haemoglobinopathies Flashcards
structure of Hb
tetramet made up of 2 alpha globin like chains + 2 beta globin like chains
1 haem group attached to each globin chain
major forms of haemoglobin
HbA - 2 alpha + 2 beta
HbA2 - 2 alpha + 2 delta
HbF - 2 alpha + 2 gamma chains
(in adults, HbA is major form present)
genetic control of globin chain production
alpha like genes - chromosome 16
beta like genes - on chromosome 11
(expression of globin genes changes during embryonic life + childhood)
relevance of Hb production chances in early life
adult levels reached bt 6-12 months of age so beta chain problems wont manifest until then
haemoglobinopathies
hereditary conditions affecting globin chain sysnthesis
- autosomal recessive disorders
- commonest monogenic disorders
- increasingly frequent in UK due to changing population demographics
2 main groups of haemoglobinopathies
thalassaemia -> decreased rate of globin synthesis
structural haemoglobin variants -> normal production of abnormal globin chain - variant haemoglobin eg HbS
thalassaemias
reduced globin chain synthesis resulting in impaired haemoglobin production
- alpha thalassaemia -> alpha chains affected
- beta thalassaemia - beta chains affected
both = autosomal recessive
overall effects = varying degrees of anaemia
pathophysio of thalassaemias
RBCs are more fragile + break down more easily
spleen acts as sieve to filter
in thalassaemia, the spleen collects all the destroyed RBCs + swells -> resulting in splenomegaly
the bone marrow expands to produce extra RBCs to compensate for chronic anaemia
- this causes susceptibility to fractures + prominent features (forehead + malar eminences)
thalassaemia presentation
microcytic anaemia
fatigue, pallor
jaundice, gallstones
splenomegaly
poor growth + development
pronounced forehead + malar eminences
diagnosis of thalassaemias
FBC - microcytic anaemia
haemoglobin electrophoresis - diagnose globin abnormalities
DNA testing
consequences of thalassaemias
inadequate Hb production -> microcytic hypochromic anaemia
if severe -
- unbalanced accumulation of globin chains which are toxic to the cell
- ineffective erythropoiesis
- haemolysis
general management of thalassaemias
Regular blood transfusions
monitor serum ferritin for iron overload
- limit transfusions + iron chelation (e.g. desferrioxamine)
alpha thalassamia
mutations affecting alpha globin synthesis
normal = aa/aa chromosome 16
AT = -a/aa or –/aa
-> results in reduced or absent alpha chain synthesis from that chromosome
—–> alpha chain present in HbA, HbA2 + HbF therefor all are affected
has to be detected through gene analysis
which chromosome is affected in alpha thalassaemia
chromosome 16
types of alpha thalassamia
trait - 1 or 2 alpha globulins affected
HbH disease - 3 affected
hydrops fetalis, Bart’s hydrops - 4
alpha thalassaemia trait
1 or 2 alpha genes missing
- asymptomatic carrier trait
- microcytic hypochromic
- BUT ferritin + Hb normal
HbH disease
only 1 alpha gene left (–/-a)
- moderate to severe anaemia
- anaemia with v low MCV + MCH
- excess beta chains from tetramets (B4) called HbH
jaundice, splenomegaly
may need transfusion
common in SE asia
Hb Barts hydrops fetalis
no function alpha genes (–/–), incompatible with life
- none inherited from either parent
- minimal or no a chain production -> HbF + HbA cant be made
risk if both parents from SE Asia where alpha thalassaemia trait prevalent
- antenatal screening to avoid risk
Fx = cardiac failure, growth retardation, almost all die in utero
beta thalassaemias
disorder of beta chain synthesis, usually caused by point mutations
- only B chains + hence only HbA affected
beta thalassaemia trait
asymptomatic, no/mild anaemia
disporportionate low MCV
raised HbA2 via HPLC = diagnostic
B thalassaemia intermedia
moderate severity requiring occasional transfuson
- similar phenotype to HbH disease
beta thalassaemia major
severe, lifelong transfusion dependency
presents age 6-24months -> AS HbF FALLS
pallor, failure to thrive
extramedullary haematopoiesis causing
- hepatosplenomegaly, skeletal changes, organ damage
complications of extramedullary haematopoiesis
(like in beta thalassaemia major)
expanding marrow
can lead to cord compression
haemolysis analysis in beta thalassamia major
mainly HbF + HbA2
no HbA
which chromosome is affected in beta thalassaemia major
chromosome 11
management of beta thalassaemia major
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
(Mx = repeated transfusion
this leads to iron overload → organ failure
iron chelation therapy is therefore important (e.g. desferrioxamine)
key complication + cause of mortality in bata thalassaemia major? investigation + management?
iron overload -> organ failure
iron chelation therapy important -> desferrioxamine
–> binds to iron which is then excreted
occurs in thalassaemia as a result of faulty creation of red blood cells, recurrent transfusions + increased absorption of iron in response to anaemia
Ix = monitor serum ferritin levels
iron overload presentation
(similar to haemochromatosis)
fatigue
liver cirrhosis
infertility + impotence
heart failure, arrythmias
arthritis
diabetes
osteoporosis + joint pain
