Haemoglobinopathy Flashcards
What type of globin chains make up each of the following types of Hb: a) HbA? b) HbA2? c) HbF?
a) 2x alpha and 2x beta b) 2x alpha and 2x delta c) 2x alpha and 2x gamma
On which chromosome are the genes for alpha globin chains? How many of these genes are in 1 chromosome?
Chromosome 16 / 2 genes per chromosome (making 4 per cell)
On which chromosome are the genes for beta globin chains? How many of these genes are in 1 chromosome?
Chromosome 11 / 1 gene per chromosome (making 2 per cell)
When are adult levels of Hb usually reached?
By 6-12 months of age
What are haemoglobinopathies?
Hereditary conditions affecting globin chain synthesis
How are haemoglobinopathies usually inherited?
Autosomal recessive
What are the two main groups of haemoglobinopathies and what do each of these cause?
Thalassaemias, where the amount of globin chain produced is decreased / structural Hb variants, where structurally abnormal globin chains are produced
What defines a thalassaemia?
Decreased globin chain production resulting in impaired Hb production
What are the two main types of thalassaemia?
Alpha and beta
Inadequate Hb production in thalassaemias leads to what type of anaemia?
Microcytic, hypochromic
In thalassaemias, there is an unbalanced accumulation of one type of globin chain (due to decreased production of the other) - what does this lead to?
Ineffective erythropoiesis which is toxic, causing haemolysis
Where are cells haemolysed in thalassaemias?
In the bone marrow, before they even enter the circulation
In what areas of the world are thalassaemias more common?
Southern Europe, Southern Asia and Africa
What causes alpha thalassaemia?
Mutations affecting alpha globin chain synthesis
Unaffected individuals should have how many normal alpha genes? Alpha thalassaemia results from what?
4 / having a deletion of one or both alpha genes from chromosome 16
What forms of Hb are affected by alpha thalassaemia?
All forms (HbA, HbA2, HbF)
How many alpha genes are deleted to cause a) alpha thalassaemia trait? b) HbH disease? c) Hb Bart’s hydrops foetalis?
a) 1 or 2 b) 3 c) 4
How many functional alpha genes must there be in the cell to have alpha thalassaemia trait?
2 or 3
How does alpha thalassaemia trait present? How is it treated?
Usually asymptomatic, potentially mild anaemia - no treatment needed
If alpha thalassaemia trait was to cause anaemia, what type would it cause?
Microcytic, hypochromic
How is anaemia from alpha thalassaemia trait differentiated from iron deficiency?
In ATT, the ferritin will be normal
How many functional alpha genes are there is HbH disease?
One
In HbH disease, there are excess beta chains. What do these do?
They form tetramers known as HbH which cannot carry oxygen
How can HbH be visualised? What does it look like?
On special stains, look like golf balls
What is the range of clinical presentation of HbH disease?
Moderate anaemia - transfusion dependent
What feature of HbH disease may arise as a result of a) extramedullary haemopoiesis? b) haemolysis and ineffective haemopoiesis?
a) splenomegaly b) jaundice
Apart from splenomegaly and jaundice, what are some other features which may occur in HbH disease?
Growth retardation, gallstones and iron overload
What are the treatment options for severe causes of HbH disease?
Splenectomy +/- tranfusion
What type of globin chains make up each of the following types of Hb seen in bart’s hydrops foetalis: a) Hb Barts’? b) HbH?
a) 4 x delta chains, b) 4 x beta chains
What will a blood film of Bart’s hydrops foetalis show?
Numerous nucleated red cells in the peripheral blood
What happens to most sufferer’s of Bart’s hydrops foetalis?
Die in utero (pretty much incompatible with life)
If a baby does survive with Bart’s hydrops foetalis, what are some potential clinical features?
Severe anaemia, cardiac failure, growth retardation, hepatosplenomegaly
What type of Hb is affected by beta thalassaemia?
HbA
What defects in the beta chains causes beta thalassaemia trait?
1 reduced or 1 absent beta chain with 1 normal beta chain
What defects in the beta chains causes beta thalassaemia intermedia?
2 reduced beta chains or 1 absent and 1 reduced beta chain
What defects in the beta chains causes beta thalassaemia major?
2 absent beta chains
What is the clinical picture of beta thalassaemia trait?
Asymptomatic, may be mild anaemia
What is the clinical picture of beta thalassaemia intermedia?
Moderate severity anaemia, requiring occasional transfusions
What is the clinical picture of beta thalassaemia major?
Severe, lifelong transfusion dependency
When and how does beta thalassaemia major usually present?
Aged 6-24 months (as HbF falls) with failure to thrive and pallor
As beta thalassaemia major progresses, it can cause extramedullary haemopoiesis which can lead to what clinical features?
Hepatosplenomegaly, skeletal changes (potential spinal cord compression), end organ damage
What will Hb analysis of someone with beta thalassaemia major show?
Mainly HbF, minimal MbA
What is the treatment for beta thalassaemia major? What is the main complication of this?
Blood transfusions / iron overload
What can be a treatment for beta thalassaemia major if detected before major complications develop?
Bone marrow transplant
What are some endocrine consequences of iron overload?
Impaired growth and puberty, diabetes, osteoporosis
What are some cardiac consequences of iron overload?
Cardiomyopathy and arrhythmias
What are some liver consequences of iron overload?
Cirrhosis and hepatocellular carcinoma
Why is venesection not a feasible treatment of iron overload as a result of transfusions for beta thalassaemia major?
These inidviduals are already anaemic
What is the treatment for iron overload as a result of transfusions for beta thalassaemia major?
Iron chelating drugs (IV/SC)
Apart from iron overload, what are some other complications of transfusions given in beta thalassaemia major?
Infections, alloantibodies, transfusion reactions, increased risk of sepsis
How do sickling disorders come about?
They are caused by a point mutation at codon 6 on the beta globin gene
What substitution occurs as a result of the mutation causing sickling disorders? What does this produce?
Glutamine - valine / Beta S
In sickling disease, the structure of Hb changes to HbS - what chains make up HbS?
2 x alpha, 2 x beta S
What happens if HbS is exposed to low oxygen levels for a prolonged period?
It polymerises, which distorts the red cell and damages the membrane
What is the genotype of individuals with sickle trait (HbAS)?
1 normal beta chain, 1 abnormal beta S chain
When may sickle trait cause problems?
At times of low oxygen e.g. high altitude, under anaesthesia
Describe the blood film seen in sickle trait? What type of Hb predominantes?
Normal / HbA (formed from the normal beta chain)
What is the genotype of individuals with sickle cell anaemia (HbSS)?
Two abnormal beta S chains
What type of Hb predominates in sickle cell anaemia?
HbS
What is a sickle crisis?
Episodes tissue infarction due to vascular occlusion because the distorted cell gets trapped
Where are some sites which may be affected by a sickle crisis?
Digits, bone marrow, lung, spleen, CNS
What are some potential precipitants of a sickle crisis?
Hypoxia, dehydration, infection, cold exposure, stress
How should a sickle crisis be treated?
Opiate analgesia, hydration, oxygen, rest
What is a treatment option for a severe sickle crisis?
Red cell transfusion
What effect does sickle cell anaemia have on the spleen?
Causes hyposplenism due to repeated infarcts
What are some long term effects of sickle cell anaemia?
Impaired growth and risk of end organ damage e.g. leg ulcers, AVN, stroke
How should the hyposplenism in sickle cell anaemia be treated?
Prophylactic penicillin and vaccination for pneumococcus, meningococcus and haemophilus
What are some long term treatments for sickle cell anaemia?
Folic acid supplements and hydroxycarbamide
What is sickle cell disease?
Essentially sickle cell anaemia with another beta chain mutation e.g. beta thalassaemia
What investigations can be used to identify the types of Hb present in an individual?
High performance liquid chromatography or gel electrophoresis
A raised HbA2 is diagnostic of what?
Beta thalassaemia trait
HPLC is normal in alpha thalassaemia trait - what is needed to confirm this diagnosis?
DNA testing
If a woman is pregnant, she will get tested to see if she is a carrier of thalassaemia. Does the father ever need to get tested?
Only if the mother comes back to be a carrier
