Haemaglobinopathies Flashcards
what is the structure of haemoglobin
Tetramer made up of 2 alpha globin like chains and 2 beta globin like chains
One haem group attached to each globin chain = 4 haem groups
what are the major forms of haemoglobin
HbA (two alpha chains and two beta chains, α2β2 )
HbA2 (two alpha and two delta, α2δ2)
HbF (two alpha and two gamma, α2γ2)
what type of haemoglobin is most common
HbA
what chromosome is the alpha like genes on
chromosome 16
how many alpha genes are present per chromosome
2
i.e. 4 per cell
what chromosome is the beta like genes on
chromosome 11
how many beta genes are present per chromosome
1
i.e. 2 per cell
expression of globin genes stays the same throughout life - true or false
false
- changes during embryonic life and childhood
what are haemoglobinopathies
Hereditary conditions affecting globin chain synthesis
behave as autosomal recessive disorders
what are the 2 main groups of haemoglobinopathies
1 - Thalassaemias; decreased rate of globin chain synthesis
2 - Structural haemoglobin variants; normal production of structurally abnormal globin chain
what is thalassaemias
Hereditary disorders of globin chain synthesis resulting in impaired haemoglobin production
what are the 2 forms of thalassaemia
Alpha thalassaemia; α chains affected
Beta thalassaemia; β chains affected
what type of anaemia is seen in thalassaemia
microcytic hypochromic
what goes wrong in thalassaemia
Inadequate Hb production → microcytic hypochromic anaemia
Unbalanced accumulation of globin chains → ineffective erythropoiesis and haemolysis
what happens in alpha thalassaemia to cause Sx
Mutations affecting α globin chain synthesis
Reduced or absent synthesis of α chains
Results from deletion of one (-α) or both (- -) alpha genes from ch 16
why does alpha thalassaemia tend to present more severely
alpha chains present in all adult forms of Hb therefore HbA, HbA2 and HbF all affected
what are the types of alpha thalassaemia
Unaffected individuals have 4 normal α genes (αα/αα)
Alpha thalassaemia trait; one or two genes missing (-α/αα), (–/αα) or (-α/-α)
HbH disease; only one alpha gene left (–/-α )
Hb Barts hydrops fetalis; no functional α genes (–/–)
what are features of Alpha thalassaemia trait
Usually (–/αα) or (-α/-α)
Asymptomatic, no Rx needed
Microcytic, hypochromic red cells with mild anaemia
what can alpha thalassaemia trait be mistaken for and how can you tell it apart
iron deficiency anaemia
in trait = ferritin normal, RBC raised
what is HbH disease
Severe form of α thalassaemia
Only one α gene per cell (–/-α )
α chain production < 30% of normal
what blood results are seen in HbH disease
anaemia with very low MCV and MCH
why is it called HbH disease
Excess β chains form tetramers (β4) called HbH which cannot carry oxygen
Red cell inclusions (HbH bodies) can be seen with special stains
what are Sx of HbH disease
From mild anaemia to transfusion dependant
Splenomegaly due to extramedullary haematopoiesis
Jaundice due to
- Haemolysis
- Ineffective erythropoiesis
what is the Tx of HbH disease
Severe cases splenectomy+/-transfusion
where is HbH disease prevalent
S.E. Asia, Middle East and the Mediterranean
what is the most severe form of alpha thalassaemia
Hb Bart’s hydrops fetalis syndrome
what happens in Hb Bart’s hydrops fetalis syndrome
No α genes inherited from either parent (–/–)
Minimal or no α chain production →HbA can’t be made
what is the majority Hb at birth
Hb Barts (γ4) and HbH (β4)
what are Sx of Hb Bart’s hydrops fetalis syndrome
Severe anaemia
Cardiac failure, oedema
Growth retardation
Severe hepatosplenomegaly
Skeletal and cardiovascular abnormalities
Most die in utero
what is beta thalassaemia
Disorder of beta chain synthesis
Reduced, or absent beta chain production
Only β chains and hence only HbA (α2β2) affected
what causes beta thalassaemia
usually a point mutation
what are the 3 forms of beta thalassaemia
beta thalassaemia trait
beta thalassaemia intermedia
beta thalassaemia major
what are the features of beta thalassaemia trait
asymptomatic
no/mild anaemia
low MCV/MCH
what are the features of beta thalassaemia intermedia
moderate severity requiring occasional transfusion
what are the features of beta thalassaemia major
severe, lifelong transfusion dependency
what are lab features of beta thalassaemia major
severe anaemia
Reticulocytosis
very low MCV/MCH
Film; microcytosis, hypochromia, anisopoikilocytosis and target cells
what is seen on HPLC in beta thalassaemia major
mainly HbF present
small amounts of HbA
what are features of beta thelassaemia major
Presents aged 6-24 months
Failure to thrive
Pallor
Extramedullary haematopoiesis causing:
- Hepatosplenomegaly
- Skeletal changes
- Organ damage
what are complications of extra medullary haematopoiesis
can cause spinal cord compression
what is Mx of beta thal major
Regular transfusion programme to maintain Hb at 95-105g/l
- suppress ineffective erythropoiesis
- inhibit over-absorption of iron
Allows for relatively normal growth and development
what can tx cause in beta thal major
iron overload > can lead to mortality
what are consequences of iron overload
Endocrine dysfunction
- Impaired growth and pubertal development
- Diabetes
- Osteoporosis
Cardiac disease
- Cardiomyopathy
- Arrhythmias
Liver disease
- Cirrhosis
- Hepatocellular cancer
what is the Mx of iron overload
Desferrioxamine - iron chelating drug
how does desferrioxamine work
Chelators bind to iron, complexes formed are excreted in urine or stool
what does iron overload make you susceptible too
bacterial infection
how is diagnosis of thalassaemia made
exclude iron deficiency first
Blood film; hypochromia, target cells, anisopoikilocytosis
HPLC: Raised HbA2 diagnostic of beta thal trait. Will be normal in alpha thal trait so DNA testing needed to confirm
what is the pathophysiology of sickle cell disease
Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine
Alters the structure of the resulting Hb→ HbS
HbS polymerises if exposed to low oxygen levels for a prolonged period
This distorts the red cell, damaging the RBC membrane
what are the two from of sickle cell disease
sickle trait (HbAS) sickle cell anaemia (HbSS)
what are features of sickle trait
One normal, one abnormal β gene (β/βs)
Asymptomatic carrier state
what are Sx of sickle trait
Few clinical features as HbS level too low to polymerise
May sickle in severe hypoxia eg high altitude, under anaesthesia
what are lab results of sickle trait
Blood film normal
Mainly HbA, HbS <50%
what are features of sickle cell anaemia
Two abnormal β genes (βs/βs) autosomal recessive
HbS > 80%, no HbA
what is sickle crisis
Episodes of tissue infarction due to vascular occlusion
what are symptoms of sickle cell anaemia
Symptoms depend on site and severity
- Digits (dactylitis), bone marrow, lung, spleen, CNS
- Pain may be extremely severe
Hyposplenism (due to repeated splenic infarcts)
Chronic haemolysis
what is uncommon in sickle cell anaemia
iron overload
what are precipitants of sickle crisis
Hypoxia (can be caused by chest infection)
Dehydration (makes HbS more likely to polymerise)
Infection
Cold exposure
Stress/fatigue
what is the Tx of a sickle crisis
Opiate analgesia Hydration Rest Oxygen Antibiotics if evidence of infection
Red cell exchange transfusion in severe crises eg chest crisis or neurological symptoms
(venesect»_space; transfuse)
what are long term effects of sickle cell anaemia
Impaired growth
Risk of sepsis
Risk of organ damage
- pulmonary hypertension
- renal disease
- avascular necrosis
- leg ulcers
- stroke
what is long term treatment of sickle cell anaemia
splenectomy
folic acid supplementation
hydroxycarbamide
what would a patient need if they had a splenectomy
prophylactic penicillin
vaccination; pneumococcus, meningococcus, haemophilus
why does a patient with sickle cell need folic acid supplementation
↑ RBC turnover so ↑demand
how does hydroxycarbamide work
reduces severity of disease by inducing HbF production
what is sickle cell disease
heterozygosity for HbS and another β chain mutation
e.g. HbS/β thalassaemia; mild if β+, severe if β0
