homozygous and have sickle cell anaemia. Individuals inheriting βS from one parent, and certain haemoglobin variants (haemoglobin C, haemoglobin DPunjab, haemoglobin OArab, haemoglobin E, haemoglobin Lepore)or a β thalassaemia gene, from the other parent will also have a variant (compound heterozygote) form of SCD. There are many other variants detected on screening that are of no clinical significance when found in combination with haemoglobin S. Sickle cell carriers Individuals who inherit βS from one parent and the normal β globin gene from the other are referred to as carriers of sickle cell, or as having sickle cell trait. Their red blood cells contain haemoglobin A and haemoglobin S. Sickle cell carriers usually have no clinical symptoms and often do not know they are carrying βS unless they have a specific blood test. Chapter 1: Overview Standards for Clinical Care of Adults with Sickle Cell Disease in the UK, 2nd Edition 30 Epidemiology Although SCD occurs predominantly in individuals of African descent, these disorders are also prevalent in the Eastern Mediterranean, Middle East, India, the Caribbean and South and Central America. The common factor is a high prevalence of malaria in the area, or migration from a malarial area, because sickle carriers have partial protection from malaria and therefore a survival advantage. 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 around 12,500 – 15,000 individuals living with SCD. It is one of the most common single gene disorders in the UK. Pathophysiology Haemoglobin S polymerises when deoxygenated. The accumulation of intracellular haemoglobin polymers results in damage to the red cell membrane causing changes in permeability to cations. The red cell becomes dehydrated, more rigid and less able to negotiate the capillary circulation. The survival of red cells in SCD is significantly reduced resulting in a haemolysis (shortening of red cell life span). However, haemoglobin S releases oxygen to tissues more readily than haemoglobin A, and this may reduce the drive to erythropoiesis. Red and white cells and platelets adhere to the lining (endothelium) of the small vessels of the circulatory system resulting in vascular damage, organ infarcts and progressive ischaemic damage. This complex process of red cell adhesion and aggregation leads to blockage of the blood vessels, known as vaso-occlusion, which impairs blood flow and prevents effective delivery of oxygen to the tissues. This is thought to be the underlying cause of acute episodes such as painful crisis as well as chronic damage such as avascular necrosis of hips and renal failure. Narrowing and occlusion of larger vessels is thought to be caused by chronic sheer-damage and adhesion of blood cells to the vessel endothelium, complicated by vasoconstriction and nitric oxide deficiency. This mechanism is likely to be responsible for complications such as pulmonary hypertension and stroke. Clinical presentation SCD is an inherited condition, which can be diagnosed at birth. The UK has a universal newborn screening programme. Clinical complications do not occur at birth – or in the first few months of life - because the high proportion of intracellular foetal haemoglobin (haemoglobin F) inhibits haemoglobin S polymerisation. During the first year of life, the proportion of haemoglobin F decreases and the proportion of haemoglobin S increases within the red cells. Consequently, pathological effects of sickling start to occur. Chapter 1: Overview Standards for Clinical Care of Adults with Sickle Cell Disease in the UK, 2nd Edition 31 The most common clinical manifestations are chronic anaemia and recurrent acute pain episodes, which in adults typically affect the limbs and trunk. Other common clinical conditions include acute complications such as splenic sequestration, overwhelming sepsis, acute chest syndrome, priapism and stroke, and chronic complications such as lung disease, sickle nephropathy, pulmonary hypertension, avascular necrosis of the hips or shoulder joints, recurrent chronic leg ulceration and retinopathy. These are described in more detail in chapters below. Clinical course and survival In its most severe form, SCD causes significant morbidity and mortality. However, SCD is variable in severity and the onset of acute and chronic complications is unpredictable. This uncertainty can add to the psychological consequences of living with a life threatening chronic disease. It may also cause severe social disruption throughout the life course. As recently as the 1970s, a patient was not expected to survive to adulthood. Nowadays, childhood mortality is relatively rare, at least in developed countries, with 99% of children in the UK surviving to adulthood. This is a result of introducing a variety of health care interventions including neonatal screening and enrolment of affected babies in a comprehensive care programme, pneumococcal prophylaxis, and early recognition and better treatment of acute complications in children. Unfortunately, the current outlook for adults is not so encouraging, with estimates of median survival for sickle cell anaemia in the 40s. Single centre data from the UK have shown estimated median survival of 67 years in patients with sickle cell anaemia and higher in patients with sickle