Sickle cell disease

Question 1

What is sickle cell disease?

Answer 1

A chronic autosomal recessive condition with sickling of red blood cells caused by inheritance of haemoglobin S (HbS)
o Sickle Cell Anaemia = Homozygous HbSS
o Sickle Cell Trait = Carrier of one copy of HbS
o Sickle Cell Disease = includes compound heterozygosity for HbS and:
*HbC (abnormal haemoglobin in which glutamic acid is replaced by lysine at the 6th position in the beta-globin chain) - HbSC
*Beta-thalassemia – HbS/Bthal

Question 2

What causes sickle cell disease?

Answer 2

• Autosomal recessive
• Caused by a point mutation in the beta-globin gene resulting in the substitution of glutamic acid in position 6 by valine. This results in the formation of abnormal haemoglobin S
• Deoxygenation of HbS alters the conformation resulting in sickling of red cells
• Sickling makes the red cells more fragile and inflexible
• These sickled red cells are prone to:
  -Sequestration and destruction (reduced red cell survival ~ 20 days)
  -Occlusion of small blood vessels causing hypoxia, which leads to further sickling and occlusion

Question 3

What factors precipitate sickling?

Answer 3

“I HAD”:
o Infection
o Dehydration
o Hypoxia
o Acidosis

Question 4

Summarise the epidemiology of sickle cell disease

Answer 4

• Rarely presents before 4-6 months (because HbF can compensate for the defect in adult haemoglobin, as they grow as the production of HbF decreases and HbS levels increase)
• Common in Africa, Caribbean, * Middle-East and other areas with a high prevalence of malaria
• Sickle cell trait or disease offers a protective effect against malaria in endemic regions and this has led to positive selection for the gene mutation
• Sickle cell trait occurs if HbS is inherited from one parent and the normal HbA from the other (sickle cell disease = child inherits sickle gene from each parent)
• Approx. 8% of black people carry the sickle cell gene

Question 5

What are the presenting symptoms of sickle cell disease?

Answer 5

Symptoms secondary to VASO-OCCLUSION or INFARCTION (common due to microvascular occlusion):
1. Autosplenectomy (splenic atrophy or infarction)
- Leads to increased risk of infections with encapsulated organisms (e.g. pneumococcus, meningococcus)
2. Abdominal Pain due to mesenteric ischaemia
3. Bones
- Painful crises affect small bones of the hands and feet causing dactylitis in CHILDREN
- Painful crises mainly affect the ribs, spine, pelvis and long bones in ADULTS
- Avascular necrosis
4. Myalgia (muscle pain) and Arthralgia (joint pain)
5. Leg ulcers
6. Low flow priapism
7. CNS
- Fits and strokes, cognitive defects
8. Retina
- Visual loss (proliferative retinopathy)

Symptoms of SEQUESTRATION CRISIS:
- NOTE: sequestration crises occur due to pooling of red cells in various organs (mainly the spleen). Mainly affects children as spleen has not yet undergone atrophy.
1. Liver –> exacerbation of anaemia
2. Lungs –> acute chest syndrome
* Breathlessness
* Cough
* Pain
* Fever
3. Corpora cavernosa
* Persistent painful erection (priapism)
* Impotence

Symptoms of APLASTIC ANAEMIA: due to parvovirus B19 with sudden reduction in marrow production, especially RBCs
- Anaemia and infection

Question 6

What investigations are used to diagnose/ monitor sickle cell disease?

Answer 6

1. Haemoglobin Electrophoresis → shows HbS, no HbA, and raised HbF. Gold Standard.
2. Blood Film → presence of sickle-shaped cells and howell-jolly bodies+target cells (due to hyposplenism)
3. FBC → haemolytic anaemia, elevated reticulocyte count (if sequestration crises)
4. Iron Studies → distinguish haemolytic anaemia from iron-deficiency anaemia
   - Sequestration Crisis = high reticulocytes + splenomegaly
   - Aplastic Crisis (parvovirus B19) = low reticulocytes + sudden anaemia (drop in Hb). Temporary cessation erythropoiesis.

Question 7

How is sickle cell disease managed?:

Answer 7

1. Vaso-Occlusive Crisis → analgesia (strong), fluids, oxygen, antibiotics if infection, blood transfusion
2. Chronic Disease → hydroxyurea (increases HbF levels - reduces frequency and duration of crises), repeated blood transfusions
   - Infection Prophylaxis ⇒ regular vaccinations (particularly against encapsulated bacteria such as pneumococcus due to hyposplenism)

Question 8

What signs of sickle cell disease can be found on physical examination?

Answer 8

Signs secondary to VASO-OCCLUSION, ISCHAEMIA or INFARCTION:
1. Bone - joint or muscle tenderness or swelling (due to avascular necrosis)
2. Short digits - due to infarction in small bones of the hands
3. Retina - cotton wool spots due to retinal ischaemia

Signs secondary to SEQUESTRATION CRISES:
1. Organomegaly
* The spleen is ENLARGED in early disease
* Later on, the spleen will reduce in size due to splenic atrophy
2. Priapism (penis maintains a prolonged, rigid erection in the absence of appropriate stimulation)

Signs of anaemia

Question 9

What complications may arise following sickle cell disease?

Answer 9

1. Aplastic crises
   o Infection with Parvovirus B19 can lead to a temporary cessation of erythropoiesis (which can cause red cell count to plummet in sickle cell patients because their red cells have a shortened life span and can’t tolerate a cessation of erythropoiesis)
2. Infection
3. Poor growth in children
4. Chronic renal failure
5. Haemolytic crises
6. Pigment gallstones
7. Retinal disease
8. Cholecystitis
9. Renal papillary necrosis
10. Leg ulcers
11. Cardiomyopathy
12. Iron overload from repeated transfusion
13. Lung damage

Question 10

Summarise the prognosis for patients with sickle cell disease

Answer 10

1. Most patients with sickle cell disease who manage their disease well will survive until around the age of 50 yrs
2. Mortality is usually the result of:
   o Pulmonary or neurological complications in ADULTS
   o Infection in CHILDREN