28. Haemoglobinopathies Flashcards
Describe the structure of heamoglobin.
What is adult Hb made up of?
4 globin subunit proteins/chains, each with an iron containing haeme prosthetic group attached. Precise subunit folding and the way they fit together = important for ability of molecule to carry/release O2.
Two alpha globin subunits and two beta subunits: HbA (a2b2).
Describe the genes for:
a) the alpha subunit oh HbA
b) the beta subunit of HbA
What are the different types of Hb subunit used from embryo to adult?
a) 2 genes for alpha subunit on chromosome 16, thus there are 4 genes in total for the alpha subunit in normal diploid cells. Zeta gene also on chromosome 16 that can produce zeta subunit
b) 5 genes for beta subunit on chromosome 11 (epsilon, gamma A, gamma B, delta and beta) and each prod slightly diff forms of the beta globin
* Several diff Hbs can be prod from diff gene combinations from chromosomes 11 and 16.*
ζ2ε2 (embryo) -> α2γ2 (foetus) -> α2β2 and some α2δ2 (adult)
How does the mammalian foetus obtain O2 from maternal blood throughout pregnancy?
Foetal Hb can bind O2 more efficiently than HbA. The first form of Hb produced in the embryonic yolk sac (up to 6w) is ζ2ε2 and has a v. high affinity for O2. DIff in affinity allows O2 transfer from mum -> foetus. Foetal myoglobin = higher affinity for O2.
After 6w α2γ2 made in liver and spleen replaces ζ2ε2. This form has lower affinity for O2 but still higher than maternal Hb.
What happens to α2γ2 after birth?
What are the percentages of Hb type in an adult compared to neonate?
From 3-6m after birth, HbA (α2β2) replaces the foetal Hb (and some HbA2 (α2δ2)). Production from bone marrow (rather than liver and spleen).
HbA: neonate = 10%, adult = 96-97%
HbA2: neonate = <1%, adult = 2-3.5%
HbF: neonate: 90%, adult = <1%
What is thalassaemia?
Describe the 2 types.
An autosomal recessive genetic defect resulting in inadequate quantities of one or the other of the subunits that make up Hb.
Alpha thalassaemia: 1/more of the alpha genes on chromosome 16 is deleted/faulty
Beta thalassaemia: point mutation on chromosome 11
What are the types of genetic defect that cause thalassaemia?
What does thalassaemia prevalance look like?
Mutation in noncoding introns/promotor/termiantion site/nonsense, or partial/total deletion of a globin gene
Alpha: meditteranean, SE Asia
Alpha thalassaemia is manifested immediately at birth. The severity depends on the number of gene alleles defective or missing. Explain the types.
1) 1 alpha gene defective: alpha thalassaemia minima: minimal effect on Hb synthesis, silent carriers, no symptoms, maybe slightly reduced mean corpuscular vol and mean corpuscular Hb.
2) 2 alpha genes defective: alpha thalassaemia minor: 2 alpha genes permit nearly normal prod of RBC but mild microcytic hyochromic anaemia. Can be mistaken for iron deficiency anaemia.
3) 3 alpha genes defective: haemoglobin H disease. 2 unstable Hbs are present in the blood: Hb Barts (γ4) and HbH (β4). Both have higher affinity for O2 than normal Hb = poor release of O2 in tissues. There is microcytic hypochromic anaemia. Exercise capacity limited.
4) 4 alpha genes defective: foetus can’t live outside uterus and may not survive gestation. Most stillborn with hydrops fetalis, or die shortly after birth. Edematous, little circulting Hb - all Hb present is tetramic γ chains (Hb Barts)
What is the therapy for alpha thalassaemia? (And also for thalassaemia major, alpha and beta)?
Regular transfusions plus iron chelators to prevent hemochromatosis and tissue damage from iron overload. If mild, may not need specific treatment except to manage low Hb. Sometimes iron supplemention useful.
Splenectomy (not usually necessary now)
Allogenic bone marrow transplant (young kids if sibling donor availble)
Future: gene therapy
What are the beta thalassaemia genotypes?
When does beta thalassaemia manifest?
What happens in untreated beta thalassaemia major?
Heterozygous (thalassaemia trait, β thalassaemia minor, β/β+ or β/β0) and homozygous (β thalassaemia major, β0/β0). Also β thalassaemia intermedia which occurs when both of the β globin genes are mutated, but still able to make some β chains (β+/β0 or β+/β+)
Manifests when the switch from γ to β chain synthesis occurs several months after birth. There may be a compensatory increase in γ and δ chain synthesis resulting in increased levels of HbF and A2.
The body’s inability to construct beta-globins leads to no HbA production -> microcytic anaemia.
Describe the pathological effects of beta thalassaemia.
Due to loss of synthesis of β globins, excess alpha globins are produced in developing erythroblasts in marrow. The alpha tetramers are unstable and ppt on the erythrocyte membrane causing intra-medullary destruction of developing erythroblasts, erythroid hyperplasia and ineffective erythropoiesis. Result = severe hypochromic microcytic anaemia.
What are the physical effects of untreated beta thalassaemia major?
- Hypochromic, microcytic anaemia
- Bone marrow expansion, splenomegaly (b/c of marrow damage, liver maintains Hb prod = splenomegaly)
- Bone deformity, extramedullary erythropoietic masses
- Failure to thrive from around 6m
- Heart failure and death by 3-4y
- Facial bone abnormalities
- Wasted limbs and palor
How do you distinguish iron deficiency anaemia from thalassaemia?
Mean Corpuscular Volume decreased MORE in THALASSAEMIA but serum iron and ferritin, TIBC, and bone marrow iron NORMAL.
In IRON DEFICIENCY, MCV, serum iron and ferritin decreased a little, TIBIC increased a little, and bone marrow iron ABSENT.
Why is iron overload bad?
How do iron chelating compounds work?
RBC broken down in spleen and haeme group seperated from globin subunit. Iron removed from haeme and attached to ferritin which binds securely. However, with excess haemolysis some free iron may be released from haeme and enter blood. If hydrogen peroxide present, Fenton reaction occurs:
H2O2 + Fe2+ -> Fe3+ + OH- + OH.
Hydroxyl radicals oxidise and damage tissues: cirrhosis, diabetes, glandular dysfunction and other effects of chronic iron overload.
Chelating compounds bind free iron and prevent Fenton reaction. Fe chelation therapies inc. once daily oral.
What is sickle cell disease?
What are the signs?
Mutation of glutamic acid to valine substitution at codon 6 of β globin chain, producing an abnormal β chain (βs), producing HbS (α2βS2). HbS may ppt or crystalise in blood. RBC becomes sickle-shaped and fragile with decreased survival time: obstruct capillaries and restrict blood flow to organ = ischaemia, pain and damage. (Actin filaments in RBC that hold it in shape are damaged).
Haemolytic anaemia: Hb levels 608g.dL, microvascular occlusion (cells adhere to endothelium, interact with WBC and wall, cause NO depletion), large vessel damage
What are the major clinical consequences of sickle cell disease?
How is sickle cell managed?
Anaemia (Hb may be 6 (norm=12-14)), increased susceptibility to infection, vaso-occlusive crisis, chronic tissue damage (e.g. stroke, avascualar necrosis of hip, retinopathy)
Infection prophylaxis, analgesics for painful crises, education, transfusions for specific acute and chronic complications, hydroxyurea (increases HbF, reduces crises), bone marrow transplantation
