Sickle cell disease

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High power photomicrograph of a sickle erythrocyte ('sickle cell').

Autosomal recessive genetic disorder caused by a single nucleotide mutation of the haemoglobin β-unit. The 6th amino acid of the resulting polypeptide becomes the hydrophobic amino acid valine instead of hydrophilic glutamic acid. The mutant protein giving rise to a defective variant of haemoglobin, called haemoglobin S (HbS).[1][2] The variant is suceptible to polymerisation in cooler or more hypoxic conditions, the precipitated haemoglobin distorts the red corpuscle causing it to resemble a sickle and ultimately damages the erythrocyte causing haemolysis.

The gene is more common among Africans and is occasionally seen in races from the Middle East and South Asia. Its prevalence is due to the relative resistance to malaria seen in sickle cell trait (the heterozygote form), due to shortened red cell lifespan. It may of course co-exist with other genetic disorders of haemoglobin structure.

Contents

Pathophysiology

Sickling is triggered by various factors, including a cold environment, acidosis, hypoxia and hyperviscosity e.g. dehydration. Blood flow in capillaries is impaired, which leads to a vicious cycle of increased tissue acidosis and hypoxia. Infarction may occur if the impairment of blood supply is sufficiently severe and acute.

Clinical

Presents in infancy or early childhood. The neonate with its high proportion of Haemoglobin F does not get symptoms until there is enough abnormal haemoglobin A produced for red cells to start to sickle.

Acute Crisis

  • Pain
  • Chest syndrome
  • Aplastic crisis
  • Gut crisis
  • Stroke
  • Priapism
  • Sepsis (may precipitate crisis or complicate it)

Pain

Pain can be widespread, but particularly involves bones, the spine, the chest.

Acute Chest syndrome

Chest involvement may mimic pneumonia, with unilateral or bilateral signs of consolidation, pleuritic pain, and hypoxia. Pain, usually in chest wall, thoracic spine and upper abdomen leads to hypoventilation, with atelectasis and subsequently worse sickling.

ACS has a high mortality, so treatment should be prompt on suspicion of the condition. Hypoxia should be managed aggressively, with respiratory support if necessary.

  • Antibiotics are used empirically, considering the possibility of infection complicating/underlying crisis.
  • Diuretics should be avoided - signs may sometimes suggest pulmonary oedema, but likely to exacerbate hyperviscosity.

Aplastic Crisis

Usually secondary to Erythrovirus B19 (formerly known as parvovirus B19) infection, which can trigger transient bone marrow arrest and hence exacerbation of chronic anaemia with an absence of reticulocytes. Classic "slapped cheek" appearance may never become apparent. Can affect multiple members of a family simultaneously.

Differential is spleen sequestration.

Abdominal crisis

Manifest as anorexia, abdominal pain, distension. Usually not diarrhoea or vomiting. Usually not rebound. Bowel sounds usually quiet.

  • Girdle or mesenteric syndrome - ileus with vomiting. Associated with liver enlargement and bilateral basal consolidation.
  • Differential includes appendicitis, biliary colic or cholecystitis, ischaemic colitis.

Stroke

Typically affects middle cerebral artery territory but may affect any region of the brain; may be transient or permanent. Seizures may occur. Predictive factors are:

  • Previous TIA/stroke
  • Chest syndrome
  • Hypertension
  • Family history of SCD related stroke
  • Low HbF and/or low total haemoglobin
  • Doppler velocities >200cm/sec in children

Differential is meningitis, subarachnoid haemorrhage (associated with multiple intracranial aneurysms).

Sequestration syndromes

Top-up transfusion may be considered if unstable with other sickle related problems (aiming for Hb 10-12g/dl). Exchange transfusion has been associated with an increased incidence of neurological events and may just delay definitive treatment unnecessarily. Where aspiration is unsuccessful (15% of cases, esp where duration >24hrs) exchange transfusion may be considered +/or surgical shunting operation eg Winter's procedure.

  • Sepsis. Children are relatively immunocompromised due to functional hyposplenism from recurrent spleen infarction. This increases susceptibility to capsulated organisms eg pneumococcus, salmonella, haemophilus.
    • Yersinia is a particular risk in children on desferrioxamine. Causes diarrhoea.

Splenic sequestration

Seen in infants and young children. Precipitated by fever or dehydration. Rapid sequestration of cells leads to sudden anaemia and may provoke cardiac failure and pulmonary oedema. Symptoms are:

  • Abdominal pain/distension
  • Rapidly expanding spleen (may or may not be painful)
  • Shock, pallor

Diagnosis is by demonstrating high reticulocyte count cf aplastic crisis. Management is by fluid resuscitation with blood (type specific/O negative if necessary).

Hepatic sequestration

Present as for splenic, although shock is less common, and with enlarging liver +/- jaundice.

Priapism

Sustained painful erection. By definition, acute is where duration >4 hours. Potentially leads to peripheral gangrene, else cavernosal fibrosis and hence impotence. Some patients present with recurrent episodes of shorter duration and less severe pain ("stuttering priapism").

Treatment response and outcome are dependent on duration of erection, so a urological emergency. Management:

  1. Warm bath, hydration, analgesia
  2. Catheterize if unable to urinate
  3. Sedation e.g. diazepam
  4. Aspiration + irrigation - ideally within 4-6hrs of onset. Adrenaline can be added to irrigation fluid. Etilefrine (alpha agonist) can be instilled after irrigation.

Acute Investigations

  • Full blood count
  • Reticulocyte count
  • Urea and electrolytes. Raised urea significant as usually low in sickle cell disease.
  • Liver function tests
  • Erythrovirus B19 IgM
  • CXR for acute chest syndrome is not 100% sensitive and clinical signs may precede visible radiological abnormalities.
  • Joint X-rays do not differentiate between infection and infarction, so are only useful in chronic symptoms where acute vascular necrosis may be identified. Ultrasound may detect periosteal changes in acute osteomyelitis.
  • CT/MRI for neurological symptoms (MR angiography good for determining duration of transfusion regimen, as risk highest in those with abnormal vasculature)

Management

  • Analgesia, aiming to get rapid symptom control with IV bolus doses of opiates eg morphine, diamorphine ideally within 30 minutes of admission, followed by infusion or regular oral doses. Paracetamol and non-steroidal anti-inflammatories may be synnergistic.
  • Oxygen, esp for acute chest syndrome. Debatable if effective for other problems.
  • Hydration, even hyperhydration eg 150% normal daily requirements, IV if necessary. Impairment of renal concentrating power may contribute to dehydration.
  • Warm environment
  • Identification and treatment of infection. Give treatment doses of penicillin (else erythromycin) even if no specific agent identified.
    • Treat with IV antibiotics if severe symptoms/signs
    • Add macrolide eg clarithromycin if chest symptoms
    • Treat empirically for Yersinia with ciprofloxacin if diarrhoea on desferrioxamine.
  • Folic acid

Transfusion

Although anaemia is common in SCD, repeated transfusions lead to the possible complications of:

  • Allo-immunization
  • Iron overload

Hence top up transfusion is only used for acute symptomatic anaemia eg cardiac failure, severe sequestration or pre-operatively. Do not transfuse above Hb 11g/dl. Regular transfusions have a prophylactic role - see on-going treatment below.

Exchange transfusion

Undertaken to rapidly reduce the percentage of sickle cells in the circulation where life-threatening eg severe chest syndrome, stroke, multi-organ failure. The aim is to reduce %HbS to <20%. Complications are common eg fluid overload, transfusion reaction.

Chronic Problems

Renal

  1. Microscopic haematuria is common. Papillary necrosis may occur, causing macroscopic haematuria and renal colic.
  2. Nocturia/enuresis common, probably due to impaired urinary concentrating ability.
  3. UTI relatively common.
  4. Chronic renal failure - rarely develops in children, but evolves in association with worsening anaemia, hypertension, proteinuria, and microscopic haematuria. Nephrotic syndrome predicts.

Eye problems

  1. Retinal vessel occlusion rare in children, but presents earlier in HbSC disease.
  2. Proliferative retinopathy, leading to vitreous haemorrhage and retinal detachment. Need annual review from puberty.

Gallstones

Causing the usual problems of cholecystitis, biliary colic, jaundice etc. Stones are radio-opaque in up to 50% of cases. Some patients develop jaundice without gallstones, and this is thought to be due to intrahepatic sickling.

Aseptic Necrosis

Typically of hips and shoulders, although symptoms may involve groin and knee. Causes chronic pain and ultimately joint damage with restriction of movement. Treatment is difficult. Transfusion pre/post-operatively is mainly to prevent progression in contralateral joint!

Endocrine

  1. Short stature and delayed puberty common. Rarely, hypothalamic infarcts are responsible.
  2. Fertility is usually normal in girls but suboptimal in boys (reduced sperm counts/motility).

Other Treatments

  1. Pneumococcal prophylaxis is essential for all children. Penicillin V should be given twice daily, else erythromycin if penicillin allergic. Immunization with conjugate pneumococcal vaccine should begin at 2 months of age and a full course should be offered to all under 5 yrs. Polysaccharide vaccine should be offered to all over 2yrs, then repeated at age 5 and then 5 yearly thereafter.
  2. Folic acid should be given (2.5mg daily age 1-3yr, 5mg daily thereafter).
  3. Hepatitis B immunization is appropriate.
  4. Splenectomy - for recurrent splenic sequestration.

On-going Treatment

Consider for:

  • Recurrent or stuttering priapism (etilefrine orally is another option here)
  • Stroke/TIA
  • Chronic organ damage eg renal failure
  • Failure to thrive
  • Intractable crises

Options:

  • Regular transfusions. The aim is to keep %HbS <25%. Compared with exchange transfusion, regular transfusions are just as good at reducing complications, are less challenging in terms of vascular access, involve less donor exposure, but cause more iron accumulation. There is an amazing reduction in stroke incidence with transfusion as demonstrated in the STOP trial.
  • Hydroxyurea. Reduces frequency of crises and transfusion requirements, improves growth. Trials ongoing. Long term risks need to be clarified (toxicity, mutagenicity, teratogenicity).
  • Bone marrow transplant

Iron overload and chelation therapy

Iron overload can be monitored by means of Ferritin levels. Chelation therapy should commence at ferritin levels of 1000mcg/l, with desferrioxamine (desferal) the chelator of choice. Treatment should include vitamin C. Ophthalmological, audiological and cardiological review is necessary.

References