Sickle cell diseases are a disorder of haemoglobin affecting red blood cells. This autosomal recessive, single gene defect results in the formation of HbS (sickle cell haemoglobin).
Contents
Types of Sickle Cell Disorders
- Sickle cell trait: heterozygous (AS) which is typically asymptomatic & usually not life-limiting
- Sickle cell anaemia: homozygous (SS) which leads to many complications & is life-limiting
- Thalassaemia: compound heterozygous states for HbS with haemoglobin C,D,E which has a varying prognosis & complication rate depending on the exact type
The issue with sickle cell haemoglobin is that it causes rigid red blood cells which lead to occlusion in the microcirculation, creating pain, infarction and susceptibility to infections, as well chronic haemolytic anaemia. Treatment is mostly supportive, aiming to control symptoms and prevention of complications. Generally, sickle cell disease is associated with lifelong morbidity and reduced life expectancy.
Epidemiology & Screening
- In the UK, it is estimated that sickle cell disease affects between 12,500 and 15,000 people. It affects 1 in 2000 live births in England making it the most common severe genetic disease.
- The sickle cell gene can be found in all ethnic groups however most people affected are of African or African-Caribbean origin. The overall prevalence of the disease is increasing due to immigration.
- Sickle cell trait (carriage of the HbS gene) is thought to affect 1 in 4 West Africans and 1 in 10 Afro-Caribbeans.
- Infants are screened as part of a national screening programme on day 3-10 after birth, with confirmation by haemoglobin electrophoresis and blood film. This allows the prevention of fatal sepsis due to penicillin being commenced to prevent encapsulated bacterial infection.
- Screening also includes all pregnant women in high prevalence area, preoperative screening in high-risk ethnic groups and occasionally prenatal with amniocentesis, chorionic villus sampling and foetal blood sampling.
Classification
As detailed above, sickle cell disease can be divided into genotypes:
- HbSS disease (Sickle cell anaemia) is a homozygous disease that usually results in a moderate to severe phenotype
- HbS/HbA (Sickle cell trait) HbA is normal haemoglobin
- HbS/beta0 thalassaemia is due to double heterozygote for HbS and Beta0 thalassaemia and has an indistinguishable phenotype to sickle cell anaemia
- HbSC disease occurs when a person is a double heterozygote for HbS and HbC and presents with an intermediate clinical severity
- HbS/beta & thalassemia gives a mild/moderate severity but is variable in ethnic populations
- HbS/HbE syndrome is very rare and generally gives a mild clinical course
Sickle Cell Trait
Generally, there is 60% HbA and 40% HbS resulting in a clinically (mostly) asymptomatic disease, which is genetically advantageous due to being protective against malaria. Sickle cell trait affects approximately 300 million people worldwide, most prevalent in Sub-Saharan Africa.
Rarely, sickle cell trait can be symptomatic with haematuria, renal papillary necrosis, splenic infarction and exercise-related sudden death. It can also be associated with renal medullary cancer. Due to the small risk of exercise-related death, individuals are advised to slowly build up training in sports with longer periods of recovery.
However, overall the average life span is similar to the general population. The only abnormality on blood tests should be positive haemoglobin electrophoresis for HbS. Sickle cell trait individuals should not have anaemia or evidence of haemolysis.
Sickle Cell Disease
In the UK, sickle cell disease is usually picked up by the national screening programme.
Symptoms usually start between 3 and 6 months of age when the infants HbF levels will begin to decrease. These symptoms include anaemia, jaundice, pallor, failure to thrive and recurrent infections. Anaemia is caused by acute splenic sequestration and red cell aplasia. Infections can be caused by encapsulated bacteria, pneumococcus and meningococcus, with a high risk before 3 years of age. Some patients can also have delayed puberty.
Sickle Cell Crisis & Complications
A crisis in the context of sickle cell means that there has been obstruction of the microcirculation by a sickled red blood cell. This causes ischaemia and therefore, pain which can range from mild to severe. Precipitants can be cold, infection, dehydration however often no cause can be identified.
Presentation signs go with sites of small vessel ischaemia and can include:
- Swollen painful joints
- Dactylitis (in infants)
- Tachypnoea
- Neurological signs
- Acute abdominal distension and pain
- Loin pain, haematuria
- Priapism
- Visual loss due to retinal occlusion
Occlusion of large vessels can also occur which can lead to devastating effects such as stroke, MI, acute sickle chest syndrome and placental infarction.
Other complications
- Aplastic crisis: this occurs when there is a cessation of erythropoiesis. This can be triggered by infection with parvovirus B19 ‘slapped cheek syndrome’. It leads to a quick drop in haemoglobin. The recovery is usually spontaneous but if not recognised the degree of anaemia can lead to a high output cardiac failure.
- Sequestration crisis: this is the sudden enlargement of the spleen which causes a decrease in haemoglobin concentration and hypovolaemic shock. This generally happens in infants and children with variable severity. Again, if unrecognised it can lead to a high mortality. If recurrent, sequestration is an indication for splenectomy.
- Acute chest syndrome: This is a ‘vaso-occlusive crisis affecting the lungs’. Symptoms include cough, hypoxia, dyspnoea and fever. This combined with pulmonary infiltrates is diagnostic of an acute chest syndrome.
Indications for hospital emergency referral
- Severe pain uncontrollable by simple analgesia
- Dehydration
- Sepsis
- Acute fall in haemaglobin
- Jaundice
- Symptoms of chest syndrome
- Acute enlargement of the spleen or liver
- Haematuria
- Fulminant priapism
Management of complications
Painful crisis
- Acute uncomplicated pain can be managed as an outpatient, with low dose opioids and community support with increased fluids and keeping warm.
- Over 90% of hospital admissions from sickle cell disease are due to the painful crisis.
- Hydroxycarbamide can reduce the frequency of painful crisis.
- General advice is for patients to avoid exposure to cold, fever, dehydration and stress.
- Infection must be ruled out as a precipitant
Acute Chest Syndrome
- Quick recognition is most important.
- Primary treatment includes oxygen and antibiotics.
- CPAP and occasionally ventilation is required.
- Exchange transfusion is used in severe cases. Hydroxyurea and periodic transfusion have been proven effective at preventing recurrences.
Priapism
- Priapism in the context of sickle disease is a medical emergency that requires prompt treatment including adequate hydration and analgesia.
- Patients are given advice to help with minor episodes, which can include bladder emptying, gentle exercise and warm baths.
- Oral etilefrine can reduce the frequency of attacks.
- Patient’s are advised to attend hospital if an episode lasts over 2 hours for which the treatment of choice is irrigation of the corpora cavernosa with adrenaline.
General management of sickle cell disease
Several studies confirm that an early diagnosis, antibiotic prophylaxis, regular blood transfusion, transcranial imagine, hydroxyurea and stem cell transplant are all accredited for improving mortality and morbidity for patients with sickle cell disease.
Care of the sickle cell patient should be managed at a specialist centre with regular outpatient review, and specialist advice sought for inpatients. Outpatient monitoring includes growth measurement, development and organ function, so that early intervention can be organised before organ failure occurs.
Other management can be subdivided into:
Long term complications
- Infection Patients are very prone to infection which can lead to osteomyelitis in some cases
- Stroke
- Nocturnal enuresis
- Heart failure: Diastolic dysfunction occurs in 13% of adults with sickle cell disease. Cor pulmonale can also occur due to pulmonary hypertension
- Chronic pain
- Chronic priapism
- Can lead to impotence
- Gallstones: these occur due to chronic haemolytic anaemia
- Chronic Leg ulcers
- Retinal haemorrhage & detachment
- Transfusion complications
- Avascular necrosis
- Chronic Kidney Disease
- Chronic organ damage: this occurs due to repeated vaso-occlusion and increased blood viscosity which can lead to liver and renal failure
- Neurological complications: these can be subtle but are important to recognise, as neuropsychological defects can be a cause of morbidity and are probably responsible for the decreased IQ seen in those with sickle cell disease compared to the normal population
Prognosis
Prognosis is as variable as the severity of the clinical disease.
Most patients have a life expectancy of 40-60 years, and with mild disease, this could be expected to be 60-70 years. However, in severe disease, substantial organ damage leads to early death. These figures are based on high-income countries and are likely to be much lower in lower-income countries.
The most common cause of death in infants is infection, with or without splenic sequestration. In adults, strokes, sepsis and acute chest syndrome are the leading causes of death.
References
- Sickle cell disease; NICE CKS, November 2016 (UK access only)
- Ballas SK, Kesen MR, Goldberg MF, et al; Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. ScientificWorldJournal. 20122012:949535. doi: 10.1100/2012/949535. Epub 2012 Aug 1.
- Piel FB, Steinberg MH, Rees DC; Sickle Cell Disease. N Engl J Med. 2017 Apr 20376(16):1561-1573. doi: 10.1056/NEJMra1510865.
- Significant haemoglobinopathies: guidelines for screening and diagnosis; British Committee for Standards in Haematology (Jan 2010)
- Sickle cell acute painful episode; NICE Clinical Guideline (June 2012)
- Sickle cell acute painful episode; NICE Quality Standards, April 2014
- Guideline on the management of Acute Chest Syndrome in Sickle Cell Disease; British Committee for Standards in Haematology (2015)
- Mousa SA, Qari MH; Diagnosis and management of sickle cell disorders. Methods Mol Biol. 2010663:291-307.
Written by Dr Ailsa Gemmell (IMT1)
Edited by Mudassar Khan (Y3 Medical student)
