, therefore HbA, HbA2 and HbF are all affected
What is the genetic problem in alpha that trait?
There are 1-2 alpha genes missing
What is the genetic problem in HbH disease?
There is only 1 functional alpha gene
There are not enough alpha chains, so excess B chains form tetramers called HbH which can’t carry oxygen
People from which parts of the world are most likely to be affected by HbH disease?
SE Asia
Middle East
Mediterranean
Why does splenomegaly occur in HbH disease?
Due to extra medullar haematopoiesis
Why does jaundice occur in HbH disease?
Haemolysis and ineffective erythropoiesis
How is HbH disease managed?
There is a big clinical spectrum varying from moderate anaemia to transfusion dependent conditions
Severe cases will need splenectomy +/- transfusions
What is Hb barts hydrops fetalis syndrome?
Most severe form of a thalassaemia in which no a genes are inherited from either parents and there is therefore minimal or no a chain production.
HbA and HbF can’t be made and thus Hb Barts and HbH form the majority of Hb at birth.
How does Hb barts hydrops fettles syndrome present clinically?
Sevre anaemia
Serve hepatosplenomegaly
Cardiac failure
Growth retardation and skeletal abnormalities
ALMOST ALL DIE IN UTERO
What is alpha thalassaemia?
Disorder of alpha chain synthesis
What is beta thalassamia?
Disorder of beta chain synthesis
What kind of mutations most commonly cause beta thalassaemia?
Point mutations
Which form(s) of Hb are affected in beta thalassaemia?
Only HbA is affected
How does B thalassaemia trait present?
Asymptomatic or mild anaemia
Low MCV, raised HbA2
How does B thalassamia intermedia present?
Simiar clinical picture to HbH disease
Moderate severity anaemia requiring ocasional transfusions
When does B thalassaemia major present?
Presents at 6-24 months as HbF falls
What would haemoglobin analysis show in B thalassamia major?
Mainly HbF and minimal HbA
How does B thalassaemia major present?
Failure to thrive
Pallor
Hepatosplenomegaly
Skeletal changes
Organ damage
Risk of cord compression
Regular transfusion can be performed to manage B thalassaemia major. What is the aim for the levels of Hb?
95-105g/L
What are the treatment options for B thalassaemia major?
Regular transfusion
Bone marrow transplant (if carried out before complications develop)
Iron overload can occur as a consequence of regular transfusion in patients with beta thalassaemia major. How does this present?
Similar clinical picture to haemochromatosis but much more severe and early onset
Endocrine dysfunction and diabetes
Impaired growth and pubertal development
Osteoporosis
Cardiac disease
Liver disease
How can ion overload be managed?( e.g due to regular transfusions in patients with b thal major)
NB venesection is not an option if the patient is already anaemic (chronic anaemia drives increased iron absorption so this is why they have been overloaded, but venesection would still worsen the underlying problem)
Iron chelating drugs e.g desferrioxamine
*the chelators bind to iron to form complexes which are excreted in urine or stool
Are sickling disorders autosomal recessive or autosomal dominant?
Autosomal recessive
What is the pathophysiology behind sickling disorders?
Point mutation in B globin gene substitutes glutamine to valine, producing Bs
This alters the structure of Hb, causing HbS
HbS polymerises if it exposed to low oxygen levels for a prolonged period - this distorts the red cell, damaging the membrane
What are the genetics behind sickle trait?
One normal and one abnormal B gene (B/Bs)
Mainly HbA present, HbS is <50%
How does sickle trait present?
Mostly asymptomatic
May sickle in severe hypoxia (e.g high altitude and when under anaesthesia)
Blood film is normal
What are the genetics behind sickle cell anaemia?
Two abnormal B genes (Bs/Bs)
There is no HbA, HbS is >80%
How does sickle cell anaemia present?
SICKLE CRISIS
- Episodes of tissue infarction due to vascular occlusion
- Presents with extreme pain
- May result in impaired growth and end-organ damage
- Symptoms depend on the site affected
What site is most likely to be affected in children presenting with sickle crisis?
Digits - causes dactylitis
How is sickle crisis managed?
Opiates
Oxygen
Antibiotics (if infection is present)
Red cell exchange transfusion (involves venesection and then transfusion of donor blood)
Hydration and rest
Does sickle cell anaemia result in splenomegaly or hyposplenism?
Hyposplenism
This is due to repeated splenic infarcts
What is sickle cell disease?
Compound heterozygosity for HbS and another B chain mutation
E.g HbS/ B thalassaemia
How are sickling disorders managed long-term?
not the management of sickle cell crisis
Folic acid supplements
(there is increased RBC turnover so increased demand)
Hydroxycarbamide (can reduce severity of the disease by inducing HbF production)
Regular transfusion
Management of hyposplenism
How is hyposplenism in sickle cell disease managed?
Prophylactic penicillin lifelong
Vaccinations; pneumococcus, meningococcus and haemophilus
