What is Sickle Cell Disease (SCD)?
SCD is an inherited disorder of haemoglobin, the oxygen carrying molecule contained within red blood cells. Haemoglobin comprises four ‘globin’ protein chains, each wrapped around an iron -containing ‘haem’ group. Newborn babies have a type of haemoglobin called fetal haemoglobin (HbF). This is largely replaced by adult haemoglobin (HbA) in the first year of life. HbA consists of two alpha (α) globin chains and two beta (β) globin chains.
The sickle mutation is a substitution of C for A at codon 6 of the β globin gene (βS). The resulting exchange of valine for glutamic acid as the sixth amino acid in the β globin chain results in sickle haemoglobin (HbS). HbS, when deoxygenated, has a tendency to bind with adjacent haemoglobin molecules and to form polymers. These damage the red cell resulting in shortened red cell survival and impaired circulation. The clinical consequences of this sickling process include haemolytic anaemia, vaso-occlusive crises and chronic tissue damage. The resultant medical complications are acute pain episodes, respiratory failure (acute chest syndrome) and acute life-threatening anaemic episodes. In the longer-term chronic tissue damage may lead to stroke, visual impairment, early arthritis, or organ dysfunction (common causing renal, hepatic, or cardiopulmonary failure).
Individuals who inherit βS from both parents have homozygous SCD (HbSS), also called sickle cell anaemia. Individuals inheriting βS from one parent, and certain beta globin variants (HbC, HbDPunjab, HbOArab HbE, Hb Lepore or β thalassaemia) from the other parent have a compound heterozygote genotype of SCD.
Individuals who inherit βS from one parent and the normal β globin gene from the other are carriers of sickle cell (also referred to as sickle cell trait). Their red blood cells contain HbA and HbS. Sickle cell carriers usually have no clinical symptoms and may not be aware that they are carrying βS unless they have a specific blood test.
Although SCD occurs predominantly in individuals of African descent, these disorders are also prevalent in the Eastern Mediterranean, Middle East, India, Caribbean, South and Central America. The gene has persisted because carriers are partially protected against malaria and therefore have a survival advantage in parts of the world where malaria is common. In Sub Saharan Africa the gene frequency of βS ranges from 10% to 30%.
In England, SCD affects about 1 in 2000 live births and there are currently estimated to be about 12,500 individuals living with SCD. It is one of the commonest single gene disorders in the UK.
Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573.
Howard J and Telfer P. Sickle Cell Disease in Clinical Practice. Springer, 2015
National screening programme
The plan to establish a linked antenatal and neonatal screening programme in the NHS for SCD and thalassaemia was agreed in 2001 and implemented over the following ten years. It had the following aims:
- To support people to make informed choices before conception and during pregnancy
- To improve infant health through prompt identification of affected babies
- To provide high quality and accessible care throughout England
- To promote greater understanding and awareness of the disorders and the value of screening
Screening of newborns for SCD is part of the National Newborn Screening Programme in England. Testing is recommended on all babies using a heel prick bloodspot sample taken at 7 days of age. The aim is to identify babies before their first clinical presentation. Babies who move into the country are entitled to newborn screening up to one year of age.There was compelling evidence, particularly from the programmes in Jamaica and the USA, that early diagnosis could improve clinical outcomes and reduce mortality during childhood. Key interventions include parental education, early initiation of oral penicillin, administration of pneumococcal vaccination and transcranial Doppler screening.
Antenatal screening for SCD and thalassaemia is offered to all women in England as part of routine antenatal care. Testing for sickle cell carrier status is universal in high prevalence areas (more than or equal to 2% of antenatal screening samples received by the laboratory are screen positive) and targeted in low prevalence areas with risk assessed by determining the family origins of baby’s mother and father using a family origins questionnaire. Carrier mothers should be offered counselling and fathers invited for testing.
When both parents are carriers, the pregnancy is regarded as ‘at risk’ (1 in 4 chance of an affected child). Prenatal diagnosis (PND) is offered to at risk couples and women where the baby's biological father's result is not available. Women and couples found to have an affected fetus require further counselling. They are given information about living with sickle cell disease and the option to terminate the affected pregnancy.
Further information about the NHS sickle and thalassaemia screening programme can be found at https://www.gov.uk/topic/population-screening-programmes/sickle-cell-thalassaemia
National care programme
A national programme of care for SCD has been evolving over the past 10 years, structured around specialist haemoglobinopathy centres, local centres and regional care networks. Organization on a national level was recognised as necessary in order to ensure good quality care for infants identified in the newborn screening programme in all parts of the country, including those regions where clinical services were previously not well developed. There was also evidence of variability in quality of care in children and adults already diagnosed with the condition, leading to adverse outcomes which could potentially have been avoided. Some of this evidence was documented in ‘ A Sickle Crisis- A Report of the National Confidential Enquiry into Patient Outcome and Death, 2008
National service developments over recent years include
- The National Haemoglobinopathy Register (NHR). A database of patients with red cell disorders (mainly Sickle Cell Disease and Thalassaemia Major) living in the UK. This collects data, which is required by the Department of Health from Haemoglobinopathy centres. The central aim of the registry is to improve patient care. Further information can be found at this website
- The West Midlands Quality Review Service, in collaboration with the UK Forum on Haemoglobin Disorders, has organised a national programme of peer review visits of health services caring for both adults and children and young people with Haemoglobin Disorders. The most recent reviews took place between October 2014 and March 2016. The joint Quality Standards for the review programme, self-assessment and process paper used for this review programme are available here
- Standards of Care for Children. (Second Edition October 2010). Accessible here
- Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK. (Second Edition 2018).
- Specialised commissioning for haemoglobinopathy services. NHS England is actively involved in developing high quality and accessible treatment through specialised commissioning of haemoglobinopathies (adult and children). A service review, overseen by a Clinical Advisory Group is currently in the consultation phase. Further information can be found here
Current standard of care
Management of SCD involves education and support of parents carers and patients, attention to health and life-style in order to stay healthy, prophylactic treatments, and management of acute and chronic complications. National management guidelines for children and adults with SCD are available (See above).
Currently there are limited treatment options to treat or cure SCD. Hydroxycarbamide (HC) is an oral agent which has been shown to reduce the frequency and severity of acute pain episodes and acute chest syndrome in both children and adults. It can have a significant benefit on a number of other symptoms of SCD, and improve quality of life. Long-term use is expected to reduce the risk of chronic complications and improve survival, but further studies are needed to demonstrate these benefits. Side effects include reduced white cell count and platelet count, skin pigmentation and thinning of hair. There are some reports of reduced sperm count in men taking HC, and patients should be made aware of a potential effect on fertility.
Regular blood transfusion can also be an effective means of reducing the severity of acute and chronic complications of SCD, and is increasingly used for patients at risk of complications such as stroke, and for those whose condition is not well controlled on HC. Chronic simple transfusion and iron chelation is suitable for younger children. For older children and adults, automated exchange transfusion is generally preferred. A NICE medical technology guidance for an automated exchange transfusion methodology has recently been published
Allogeneic stem cell transplantation is available on the NHS for children up to the age of 18. It is generally recommended for children with severe disease who have an HLA-matched sibling donor. Alternative donor or haplo-identical transplantation is sometimes considered for children with progressive cerebral ischaemia and/or vasculopathy whose condition cannot be stabilised on standard transfusion therapy.
New therapeutic products and procedures
At present there are a number of products at different stages of drug development, targeting different disease mechanisms and SCD complications. Several Phase 2 and Phase 3 trials are open to patients treated in UK centres. Information on current trials can be accessed here.
Basic research and clinical trials using different approaches to Gene therapy for SCD are progressing, and there is cautious optimism that the gene therapy approach will provide another means of curing SCD in the future. The first patient successfully treated was reported in 2017 in France. It is likely that clinical trials of gene therapy for SCD will begin in the UK in the next 1-2 years.
BSH would like to thank Dr Paul Telfer for writing this article
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