Haemoglobinopathy

Question 1

What are the major forms of Hb?

Answer 1

HbA (two alpha, two beta) (97%)
HbA2 (two alpha and two delta) (2.5%)
HbF (two alpha and two gamma) (0.5%)

Question 2

Where are alpha like genes located?

Answer 2

Ch 16 (two alpha genes per chromosome, 4 per cell)

Question 3

Where are beta like genes located?

Answer 3

Ch 11 (one beta per chromosome, 2 per cell)

Question 4

In what order are Hb genes arranged?

Answer 4

Expression, from embryo to foetus to adult

Question 5

When are adult Hb levels reached?

Answer 5

6-12 months

Question 6

What are haemoglobinopathies?

Answer 6

Hereditary conditions affecting globin chain synthesis

Generally behave as AR disorders

Question 7

What are the two main groups of haemoglobinopathies?

Answer 7

Thalassaemias: decreased rate of globin chain synthesis

Structural Hb variants: normal production of structurally abnormal globin chain, leading to variant Hb e.g. HbS

Question 8

What do thalassaemias cause?

Answer 8

Inadequate Hb production, leading to microcytic hypochronic anaemia
Unbalanced accumulation of globin chains, leading to ineffective erythropoiesis and haemolysis

Question 9

What is the most common monogenic disorder?

Answer 9

Thalassaemia

Question 10

Why have thalassaemia mutations flourished in malaria endemic areas?

Answer 10

Selective pressure

Question 11

What is affected in alpha thalassaemia?

Answer 11

Alpha globin chain synthesis- reduced or absent synthesis of a chains

Question 12

What does alpha thalassaemia result in?

Answer 12

Deletion of one or both alpha genes from Ch 16

Alpha chains present in all adult Hb, therefore all affected

Question 13

What are the classifications of alpha thalassaemia?

Answer 13

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 (–/–)

Question 14

Describe alpha thal trait

Answer 14

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)

Question 15

Describe HbH disease

Answer 15

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

Question 16

What are the clinical features of HbH disease?

Answer 16

From mild anaemia to transfusion dependent
Splenomegaly due to extramedullary haematopoiesis
Jaundice: haemolysis, ineffective erythropoiesis

Question 17

What is the treatment for HbH disease in severe cases?

Answer 17

Splenectomy +- transfusion

Question 18

Where is HbH disease most common?

Answer 18

SE Asia, Middle East and Mediterranean where (–/aa) is prevalent

Question 19

Describe Hb Barts hydrops fetalis syndrome

Answer 19

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

Question 20

What are the clinical features of Hb Barts hydrops fetalis syndrome?

Answer 20

Severe anaemia
Cardiac failure, oedema
Growth retardation
Severe hepatosplenomegaly
Skeletal and CV abnormalities
Most die in utero

Question 21

Describe beta thalassaemia

Answer 21

Disorder of B chain synthesis
Reduced (B+) or absent (B0) beta chain production
Only B chains and hence only HbA affected

Question 22

What is B thal usually caused by?

Answer 22

Point mutations

Question 23

How is B thalassaemia classified?

Answer 23

B thal trait (B+/B or B0/B)
B thal intermedia (B+/B+ or B0/B+)
B thal major (B0/B0)

Question 24

What are the features of B thal trait?

Answer 24

Asymptomatic

No/mild anaemia, low MCV/MCH

Question 25

What are the features of B thal intermedia?

Answer 25

Moderate severity requiring occasional transfusion

Question 26

What are the features of B thal major?

Answer 26

Severe, lifelong transfusion dependency

Question 27

What are the lab features of B thal major?

Answer 27

Severe anaemia Reticulocytosis, very low MCV/MCH Film; microcytosis, hypochromia, anisopoikilocytosis and target cells HPLC- mainly HbF, small amounts of HbA

Question 28

What are the clinical features of B thal major?

Answer 28

Presents aged 6-24 months Failure to thrive Pallor Extramedullary haematopoiesis causing- Hepatosplenomegaly, Skeletal changes (cord compression), Organ damage

Question 29

What is the management of B thal major?

Answer 29

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

Question 30

What is the main cause of mortality in treated B thal major?I

Answer 30

Iron overload from transfusion

Question 31

What are the consequences of iron overload?

Answer 31

Endocrine dysfunction: impaired growth and pubertal development, diabetes, osteoporosis Cardiac disease: cardiomyopathy, arrhythmias Liver disease: cirrhosis, hepatocellular cancer

Question 32

What is the management of iron overload?

Answer 32

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

Question 33

What are transfusion related complications of iron overload?

Answer 33

Viral infection - HIV, Hepatitis B and C Alloantibodies – hard to crossmatch suitable blood Transfusion reactions Increased risk of bacterial sepsis

Question 34

How is thalassaema diagnosed?

Answer 34

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

Question 35

What is raised HbA2 diagnostic of?

Answer 35

Beta thal trait

Question 36

What is the pathophysiology of sickling disorders?

Answer 36

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

Question 37

Describe sickle trait (HbAS)

Answer 37

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%

Question 38

Describe sickle cell anaemia (HbSS)

Answer 38

Two abnormal β genes (βs/βs): autosomal recessive HbS > 80%, no HbA Episodes of tissue infarction due to vascular occlusion – sickle crisis

Question 39

What are the symptoms of sickle cell anaemia?

Answer 39

Depend on site and severity: Digits (dactylitis), bone marrow, lung, spleen, CNS Pain may be extremely severe

Question 40

What are some consequences of sickle cell anaemia?

Answer 40

Chronic haemolysis – shortened RBC lifespan Sequestration of sickled RBCs in liver and spleen Hyposplenism due to repeated splenic infarcts

Question 41

What does sickle cell vaso-occlusion cause?

Answer 41

Tissue ischaemia and severe pain

Question 42

What are the precipitants of sickle crisis?

Answer 42

``` Hypoxia ‏ Dehydration Infection Cold exposure Stress/fatigue ```

Question 43

What is the treatment of a painful sickle crisis?

Answer 43

``` Opiate analgesia Hydration Rest Oxygen Antibiotics if evidence of infection Red cell exchange transfusion in severe crises eg chest crisis or neurological symptoms ```

Question 44

What are the long term effects of sickle cell?

Answer 44

Impaired growth Risk of sepsis Risk of organ damage: pulmonary HT, renal disease, avascular necrosis, leg ulcers, stroke

Question 45

What is the long term treatment of sickle cell?

Answer 45

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

Question 46

What are some other sickling disorders (sickle cell disease)?

Answer 46

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

Question 47

What screening is carried out for haemoglobinopathies?

Answer 47

Antenatal screening standard: family origin questionnaire and FBC, further testing if from high risk area or abnormal RBC indices