Haemoglobinopathy Flashcards
what is the role of the globin chains
keep haem soluble and protect it from oxidation
what are the major forms of haemoglobin
HbA- 2 alpha and 2 beta (97% of Hb in adults)
HbA2- 2 alpha and 2 delta (important in beta thalassemia, 2.5% in adults )
HbF- 2 alpha and 2 gamma (fetal, 0-0.5% in adults)
what genes control the globin chain production
alpha chromosome 16
beta chromosome 11
when does Hb become adult
reached by 6-12 months of age (beta chains wont manifest till then)
what happen around birth to haemoglobin
increasing beta globin production and dropping gamma production
implications of this mean at birth wont know if problem with beta chain production as still have some gamma synthesis
what are haemoglobinopathies
hereditary conditions affecting globin chain synthesis
what is the inheritance of haemoglobinopathies
behave as autosomal recessive disorders
what are the two main groups of haemoglobinopathies
thalassaemias= decreased rate of globin chain synthesis = impaired Hb production
structural haemoglobin variants= normal production of abnormal globin chain creating variant haemoglobins (e.g. HbS- sickle cells)
what are the types of thalassaemias
alpha= affects alpha chains beta= affects beta chains
what are the consequences of thalassaemias
inadequate Hb production = microcytic hypochromic anaemia
if severe:
-unbalanced accumulation of globin chains (dysfunctional globin toxic to the cell)
-haemolysis
-ineffective erythropoiesis = severe anaemia
=jaundice (due to increased apoptosis and haemolysis)
what is the commonest monogenic disorder
haemoglobinopathies- big cause of mortality worldwide
where is thalassaemia common
in areas of malaria endemic - has driven these mutations as carrier states for thalassaemia makes you less likely to contract malaria
what is the genetics behinds alpha thalasaemia
mutations affecting globin chain synthesis
(unaffected have four normal alpha genes- 2 fro each parent)
affected will have deletion of one or both alpha genes resulting in reduced or absent synthesis from that chromosome which affects alpha chain in AHb, HbA2, HbF
how do you classify the types alpha thalassaemias
based on number of alpha genes
alpha thalassaemia trait= one/ two alpha chains missing
HbH disease= only one alpha gene left
Hb barts hydroos fetalis= no functional alpha genes (not compatible with life)
what are the features of alpha thalassaemia trait
asymptomatic carrier state, no Tx needed
microcytic hypochromic red cells with milkd anaemia
(important to distinguish from iron deficiency- ferritin will be normal here)
what is HbH disease
more severe form of alpha thalassaemia where only one working alpha gene per cell
what are the clinical features of HbH disease
anaemia with very low MCV and MCH (mean corpuscular Hb)
(the more genes you loose the smaller then rbcs are going to be)
jaundice, splenomegaly, may need transfusion
(jaundice because of ineffective erythropoiesis and chronic haemolysis)
common in SE asia
what must happen for HbH disease to be inherited
both parents must be alpha thalassaemia carriers (AR inheritance)
(need to get 3/4 alpha genes affected- one parent will have 2 affected, one will have 1)
what are the features of beta thalassaemia major
severe, lifelong transfusion dependency
presents aged 6-24 months as HbF falls with pallor and failure to thrive
extramedullary haematopoiesis causes: hepatosplenomegaly (extramedullary haematopoiesis), skeletal changes (expansion of bone marrow to try and make rbcs), organ damage
what is the treatment for beta thalassaemia major
transfusion lifelong want to maintain Hb at 95-105 as this: Suppresses ineffective erythropoiesis Inhibits over-absorption of iron allows normal growth and development
bone marrow transplant an option before comps develops (curative)
what is the major cause of death in beta thalassaemia major
iron overload from transfusion
(With a severe anaemia; body will try to increase iron absorption to increase Hb production resulting in iron overload as there is no globin for the haem to bind to)
what are the consequences of iron overload
endocrine dysfunction (impaired growth and pubertal development, diabetes, osteoporosis)
cardiac disease (cardiomyopathy, arrhythmias)
liver disease (cirrhosis, hepatocellular cancer)
what does a rb cell look like in sickle disorders
distorted, not biconcave disc
what can precipitate a sickle crisis
hypoxia dehydration infection cold exposure stress/ fatigue
(can happen with no obvious trigger)
what is the long term management for sickling disorders
MOST IMPORTANT:
as hyposplenism need to reduce risk of infections
-prophylactic penicillin
-vaccination: pneumocccus, meningococcus, haemophilus
folic acid supplementation (increase rbc turnover so increased demand) (as for any chronic anaemia)
hydroxycarbamide (induces HbF production, reduces disease severity)
regular transfusion to prevent stroke in some cases
how are haemoglobinopathies diagnosed
FBC
Hb
red cell indices
blood film (helpful for sickle cell and HbH- alpha thal disease)
(are the micro or macro, are the hypochromic)
how are haemoglobinopathies diagnosed
FBC
Hb
red cell indices
blood film (helpful for sickle cell and HbH- alpha thal disease)
(are the micro or macro, are the hypochromic)
ethnicity important
HPLC or electrophoresis to quantify Hb:
RAISED HbA2 DIAGNOSTIC OF BETA THAL TRAIT
identifies abnormal Hb e.g. HbS
what are Hb analysis like in a normal patient
HbA >80%
HbF >1%
HbA2 1.5-3.5%
what will Hb and MCV be like in sickle cell trait
MCV normal
Hb normal value but HbS
what should you suspect in microcytic hypochromic anaemia with normal ferritin
thalassaemias
how is beta thal trait diagnosed
raised HbA2
what screening is done for haemoglobinopathies
antenatal screening to identify carrier parents
family origin questionaire and FBC
further testing is high risk area/ abnormal RBC indices
counselling
prenatal diagnosis offered
newborn screening
