Sickle cell disease (SCD), or sickle cell anemia, is a group of genetic conditions, resulting from the inheritance of a mutated form of the gene coding for the β globulin chain of the hemoglobin molecule, which causes malformation of red blood cells (RBCs) in their deoxygenated state. Specifically, this single point mutation occurs at position 6 of the β globulin chain, where a valine is substituted for glutamic acid (Ballas et al. 2012). This abnormal hemoglobin causes a characteristic change in the RBC morphology, where it becomes abnormally rigid and sickle-like, rather than the usual biconcave disc. These cells do not flow as freely throughout the circulatory system as the normal phenotype, and can become damaged and hemolysed, resulting in vascular occlusion (Stevens and Lowe 2002).
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SCD is an autosomal recessive condition, thus patients with SCD will have inherited a copy of the mutated gene from each of their parents (homozygous genotype). Individuals who only inherit one copy (heterozygous genotype) are termed sickle cell (SC) carriers, who may pass on the affected gene to their children (Stevens & Lowe 2002). The severity of SCD varies considerably from patient to patient, most likely as the result of environment or other unknown genetic factors (Bean et al. 2013).
Patients with SCD are typically of African or African-Caribbean origin, but all ethnic groups may be affected. In 2014 the National Institute of Clinical Excellence (NICE) estimated that between 12,500 and 15,000 people in the UK suffer from SCD (NICE quality standard 58, 2014), with more than 350 babies born with SCD between 2007 and 2008. Patients in developed countries typically live into their 40s and 50s. However in developing countries, it is estimated that between 50% (Odame 2014) and 90% of children die by the age of 5 (Gravitz and Pincock 2014).
SCD is more prevalent in the ethnic African population because SCD carriers exhibit a 10-fold reduction in severe malarial infection, which is common in many African countries and associated with significant mortality. One proposed mechanism for this is that on infection with the malarial plasmid, RBCs in SCD carriers become sickle shaped and are then removed from the circulation and destroyed. Consequently, it is genetically beneficial to be a SCD carrier, thus more SCD carriers survive to reproduction age, in turn increasing the incidence of the SCD mutation in the population. (Kwiatkowski 2005).
SC patients experience periods of acute illness termed “crises” resulting from the two different effects of SCD; vaso-occlusion (pain, stroke and acute chest syndrome) and those from hemolysis (for example, anemia from RBC destruction and inefficient oxygen carrying capacity) (Glassberg 2011). The frequency of these may be several times a week, or less than once a year. Patients typically present with anemia, low blood oxygen levels and pyrexia (NICE quality standard 58, 2014).
There are 3 classifications of crises:
1. Sequestration crisis (rapid pooling of RBCs in organs, typically the spleen, which may result in patient death from the acute reduction in available red cells for oxygen transportation).
2. Infarctive crisis (blockage of capillaries causing an infarction).
3. Aplastic crises (where the spleen is damaged from 1&2 which compromises RBC production (Stevens & Lowe 2002).
The result of these crises can be irreversible damage to a wide range of organs from the spleen to the retina which can cause extreme pain (Stevens & Lowe 2002). However, patients not currently experiencing a crisis can also present with anemia as the result of poor oxygen transport function, loss of RBCs due to sequestration in organs such as the spleen and reduced red cell production as the result of impaired spleen function (Ballas et al. 2012).
Typically, patients will initially present with an enlarged spleen in early childhood (due to pooling of malformed RBCs), which then becomes hypertrophied, ultimately resulting in a state of almost complete loss of function (autosplenectomy). Several complications of SCD are recognised, including impaired neurocognitive function, which is most likely the result of anemia or silent cerebral infarcts (Ballas et al. 2012).
In the UK, SCD is usually diagnosed antenatally or in the first few weeks of life. Prenatal screening is offered to parents who may be at risk of carrying the SCD causing gene. NICE recommend that screening is offered early in pregnancy for high risk groups (ideally before 10 weeks gestation) or via a family origin questionnaire in low risk groups. Full screening can then be offered if family history is suggested. In the case of a positive test, counselling should be offered immediately, and the parents offered the option of termination of pregnancy (NICE Clinical Guideline 62, 2014). However, if screening has not occurred, SCD is one of the diseases screened for by the newborn heel prick test in the first week of life (NICE quality standard 58, 2014). In older patients or those not in countries where screening is offered, patients present with anemia or acute crisis. Histological analysis of blood samples can also reveal sickle shaped RBCs and the characteristic abnormal hemoglobin can be identified by high performance liquid chromatography or electrophoresis (Glassberg 2011).
There are three approaches to treatment of SCD. The first is to manage the condition prophylactically in the hope of reducing the incidence of complications and crises. The second is to effectively manage crises, both to reduce the risk of organ damage and life threatening events, as well as control the severe pain associated with a SCD crisis. The third approach is to target the cause of the condition itself.
Penicillin (de Montalembert et al. 2011) and folic acid are usually offered to patients in order to prevent complications by bacterial disease and are associated with a significant increase in survival and quality of life (NICE quality standard 58, 2014). Children are also vaccinated against pneumococcal infection. Transcranial doppler imaging of the cerebral vessels can be used to identify children at risk of stroke (de Montalembert et al. 2011). As previously discussed, SCD carriers are conferred some protection from malarial infection. Paradoxically, SCD sufferers display an increased sensitivity to malarial infection and should also be treated with anti-malarial prophylaxis where appropriate (Oniyangi and Omari 2006).
Hydroxyurea has been used in the treatment of SCD, as it appears to increase the production of fetal hemoglobin (HbF), thus reducing the proportion of abnormal hemoglobin although the exact mechanism of this is unclear (Rang et al. 1999). Suggested mechanisms include induction of HbF by nitric oxide, or by ribonucleotide inhibition. Other suggested mechanisms include the increasing of RBC water content and reduced endothelial adhesion, which reduces the incidence of infarction (Charache et al. 1995).
Blood transfusion is an important tool in treating SCD, especially in children. It almost immediately improves the capacity of the blood to transport oxygen, and in the longer term as the “healthy” donor RBCs are not as destroyed as quickly as the sickle shaped RBCs, repeated transfusion is associated with a reduction in erythropoiesis (RBC production) in the SCD patient, thus reducing the proportion of sickle shaped RBCs in circulation, which in turn reduces the risk of a crisis or stroke. Exchange transfusion is also possible, whereby abnormal sickle RBCs are removed from the circulating volume prior to transfusion with donor blood. However there are drawbacks to transfusion, namely the inherent safety risks such as immunological sensitivity, contamination of blood products with infectious disease and a lack of available donated blood (Drasar et al. 2011).
The severe pain of a crisis must be controlled, most often with opioid analgesics. These are effective analgesics which act by binding to µ, κ and δ receptors. The common approach is intravenous infusion of morphine either by continuous drip or patient controlled analgesia (PCA) pump infusion. Non-opioid drug options, including paracetamol, tramadol and corticosteroids may also be considered, but these drugs have a limit to the analgesia they can produce, whereas opioid drugs are more often limited by their side effects, such as respiratory suppression, vomiting and itching (Ballas et al. 2012).
Bone marrow transplant is currently the only curative therapy for SCD. However it is dependent on locating a suitable donor with a HLA tissue match, usually from a healthy sibling. It is associated with some risks and complications including grant rejection, but generally is associated with a very positive prognosis (Maheshwari et al. 2014). As SCD is an autosomal recessive disease with one well identified causative gene, gene therapy to replace one copy of the faulty gene with a normal copy is of great interest to researchers. However this is very much still in development in humans and a 2014 review of SCD clinical trials found no trials of gene therapy as yet (Olowoyeye and Okwundu 2014)
In addition to the acute effects of SCD, patients are also at risk from a number of potentially fatal consequence of SCD such as acute splenic sequestration. In this condition, which often occurs after an acute viral or bacterial infection (classically parvovirus B19), the malformed RBCs become trapped in the sinuses of the spleen causing rapid enlargement. Patients will present with often severe abdominal pain and enlargement, pallor and weakness and potentially tachycardia and tachypnea. Patients may also suffer from hypovolemic shock from the significant reduction of available hemoglobin (acute aplastic crisis). This is managed by emergency treatment of the hypovolemia and transfusion of packed RBCs. Because the rate of recurrence for splenic sequestration is high (approximately 50%), a splenectomy may be performed after the patient has recovered from the event (NICE quality standard 58, 2014).
Acute chest syndrome is also a serious complication of SCD and may be fatal. It is characterised by the occlusion of the pulmonary blood vessels during an occlusive crisis. Patients typically present with chest pain, cough and low oxygen levels (Ballas et al. 2012). It is also associated with asthma, and it is recommended that asthma in patients with SCD be carefully monitored. Treatment of acute chest syndrome is usually by antibiotics, bronchodilators if indicated and transfusion or exchange transfusion also considered (de Montalembert et al. 2011).
Another consequence of rapid turnover of the abnormally shaped RBCs is the increased production of bile, which may cause hepatobiliary disease, specifically gallstones and vascular conditions of the liver. Liver pathology can result from ischemia-reperfusion injury following a crisis, endothelial dysfunction and overloading with iron as the result of the liver sequestering iron from the destroyed RBCs (Ballas et al. 2012). SCD patients are also at significant risk of ischemic stroke, resulting from a cerebral infarctive crisis, with one study suggesting that 11% of patients will suffer a stroke by 20 years of age, and 24% by 45. Children who suffer stroke may also go on to develop moya-moya syndrome, which is associated with s significant decrease in cognitive function and increased risk of further stroke (Ballas et al. 2012).
SCD is a complex condition and is associated with significant challenges in treatment as it requires the use of a multi-disciplinary team to cover the wide range of its affects and significant prophylactic treatments. As discussed, the effects of these potential complications can be life threatening and have life changing consequences.
An additional difficulty is that while screening, prophylactic and curative treatments are available in the developed world, they are not in the developing world where rates of the disease are in fact highest. In sub-Saharan Africa mortality is estimated to be between 50% (Odame 2014) and 90% (Gravitz & Pincock 2014) yet in developed counties life expectancy ranges from 40s to 50s (Gravitz & Pincock 2014). Currently, laboratory diagnosis and screening is prohibitively expensive in developing countries thus there is a need for the development of low cost techniques. The Gavi Vaccine Alliance also endeavors to make prophylactic treatment more available, specifically the pneumococcal vaccine. Of the therapies discussed here, hydroxyurea is likely to be the most affordable and increasing the availability of this would be of significant benefit and clinical trials have commenced in Africa in 2014 (Odame 2014).
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