Haemoglobinopathies Flashcards
structure of haemoglobin?
tetramer made of 2 alpha globin like chains and 2 beta globin like chains
one haem group attached to each globin chain
what do globin chains do?
keep haem soluble and protect haem from oxidation
what are the major forms of Hb?
HbA (2 alpha chains and 2 beta chains)
HbA2 (2 alpha and 2 delta chains)
HbF (2 alpha and 2 gamma chains)
which Hb is the major form present in adults?
HbA = 97% HbA2 = 2.5% HbF = 0-0.5%
genetic control of globin chain production?
alpha like genes = chromosome 16 (2 alpha genes per chromosome, 4 per cell)
beta-like genes are on chromosome 11 (one beta gene per chromosome, 2 per cell)
expression of globin genes changes during embryonic life and childhood
when does amount of Hb reach adult levels? clinical implication of this?
6-12 months of age
beta chain problems wont manifest until then
what are haemoglobinopathies?
hereditary conditions affecting globin chain synthesis
mutations behave as autosomal recessive disorders
2 main groups of haemoglobinopathies?
thalassaemias (decreased rate of globin chain synthesis)
structural haemoglobin variants (normal production of abnormal globin chain - cariant Hb such as HbS)
what is thalassaemia and what are the types?
reduced globin chain synthesis resulting in impaired haemoglobin production
- alpha thalassaemia (alpha chains affected)
- beta thalassaemia (beta chains affected)
consequences of thalassaemia?
inadequate Hb production leading to microcytic hypochromatic anaemia
if severe can lead to: unbalanced accumulation of globin chains (toxic to cell), haemolysis and ineffective erythropoiesis
where is thalassaemia most common?
malaria endemic areas
how does alpha thalassaemia occur?
depletion of one alpha or both alpha genes from chromosome 16
results in reduced (alpha+) or absent (alpha0) alpha chain synthesis from that chromosome
all types of Hb are affected as all types have alpha chains
classifications of alpha thalassaemia?
based on number of alpha genes
unaffected = 4 normal alpha genes
alpha thalassaemia trait = 1 or 2 alpha genes missing
HbH disease = only one alpha gene left
Hb Barts hydrops fetalis = no functional alpha genes
describe alpha thalassaemia trait?
1 or 2 alpha genes missing asymptomatic carrier no treatment needed causes microcytic hypochromatic red cells with mild anaemia low iron but normal ferritin
what is HbH disease?
more severe form of alpha thalassaemia with only 1 working alpha gene per cell
anaemia with very low MCV and MCH
how is HbH inherited?
…
what causes HbH disease?
excess beta chains form tetramers (beta4) called HbH
red cell inclusions of HbH can be seen with special stains
how might HbH present?
jaundice
splenomegaly
what is Hb Barts Hydrops Foetalis syndrome?
most severe form of alpha thalassaemia
no alpha genes inherited from either parent
minimal/no alpha chain production (therefore HbF and HbA cant be made)
no alpha chains to bind to so tetramers of Hb barts (gamma4) and HbH (beta4) produced
clinical features of Hb Barts Hydrops Foetalis syndrome?
profound anaemia cardiac failure growth retardation severe hepatosplenomegaly skeletal and cardio abnormalities almost all die in utero
blood film in Hb barts hydrops foetalis syndrome?
numerous nucleated RBCs in peripheral blood
what causes beta thalassaemia?
disorder of beta chain synthesis usually caused by point mutations
reduced (Beta+) or absent (Beta0) beta chain production depending on mutation
only beta chains affected so only HbA affected
classification of beta thalassaemia?
based on clinical severity
beta thalassaemia trait
beta thalassaemia intermedia
beta thalassaemia major
what is beta thalassaemia trait?
Beta+/beta or beta0/beta
asymptomatic, no/mild anaemia, low MCV/MCH, raised HbA2 is diagnostic
what is beta thalassaemia intermedia?
beta+/beta+ or Beta0/beta+
moderate severity requiring occasional transfusion (similar phenotype to HbH disease)
what is beta thalassaemia major?
beta0/beta0
severe, lifelong transfusion dependency
clinical features of beta thalassaemia major?
presents aged 6-24 months (as HbF falls)
pallor and failure to thrive
extramedullary haematopoiesis causing hepatosplenomegaly, skeletal changes and organ damage
Hb analysis in beta thalassaemia major?
mainly HbF
no HbA
complications of extramedullary haematopoiesis?
cord compression
how is beta thalassaemia major managed?
regular transfusion programme to maintain Hb at 95-105g/L (suppresses ineffective erythropoiesis, inhibits over-absorption of iron)
bone marrow transplant may be an option if carried out before complications develop
main cause of mortality in treated beta thalassaemia major?
iron overload
conseqences of iron overload?
endocrine dysfunction (impaired growth and puberty development, diabetes, osteoporosis) cardiac disease (cardiomyopathy, arrhythmias) liver disease (cirrhosis, hepatocellular cancer)
how is iron overload managed?
cant do venesection as already anaemic
iron chelating drugs (e.g desferrioxamine) bind to iron which is then excreted
why does iron overload occur in treatment of beta thalassaemia major?
250mg of iron per unit of packed red cells
chronic anaemia drives increased iron absorption so a lot of the iron is absorbed
other complications of transfusion?
viral infection alloantibodies (hard to crossmatch)
transfusion reactions
increased risk of sepsis (bacteria like iron)
pathophysiology of sickle cell disease?
point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine producing betaS
this alters the structure of the resulting Hb > HbS
HbS polymerises if exposed to low oxygen levels for a prolonged period
polymerised HbS distorts the RBC, damaging the RBC membrane
describe sickle cell trait
one normal, one abnormal beta gene (beta/betaS)
asymptomatic carrier state with few clinical features as HbS level is too low to polymerise
can happen in severe hypoxia (e.g altitude)
normal blood film
Hb components in sickle cell trait?
mainly HbA (<50% HbS)
describe sickle cell anaemia?
two abnormal beta genes (betaS/betaS)
episodes of tissue infarction due to vascular occlusion (sickle crisis)
clinical features of sickle cell anaemia?
symptoms depend in site and severity of infarction in sickle crisus
pain may be severely severe
chronic haemolysis (short RBC lifespan)
sequestration of sickled RBCs in liver and spleen
hyposplenism due to repeated splenic infarcts
other sickling disorders (sickle cell disease)
compound heterozygosity for HbS and another beta chain mutation, e.g
- HbS/Beta thalassaemia
- HbSC disease (milder but increased risk of thrombosis)
what is sickle crisis?
sickle vaso-occlusion resulting in tissue ischaemia and pain
what can precipitate a sickle crisis?
hypoxia dehydration infection cold exposure stress/fatigue
how is a sickle crisis managed?
opiate analgesia hydration rest oxygen antibiotics if infection present red cell exchange transfusion (alternating venesection and transfusion) in severe crisis (e.g lung crisis or stroke)
how are sickle disorders managed long term?
hyposplenism (reduce risk of infection) via prophylactic penicillin and pneumococcus/meningococcus/haemophilus vaccination
folic acid supplementation (increased RBC turnover so increased demand)
hydroxycarbamide can reduce severity of disease by inducing HbF production
regular transfusion in selected cases
how is haemoglobinopathy diagnosed?
bloods (FBC, Hb, RBCs)
blood film
ethnic origin
high performance liquid chromatography (HPLC) or electrophoresis to quantify haemoglobins present
what does HPLC show in haemoglobinopathy?
abnormal haemoglobins (e.g HbS) raised HbA2 = diagnostic of beta thalassaemia trait
HPLC in normal patient?
HbA >80%
HbF <1%
HbA2 1.5-3.5%
commonest monogenic disorders worldwide?
haemoglobinopathies
inheritance of haemoglobinopathies?
AR
carriers unaffected
general definition of thalassaemias?
decreased rate of globin chain synthesis
when should thalassaemia be suspected?
microcytic hypochromic anaemia with normal ferritin
how is beta thalassaemia trait diagnosed?
raised HbA2
main structural haemoglobin problem?
sickle cell anaemia
what causes sickle cell anaemia?
point specific mutation in beta globin gene
causes HbS to polymerise and distort RBC shape and cause vaso-occlusion
why is lifelong penicillin and vaccinations needed in sickle cell anaemia?
hyposplenism
