Haemoglobinopathy

Question 1

Describe the structure of haemoglobin

Answer 1

Tetramer made up of 2 alpha globin like chains and 2 beta globin like chains One haem group attached to each globin chain

Question 2

What are the 3 major forms of Hb?

Answer 2

HbA (2 alpha and 2 beta chains), HbA2 (2 alpha and 2 delta chains) and HbF (2 alpha and 2 gamma chains)

Question 3

Where are the alpha like genes found?

Answer 3

Chromosome 16 - 2 alpha genes per chromosome (4 per cell)

Question 4

Where are the beta like genes found?

Answer 4

Chromosome 11 - one beta gene per chromosome (2 per cell)

Question 5

What is a haemoglobinopathy?

Answer 5

A hereditary condition affecting globin chain synthesis

Question 6

What are the 2 main groups of haemoglobinopathies?

Answer 6

Thalassaemias and structural haemoglobin variants

Question 7

What is the difference between thalassaemias and structural haemoglobin variants?

Answer 7

Thalassaemia - decreased rate of globin chain synthesis resulting in impaired Hb production Structural haemoglobin variants - normal production of structurally abnormal globin chain -> variant Hb e.g. HbS

Question 8

What happens as a result of thalassaemias?

Answer 8

Inadequate Hb production -> microcytic hypochromic anaemia. Unbalanced accumulation of globin chains is toxic -> ineffective erythropoiesis and haemolysis

Question 9

Where are thalassaemias most common?

Answer 9

Parts of Africa, SE Europe, India and most of Asia

Question 10

What is alpha thalassaemia?

Answer 10

Mutations affecting alpha globin chain synthesis. Results from deletion of one a+ or both a0 alpha genes from chromsome 16. Reduced a+ or absent a0 alpha chain synthesis. a chains present in all adult forms of Hb therefore HbA HbA2 and HbF all affected

Question 11

How is alpha thalassaemia classified?

Answer 11

alpha thal trait - one or two genes missing HbH disease - only one alpha gene left Hb Barts hydrops fetalis - no functional alpha genes

Question 12

How does alpha thalassaemia trait present and how is it managed?

Answer 12

Asymptomatic, no treatment needed.

Question 13

Describe the red cell appearance in alpha thalassaemia trait

Answer 13

Microcytic, hypochromic red cells with mild anaemia

Question 14

What is the pathophysiology of HbH disease?

Answer 14

Severe form of alpha thalassaemia. Only one alpha gene per cell. Anaemia with very low MCV and MCH. Excess beta chains form tetramers called HbH which can’t carry oxygen. Red cell inclusions of HbH can be seen with special stains

Question 15

Where is HbH disease most common and what are the clinical features?

Answer 15

Most common in SE Asia, Middle East and Mediterranean where a0 is prevalent. Features - moderate anaemia, splenomegaly, jaundice, growth retardation, gallstones and iron overload

Question 16

What is Hb Barts hydrops foetalis syndrome?

Answer 16

Severest form of alpha thalassaemia. No alpha genes inherited from either parent. Minimal or no alpha chain production -> HbA can’t be made! Hb Barts and HbH are the majority of Hb present at birth

Question 17

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

Answer 17

Severe anaemia, cardiac failure, growth retardation, severe hepatosplenomegaly, skeletal and cardiovascular abnormalities, almost all die in utero

Question 18

What is beta thalassaemia?

Answer 18

Disorder of beta chain synthesis. Only have beta chains and hence only HbA affected

Question 19

What causes beta thalassaemia?

Answer 19

Usually point mutations. Reduced or absent beta chain production depending on the mutation.

Question 20

How is beta thalassaemia classified?

Answer 20

Based on clinical severity: - beta thalassaemia trait - asymptomatic - beta thalassaemia intermedia - moderate severity, occasional transfusions - beta thalassaemia major - severe, lifelong transfusions

Question 21

How does beta thalassaemia major present?

Answer 21

Presents aged 6-24 months, as HbF falls, with pallor and failure to thrive

Question 22

What does beta thalassaemia major cause?

Answer 22

Extramedullary haematopoiesis which causes hepatosplenomegaly, skeletal changes, organ damage, cord compression

Question 23

How is beta thal major treated?

Answer 23

Regular transfusions to maintain Hb at 95-105g/L Bone marrow transplant may be an option if done before complications develop

Question 24

What is the main cause of mortality in beta thal major?

Answer 24

Iron overload! (>70% of deaths are due to iron)

Question 25

What are some of the consequences of iron overload?

Answer 25

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

Question 26

How is iron overload managed?

Answer 26

Iron chelating drugs such as desferrioxamine are necessary (chelators bind to iron, complexes formed are excreted in urine or stool) Venesection is not feasible as they’re already anaemic

Question 27

What is the pathophysiology behind sickling disorders?

Answer 27

Point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine producing beta S. This 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 making it sickling

Question 28

What is sickle trait?

Answer 28

One normal, one abnormal gene. Asymptomatic carrier state. Few clinical features as HbS level too low to polymerise. May sickle in severe hypoxia e.g. high altitude. Mainly have HbA (HbS <50%)

Question 29

What is the cause of sickle cell anaemia?

Answer 29

2 abnormal beta genes, autosomal recessive. HbS >80%, no HbA

Question 30

What happens as a result of sickle cell anaemia?

Answer 30

Episodes of tissue infarction due to vascular occlusion - sickle crisis - common sites include; digits, bone marrow, lung, spleen, CNS. Chronic haemolysis - shortened RBC lifespan Sequestration of sickled RBCs in liver and spleen Hyposplenism due to repeated splenic infarcts

Question 31

What is sickle cell disease?

Answer 31

Compound heterozygosity for HbS and another beta chain e.g. HbS/beta thalassaemia or HbSC disease (increased risk of thrombosis)

Question 32

Name some precipitating factors for sickle crisis

Answer 32

Hypoxia, dehydration, infection, cold exposure, stress/fatigue

Question 33

How is a sickle crisis treated?

Answer 33

Opiate analgesia, hydration, rest, oxygen, antibiotics (if infection), red cell exchange transfusion in severe crises e.g. stroke

Question 34

What are the long term effects of sickle cell anaemia?

Answer 34

Impaired growth, risk of end-organ damage (PHT, renal disease, avascular necrosis, leg ulcers, stroke)

Question 35

How is sickle cell anaemia managed in the long term?

Answer 35

Hyposplenism (risk of infection) - prophylactic penicillin + vaccinations (pneumococcus, meningococcus, haemophilus) Folic acid supplements Hydroxycarbamide can reduce severity of disease by inducing HbF production Regular transfusions in some cases

Question 36

How are haemogolbinopathies investigated?

Answer 36

FBC, Hb, red cell indices, blood film, ethnic origin, high performance liquid chromatography (HPLC) gel electrophoresis to identify abnormal Hb e.g. HbS

Question 37

How are haemoglobinopathies screened for?

Answer 37

Antenatal screening to identify carrier parents is now standard. Further testing is done if from high-risk area or abnormal RBC indices Newborn screening programme is also in place