Haemoglobinopathy Flashcards
What are the major forms of Hb?
HbA (two alpha, two beta) (97%)
HbA2 (two alpha and two delta) (2.5%)
HbF (two alpha and two gamma) (0.5%)
Where are alpha like genes located?
Ch 16 (two alpha genes per chromosome, 4 per cell)
Where are beta like genes located?
Ch 11 (one beta per chromosome, 2 per cell)
In what order are Hb genes arranged?
Expression, from embryo to foetus to adult
When are adult Hb levels reached?
6-12 months
What are haemoglobinopathies?
Hereditary conditions affecting globin chain synthesis
Generally behave as AR disorders
What are the two main groups of haemoglobinopathies?
Thalassaemias: decreased rate of globin chain synthesis
Structural Hb variants: normal production of structurally abnormal globin chain, leading to variant Hb e.g. HbS
What do thalassaemias cause?
Inadequate Hb production, leading to microcytic hypochronic anaemia
Unbalanced accumulation of globin chains, leading to ineffective erythropoiesis and haemolysis
What is the most common monogenic disorder?
Thalassaemia
Why have thalassaemia mutations flourished in malaria endemic areas?
Selective pressure
What is affected in alpha thalassaemia?
Alpha globin chain synthesis- reduced or absent synthesis of a chains
What does alpha thalassaemia result in?
Deletion of one or both alpha genes from Ch 16
Alpha chains present in all adult Hb, therefore all affected
What are the classifications of alpha thalassaemia?
Alpha thal trait: one or two genes missing (-a/aa), (–/aa), or (-a,-a)
HbH disease: only one alpha left (–/-a)
Hb Barts hydrops fetalis: no functional a genes (–/–)
Describe alpha thal trait
Usually (–/aa) or (-a/-a)
Asymptomatic, no Rx needed
Microcytic, hypochromic cells with mild anaemia
Can be mistaken for iron deficiency (but ferritin normal and RBC count raised)
Describe HbH disease
Severe form of a thalassaemia (–/-a)
a chain production <30%
Anaemia with very low MCV and MCH
Excess B chains form tetramers called HbH which cannot carry oxygen
Red cell inclusions (HbH bodies) can be seen with special stains
What are the clinical features of HbH disease?
From mild anaemia to transfusion dependent
Splenomegaly due to extramedullary haematopoiesis
Jaundice: haemolysis, ineffective erythropoiesis
What is the treatment for HbH disease in severe cases?
Splenectomy +- transfusion
Where is HbH disease most common?
SE Asia, Middle East and Mediterranean where (–/aa) is prevalent
Describe Hb Barts hydrops fetalis syndrome
Severest form of a thalassaemia
No a genes inherited (–/–)
Minimal or no a chain production- HbA can’t be made
Hb Barts (gamma4) and HbH (beta4) majority at birth
What are the clinical features of Hb Barts hydrops fetalis syndrome?
Severe anaemia Cardiac failure, oedema Growth retardation Severe hepatosplenomegaly Skeletal and CV abnormalities Most die in utero
Describe beta thalassaemia
Disorder of B chain synthesis
Reduced (B+) or absent (B0) beta chain production
Only B chains and hence only HbA affected
What is B thal usually caused by?
Point mutations
How is B thalassaemia classified?
B thal trait (B+/B or B0/B)
B thal intermedia (B+/B+ or B0/B+)
B thal major (B0/B0)
What are the features of B thal trait?
Asymptomatic
No/mild anaemia, low MCV/MCH
What are the features of B thal intermedia?
Moderate severity requiring occasional transfusion
What are the features of B thal major?
Severe, lifelong transfusion dependency
What are the lab features of B thal major?
Severe anaemia
Reticulocytosis, very low MCV/MCH
Film; microcytosis, hypochromia, anisopoikilocytosis and target cells
HPLC- mainly HbF, small amounts of HbA
What are the clinical features of B thal major?
Presents aged 6-24 months
Failure to thrive
Pallor
Extramedullary haematopoiesis causing- Hepatosplenomegaly, Skeletal changes (cord compression), Organ damage
What is the management of B 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
Bone marrow transplant may be an option if carried out before complications develop
What is the main cause of mortality in treated B thal major?I
Iron overload from transfusion
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 is the management of iron overload?
250mg of iron per unit of red cells
Chronic anaemia → increased absorption of iron from gut
Venesection not feasible – already anaemic!
Iron chelating drugs such as Desferrioxamine necessary
Chelators bind to iron, complexes formed are excreted in urine or stool
What are transfusion related complications of iron overload?
Viral infection - HIV, Hepatitis B and C
Alloantibodies – hard to crossmatch suitable blood
Transfusion reactions
Increased risk of bacterial sepsis
How is thalassaema diagnosed?
Thal trait usually suspected from red cell indices and ethnic origin (exclude iron deficiency first)
Blood film; hypochromia, target cells, anisopoikilocytosis
HPLC: quantifies HbA, HbA2, HbF present, identified abnormal Hb, will be normal in alpha thal trait so DNA testing
What is raised HbA2 diagnostic of?
Beta thal trait
What is the pathophysiology of sickling disorders?
Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine producing S
This alters the structure of the resulting Hb→ HbS (α2βs2)
HbS polymerises if exposed to low oxygen levels for a prolonged period
This distorts the red cell, damaging the RBC membrane
Describe sickle trait (HbAS)
One normal, one abnormal β gene (β/βs)
Asymptomatic carrier state
300 million people worldwide
Few clinical features as HbS level too low to polymerise
May sickle in severe hypoxia eg high altitude, under anaesthesia
Blood film normal
Mainly HbA, HbS <50%
Describe sickle cell anaemia (HbSS)
Two abnormal β genes (βs/βs): autosomal recessive
HbS > 80%, no HbA
Episodes of tissue infarction due to vascular occlusion – sickle crisis
What are the symptoms of sickle cell anaemia?
Depend on site and severity:
Digits (dactylitis), bone marrow, lung, spleen, CNS
Pain may be extremely severe
What are some consequences of sickle cell anaemia?
Chronic haemolysis – shortened RBC lifespan
Sequestration of sickled RBCs in liver and spleen
Hyposplenism due to repeated splenic infarcts
What does sickle cell vaso-occlusion cause?
Tissue ischaemia and severe pain
What are the precipitants of sickle crisis?
Hypoxia Dehydration Infection Cold exposure Stress/fatigue
What is the treatment of a painful 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
What are the long term effects of sickle cell?
Impaired growth
Risk of sepsis
Risk of organ damage: pulmonary HT, renal disease, avascular necrosis, leg ulcers, stroke
What is the long term treatment of sickle cell?
Hyposplenism- reduce the risk of infection: prophylactic penicillin, vaccination; pneumococcus, meningococcus, haemophilis
Folic acid supplementation (increased RBC turnover so increased demand)
Hydroxycarbamide can reduce severity of disease by inducing HbF production
What are some other sickling disorders (sickle cell disease)?
Compound heterozygosity for HbS and another β chain mutation eg
HbS/β thalassaemia; mild if β+, severe if β0
HbSC disease; milder, but increased risk of thrombosis
What screening is carried out for haemoglobinopathies?
Antenatal screening standard: family origin questionnaire and FBC, further testing if from high risk area or abnormal RBC indices
