Haemaglobinopathies Flashcards
What is Hb made up of?
4 subunit proteins which each have an haem prosthetic group containing iron, subunits are alpha beta and gamma
What is adult Hb made up of?
2 x alpha
2 x beta
What are the genes for the alpha subunit?
2 genes on chromosome 16
What are the genes for the beta subunit?
5 genes on chromosome 11
Why is fetal haemoglobin more efficient than adult Hb? What is the significance of this?
Fetal Hb can bind oxygen more efficiently than adult Hb hence has a greater affinity for oxygen
Allows transfer of oxygen from mother to fetus
Fetal myoglobin has even higher affinity for oxygen so molecules pass from fetal Hb for storage and use in muscle
What is the first form of Hb produced in the embryonic yolk sac? When does this happen?
zeta 2 epsilon 2 (Hb Gower- 1)
up to 6 weeks
has a very high oxygen affinity
What happens to fetal Hb after 6 weeks of gestation?
zeta gene is switched off and fetal Hb (HbF) is made up of 2 alpha and 2 gamma subunits, made in the liver and spleen
Compare HbF with zeta 2 epsilon 2?
HbF has a lower affinity for oxygen but still higher than maternal Hb
When does HbA replace HbF?
3-6 months after birth
What are the normal Hb proportions in a neonate compared to an adult?
HbA - 10% vs 96-97%
HbA2 - <1% vs 2-3.5%
HbF - 90% vs. <1%
What is thalassaemia?
genetic defect resulting in inadequate quantities of one or other of the subunits making up Hb
What is the difference in types of thalassaemia?
alpha thalassaemia - one or more of the alpha genes on chromosome 16 is deleted or faulty
beta thalassaemia - point mutation on chromosome 11
When does alpha thalassemia manifest?
Immediately at birth
What does the severity of alpha thalassaemia depend on?
Number of gene alleles defective/missing
How does alpha thalassaemia minima present?
one alpha gene defective, minimal effect on Hb synthesis, 3 alpha globin genes enough to permit normal Hb production, no clinical symptoms, silent carriers, slightly reduced MCV and MCHb
How does alpha thalassemia minor present?
2 alpha genes defective,2 permit nearly normal RBC production, mild microcytic hypochromic anaemia, can be mistaken for iron deficiency anaemia and treated inappropriately with iron
How does haemoglobin H disease present?
3 alpha genes defective, 2 unstable Hb present (haemoglobin Barts and haemoglobin H) which have higher affinity for oxygen than hormal Hb, poor release of oxygen in tissues, microcytic hypochromic anaemia
How does four alpha genes defected present?
fetus cannot live once outside uterus, may not survive gestation, most stillborn with hydrops fetalis, those born alive die shortly after birth, edematous, little circulating Hb, all Hb is Hb Barts
What is the inheritance pattern of beta thalassaemia?
autosomal recessive
What are the 2 main genotypes for beta thalassemia?
Heterozygous - thalassemia trait, beta thalassemia minor
Homozygous - beta thalassemia major
(+ beta thalassemia intermedia, both beta globin genes mutated but still able to make some beta chains)
When does beta thalassemia manifest itself?
When the switch from gamma to beta subunits occur from HbF to HbA several months after birth
What is the compensatory mechanism for beta thalassemia?
More gamma and alpha chain synthesis resulting in increased HbF and A2 levels
How does beta thalassemia lead to severe hypochromic microcytic anaemia?
Loss of beta globin synthesis, excess alpha produced in developing erythroblasts in marrow, alpha tetramers unstable and precipitate on erythrocyte membrane, intra-medullary destruction of developing erythroblasts = erythroid hyperplasmia = ineffective erythropoiesis = severe hypochromic microcytic anaemia
What are the effects of untreated beta thalassemia major?
- hypochromic microcytic anaemia
- bone marrow expansion, splenomegaly
- bone deformity, extramedullary erythropoietic masses
- failure to thrive from 6 months of age
- heart failure and death by age 3-4
- facial bone abnormalities (skull bossing, maxilla hypertrophy, upper teeth exposed, nasal bridge depression, periorbital puffiness)
- B thalassemia major: pallor, short stature, massive hepatosplenomegaly, wasted limbs
How do you treat thalassemia major?
- regular transfusions (but get iron overload)
- iron chelation therapy
- splenectomy
- allogeneic bone marrow transplant
- HbF modulating agents under trial
- gene therapy
How is iron deficiency anaemia distinguished from thalassaemia?
thalassaemia - MCV very low and normal TIBC normal (total iron binding capacity), normal serum iron and ferritin
iron deficiency - MCV little bit low and higher TIBC
Why is iron overload bad?
Excess haemolysis means haem that has been removed from RBCs will remain as free iron in the blood instead of being attached to ferritin, the Fenton reaction then occurs producing hydroxyl radicals oxidising and damaging tissues
What is the fenton reaction?
responsible for cirrhosis, diabetes, glandular dysfunction
hydrogen peroxide + Fe2+-> Fe3+ + OH- + hydroxyl radical
How is the fenton reaction prevented?
By iron chelating compounds which bind free iron
What are the 3 iron chelation therapies?
1) Desferoxamine
2) Deferiprone
3) Deferasirox
What is desferoxamine?
chelation enhanced with ascorbate
toxicity with higher doses (diarrhoea, vomiting, fever, hearing loss, eye problems)
infusion 5-7 days per week
What is deferiprone?
oral iron chelator
75-100mg/kg/day
neutropenia may occur
not for pregnancy use
What is deferasirox?
once daily oral iron chelator
can cause GI bleeding and kidney/liver failure
How does sickle cell disease occur?
Mutant form of beta Hb subunit causes RBCs to become sickle shaped, cells obstruct capillaries and restrict blood flow to organ = ischemia, pain, organ damage
What are some signs of SC disease?
haemolytic anaemia
microvascular occlusion - rigid SC adhere to endothelium and interact with WBCs and vessel wall so you get NO depletion
- large vessel damage
What is the pathophysiology of SC?
Glutamic acid to valine
GAG-GTG
substitution at codon 6 of beta globin chain
produces HbS abnormal type
In deox conditions HbS may crystallise/precipitate so RBCs distorted into sickle shape, fragile, destroyed = anaemia
SC have decreased survival time and occlude capillaries = ischemia and infarction of organs downstream of blockage
What are the major clinical consequences of SC disease?
anaemia
increased infection susceptibility
vaso-occlusive crises
chronic tissue damage
How is SC managed?
infection for prophylaxis analgesics for painful crises education, lifestyle, avoid precipitants transfusions for acute/chronic complications hydroxyurea (increases HbF) bone marrow transplantation
How is carrier detection screening done?
- enables identification of couples at risk of producing offspring
- individuals/couples then counselled about genetic risk and consequences of having child who is affected
- easily done with simple FBC and haemoglobinopathy screen
- can be done early in pregnancy, better before
How is neonatal screening done?
- infancy is high risk time for SC
- diagnosis soon after birth reduces morbidity and mortality
- enables treatment: antibiotic prophylaxis, parental education, early intervention
- cord blood or heel prick sample used
