Haemoglobinopathies Flashcards
1
Q
Describe the structure of haemoglobin (adult).
A
A tetramer made up of 2 alpha globin like chains and 2 beta globin like chains
+
One haem group attached to each globin chain
2
Q
Globin chains keep haem _______, and protect it from _________
A
- Soluble
2. Oxidation
3
Q
What are the 3 major forms of haemoglobin and what chains are these composed of?
A
- HbA = 2 alpha chains and 2 beta chains; α2β2.
- HbA2 = 2 alpha and 2 delta; α2δ2.
- HbF = 2 alpha and 2 gamma; α2γ2.
4
Q
In adults, what proportion of the haemoglobin is made up of each of the above types?
A
HbA - 97%.
HbA2 - 2.5%.
Hbf - 0.5%.
5
Q
What chromosome are alpha like genes on?
A
16
6
Q
How many alpha genes are there per i) chromosome? ii) cell?
A
i) 2.
ii) 4.
7
Q
What chromosome are beta like genes on?
A
11
8
Q
How many beta genes are there per i) chromosome? ii) cell?
A
i) 1.
ii) 2.
9
Q
When does the expression of globin genes change?
A
During embryonic life and childhood.
10
Q
At what age are alpha Hb levels reached?
A
6-12 months
11
Q
What are genes arranged in order of?
A
Expression
12
Q
What are haemoglobinopathies?
A
Hereditary conditions affecting globin chain synthesis
13
Q
What is the mode of hesitance of haemoglobinopathies?
A
Autosomal recessive
14
Q
What are the 2 main groups of haemoglobinopathies?
A
- Thalassaemias
* Structural haemoglobin variants
15
Q
What are thalassaemias?
A
Conditions where there is a decreased rate of globin chain synthesis
16
Q
‘Conditions where there is a decreased rate of globin chain synthesis’ - name the condition.
A
Thalassaemia
17
Q
What are structural haemoglobin variants?
A
Conditions where there is normal production of structurally abnormal globin chains - variant haemoglobin e.g. HbS.
18
Q
What is a thalassaemia?
A
Reduced globin chain synthesis, resulting in impaired haemoglobin production
19
Q
What are the 2 main groups of thalassaemias?
A
- Alpha thalassaemia; α chains affected.
* Beta thalassaemia; β chains affected.
20
Q
What does the inadequate Hb production in thalassaemias result in?
A
Microcytic Hypochromic Anaemia.
21
Q
Thalassaemias can be toxic. Explain why.
A
There is unbalanced accumulation of globin chains and this results in:
- Ineffective erythropoiesis
- Haemolysis.
22
Q
Why are thalassaemias imprortant?
A
They are the commonest myogenic disorder
23
Q
What do the mutations in alpha thalassaemias affect?
A
α globin chain synthesis
24
Q
How many alpha genes do unaffected individuals have?
A
4 - αα/αα.
25
What happens to alpha chains in alpha thalassaemia?
There is reduced α+ or absent α0 synthesis of α chains
26
What does an absent a chain result from?
Deletion of one α+ (-α) or both α0 (--) alpha genes from chromosome 16.
27
What type of Hb is affected in alpha thalassaemias?
HbA, HbA2 and HbF are all affected
Because alpha genes are present in all adult forms of Hb
28
What would the genes of someone without an alpha thalassaemia look like?
4 normal α genes (αα/αα).
29
What is an alpha thalassaemia trait?
Where there are one or two genes missing
30
Outline the different options of an alpha thalassaemia trait.
α+/α (-α/αα)
α0/ α (--/αα)
α+/α+(-α/-α)
31
What is HbH disease?
Where there is only one alpha gene left α0/α+(--/-α )
32
What is it called when there are no functional α genes α0/α0 (--/--)?
Hb Barts hydrops fetalis
33
What is Hb Barts hydrops fetalis?
When there are no functional α genes α0/α0 (--/--)
34
What are the genetics of an alpha thalassaemia trait?
α+/α (-α/αα) or α0/α (--/αα)
35
Look at the different alpha traits below, would any of them cause a problem?
i) α+/α (-α/αα)
ii) α0/α (--/αα)
NO - these will both be asymptomatic and cause no problems
36
On investigation, what will the clinical picture be with someone with...
i) α+/α (-α/αα)
ii) α0/α (--/αα)
Microcytic, hypochromic red cells with mild anaemia
37
What is Microcytic, hypochromic red cells with mild anaemia important to distinguish from?
Iron deficiency.
* Ferritin will be normal and red blood cell count raised
38
What, essentially, is alpha thalassaemia trait?
Not a disease but a mild anaemia
39
What is HbH disease?
A severe form of alpha thalassaemia in which there is only 1 alpha globin chain
40
What is the genetics for HbH?
There is only one α gene per cell α0/α+(--/-α )
41
What do the blood tests of HbH disease show?
Anaemia with very low MCV and MCH
42
What does the HbH in HbH disease refer to?
Excess β chains form tetramers (β4) called HbH which can’t carry oxygen
43
What can be seen with special stains in HbH?
Red cell inclusions of HbH
44
Outline the clinical features of HbH disease?
* Moderate anaemia to transfusion dependant
* Splenomegaly
* Extramedullary haematopoiesis
* Jaundice
45
What might severe cases of HbH disease require?
Splenectomy +/- transfusion
46
In what ethnic groups in HbH common? Why?
S.E Asian, Middle Eastern and Mediterranean.
- α0 is prevalent there
47
How is HbH disease inherited?
If get no alpha globulin genes from one parent, and one alpha globulin gene from the other
48
What is Hb Barts hydrops fetalis syndrome?
The severest form of alpha thalassaemia
49
What are the genetics of Hb Barts hydrops fetalis syndrome?
No α genes inherited from either parent α0/α0(--/--).
50
What is the result of no alpha genes being inherited in Hb Barts?
There is minimal or no α chain production, meaning HbA can’t be made
51
What comprise the majority of Hb at birth in Hb Barts?
Hb Barts (γ4) and HbH (β4).
52
List the main clinical features of Hb Barts.
* Severe anaemia.
* Cardiac failure.
* Growth retardation.
* Severe hepatosplenomegaly.
* Skeletal and cardiovascular abnormalities.
* Almost all die in utero.
53
What are beta thalassaemias?
A disorder of beta chain synthesis
54
What are beta thalassaemias usually caused by?
Point mutations.
Over 200 mutations identified so far
55
What does a point mutation (in b thalassaemia) result in?
Reduced (β+), or absent (β0) beta chain production
56
What type of Hb does beta thalassaemias affect?
Only HbA (α2β2) because only beta chains are affected.
57
What is classification of beta thalassaemia based on?
Severity
58
Outline the 3 different classifications of beta thalassaemias.
β thalassaemia trait (β+ /β or β0/ β)
* Asymptomatic
* No/mild anaemia, low MCV/MCH, raised HbA2
β thalassaemia intermedia (β+ /β+ or β0 /β+)
* Moderate severity requiring occasional transfusion
β thalassaemia major (β0 /β0)
* Severe, lifelong transfusion dependency
59
When does beta thalassaemia major present?
Aged 6-24months as HbF falls offAged 6-24months as HbF falls off
60
What does beta thalassaemia major present with?
With pallor and failure to thrive
+
Extramedullary haematopoiesis
61
What process occurs to try and compensate for the anaemia in beta thalassaemia major? What are the clinical manifestations of this?
Extramedullary haematopoiesis.
This causes: hepatosplenomegaly, skeletal changes, organ damage.
62
On Hb analysis of someone with beta thalassaemia, what is found?
Mainly HbF, with minimal HbA.
63
What is the mainstay treatment of beta thalassaemia major?
Regular transfusion to maintain Hb at 95-105g/l.
64
What are the effects of regular transfusion in beta thalassaemia major?
* Suppression of ineffective erythropoiesis
* Inhibition of over-absorption of iron
... allowing for relatively normal growth and development
65
In beta thalassaemia major the main tx is regular transfusion. Before this the patient is at risk of dying. Once you start tx, what becomes the biggest risk of dying?
Iron overload from transfusion
66
If regular transfusion is not working in beta thalassaemia, what can be done?
Bone marrow transplant – if carried out before complications develop
67
Outline the different consequences of iron overload.
* Endocrine dysfunction:
- impaired growth and pubertal development.
- diabetes.
- osteoporosis.
* Cardiac disease:
- cardiomyopathy.
- arrhythmias.
* Liver disease:
- cirrhosis.
- hepatocellular cancer.
68
How much iron is in each unit of red cells?
250mg. (because 500ml blood / 2 = 250mg)
69
Why is iron overload such a problem?
Chronic anaemia drives increased iron absorption
70
What is the treatment for iron overload?
Venesection
71
Why can venesection not be used to treat patients with iron overload in beta thalassaemia major (who are receiving regular transfusions)?
Not done because pt is already anaemic
72
What is used to treat iron overload in patients with beta thalassaemia major (who are receiving regular transfusions)?
Iron chelating drugs, such as desferrioxamine.
73
What is used to treat iron overload in patients with beta thalassaemia major (who are receiving regular transfusions)?
Desferrioxamine
Iron chelating drugs, such as desferrioxamine.
74
How does Desferrioxamine work?
Chelators bind to iron, and complexes formed are excreted in urine or stool
75
List some transfusion related complications in beta thalassaemia.
* Viral infections – HIV, hep B and C.
* Alloantibodies – hard to crossmatch suitable blood.
* Transfusion reactions.
76
Why are people with beta thalassaemia, receiving regular transfusions, at increased risk of sepsis?
Bacteria likes iron
These patients are in iron overload
77
Describe (from genes to pathology) the pathophysiology of sickling disorders.
* Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine producing bS
* 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
78
What are sickling disorders?
There is abnormal haemoglobin called haemoglobin S with an unusual sickle or crescent shape, meaning they are not as good at transporting oxygen
79
What does the point mutation in codon 6 of the beta globin gene do?
Substitutes glutamine to valine, producing bS
80
What does the substitution of glutamine to valine do?
The structure of Hb is altered to HbS (α2βs2).
81
What is the problem when Hb changes to HbS?
HbS POLYMERISES if exposed to low oxygen levels for a prolonged period.
This distorts the red cell, damaging the RBC membrane
82
In terms of genetics, what causes sickle cell trait?
One normal and one abnormal β gene (β/βs).
83
Is sickle trait problematic?
NO - millions have it and are asymptomatic
84
Why in sickle trait are there little clinical features?
HbS level is too low for polymerisation to occur
85
When may cells sickle in sickle trait?
In severe hypoxia e.g. high altitude, under anaesthesia.
86
What is the blood film like in someone with sickle trait?
Normal
87
What is the main form of Hb in sickle trait?
HbA!
- HbS <50%.
88
In terms of genetics and inheritance, what is sickle cell anaemia caused by?
Two abnormal β genes (βs/βs), autosomal recessive
89
Describe the Hb composition in sickle cell anaemia.
HbS >80%, no HbA
90
What is the effects of sickle cell anaemia on the body.
Sickle crisis
91
In terms of HbS, what is the difference between ...
I) Sickle cell trait
ii) Sickle cell anaemia
i) <50% of HbS
| II) >80% HbS
92
What is sickle crisis?
Episodes of tissue infarction due to vascular occlusion
93
What do symptoms in sickle crisis depend on?
Site and severity
94
What may sickle crisis affect?
Digits (dactylitis), bone marrow, lung, spleen, CNS.
95
What symptom may be extremely severe in sickle crisis?
Pain
96
What 3 major things can happen to the body in sickle cell anaemia?
* Sickle crisis
* Chronic haemolysis
* Hyposplenism
97
Why does chronic haemolysis occur in sickle cell anaemia?
Due to shortened RBC life span
SEQUESTRATION OF SICKLED RBC’s IN LIVER AND SPLEEN.
98
Why does hyposplenism occur in sickle cell anaemia?
Due to repeated splenic infarcts
99
When do other sickling disorders occur?
Where there is compound heterozygosity for HbS and another β chain mutation.
100
Give examples of other sickling disorders.
* HbS/β thalassaemia; mild if β+, severe if β0
| * HbSC disease; milder, but increased risk of thrombosis.
101
What are the consequences of sickle cell vast-occlusion?
Tissue ischaemia and severe pain.
102
What are the precipitants of a sickle crisis?
* Hypoxia.
* Dehydration.
* Infection.
* Cold exposure.
* Stress/fatigue.
103
What can help reduce the risk of a sickle crisis?
Education !!!
104
Outline the treatment of a painful crisis.
- Opiate analgesia.
- Hydration.
- Rest.
- Oxygen.
- Antibiotics if evidence of infection.
105
What constitutes for a severe sickle crisis?
Chest or neuro crisis
106
What is the treatment of a severe sickle crisis?
Red cell exchange transfusion.
107
How does a red cell exchange transfusion work in the treatment of a severe sickle crisis?
It decreases the concentration of HbS and improves tissue function
108
What are the long term effects of a sickle crisis?
* Impaired growth.
```
* Risk of end-organ damage:
pulmonary hypertension.
renal disease.
avascular necrosis.
leg ulcers.
stroke.
```
109
Outline the key factors to be addressed in the long-term management of sickle cell disease.
* Hyposplenism
| * Folic acid supplementation
110
How is hyposplenism managed long term?
1. Prophylactic penicillin.
| 2. Vaccination: pneumococcus, meningococcus, haemophilus.
111
Why is folic acid supplementation needed long term in sickle crisis?
There is increased demand due to increased RBC turnover.
112
What can reduce the severity of sickle crisis long term?
Hydroxycarbamide – by inducing HbF production
113
Outline the key areas addressed in reaching a haemoglobinopathy diagnosis.
* FBC; Hb, red cell indices.
* Blood film.
* Ethnic origin.
* High performance liquid chromatography (HPLC) or gel electrophoresis
114
What does HPCL do?
Quantifies haemoglobins present, and identifies abnormal haemoglobins e.g. HbS in sickle cell disease
115
What is the diagnostic test of beta thalassaemia trait?
Raised HbA2
116
What is HPLC (high performance liquid chromatography) like in alpha thal trait?
Normal
117
How is a diagnosis of alpha thalassaemia trait diagnosed if HPLC is normal in this condition?
DNA testing
118
Antenatal screening to identify carrier parents for thalassaemis is now standard in the UK. Describe this.
* Family origin questionnaire and FBC.
| * Further testing if from high-risk area or abnormal RBC indices.
