4 The clinical features of sickle cell disease

4 The clinical features of sickle cell disease G R A H A M R. SERJEANT

A MOLECULAR CHANGE A single base change in the nucleotide triplet of the genetic code from GAG to GUG dictates the substitution of valine for glutamic acid at position 6 from the amino-terminus of the [3-globin chain and determines the consequences of sickle cell disease. Such amino acid substitutions in the polypeptide chains of haemoglobin are not uncommon but the unusual aspect of the substitution giving rise to sickle haemoglobin (HbS) is that it confers a survival advantage in areas of falciparum malaria. Children carrying the HbS mutation (sickle cell trait) have a relative resistance to malaria during a critical period of early childhood (Allison, 1957), They are consequently more likely to survive, breed and pass on their genes, and over generations, the sickle cell trait became common in malarial areas. The initial distribution of the sickle cell gene was determined by two factors, the occurrence of the HbS mutation and the presence of malaria to act as a selective factor, these conditions occurring in Equatorial Africa, the Arabian peninsula and central India. This primary distribution was modified in ancient times by gene flow around the Mediterranean to northern Greece, southern Turkey and Sicily, by the slave trade 150-350 years ago and in the last 30 years by voluntary migration from the Caribbean and Africa to Europe especially the United Kingdom, France, Belgium and the Netherlands and from Turkey to Germany.

I~-GLOBIN HAPLOTYPES Studies of DNA structure surrounding the [3-globin locus suggest that the HbS mutation has become superimposed on a variety of different ancestral DNA structures and their possible evolutionary significance is discussed in Chapter 8. These genetic subgroups are called 13-globin haplotypes and are named after the areas or populations where they were originally identified, the Senegal haplotype in Atlantic West Africa, the Benin in West Africa and the Bantu or Central African Republic haplotype in Central and East Africa (Chebloune et al, 1988). To these African forms may be added the Asian haplotype characterizing the disease in the Eastern Province of Saudi Arabia and central India (Kulozik et al, 1986). Most of the populations of Bailli~re' s Clinical Haematology--

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African origin occurring in North and South America, the Caribbean and Europe are of the Benin haplotype which also characterizes the disease occurring in Sicily, Greece, Turkey and the south west of Saudi Arabia. The potential clinical interest of these haplotypes is their influence on clinical and haematological expressions of the disease (Nagel et al, 1987, 1991; Schroeder et al, 1989) and the mechanisms of such effects (see section on Variability of clinical features). BALANCED POLYMORPHISM

The survival advantage of HbS in the heterozygote is offset by the deleterious consequences of high levels of HbS in the homozygote and in doubly heterozygous conditions in which HbS is associated with HbC, or the traits for 13°- or 13+-thalassaemia. In these conditions in which the percentage of HbS is 50% or greater, deoxygenation of the molecule results in a tendency to form long polymers distorting the cell and raising the intracellular viscosity. Cells containing high levels of HbS lack the fluidity or membrane pliability to traverse the capillary beds with the result that they undergo premature destruction and may block blood flow with ischaemia or necrosis of the tissue supplied. The pathological processes of the disease are mostly attributable to the basically independent but closely related mechanisms of chronic haemolysis and vaso-occlusion. Haemolysis is generally well tolerated but vaso-occlusion may lead to severe organ impairment and premature death. The increased mortality of HbS homozygotes creates a selective loss of HbS genes which offsets the survival advantage of heterozygotes producing a relatively steady gene frequency in a population, a concept known as balanced polymorphism (Allison, 1954). HAEMOLYSIS Anaemia

Red cell destruction is accelerated in all genotypes of sickle cell disease, the normal red cell survival of 120 days being reduced to 20-30 days in mild haemolytic conditions such as sickle cell-haemoglobin C (SC) disease and S13+-thalassaemia and to 5-15 days in the more severe haemolysis of homozygous sickle cell (SS) disease and S13°-thalassaemia. The accelerated haemolysis is compensated for by an expansion and increased turnover of erythropoietic precursors. Bone marrow space is expanded in the long bones, spine, pelvis and facial bones leading to cortical thinning, diploic expansion and enlargement of the maxilla resulting in a prominent upper gum and teeth and occasionally anterior angulation of the teeth known as gnathopathy. Increased metabolic demands

This expanded bone marrow has high metabolic demands both in terms of

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haematinics such as iron, folic acid and protein but also oxygen so that transient obstruction or shunting away of blood supply from the active marrow may result in its necrosis and the bone pain associated with dactylitis and the painful crisis. Of the metabolic demands, the iron requirements are usually met by recycling of iron unless iron stores are depleted by nutritional deficiency, blood loss or repeated pregnancies. Fo/ate Folate requirements are markedly increased and the outcome depends on dietary availability. In West Africa, dietary folate content is low and folate deficiency is common even with the erythropoietic stress of pregnancy in normal women. In this environment, folate deficiency with consequent megaloblastic change commonly complicates SS disease in childhood (Watson-Williams, 1962) and routine daily folate supplementation is logical and cost effective. In Jamaica, on the other hand, dietary folate availability is good and megaloblastic change in SS disease is unusual (Rabbet al, 1983), except in the wake of natural disasters such as Hurricane Gilbert (Readett et al, 1989). In this environment, routine folate supplementation does not appear justified and the risks of psychological dependence on folic acid must be avoided. Policies on folate supplementation, therefore, need to be tailored to local conditions.

Energy The metabolic cost of the increased consumption of amino acids and calories has only been recently recognized with an approximate 20% increase in resting metabolic rate (Singhal et al, 1993). The syndrome of hypersplenism in which an additional haemolytic load and further marrow expansion is superimposed upon the already increased requirements of SS disease offers an elegant model in which splenectomy can reverse the effects of this additional load. Growth may slow or cease in hypersplenic children and a growth spurt follows splenectomy (Singhal et al, 1993) which is also associated with a 25% reduction in protein turnover (Badaloo et al, 1991). The relationship of the metabolic demand of the expanded bone marrow to the growth abnormalities common in SS disease is an area of interest which remains to be explored.

Aplastic crisis The expansion and increased turnover of erythropoietic precursors in SS disease maintains haemoglobin levels of 6-9 g/dl with proportional reticulocyte counts of 5-15% in most patients with African forms of the disease. Infection by human parvovirus destroys erythropoietic precursors leading to an absence of reticulocytes and a fall in haemoglobin level of approximately 1 g/day (Serjeant et al, 1981). The marrow aplasia in the aplastic crisis is self-limited and spontaneously recovers after 7-10 days but, without treatment by transfusion, some patients with SS disease die before marrow

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recovery. Aplastic crises are virtually all attributable to human parvovirus infection, occur in epidemics, affect children usually under 15 years, and cluster in families. Recurrence rarely, if ever, occurs and a parvovirus vaccine is under development. Gallstones

The rapid breakdown of the haemoglobin molecule in haemolysis generates increased bilirubin excretion reflected both in clinical jaundice and an increased tendency to gallstone formation. Gallstones are generally of calcium bilirubinate, small and multiple, and occur in approximately 30% of SS children by the ages of 15-17 years (Webb et al, 1989). Most are asymptomatic but they may be associated with acute or chronic cholecystitis or obstruction of the common bile duct. Cholecystectomy is indicated if specific symptoms develop but asymptomatic stones should be treated conservatively since the frequency with which specific symptoms develop is unknown. BONE MARROW NECROSIS

Dactylitis and the painful crisis are also to some extent a consequence of the erythropoietic expansion. Both result from avascular necrosis of bone marrow and the pain is presumed to reflect the increased intramedutlary pressure associated with the ensuing inflammatory process. In both conditions, the pain is confined to sites occupied by active bone marrow. Dactylitis

In childhood the small bones of the hands and feet are affected, and the clinical picture of dactylitis (hand-foot syndrome) causes a painful swelling which may vary from one segment of a single finger to involvement of all four extremities. This is often the first manifestation of sickle cell disease (Watson et al, 1963) occurring from 3-4 months and becomes increasingly uncommon after the age of 5 years when active bone marrow withdraws from the peripheral small bones. Painful crisis

At later ages, active marrow becomes localized to the juxta-articular areas of the long bones, flat bones such as the sternum, ribs and pelvis, and the vertebral column. This is also the distribution of pains in the painful crisis which, although often interpreted as the joints, generally involves the juxta-articular areas of the long bones. The painful crisis is one of the most characteristic features of the disease and a major problem in adolescents and young adults, leading to multiple hospital admissions each year in some patients. Painful crisis frequency increases markedly in males between 15 and 25 years (Baum et al, 1987) and decreases in frequency and severity over

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the age of 30 years, disappearing completely over the age of 40 years in many patients. Risk factors for painful crises include a high haemoglobin (Baum et al, 1987; Platt et al, 1991) and the last trimester of pregnancy. A high level of fetal haemoglobin (HbF) may be protective (Platt et al, 1991) although painful crises are a major manifestation of the disease in some populations with high HbF levels such as the Eastern Province of Saudi Arabia. Many patients recognize clearly defined precipitating factors which include cold exposure, exercise, stress and infections and avoiding such factors may reduce the frequency of pains. Treatment of established painful crisis is traditionally based on warmth, rest, hydration and effective pain relief, although there are concerns over the repeated use of potentially addictive narcotic agents. The cause of bone marrow necrosis was assumed to be vaso-occlusion of the bone marrow blood supply by sickled cells, but conditions with less intravascular sickling, such as SS disease with homozygous oL+-thatassaemia and S[3°-thalassaemia, have more rather than less painful crises (Bailey et al, 1991). Furthermore, random vaso-occlusion fails to explain the frequently bilateral pattern of bone pains or the common relationship with skin cooling. A recent hypothesis proposes that skin cooling may initiate reflex changes in the distribution of blood flow which results in a centrally mediated reflex shunting of blood away from the bone marrow (Serjeant and Chatmers, 1990).

Hip disease Avascular necrosis of the femoral head is another form of bone marrow necrosis with particular implications because of its critical site and function. The clinical outcome depends upon the age at infarction, and whether it affects the immature capital epiphysis or the mature femoral head. Infarction of the capital epiphysis usually before the age of 18 years results in softening of the epiphysis which, with continued weight-bearing, softens into a mushroom shape. The acetabulum moulds to fit the new-shaped femoral head, the femoral neck is widened, a good joint space is preserved and the joint generally functions well. Infarction of the mature head is usually segmental, most commonly the anterosuperior aspect and continued weight-bearing leads to fractures of the articular surface and depression of the softened avascular segment. The joint space is narrowed and there is often a painful limitation of adduction because the remaining normal lateral portion of the femoral head projecting in a cephalic direction strikes the lateral margin of the acetabulum on attempted adduction. There may be real shortening of the leg with limp from the caudal migration of the weight-bearing medial and damaged portion of the femoral head. Risk factors for femoral head necrosis include a high haemoglobin level (Hawker et al, 1982; Milner et al, 1991), low mean cell volume, low aspartate aminotransferase, and frequent painful crises (Milner et al, 1991). Alpha thalassaemia appears to be an independent risk factor but only at low haemoglobin levels (Ballas et al, 1989; Mitner et al, 1991). A very high frequency of avascular necrosis of the femoral head has been reported from Saudi Arabia (Padmos et al, 1991) which was not attributable to the high

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frequency of a thalassaemia in that area and the risk factors for this are currently unknown. Magnetic resonance imaging appears to be the most sensitive method for early diagnosis (Genez et al, 1988). Effective treatment depends on early diagnosis before articular surface damage develops, at which stage avoidance of weight-bearing may allow healing. Treatment at later stages may require remodelling of the femoral head or total hip replacement, although experience with arthroplasty in sickle cell disease suggests a high failure rate (Hanker and Amstutz, 1988). Core decompression, advocated in other forms of avascular necrosis (Hungerford, 1989), has not been assessed in sickle cell disease. Avascular necrosis of other bones

Avascular necrosis of other bones affects most commonly the intermediate segment of long bones between the two principal blood supplies, the nutrient artery and the perforating synovial branches. This pathology shares with the painful crisis a common mechanism of bone marrow necrosis, but differs because of the greater degree and more localized nature of the damage. Sites commonly affected are the upper third of the tibia, the upper or lower third of the radius or ulna, and the lower third of the humerus. There is usually local tenderness, swelling, and at superficial sites, a palpable periosteal elevation. Lesions are generally single, but may be multiple, and occasionally affect a whole bone such as the humerus or clavicle. Osteomyelitis

Osteomyelitis in sickle cell disease is most frequently caused by salmonella (Diggs, 1967). It has a similar distribution to that of avascular necrosis and probably represents chance colonization of dead bone following a transient salmonella bacteraemia. Differential diagnosis from uninfected avascular necrosis is unsatisfactory but based on greater swelling, greater radiological change, more marked systemic disturbances such as fever, and isolation of the organism from blood cultures, sinuses or direct bone drainage. Combinations of scintigraphic techniques (Amundsen et al, 1984; Koren et al, 1984; Kim et al, 1989) may provide earlier more sensitive diagnosis. The frequency of salmonella osteomyelitis in a population with sickle cell disease probably reflects the frequency of salmonella carriage in the general population, and is high in West Africa and in Saudi Arabia and relatively low m North America. In Jamaica there is a clinical impression that new cases of salmonella osteomyelitis are less frequent than 20 years ago, possibly reflecting a general improvement in health standards.

THE SPLEEN

The spleen is central to much of the early pathology in sickle cell disease. It has a complex vascular system uniquely capable of detecting abnormal red

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cells which are required to squeeze through openings in the basement membrane between adjacent endothelial cells, in order to enter the splenic sinuses and gain access to the general circulation again. This interaction between the relatively undeformable cells in SS disease and the splenic sieving function contributes to splenomegaly, an early loss of splenic function expressed in a susceptibility to pneumococcal septicaemia, acute splenic sequestration, hypersplenism and splenic atrophy.

Splenomegaly The spleen is not palpable at birth but becomes so during the first year of life in approximately 70% of children with SS disease (Rogers et al, 1978). Splenomegaly develops earliest in children with the lowest HbF levels (Stevens et al, 1981), suggesting that it is consequent on the production of low HbF containing poorly deformable red cells. There is then a pattern of progressive splenic disappearance proceeding more slowly in patients with homozygous c~÷-thalassaemia (Higgs et al, 1982) and high HbF levels (Serjeant, 1970), both factors inhibiting intravascular sickling and allowing the splenic vasculature to persist. Splenic atrophy is a common finding at autopsy but cannot be inferred from the disappearance of splenomegaly, since the spleen may remain clinically impalpable but visible on ultrasonography for many years.

Functional asplenia and pneumococcal septicaemia Even the enlarged spleen may lose the function to take up 99mTc sulphur colloid as early as the first year of life (Pearson et al, 1979). This dissociation of splenic size and function (functional asplenia) was originally advanced by Pearson et al (1969) who found that it could be reversed by transfusion in young children (Pearson et al, 1970). The loss of splenic function, as indicated by 99mTc colloid scans, correlates with other indices of splenic dysfunction, such as pitted red cell counts and clearance of heat-damaged autologous red cells. It also relates to the susceptibility to pneumococcal septicaemia which is greatest in patients developing splenomegaly earliest (Rogers et al, 1978), and by inference those losing splenic function earliest. Pneumococcal septicaemia is predominantly a problem of early childhood, 80% of infections in Jamaica occurring before the age of 2 years (John et at, 1984). Infection may be prevented by penicillin prophylaxis either parenterally (John et al, 1984) or orally (Gaston et al, 1986) and all children with SS disease should commence prophylaxis from the age of 4-6 months. The optimal duration of prophylaxis is unclear and under assessment. Stopping penicillin at age 3 years is too early and was followed by a cluster of septicaemias in Jamaica (John et al, 1984). The currently used protocol in Jamaica is penicillin from 6 months to 4 years with the 23 valent vaccine at 2 years and a booster dose at 4 years before stopping penicillin. In the USA, trials are underway stopping penicillin at age 5 years or continuing indefinitely, but results are not yet available.

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Acute splenic sequestration Acute splenic enlargement trapping the circulating red blood cells and causing an acute life-threatening fall in haemoglobin level was one of the commonest causes of early mortality in the Jamaican cohort study. These events tended to be recurrent with decreasing intervals and increasing mortality on recurrences. The precipitating factors for these events are unknown but patients with low H b F levels appear at greater risk (Stevens et al, 1981). Treatment of the acute episode depends upon early diagnosis and immediate transfusion. In Jamaica, it is usual to perform prophylactic splenectomy after two severe attacks of acute splenic sequestration and parents have been successfully trained to palpate spleens and diagnose events. The combination of parental diagnosis allowing earlier intervention and prophylactic splenectomy has decreased mortality of this condition by approximately 90% (Emond et al, 1985).

Chronic hypersplenism Chronic splenic enlargement may be associated with chronic splenic sequestration of red cells (Jandl et al, 1956), marked decreases in red cell survival and expansion of the bone marrow to maintain haemoglobin levels at a new equilibrium well below steady-state values. Reticulocytes are increased and platelets and white cell counts lowered compared with previous steady-state values. Definition of hypersplenism is necessarily based on arbitrary criteria but the working definition used in Jamaica includes a spleen of 4 cm or more below the left costal margin, a haemoglobin level below 6.0g/dl, reticulocytes above 15% and platelet counts below 260 x 109/1. Such patients frequently have a mean red cell survival of 2-3 days and are consequently at great risk from superimposed aplastic crisis or acute splenic sequestration. The intense erythropoietic expansion produces bony changes, most obvious in the facial bones such as the maxilla and the enormous metabolic demands of this bone marrow compete with those of growth so that growth may cease. The thrombocytopenia may lead to life-threatening haemorrhage. Despite all these potential complications, the tendency in the past has been for conservative treatment with chronic transfusion while awaiting spontaneous resolution and eventual splenic atrophy. Jamaican experience suggests that the cost of this conservative approach is too high and most cases if greater than 6 months duration are treated by splenectomy. This causes an immediate marked improvement in haematology and red cell survival and is usually followed by a growth spurt for 6-12 months. All patients are given pneumococcal vaccine before splenectomy and prophylactic penicillin for 3 years following the operation. Hypersplenism appears common in India (Kar et al, 1986) and Saudi Arabia (Padmos et al, 1991), both populations characterized by high levels of HbF and frequent e~+-thalassaemia and one of these factors is usually associated with hypersplenism in Jamaica. Both factors also favour the persistence of splenomegaly but this may occur without the features of

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hypersplenism. The relationship between splenomegaly, acute splenic sequestration and chronic hypersplenism and the nature of the differences between acute and chronic splenic sequestration remain to be explored.

THE LUNGS Acute chest syndrome

The lungs are frequently affected in sickle cell disease and the acute chest syndrome is the commonest cause of death at all ages after 2 years (Thomas et al, 1982). The acute chest syndrome represents a spectrum of pathology including infection, infarction and pulmonary sequestration in which the relative contributions of the individual components are difficult to quantitate. Patients with 'pneumonia' run more complicated courses than pneumonia in otherwise normal people (Petch and Serjeant, 1970), and it seems likely that primary infection may develop secondary areas of infarction and primary infarction becomes secondarily infected, a combined pathology possibly accounting for the slow resolution on treatment and the difficulty in establishing a clear diagnosis. Pulmonary sequestration

The third component of the acute chest syndrome, pulmonary sequestration, is better defined. Acute cases may undergo rapid clinical and radiological deterioration, and steeply falling oxygen saturation levels below 80% are a bad prognostic sign requiring emergency exchange transfusion following which there may be the most dramatic improvement in clinical status, oxygen saturation and chest radiology. Radiological findings of a complete 'white out' may clear almost completely within 24 hours along with the clinical improvement. Such readily reversible pathology is unlikely to be infective or infarctive in origin and it is presumed that extensive sequestration had occurred within the pulmonary capillaries, interfering with gas exchange, leading to further desaturation, sickling and more sequestration. Autopsies in some patients have revealed pulmonary arterioles strikingly distended with tightly packed aggregates of sickle cells (Diggs, 1973) and it is presumed that in some cases exchange transfusion is able to overcome and reverse these changes. Bone marrow embolism

Bone marrow embolism is another clearly defined entity in which severe painful crisis or avascular necrosis of bone may be followed by the embolism of avascular bone marrow with fatty globules which may be seen in the lungs, eyes, brain and urine. Most cases have occurred during pregnancy (Hendrickse and Watson-Williams, 1966) and there is usually a stormy clinical course, rapidly developing desaturation and a high mortality.

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Chronic pulmonary fibrosis Apart from the acute chest syndrome, pulmonary fibrosis and other chronic changes may occur. The frequency with which these changes cause elevation in pulmonary artery pressure is unknown but cor pulmonale secondary to pulmonary hypertension although described, seems uncommon (Collins and Orringer, 1982). However, chronic fibrosis may limit the exercise capacity of patients, and chronic lung disease has been reported as an important determinant of morbidity and mortality in some populations (Powars et al, 1988).

THE KIDNEYS The kidneys with their extensive blood supply sustain medullary damage early in life, impairing renal tubular functions and contributing to haematuria and developing extensive glomerular disease in later life leading to chronic renal failure.

Medullary changes Within the renal medulla, the low oxygen tension, acid pH and hypertonicity are all uniquely conducive to sickling and the elegant microradioangiographic studies of Statius van Eps et al (1970) have demonstrated the damage and disorganization of the v a s a r e c t a e system. The countercurrent multiplier system for maintaining a hyperosmolar medulla is consequently ineffective with inability to concentrate the urine leading to polyuria, nocturia and possibly contributing to the enuresis common in children with SS disease. A variety of other abnormalities in tubular function are also recognized (Ho Ping Kong and Alleyne, 1968, 1971; Goossens et al, 1972). These tubular changes are widespread but do not appear to cause serious morbidity or mortality from the disease.

Giomerular changes On the other hand, glomerular changes may cause chronic renal failure which is a major contributor to or cause of death, especially in patients aged over 40 years. This renal failure is predominantly due to glomerular obsolescence the cause of which is not understood. In young children, glomerular filtration rates exceed normal (Etteldoff et al, 1955) and glomerular size is significantly greater than in normal controls (Elfenbein et al, 1974). In adults, this glomerular filtration rate declines at a much faster rate than in normal controls and glomerular fibrosis or obsolescence occur. One theory reconciling these observations proposed that glomerular damage results from hyperfiltration. If so, children with the highest glomerular filtration rates might be expected to manifest the most rapid age-related declines in glomerular filtration rate, the greatest degree of glomerular obsolescence and the earlier renal failure but currently there are no data providing direct support for the hypothesis. The definition of renal

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failure may provide a further problem in SS disease since the distribution of serum creatinine levels is lower than normal, possibly because of lower creatinine synthesis secondary to the lower muscle mass or the expanded plasma volume. Creatinine levels in the high normal range in SS disease may represent a considerable elevation compared to steady-state levels and reflect significant renal impairment. Clinically, patients with chronic renal failure may remain in apparently good health for years and progressive renal impairment may only be apparent from serial biochemistry or gradually falling haemoglobin levels associated with erythropoietin deficiency (Morgan et al, 1982). Haemoglobin levels in the 5-7 g/dl range may be well tolerated, but lower levels may result in exercise intolerance and cardiac failure requiring treatment by either erythropoietin or transfusion. End-stage renal impairment may require haemodialysis or peritoneal dialysis and patients may respond well to renal transplantation (Cruz et al, 1982), although sickle nephropathy may develop in the transplanted kidney (Miner et al, 1987). CENTRAL NERVOUS SYSTEM Stroke

Stroke occurs in approximately 8% of patients with SS disease and is most common between 3 and 10 years (Balkaran et al, 1992). The pathology is usually cerebral infarction although subarachnoid haemorrhage from berry aneurysms is also more frequent than expected. The pathological basis of cerebral infarction may be narrowing or occlusion of vessels arising from the Circle of Willis but a surprisingly common finding is occlusion of major vessels such as the carotid or vertebral arteries. The mechanism of the occlusion of such large vessels in a disease characterized by small vessel occlusion is still unknown. Hemiplegia is the most common manifestation and between half and two-thirds of cases develop recurrence within 3 years of the initial lesion (Powars et al, 1978; Balkaran et al, 1992). Risk factors may include a low HbF level (Powars et al, 1980), preceding meningitis (Seeler and Royal, 1980), upper airway obstruction (Robertson et al, 1988; Davies et al, 1989) and high white cell counts (Balkaran et al, 1992) and precipitating factors include acute anaemia and painful crisis (Balkaran et al, 1992). Currently, treatment depends on prevention of recurrence by chronic transfusion programmes and chelation to prevent iron accumulation. The optimal duration of transfusion is unknown and a high recurrence rate may follow cessation of transfusion (Wilimas et al, 1980; Wang et al, 1991). Bone marrow transplantation may conceivably be justified in patients prone to recurrent strokes. There is currently no way to predict or prevent initial episodes. Recent developments of interest include transcranial Doppler ultrasonography to detect stenosis of cerebral blood vessels which may be predictive of stroke (Adams et al, 1992) and of a possible predictive role of upper airway obstruction and snoring secondary to tonsillar hypertrophy (Davies et al, 1989).

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Eyes The most important consequence of vaso-occlusion in the eye is ischaemia of the peripheral retinal vasculature and proliferative sickle retinopathy (PSR). Proliferation of abnormal vessels affects predominantly the extreme retinal periphery and may cause vitreous haemorrhage with transient visual impairment or retinal detachment with permanent blindness. Proliferative sickle retinopathy is most common in an otherwise relatively benign genotype, sickle cell-haemoglobin C (SC) disease in which the frequency may be as high as 75% (Condonet al, 1980). This unexpected observation suggests that PSR is not simply a consequence of vaso-occlusion but may represent a manifestation of mildness in the sense that this abnormal capillary bed has not been spontaneously occluded. Thus, patients with PSR could be viewed as having sufficient vaso-occlusion to cause peripheral retinal ischaemia and a stimulus to PSR formation but not enough to infarct the abnormal vessel systems as they develop. Concerns on the dangers of visual loss from PSR have led to a series of treatments including diathermy and cryopexy, and therapeutic trials with feeder vessel photocoagulation by xenon arc or argon laser, and sectoral retinal ablation by argon laser. Controlled trials have shown the latter to significantly reduce visual loss from vitreous haemorrhage (Father et al, 1991; Jampol et al, 1991) without the high frequency of choroidal neovascularization which attended feeder vessel treatment by xenon arc (Jampol et al, 1983). These trials have highlighted the ignorance of the natural history of PSR which in the great majority of patients either undergoes autoinfarction or fails to progress and does not threaten vision. Perhaps a more important goal at present is a greater understanding of this natural history and of its determinants so that patients at risk of progression and visual loss may be identified and treated leaving untreated those likely to undergo spontaneous autoinfarction.

Genitourinary system Males

Sexual development is commonly retarded and there is evidence of hypogonadism in SS adults with significantly lower testosterone levels and a poor response to gonadotrophin-releasing hormone (GnRH) suggestive of relative target organ failure (Prasad et al, 1981). Priapism is c o m m o n and presents two forms, stuttering nocturnal attacks lasting 2-6 hours with normal intervening sexual function and major attacks lasting more than 24 hours and usually followed by impotence. Stuttering attacks are predictive of major episodes (Emond et al, 1980) and may be prevented by stilboestrol (Serjeant et al, 1985). Major attacks need pain relief and urgent decompression most readily achieved by cavernosus spongiosum shunts. Impotence is due to failure of the vascular erectile system and intercourse may be satisfactorily achieved by the insertion of a simple penile prosthesis (Douglas et al, 1990).

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Females

Sexual development is retarded in females, the mean age of menarche occurring approximately 2.5 years later than in Jamaican controls (Graham et al, 1986) and accounted for predominantly by the subnormal weight of SS patients (Platt et al, 1984). There are no convincing data to support the frequent claims of infertility in SS disease, the interval between first sexual exposure and pregnancy being similar to normal controls (Alleyne et al, 1981). Pregnancy has higher risks for both mother and fetus. Fetal wastage is increased from abortions, still births, and neonatal deaths and children born to mothers with SS disease have significantly lower birth weight (Charache et al, 1980; Milner et al, 1980). During pregnancy, mothers are more prone to painful crises, especially in the last trimester and immediate postpartum period, and also to the acute chest syndrome which is the greatest cause of morbidity and mortality. Regular antenatal monitoring and hospital delivery of SS mothers is strongly advisable. Partial exchange transfusion has been advocated in the management of pregnancy (Morrison et al, 1980) but a controlled trial failed to show benefit in fetal outcome, although there was improvement in maternal morbidity (Koshy et al, 1988). Effective contraception is essential for SS patients desiring to avoid further pregnancy and is frequently denied on the basis of theoretical dangers. There can be little doubt that any theoretical risks of contraception are far outweighed by the real risks of pregnancy and patients should be offered the best contraceptive means available. Oral contraceptives are most widely acceptable but injections of medroxyprogesterone acetate have been shown to confer clinical and haematological benefit (De Ceulaer et al, 1982) in addition to reliable contraception. Intrauterine devices may also be used and there is no evidence of increased risk of uterine infection and tubal ligation should be offered for patients desiring permanent contraception.

CHRONIC LEG ULCERATION Chronic leg ulceration is rarely a cause of mortality, but persists as a major cause of morbidity, especially in Jamaica where the prevalence reaches 75 % (Serjeant, 1974). Prevalences elsewhere appear much lower, leg ulceration being rare in India (Kar et al, 1986), absent in Saudi Arabia (Padmos et al, 1991), and affecting 5% in the USA (Koshy et al, 1989). Leg ulcers develop most commonly between 10 and 20 years and typically run a healing/ relapsing course over many years. Onset may be traumatic or nontraumatic, the latter starting as small deep painful lesions suggestive of skin infarction. Rarely associated with tetanus, or other serious medical complications, the major impact of chronic leg ulceration is on education, employment and social relationships. In Jamaica, there is a direct relationship between age at onset of leg ulceration and educational attainment (Alleyne et al, 1977) and much of the morbidity of leg ulceration could be prevented by a greater understanding of this complication by patients and the

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community. Treatment is generally unsatisfactory and depends on keeping ulcers clean and relieving the effects of venous and lymphatic stasis by supportive dressings. Debridement may be necessary and oral zinc sulphate improves the healing rate (Serjeant et al, 1970). Skin grafting is disappointing and has a high recurrence rate. The spontaneous type of ulcer believed to be due to skin infarction heals relatively quickly but all ulcers are prone to spontaneous or traumatic occurrence and care should be taken to protect the skin around the ankles, especially scars, from further trauma.

GROWTH AND BODY HABITUS

Growth and body habitus may be affected in SS disease, although the mechanisms are only now beginning to be understood. As a population, SS patients tend to have subnormal weight throughout life, the difference reaching significance before 2 years of age (Stevens et al, 1986). Height is more complex, being subnormal in childhood, the difference becoming marked in adolescence when normal children enter puberty and the puberty-associated growth spurt approximately 2.5 years before the mean age in SS disease. Cessation of longitudinal bone growth by epiphysial fusion is also delayed in SS disease, the ultimate height being determined by the degree of delay. Thus, low levels of HbF are associated with greater delay in epiphysial fusion (Serjeant and Ashcroft, 1973), greater height and more abnormal body build with long limbs and an increased lower segment to upper segment ratio (Ashcroft and Serjeant, 1972). The so-called characteristic habitus of SS disease with long thin limbs, narrow pectoral and pelvic girdles and a hoop-shaped chest is largely a consequence of delayed epiphysial fusion. The low weight is not simply a consequence of low height because the weight over height ratio is decreased. Skinfolds are typically thin and body fat reduced, possibly related to the metabolic demands of the active bone marrow (see earlier).

NUTRITION The metabolic demands on the expanded bone marrow and the increased cardiac work consequent on anaemia increase demand for protein, energy and minerals. The low weight and paucity of body fat suggest that energy requirements are barely met by intake and this is supported by the increased growth achieved on supplementation (Heyman et al, 1985). The level of the increased demand is suggested by the 20% increase in resting metabolic rate (Singhal et al, 1992) but the reason why calorie intake is not increased to meet these demands is unknown. The increased requirements of folic acid have already been discussed and there is some evidence of increased zinc requirements (Prasad and Cossack, 1984).

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VARIABILITY OF CLINICAL FEATURES Effect of genotype

There are four major genotypes within the definition of sickle cell disease: homozygous sickle cell (SS) disease, sickle cell-haemoglobin C (SC) disease, sickle cell 13+-thalassaemia (SI3+-thalassaemia), and sickle cell-13°-thalas saemia (S~°-thalassaemia). Their frequency within a population is determined by the respective gene frequencies and by their relative survival. In Jamaica, the relative frequencies at birth are 1 in 300, 1 in 500, 1 in 3000 and 1 in 7000 respectively (Serjeant et al, 1986). Mortality is highest in SS disease so the relative frequencies of SS and SC disease will change with age and SC disease would predominate in patients over the age of 30 years. Generally SS disease and SI3°-thalassaemia are severe and SC disease and S[3+-thalassaemia mild, although ocular complications of PSR are more common. However, even within SS disease there is marked clinical and haematological diversity accounted for to some extent by the interaction of other genetic factors. Effect of other genetic factors

~-Thalassaemia is commonly associated with SS disease, heterozygosity occurring in 35% of patients of West African origin and in 50-55% of patients in Saudi Arabia and central India. Northern Greece has the only SS population in whom ~-thalassaemia is rare (Christakis et al, 1990). ~Thalassaemia lowers the mean corpuscular haemoglobin concentration (MCHC) and consequently tends to inhibit polymerization of HbS. There is a reduction in haemolysis and in some cases sickling-related manifestations such as leg ulceration and acute chest syndrome (Higgs et al, 1982). However, the advantages of inhibition of sickling are offset by the reduction in haemolysis and increase in total haemoglobin rendering such patients more prone to painful crisis and to avascular necrosis of the femoral head. These effects are most marked in patients with homozygous cx-thalassaemia but the model illustrates the complex interactions of haematology and clinical features. Persistence of H b F also inhibits polymerization of HbS and if HbF levels are high enough and spread evenly throughout the red cell population as in the HbS/classical hereditary persistence of HbF syndrome, there are few if any clinical consequences. This observation has led to attempts to manipulate HbF levels therapeutically but high levels of HbF do not necessarily confer protection against all manifestations (Powars et al, 1980, 1984), and painful crises and avascular necrosis of the femoral head remain major causes of morbidity in the Eastern Province of Saudi Arabia and in central India despite mean HbF levels of 16% (Kar et al, 1986; Padmos et al, 1991). Much more needs to be known about the mechanisms of complications before the role of manipulating HbF in the therapy of SS disease can be defined. [3-Globin haplotypes may influence some expressions of the disease,

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although the data are still conflicting. HbF levels are generally higher in the Senegal and Asian haplotypes and lower in the Bantu haplotype, although whether these effects require one or two copies of the haplotype is controversial. The Asian haplotype generally manifests high haemoglobin levels, persistence of splenomegaly, rarity of leg ulceration and priapism, but relatively severe bone problems and painful crises. However, since the Asian haplotype is usually associated with homozygous e~+-thalassaemia, the relative contributions of the two genetic factors is debatable. The Bantu haplotype is more severe.

Effect of haematology Many factors contribute to the marked haematological diversity of SS disease, o~-Thalassaemia and persistence of HbF are associated with higher haemoglobin levels. The combination of high haemoglobin levels and low HbF levels in patients with SS disease and homozygous oL+-thalassaemia increases the risk of painful crises, avascular necrosis of the femoral head and proliferative sickle retinopathy. The combination of high haemoglobin levels with high HbF levels does not carry the same risk. ~-Thalassaemia is associated with microcytosis which may improve capillary flow, whereas patients with high HbF levels commonly.have an increased mean cell volume (Maude et al, 1987). Both SS disease with ~-thalassaemia and S[3°thatassaemia lower mean cell volumes (MCV) and MCHC and are likely to inhibit polymerization of HbS. Patients with SS disease have high but very variable platelet and white cell counts, possibly consequent on splenic atrophy. The pathological significance of these findings is unknown, although a high white cell count may be a risk factor for stroke (Balkaran et al, 1992).

Eff~tofs~ial~c~rs There is a strong clinical / impression but limited data to support a more , benign clinical course in panents with better socioeconomic circumstances. This would be expected, since such patients are likely to have better nutrition, warmer clothing, better public health measures, immunization and infection prophylaxis. Telephones and motor cars ensure easier access to medical care with more prompt treatment of complications. Parents with the time and intelligence td manage an affected child are also more likely to detect complications at an earlier and more treatable stage and to detect and avoid risk factors such as the relationship of cold exposure and the painful crisis. The mechanisms of the effects of social factors and expression of the disease may be poorly understood and difficult to define but these mechanisms may offer the greatest opportunities for intervention and amelioration of the digease.

Geographical variation Some of the geographical differences may be attributable to differences in

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frequency of o~-thalassaemia, the genes determining persistence of HbF or the 13-globin haplotype. Other differences suggest genetic or environmental factors not yet recognized. The significantly higher haemoglobin, lower reticulocytes and persistence of splenomegaly in Greek subjects cannot be attributed to either tx-thalassaemia or high HbF levels which account for these findings in patients of West African origin and some other factor ameliorating haemolysis, and possibly sickling may be operative in this group. The high frequency of leg ulceration in Jamaica was assumed to be due to poor socioeconomic circumstances until this complication was found to be rare in the central Indian population living under similar social conditions, suggesting that another difference between these patient groups was responsible. High levels of HbF which characterize both Indian and Saudi Arabian patients may inhibit spontaneous skin infarction and possibly promote rapid healing of traumatic lesions. In this way, comparative studies of the disease in different environments may contribute to an understanding of this variability. Classification of severity This clinical and haematological diversity emphasizes the need for a classification of clinical severity in SS disease which would be useful in studies of the natural history as well as assessing response to treatment. The existing classifications depend upon points systems using a controversial weighting of different diagnoses or numerical assessments of days of hospitalization or numbers of transfusions which generally reflect arbitrary clinical decision (Powars and Schroeder, 1978; Smith et al, 1978). Concepts of haematological mildness, such as high haemoglobin levels, do not necessarily relate to clinical mildness and much greater knowledge of the disease is necessary before a logical classification of severity can be developed. This is further complicated by the element of random factors such as contact with the human parvovirus, pneumococcus, salmonella, or the site of vaso-occlusion which has much greater implications in the brain than in the skin or conjunctiva. Until and if such a classification becomes available, it is probably better to define severity on individual aspects of pathology such as haemolytic rate or painful crisis frequency, rather than some theoretical and conceptually inappropriate 'global severity'. THE FUTURE The underlying genetic defect of sickle cell disease cannot be cured and genetic engineering or genetic manipulation are unlikely to achieve this in the foreseeable future, nor is such technology ever likely to be applicable on a population basis. Bone marrow transplantation which has the capacity to cure the effects of the disease by changing the genotype of erythropoietic precursors is a complex and expensive technology with an immediate or short term mortality of 15-20%. Such risks may be justified in a child known to be at high risk for a severe clinical course or devastating complication such

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as stroke but currently such indications are not predictable. The extremely variable clinical course of SS disease is a major factor confounding any possible role of bone marrow transplantation which again will never provide a technology applicable on a population basis. Other forms of genetic manipulation which do have broader immediate application are genetic counselling and antenatal diagnosis. Population education and screening to the extent that all young persons know whether they have the sickle cell trait, understand the genetics of sickle cell disease, and the implications of a child with sickle cell disease may influence mating patterns and reduce the frequency of relationships between carriers with the sickle cell trait. Societies with arranged marriages might be particularly amenable to this type of counselling but no good data are available on the effects of such an approach. Antenatal diagnosis offers another option to couples known to be at risk for a child with sickle cell disease but again the inability to predict the clinical course of an affected child limits the impact of this technology and has resulted in the decision of approximately 70% of families electing to continue the pregnancy of an affected offspring (Alter, 1987). Approaches to amelioration of the disease by increasing HbF levels have been made possible by a variety of agents such as 5-azacytidine, sodium butyrate and hydroxyurea. The mechanisms of their effects are still being clarified but preliminary experience with hydroxyurea indicates that marked haematological changes and some clinical improvement may occur (Charache et al, 1992). A large clinical trial of hydroxyurea has recently been started in the USA. All of these approaches may make some contribution but the inescapable conclusion is that children with sickle cell disease will continue to be born in large numbers in high-risk areas and that these will require optimum treatment for their disease. It is now clear that many of the complications of the disease may be prevented or more effectively treated but delivery and implementation of this basic knowledge remains a major public health challenge. Prophylactic programmes require implementation early in life and this can only be achieved by neonatal diagnosis of the condition. The major priority therefore must be the early detection of the disease so that pneumococcal and malarial prophylaxis, parental instruction on acute splenic sequestration and general education on management of the disease can be instituted. The implementation of such simple technology is a major public-health challenge but offers the greatest immediate benefit to the populations with sickle cell disease worldwide. SUMMARY Evidence from structural studies of DNA suggest that the sickle cell mutation has arisen on at least three separate occasions in Africa and as a fourth independent mutation in the Eastern Province of Saudi Arabia or India. The pathophysiology of sickle cell disease is essentially similar in these different areas although the frequency and severity of complications

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m a y vary b e t w e e n areas. Generally, the chronic haemolysis and resulting a n a e m i a is well tolerated, a l t h o u g h serious morbidity and occasionally mortality m a y be associated with the aplastic crisis o r cholelithiasis. E x a c e r b a t i o n o f a n a e m i a b e l o w steady state levels occurs with chronic glomerular d a m a g e and renal failure, especially in older patients. M o s t o f the morbidity of the disease arises f r o m b o n e m a r r o w necrosis in the painful crisis o r f r o m vaso-occlusive manifestations. C h a n g e s in the splenic circulation result in life-threatening episodes of acute splenic sequestration, the chronic m o r b i d i t y of hypersplenism, and splenic dysfunction renders children p r o n e to p n e u m o c o c c a l septicaemia. Chronic o r g a n d a m a g e contributes to chronic leg ulceration in adolescence and progressive renal, p u l m o n a r y , and occasionally cardiovascular i m p a i r m e n t in later life. T h e clinical s p e c t r u m of h o m o z y g o u s sickle cell disease varies widely b e t w e e n patients. Factors contributing to this variability include ot-thalassaemia, persistence of high H b F levels, h a e m a t o l o g y , social circumstances, and geographical and climatic variation. M a n y of the causes of mortality m a y be p r e v e n t e d or m o r e effectively treated, leading to increased survival and an increased quality o f life in affected subjects.

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