33 - Haemoglobinopathies Flashcards
What is adult haemoglobin
2 alpha
2 beta
(Haemoglobin A)
How many genes are there for the alpha subunit
2
(4 genes in a normal diploid)
also a zeta gene
What chromosome is the alpha subunit on
16
How many genes are there for the beta subunit and what are they called
5
Epsilon, gamma A, gamma G, delta and beta
Where is the first form of hb made
Embryonic sac
What is the 1st form of hb called and what is it made up of
Hb Gower 1
Zeta x2
Epsilon X2
What other variants of Hb can occur in the early weeks
Gower 2 - A2E2
Portland - Z2E2
What is the form of Hb that is produced after 6 weeks and what is it made up of
Fetal haemoglobin F
HbG
Alpha x2
Gamma x2
This replaces Hb Gower 1
Where is HbG produced
Liver and spleen
After 3-6months of birth what replaces HbG
HbA
What is thalassemia
Genetic defect resulting in inadequate quantities of one or other of the subunits that make up haemoglobin
What is alpha thalassemia
one or more of the alpha genes on chromosome 16 is deleted/faulty
Manifested at birth
Severity depends on no of genes alleles that are defective
One alpha gene defective
Alpha thalassemia minima
Minimal effect on Hb synthesis
No clinical symptoms
Slightly reduced MCV and MCHb
Two alpha genes defective
Alpha thalassemia Minor
Mild microcytic hypochromatic anaemia
Three alpha genes defective
Haemoglobin H disease
2 unstable Hb in blood
Microcytic hypochromatic anaemia
Higher affinity for oxygen so poor release of O2 in tissues
What are the 2 abnormal hb in haemoglobin H disease
Hb Barts - G4
Hb H - B4
Four alpha genes defective
Fetus cannot live outside the uterus - stillborn
Hydrops fetalis
Little circulating Hb
What is the Hb that is present in thalassemia with 4 alpha genes defective
Hb Barts - tetrameric y chain (gamma)
What is beta thalassemia
a point mutation on chromosome 11 in Hb B gene
What inheritance is B thalassemia
Autosomal recessive inheritance
What is the difference between heterozygous and homozygous thalassemia
Beta thalassemia minor
Beta thalassemia major (B0 Cooley’s anaemia)
Beta thalassemia intermedia
Both beta globin genes are mutated but the body can make some
When does B thalassemia manifest
When switch from gamma to beta chain after birth
may be compensatory but you get an increase in HbF and A2
What are the pathological effects of B thalassemia
Excess alpha globins (unstable) which precipitate on erythrocyte membrane
This causes intramedullary destruction of erythroblasts
= SEVERE HYPOCHROMATIC MICROCYTIC ANAEMIA
What are untreated effects of B thalassemia major
- Hypochromatic, microcytic anaemia
- Bone marrow expansion, splenomegaly
- Bone deformity, extramedullary erythropoeitic masses
- Failure to thrive from 6 months of age
- Pallor, short stature, facial bone abnormalities
What are causes of B thalassemia
Mutation in non-coding introns
deletion of globin gene
mutation in promotor, nonsense mutation
Treatment of thalassemia major
Regular transfusions
Iron chelation therapy
Splenectomy
Allogenic bone transplant
Why do you need iron chelation therapy
The regular transfusions can cause iron overload
How do you distinguish iron deficiency anaemia from thalassaemia
Thalassemia has normal serum iron and ferritin
Why is excess iron a bad thing?
Causes excess haemolysis
Free iron can be released into the blood from haem
What is the fenton reaction
If hydrogen peroxide is present
the fenton reaction occurs
hydroxyl radicals are produced = Oxidise and damage biological tissues
What diseases are fenton reaction responsible for
Cirrhosis
Diabetes
glandular dysfunction
What do iron chelating compounds do
Bind free iron and prevent the fenton reaction
What are some examples of iron chelation therapies
Desferoxamine (desferal)
Deferiprone, Ferriprox
Desferasirox, exjade
Desferoxamine (desferal)
Chelation enhanced with ascorbate
Toxicity with higher doses
Deferiprone, Ferriprox
Oral iron chelator
Not to be used in pregnancy
Deferasirox, Exjade
A once daily oral iron chelator
Can cause GI bleeding and kidney or liver failure
What is sickle cell disease
Mutant form of Beta haemoglobin subunits -red cells to become sickle shaped
Why are sickle shaped RBC not good
Obstruct capillaries and restrict blood flow
Causes ischemic pain and organ damage
What are signs of SCD
Haemolytic anaemia: haemoglobin levels in the range of 6–8 g/dL
(usually 12 -17)
Large vessel damage
Microvascular occlusion
What is the mutation in sickle hb (HbS)
Glutamic aid to valine (GAG-GTG)
Substitution at codon 6 of the B globin chain
What is Haemoglobin S made up of
Alpha 2 Bs 2 (abnormal B chain)
When does HbS distort the RBC to sickle shape
When the blood is deoxygenated
Clinical consequences of SCD
Anaemia
Increased susceptibility to infection Vaso-occlusive crises
Chronic tissues damage
Management of SCD
Infection prophylaxis Analgesics for painful crises Education, lifestyle Transfusions Bone marrow transplants
Screening
Blood screen
genetic councelling
Neonatal
Treat with antibiotic prophylaxis
Education
Heel-prick sample
Haemoglobin C
Abnormal B sub unit
Reduced plasticity and flexibility of the erythrocytes (excess haemolysis)
Hb C disease
Haemoglobin E
Abnormal Hb with single point mutation in the B chain Inherited from both parents Mild B-thalassemia symptoms after 3-6 months Mild splenomegaly
Haemoglobin A2
Minor component of Hb
Found in RBC after birth (3%)
2A
2Delta
Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)
X-linked recessive error of metabolism Haemolysis and jaundice in response to triggers Broad beans and oxidative drugs Mediterranean - common protected from malaria
