4 The management of haemoglobinopathies

4 The management of haemoglobinopathies S A L L Y C. D A V I E S BEATRIX WONKE

The haemoglobinopathies are disorders which result either from the synthesis of structurally abnormal haemoglobin (Hb) chains (the Hb variants), or from the defective synthesis of Hb chains (the thalassaemia syndromes). They are the most commonly inherited genetic disorders worldwide with some 240000 infants born annually with major haemoglobinopathies and at least 190 million carriers worldwide. They are all inherited in a Mendelian recessive manner so that persons with the carrier, or trait, states are generally healthy. Patients manifesting clinically significant disease may be homozygous for any one condition or compound heterozygotes for two or more haemoglobinopathy genes which interact. The haemoglobinopathies have arisen as a result of mutations and deletions in and around the globin genes on chromosomes 16 and 11. While these mutations occurred spontaneously they have persisted within particular ethnic groups because of the selective advantage against Plasmodium falciparum malaria offered by the carrier states. The haemoglobinopathies are therefore rarely found in the autochthonous Northern European populations but have come to Europe and North America with the population migrations (WHO, 1987). As a result the patients in Northern Europe are generally found domiciled in industrial conurbations, often associated in groups related to their countries of origin.

PATHOPHYSIOLOGY OF HOMOZYGOUS 13 THALASSAEMIA AND SICKLE CELL DISEASE

Homozygous [3 thalassaemia is an inherited disorder of Hb resulting from an unbalanced rate of [3 globin chain synthesis. As a direct result of the basic genetic defect the [3 thalassaemic red cells contain an excess amount of Hb subunits. Following oxidation, these subunits generate free oxygen radicals such as superoxide and hydroxy radicals. These oxygen radicals start a chain of oxidative events which leads to the formation of methaemoglobin and hemichromes. Hemichromes are known as Heinz bodies in [3 thalassaemia. Heinz bodies are monomeric unstable chains which bind to different membrane proteins altering the normal structure and function which leads to Bailli~re"s Clinical Haematology--

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early death of the red blood cells before the erythroblasts are well haemoglobinized (Shinar and Rachmilewitz, 1990). This ineffective erythropoiesis leads to anaemia, increased production of erythropoietin and an expansion of the bone marrow of 15-30 times normal. This marrow expansion results in distortion and fragility of the bones and an increased blood volume. The reticuloendothelial cells become congested by these abnormal cells and consequently hepatosplenomegaly develops, which increases the anaemia and causes thrombocytopenia and neutropenia. The child's growth and maturation are retarded. The overactive marrow also enhances gastrointestinal iron absorption resulting in haemosiderosis. In the absence of diagnosis and treatment most patients with 13thalassaemia major die before the age of 5 years, Modell and Berdouskas (1984). With recommended treatment, which will be discussedin detail, all the above-mentioned complications are avoidable or treatable and consequently the overall prognosis is now open-ended. Sickle cell disease (SCD) is a generic term for a family of haemoglobin disorders having in common the inheritance of the sickle 13globin gene ([3s). Sickle cell anaemia is the homozygous state (SS) when the [3~ gene is inherited from both parents. The other commonly encountered SCDs result from the coinheritance of 13swith either a t3 thalassaemia gene (S[3° or $13+) or with another 13 chain structural variant such as 13c which gives rise to haemoglobin SC. The 13sgene has a point mutation in the DNA from adenine to thiamine resulting in amino acid substitution of valine for glutamic acid at the sixth position of the [3 globin chain so that the 13s protein chains gel on deoxygenation. These liquid crystals distort the red blood cells into their pathognomonic rigid sickle shape. It is blockage by the sickled cells of the microvasculature that gives rise to the pathology associated with SCD. INHERITANCE AND GENETIC LESIONS OF [$ THALASSAEMIA MAJOR AND SICKLE CELL DISEASE When two carriers (trait) mate there is a one in four chance in each pregnancy that they will produce an affected child. This is so whether the parents carry the same trait, in which case the child is homozygous, or different haemoglobinopathy traits, when the child is a double heterozygote. Thalassaemia carriers may have a slightly reduced Hb and typically low red blood cell indices (Hb 11-13 g d1-1, MCH < 27 pg, and a red cell count > 5.0 X 1012L-t). The diagnosis is confirmed with a raised HbA2 (> 3.6%). Hb F levels are variable. Once 'at risk' couples are identified, a clear explanation about the significance of the condition is essential; the genetic risk being the most important information, followed by advice about the various prenatal diagnostic possibilities for the purpose of prevention. Safe and accurate prenatal diagnosis is possible in all cases of SCD and the majority of cases before 12 weeks of gestation by chorionic villus sampling (CVS). Diagnosis by CVS depends on gene mapping. By March 1990, 91 point mutations had

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been discovered in [3 thalassaemia major (Kazazian, 1990). Each major population group, Mediterranean, Indian, Chinese and Afro-Caribbean/ African has its own spectrum of [3 thalassaemia mutations. Prenatal diagnosis has led to a marked reduction in the incidence of 13thalassaemia in Europe (Cao et al, 1984; Modell et al, 1984). HOMOZYGOUS 13 THALASSAEMIA The disease commonly presents during the first year of life, although occasionally a severe transfusion-dependent patient presents at 3 to 4 years of age--these cases are now called late onset thalassaemia major. Those patients with homozygous [3 thalassaemia who manifest a mild course and are therefore transfusion-independent are called thalassaemia intermedia (see below). Affected infants can present with a variety of symptoms including: failure to thrive, poor weight gain, feeding problems and irritability. Fever, diarrhoea and vomiting with a distended abdomen and increasing pallor may alert parents that their child has a serious disease, while the clinical findings often only reveal anaemia and sometimes splenomegaly. An accurate diagnosis can be made from a simple blood test which always shows a severe degree of anaemia with microcytosis and hypochromia. The red cells show strikingly abnormal morphological appearances with microcytosis, hypochromia, anisocytosis, poikilocytosis, distorted red cells and a variable number of erythroblasts relating to the degree of anaemia. Hb electrophoresis confirms the diagnosis with elevated fetal haemoglobin (HbF) levels, reduced or absent adult haemoglobin (HbA) and a variable haemoglobin A2 (HbAz). D N A studies should be undertaken in order to define the precise genetic lesion. This gives both information about the possibility of CVS sampling for future pregnancies and also as to the probable disease severity ([3 thalassaemia major or intermedia).

Management of homozygous 13 thalassaemia Blood transfusions The recommended treatment for homozygous [3 thalassaemia involves regular (three-weekly or more frequent) blood transfusions, not allowing the Hb level to fall below 10 g d1-1 . This ensures erythroid marrow suppression and preserves excellent health with normal growth and development. It is a clinical decision as to when to start regular blood transfusion. In the majority of cases the decision to transfuse is obvious. In the few others the decision should be based on clinical parameters rather than any set Hb level. All children should be followed and monitored carefully for signs of anaemia, heart failure, splenomegaly, variable Hb level, lassitude, poor weight gain and low growth velocity. In practice, one aims to transfuse not more than 20 ml kg-1 body weight of

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packed filtered red cells over a period of 2-3 hours. The post-transfusion Hb should not rise above 15.0 g dl-1 as higher levels increase blood viscosity and the risk of thrombosis and result in unnecessarily high blood consumption. Patients with cardiac failure or very low initial Hb levels (<5.0gd1-1) should receive 5mlkg -1 body weight of packed filtered red cells in 3-4 hours. The effectiveness of blood transfusion can be measured by the rate of Hb fall. In splenectomized patients this is in the order of 1 g of Hb a week, while in non-splenectomized patients it may be as high as 1.5 g of Hb a week. The frequency of blood transfusions can be calculated from the rate of Hb fall. When the Hb fall is greater than expected, as calculated above, then the following causes should be considered: alloimmunization of red cells, hypersplenism or even poor quality of blood used for transfusion.

Side-effects of transfusion Chronic transfusions may be associated with serious side-effects. Allosensitization of clinically important blood group antigens occurs in up to 25% of the multiply-transfused thalassaemia patients. Therefore, patients' ABO, rhesus, Kell, Kidd and Dully systems should be typed at diagnosis or before institution of transfusion therapy and patients' blood should always be matched with donor blood in ABO, rhesus and Kell systems. Febrile, urticarial transfusion reactions, cytomegalovirus (CMV) infection and immunosuppression occur when transfused blood is not filtered. These complications can easily be avoided by simple filtration of the units of blood at the bedside of the patient. These filters have a 99.6% white cell removal efficiency in minimal time and easy handling. Not more than two units can be transfused through each of the available systems; Miramed (Italy), PALL (America), Sepacell (Japan) and Cellselect (Holland) which take one per filter. The most common cause of death in homozygous 13thalassaemia is heart failure secondary to iron overload. The second commonest cause is liver failure due to transfusion-transmitted viruses in thalassaemic patients. It is therefore essential that donor blood should be tested for hepatitis B virus (Moroni et al, 1984). Hepatitis B vaccination should be administered to all newly diagnosed thalassaemic patients and to those older patients who lack demonstrable antibodies to hepatitis B virus. Low-dose intradermal hepatitis B vaccination has been found to be protective against hepatitis B virus and considerably more cost-effective than the conventional dose recommended by the manufacturers of the vaccine (Mok et al, 1989). Transfusion-associated non-A, non-B hepatitis (hepatitis C) remains the most important problem in multiply-transfused thalassaemia major patients. In a recent report, the incidence of positive antibodies to Hepatitis C virus was 23.2% in multiply-transfused thalassaemia major patients (Wonke et al, 1990). Over 60% of these infections progress to chronic active hepatitis and eventually to cirrhosis. All chronically-transfused thalassaemic patients should be tested for HCV antibodies and patients suffering from chronic active hepatitis should be considered for treatment with ~ interferon

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(Donohue et al, 1990). Blood transfusions will become safer with the introduction of donor screening for anti-HCV. Since the introduction of anti-HIV donor screening, the risk of acquisition of human immunodeficiency virus (HIV) by transfusion has been reduced to 1 in 150 000 units (Cumming et al, 1989). Thalassaemia patients infected with HIV should be informed, counselled and appropriately investigated. The European Mediterranean W H O Working Group on Haemoglobinopathies is currently studying the HIV seropositive thalassaemia patients. The aim of this study is to learn about factors (e.g. splenectomy and altered immunity) affecting the natural history of HIV and to give information and recommendations regarding treatment. Preliminary data were reported at the Cooley Care meeting in Athens in June 1990 (Girot, 1990). Over 100 thalassaemia patients of both sexes, collected from more than 12 countries, have been reported to be anti-HIV positive. The disease appears to have a slow evolution, 2 years or longer, and the rate of progression to symptomatic disease is 26% after 6 years of seropositivity. Recommendations of this group include the following; all HIV seropositive thalassaemia patients are to be monitored clinically and investigated every 6 months. Particular emphasis should be placed on the following clinical problems; lymphadenopathy, constitutional disorder, neurological problems, secondary infections and secondary cancers. Investigations should include the following; absolute CD4 + (T-helper cells) lymphocyte count, presence of p24 antigen, loss of p24 antibody, serum IgG, IgA levels and erythrocyte sedimentation rate (ESR). The treatment of symptomatic patients should be routine, while for those asymptomatic seropositive thalassaemia patients with a falling CD4 + count it remains controversial. Low-dose zidovudine (AZT) should, we believe, be used when the absolute CD4 + counts are _<5 x 10~L -1. The efficacy in preventing disease of the central nervous system and the development of resistance is unknown (Swart and Weller, 1990), but at such low doses prophylactic AZT has minimal marrow toxicity.

Chelation therapy Maintenance transfusion preserves excellent health but, without treatment of iron overload, it leads to severe iron damage. Excess iron resulting from transfusions leads to endocrine disturbances, growth retardation, failure of puberty, and diabetes. Death in early life is generally the result of intractable heart failure. At present the only way to avoid this outcome is by regular subcutaneous (s. c.) infusion of the iron-chelating agent desferrioxamine (DF) from a small portable syringe driver pump, over 8 to 12 hours, at least five to six nights a week. Iron overload is monitored by serum ferritin assay. Monitoring urinary iron excretion over 24 hours is the best way to appraise DF therapy, as serum ferritin levels may not reflect the true extent of iron overload. Chelation therapy should commence by the time the serum ferritin has reached 1000 ~g L-I; this, in practice, is around the twelfth to fourteenth transfusion. It is easiest to start early in order to habituate the child and family to the burdensome regimen.

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It is important not to over-chelate these infants, when the iron burden is still low, in order to avoid DF-related toxicity. The initial recommended dose is 20mgkg -1 4 or 5 nights each week. 100mg oral vitamin C supplements should be given on the days of infusion, as this increases urinary iron excretion. In the older, more iron-overloaded patients, DF should not exceed 50 mg kg- 1 body weight, with 200 mg oral vitamin C. In patients with cardiac complications continuous intravenous (i.v.) infusion of DF in doses of up to 200 mg kg -1 body weight for 24 hours has been used in an attempt to reverse cardiomyopathy (Marcus et al, 1984). In our centre, once early cardiomyopathy secondary to iron overload is diagnosed by M U G A scan (multiple gated imaging with Tc99-1abelled autologous red cells) the DF treatment is intensified. This usually entails the insertion of an intravenous delivery system (Port-a-Cath or Hickman line) which allows continuous i.v. DF infusions. We use low-dose DF (between 3-4 g in 24 hours) with low-dose vitamin C (200 mg) oral supplementation. Combined regular transfusion and iron chelation therapy (optimal treatment) appears to ensure good health in the long term and, if DF chelation begins before the age of 10 years and is complied with then the patient can be expected to survive, free of cardiac disease for an indefinite duration.

Desferrioxamine toxicity Desferrioxamine chelation treatment is burdensome, painful, expensive and lifelong. If DF is infused subcutaneously it tends to leave painful lumps at the site of injection because of the relatively slow absorption of the drug. This problem may be solved either by the addition of small doses of hydrocortisone added to the DF (1 to 2mg per syringe) or by increasing the volume of the solution. Poor hygiene techniques can give rise to the development of infection and abscesses, even requiring surgical drainage as well as antibiotics. It is, therefore, essential that the parents are fully instructed in the correct techniques and provided with the proper equipment (swabs, butterfly needles, sterile water and syringes). Hypersensitivity occasionally develops to DF but most patients can be successfully desensitized by using small repeated injections of DF with gradually increasing doses. Both ophthalmic and oto-toxicity have now been described in patients receiving high dose i.v. DF or inappropriately high doses of s.c. DF for their degree of iron overload (Olivieri et al, 1986). Tables 1 and 2 summarize the symptoms, signs and clinical investigation of the ophthalmic complications. While the cataracts, which are a rare complication, do not improve on reducing the DF dose, the retinal symptoms do. The risk of oto-toxicity is also related to the dose of DF and is most commonly encountered in children with low serum ferritin levels ( - 2000 p.g 1-1) who have received DF treatment in doses _>50 mg kg -1 daily dose. We therefore recommend that hearing tests are performed yearly and if hearing loss is demonstrated then the DF dose is adjusted. The more severely affected children, who may present with speech or school problems, may require hearing aids and a change of chelation agent. Calcium diethylene

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Table 1. Ophthalmological changes in desferral toxicity seen by clinical examination. Symptoms and signs

Method of assessment

Retinal appearance

Fundoscopy

Blurred vision Tunnel vision

Visual acuity Perimetry

Night blindness

Adaptometry

Reduced light and colour sensation

Colour tests particularly blue/ yellow (tritan)

Pathological changes Pigmentary changes, oedema, vessels narrowed, later atrophic changes (N.B. anterior eye changes also occur.) Variable decrease in VA* Peripheral field loss, possible annular scotoma, RP-like; collapse of field with small and dim targets* Variable increase of rod and cone thresholds 100-Hue test show tritan axis loss*, contrast sensitivity reduced for low spatial frequencies*

* Abnormalities may be detected before subjective disturbances begin: useful for monitoring retinal state. Table 2. Ancillary ophthalmological tests, Ancillary tests

Findings

Fluorescein angiography Electro-oculography (EOG) Ganzfeld electroretinography (ERG) Pattern electroretinography (PERG) Visual evoked potentials (VER)

Pigmentary changes lead to window defects; oedema May be reduced acutely, unreliable Loss of scotopic sensitivity*, delayed responses* Reduced responses* Delayed responses*

*Abnormalities may be detected before subjective disturbances begin: useful for monitoring retinal state.

triamine pantacetic acid (Ca-DTPA) with oral zinc supplementation may be used. The plasma zinc levels should be monitored. In the severe cases recovery is a rare occurrence. These children will require additional speech therapy and support (Wonke et al, 1989a). The toxic effect of high doses of DF on skeletal growth is still unclear. It is known that DF inhibits DNA synthesis, fibroblast proliferation, collagen formation and may also cause zinc deficiency. Patients who received inappropriately high doses of DF when their iron burden is minimal frequently complain of pain in the hips, lower back and have difficulty in walking, with growth arrest or a reduction of growth velocity. The body measurements of children and adults are disproportionate: characteristically they have a short trunk with discrepancy between pubis-heel and crown-pubis and span measurements. Swelling of the wrists and knees and genu valgum of variable severity is often found. These patients have almost always a normal onset of puberty and pubertal development. Once the epiphyses have fused (puberty) alteration of the chelation regimen cannot improve growth. In pre-pubertal children reduction in the DF dose and oral zinc supplementation can achieve a partial improvement but they never regain their original centile. Growth hormone treatment is being piloted in these children but, as yet, the data is incomplete.

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Infection with Yersinia spp. is a common complication in DF-treated patients (Porter and Huehns, 1989). The Yersinia family of bacteria has a low pathogenicity but an unusually high requirement for iron. They do not secrete a siderophore but have receptors for ferrioxamine and become pathogenic when more iron is available in the tissues, as in thalassaemic patients on DF. Thus Yersinia presents an important hazard to any patient receiving this drug. Clinicians should be alert to the possibility of Yersinia infection in any child who presents with an abdominal complaint, including: acute abdomen, pain, diarrhoea, vomiting, fever and sore throat. DF treatment must be stopped immediately. Appropriate cultures of stool, in discussion with the microbiologist, should be taken. Empirical treatment must be commenced as a medical emergency with either an aminoglycoside or co-trimoxazole. For the future, an effective cheap non-toxic oral iron chelator would clearly provide a better alternative. Many compounds are currently under investigation. Porter et al (1989) have reviewed this topic. Clinical trials are being undertaken in several centres with the oral chelator 1-2 dimethyl-3hydroxy pyrid-4-one (L1). In the longest trial reported to date, (Bartlett et al, 1990) nine patients with [3 thalassaemia major, aged between 12 and 38 years, of both sexes were given daily L1 for up to 15 months. The drug was generally well tolerated with no significant side-effects in the thalassaemics. Three patients developed muscle and joint pains and one of these had an anti-rheumatoid factor that rose from 1:80 to 1:640 after six months on treatment. L1 therefore, appears to be a safe iron-chelation agent in thalassaemics.

Complications of 15 thalassaemia major Most of the complications of thalassaemia major are attributable to iron overload. This may be the result of economic circumstances, late onset of chelation therapy or poor compliance with DF therapy. In iron overload the excess iron which is deposited in the tissues causes damage. The mechanisms by which iron damages the organs have only recently been identified. Toxicity begins when the iron load in a particular tissue exceeds the tissue or blood binding capacity of iron, and free nontransferrin iron appears. This 'free iron' is a catalyst of the production of oxygen species that damage cells and peroxidize membrane lipids leading to cell destruction (Shinar and Rachmilewitz, 1990). Liver has a large capacity to produce proteins which bind the iron and store it in the form of ferritin and haemosiderin. Heart cells generate only small amounts of storage proteins and are therefore sensitive to 'free iron'induced oxygen radicals. Therefore, cardiomyopathy frequently occurs with relatively little iron in the myocardial cells (Gutteridge and Halliwell, 1989). Cardiac complications Normal myocardial function requires adequate tissue oxygen, as chronic anaemia increases cardiac output by increasing stroke volume. Iron

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deposition in the heart causes cardiac complications including; hypertrophy, dilatation, degeneration of myocardial fibres and myocardial fibrosis. The extent of damage is directly related to the transfusional iron load in the absence of, or with poor compliance to, chelation therapy (Wonke et al, 1989b). In our experience, clinical assessment, chest X-ray, electrocardiogram, 24-hour ECG monitoring and even echocardiography are relatively insensitive techniques in detecting early myocardial damage before the onset of clinically apparent disease. Furthermore, age, serum ferritin levels, number of units transfused, liver disease and sexual maturation do not correlate with cardiac abnormality (Wonke et al, 1989b). M U G A scan is the most sensitive method to evaluate early damage and it also helps in monitoring cardiac function after intensification of DF chelation therapy (Aldouri et al, 1990; see i.v. chelation).

Reduced growth Iron-overloaded thalassaemic children of both sexes show reduced growth around the age of 10 to 11 years. The cause of this is not fully understood, but several mechanisms have been reported: growth hormone deficiency secondary to pituitary damage by haemosiderosis (Pintor et al, 1986); defective hepatic synthesis of somatomedin (TGF-1) (Saenger et al, 1980); sex steroid deficiency. Serum ferritin levels are usually high and bone age is at least 2 years behind chronological age. Treatment for these patients consists of intensification of chelation therapy and in cases of growth hormone deficiency replacement therapy is indicated.

Hypothyroidism Hypothyroidism is observed in > 17% of iron-overloaded patients (Sabato et al, 1983). It affects both sexes equally and occurs after the age of 10 years. Three types of thyroid dysfunction have been recognized in thalassaemics; pre-clinical, mild and overt hypothyroidism. Classical symptoms of hypothyroidism in patients with pre-clinical or mild hypothyroidism are absent, whereas in overt hypothyroidism a whole spectrum of clinical features have been observed; growth retardation, decreased activity, dry skin, cardiac failure and pericardial effusion. The thyroid gland is not usually enlarged (see Table 3). Treatment depends on the severity of the organ failure. Replacement with L-thyroxine is recommended in symptomatic patients. In the remaining patients, intensification of iron chelation may improve thyroid dysfunction. Table 3. Investigationsfor hypothyroidism. TSH response Hypothyroidism SerumT4 Serum FT4 Serum TSH to TRH Pre-clinical Normal Normal Marginallyincreased Increased Mild Marginally low Marginallylow Elevated Exaggerated Overt Low Low Elevated Exaggerated

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Hypoparathyroidism The incidence of hypocalcaemia related to hypoparathyroidism, in ironoverloaded thalassaemic patients is 7% (Wonke and De Sanctis, 1991). The majority are older than 15 years of age; males are more commonly affected than females (3 : 1). It is almost always associated with bone complications; spontaneous fractures which are slow to heal, genu valgum of variable severity and short stature. Serum calcium is low, phosphate high and the PTH low or inappropriate for the serum calcium level. There is also a low excretion of 1,25 dihydroxycholecalciferol (1,25(OH)2D). There is a reduction of 24-hour urinary calcium and phosphate. Treatment is with oral vitamin D or one of its analogues. If high serum phosphate concentrations persist a phosphate binder is recommended.

Diabetes mellitus The incidence of diabetes mellitus (DM) in iron-overloaded patients varies between 8 and 14.5% (Wonke and De Sanctis, in press). The onset of DM in the majority of patients is in the late teens and both sexes are affected equally. Frequently, impaired oral glucose tolerance precedes frank diabetes. This is asymptomatic while DM itself presents with the classical symptoms accompanied by ketosis or ketoacidosis. In asymptomatic patients treatments, including carbohydrate-reduced diet or an oral hypoglycaemic agent, are controversial. In our experience carbohydrate-reduced diet, together with vigorous iron-chelation therapy, improves biochemical diabetes. In symptomatic patients insulin treatment is essential; metabolic control can be difficult to achieve. Patients with insulin-dependent diabetes have a higher incidence of cardiac failure, liver cirrhosis and cerebral thromboembolism. Diabetic retinopathy is a rare complication; albuminuria may be present at the time of diagnosis or during the course of the disease.

Sexual complications In a large study of 1240 thalassaemic patients 41% of males and 45% of females over the age of 15 years were pre-pubertal (De Sanctis, personal communication). Many of the affected patients began DF therapy well after the age of 10 years. In a smaller study data suggest that long-term DF therapy, begun before the age of 10, may ensure, in the majority of patients, normal sexual function (Bronspiegel et al, 1990). The clinical presentation is variable. Some patients have delayed puberty, defined, as a complete lack of pubertal development in girls by their 13th birthday and boys by their 14th birthday. A few patients have arrested puberty which is characterized by lack of progression of puberty for 12 months or longer with reduced or absent growth velocity. In the majority of cases primary hypogonadism is present. In these patients there are no signs of puberty at the age of 18 years; they are also short and their weight corresponds to their height. Secondary hypogonadism occurs where hypogonadism develops after complete pubertal maturation. In males this is

Basal plasma gonadotrophins

Pre-pubertal range Low Low Low

Sexual maturation

Delayed puberty Arrested puberty Primary hypogonadism Secondary hypogonadism

Reduced response Reduced response Poor or absent response Reduced or absent response

Gonadotrophins response to GnRH Low Low Low Low

Basal plasma sexual steroids

Normal response Normal response Normal or reduced response Variable response (normal, low, absent)

Sexual steroids response to HCG or HMG

Table 4. Pituitary and gonadal function tests in thalassaemic patients.

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manifested by impotence and in females with secondary amenorrhoea, weight gain, hot flushes and bone pain. Another characteristic clinical finding in male thalassaemic patients is the reduced beard appearance and the absence of facial acne during puberty. These aspects are not fully understood. Diagnostic findings are summarized in Table 4. Treatment of delayed puberty depends on the following factors; age, severity of iron overload, chronic liver disease and presence of psychological problems resulting from delayed puberty. Teenagers with psychological problems need hormone treatment in order to minimize the risk of complete rejection of thalassaemia treatment (DF chelation and even transfusion). Treatment should be withheld in the well chelated age groups without psychological problems but regular follow up is necessary. Patients with pubertal arrest are treated with oestrogen/progesterone or i.m. testosterone. In hypogonadism treatment consists of oral sexual steroids. In secondary hypogonadism replacement therapy is indicated. Induction of fertility in both sexes is a frequent request. This involves the co-operation of the haematologist and the reproductive endocrinologist. Experience in this field is limited but encouraging.

Bone change The bone changes commonly found in the older thalassaemic patients are the result of inadequate transfusion in childhood. These changes are due to the expansion of the bone marrow mass secondary to the anaemia. The changes may be mild, moderate or severe. The characteristic facial appearance with bossing, flat nose, mongoloid slant of the eyes and prominent molar eminences (or protrusions) are permanent disfigurations. In extreme cases these can cause nasal airway obstruction, speech defect and difficulties with eating. Cosmetic surgery is required as improved treatment has no affect on bone changes. Cortical thinning of the long bones leads to spontaneous fractures which are slow to heal, often resulting in deformities. Premature fusion of the epiphyses of the humerus and femur results in shortening of the arms or legs and considerable restriction in movement. With time, osteo-arthritic changes develop in the affected joints. Treatment is palliative only. The most serious complication is spinal cord compression, either from collapsed vertebrae or extramedullary haematopoiesis in the spinal canal. Surgical intervention or radiotherapy is necessary to treat these cases. Bone changes are entirely preventable by optimal treatment. Cholelithiasis is associated with all haemolytic anaemias. In patients with sickle cell anaemia the biliary calculi are reported to occur in 10-37% of cases (Bond et al, 1987; Webb et al, 1989). The incidence of gallstones in thalassaemia appears to be about the same as in sickle cell anaemia; it also occurs as early as 10 years of age. Prophylactic cholecystectomy to protect patients from future formation of gallstones has been proposed by Feretis et al (1985).

Hypersplenism Optimal treatment usually prevents splenomegaly. Inadequate transfusion

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invariably leads to massive hypersplenism caused by extramedullary haematopoiesis. Hypersplenism is associated with worsening of anaemia (Hb fall is greater than 1.5 g 1-1 per week), neutropenia and even thrombocytopenia. Splenectomy should not be undertaken before the age of 5 years due to the risk of overwhelming pneumococcat sepsis in infants. Treatment with pneumococcal vaccine should precede elective surgery by 3 to 4 weeks and penicillin prophylaxis is recommended for life after splenectomy. In patients with 13 thalassaemia intermedia post-splenectomy high platelet counts may cause thromboembolic complications. Low dose soluble aspirin 75 mg daily or an antiplatelet aggregating agent is recommended. Bone marrow transplantation

Bone marrow transplantation is the only cure available for thalassaemia at present. For transplantation a histocompatible bone marrow donor is required. A suitable bone marrow donor is a sibling or occasionally a parent, where parents are first cousins. In younger patients on optimal treatment the overall success rate is 94% whilst in patients of older age groups with liver fibrosis or liver enlargement the survival rate is 65-75% (Lucarelli et al, 1990). Mortality results from infections, heart problems and graft versus host disease. The world experience of bone marrow transplantation is shown in Figure 1. Bone marrow transplantation is far less expensive than the cumulative cost of conventional life-long treatment, so it is reasonable to set up transplant centres in countries with a high incidence of thalassaemia. It is also recommended in those children, both with thalassaemia and sickle cell disease (Vermylen et al, 1988), where conventional treatment is not readily available.

Survival with thalassemia 130

Event-free survival 68%

Figure 1. Collected world figures for bone marrow transplantation in homozygous 13 thalassaemia, to December 1989.

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The improved survival in homozygous ~ thalassaemia means that we must recognize and manage the psychosocial problems associated with the disease. Patients and their families require support and psychosocial intervention at an early age in order to maximize their full integration into society (Politis et al, 1990). [3 THALASSAEMIA INTERMEDIA In 0 thalassaemia intermedia the clinical picture is milder than 0 thalassaemia major despite the same pattern of inheritance as homozygous ~ thalassaemia. It is a clinical definition based on the patient's rare requirements for blood transfusion. The Hb level is usually above 7.0 g dl- ~, red cellindices are as in thalassaemia major and Hb electrophoresis shows variable levels of HbA,

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AVASCULAR NECROSIS HYPOSTHENURIA DELAYED GROWTH & DEVELOPMENT

Figure 2. T h e clinical problems of sickle cell disease by age.

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HbF and HbA2. The genetic factors ameliorating the disease include: the inheritance of a mild [3+ thalassaemia gene, coinheritance of et thalassaemia and increased ~/chain production (Thein et al, 1987). Patients with [3 thalassaemia intermedia grow and develop normally. The complications commonly encountered in this group are: hypersplenism, gall stones and ankle ulcers. Haemochromatosis from excess dietary iron absorption is rarely significant. Treatment consists of clinical surveillance, folic acid supplementation, periodic blood transfusions and, in iron overload, DF chelation. The treatment of leg ulcers is the most problematic. Blood transfusions, bed rest, supportive surgical stockings, zinc ointments and tablets may be of help. THE MANAGEMENT OF SICKLE CELL DISEASE

Despite our understanding of the molecular basis of sickle cell disease (SCD) and the pathology of the sickling phenomenon the condition remains a major risk to health with a high mortality and morbidity at all ages (Grey et al, 1991). The clinical problems of SCD by age are summarized in Figure 2. In childhood the peak incidence of death is between 1 and 3 years of age, predominantly related to infection (Leikin et al, 1989). In adolescence cerebrovascular accidents are the most common cause of death and in adults deaths are most often related to respiratory complications. With active management the proportion of patients expected to survive to 20 years of age is now approximately 89 % and approximately 85 % for SS patients (Leikin et al, 1989). The greatest contribution to the reduction in infant mortality in SCD has been the introduction of neonatal screening programmes for the early detection of the disease and subsequent medical care with the prescription of prophylactic penicillin (Editorial, 1986; Gaston et al, 1986). While SS patients generally have the most severe clinical course, many with S[3° thalassaemia, in particular those arising from the Mediterranean region, often follow a similarly severe course. Haemoglobin SC disease usually presents fewer problems in childhood but the patients are also at risk of infection, sudden death and have a higher incidence of the proliferative retinopathy and avascular necrosis of bones. The greatest challenge in the management of SCD is why some patients are more severely affected than others, and why some fluctuate between periods of relatively good health and frequent, severe complications. A number of ameliorating factors are known; including the persistent production into adolescence and adult life of HbF. A level of -- 10% HbF offers protection against stroke and avascular necrosis while _>20% HbF offers protection from episodic manifestations such as painful crises or pulmonary complications (Powars et al, 1984). Co-inheritance of etthalassaemia has been shown to reduce the levels of haemolysis as judged by higher Hb and lower reticulocyte and serum bilirubin levels (Higgs et al, 1978). Environmental factors and poor socio-economic status can precipitate sickling. It is important that patients should be aware of, and avoid the following: infection, hypoxia, dehydration, cold and exhaustion.

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Infancy In infancy the most important clinical problems relate to infection, splenic sequestration and dactylitis. At birth infants are protected from the problems of SCD because of their high levels of HbF which interferes with the molecular gelation of the 13s. Painful vaso-occlusive crisis is therefore, rarely seen before 6 months of age and almost never before four months of age. Fulminant pneumococcal septicaemia and acute splenic sequestration crises do however, present before 6 months often in previously undiagnosed cases leading rapidly to a fatal outcome (Powars, 1989). When children with SCD become ill they easily become dehydrated because of both the reduced fluid intake and also their inability to concentrate their urine; related to the sickle damage to the renal tubules. This hyposthenuric defect is evident in children by the age of 2 or 3 years. Consequently patients' clinical state can deteriorate very rapidly. It is essential that the patient's 'steady state' laboratory parameters are known and monitored for the purposes of comparison. Indications for hospital admission are as follows: 1. 2. 3. 4.

The vaso-occlusive pain is uncontrolled by oral analgesia. There is a severe associated constitutional upset, e.g. tachycardia -_-100, pyrexia _>38.5°C. There is any visceral involvement, e.g. tachypnoea -> 16 per min, absent bowel sounds. Presence of any neurological signs.

The spleen is a major site of sickling because of the relative hypoxia and acidosis. This results in auto-splenectomy with impaired immune function in all types of SCD resulting in a high risk of the infection, in particular Streptococcus pneumoniae and Salmonella (Rogers et al, 1982). Infection with salmonella may present in unusual ways such as with hepatic sequestration, though it most commonly presents with septicaemia and/or osteomyelitis. Meningitis and chest infections are also more common in infants with SCD, affecting particularly SS children, also often caused by Haemophilus influenzae (Powars et al, 1983). Paradoxically the children with palpable spleens at, or before, the age of 1 year are those most prone to pneumococcal infection during the first years of life. The necessity and efficacy of penicillin prophylaxis has been tested and proved by the American National Cooperative Study of Sickle Cell Disease (Gaston et al, 1986). It is therefore, essential that all children with any type of SCD should take oral penicillin prophylaxis, which should be commenced not later than 4 months of age; in a dose of 62.5 mg twice daily (b.i.d.) up to the age of one year, rising to 125 mg b.i.d, from one to three years and 250mg b.i.d, thereafter until adult life. This regimen requires parental compliance which must be emphasized; a recent study has shown that only 47% of SCD children were proven to be taking penicillin (Cummins et al, 1991). Pneumococcal vaccine as discussed for pre-splenectomy under 13 thalassaemia major (see above) should be used as a complement to penicillin.

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Doctors should be alert to the risk of infection in these children and institute prompt therapy with antibiotics in the presence of a fever. It is important to treat with benzyl penicillin, or a penicillin ester, parenterally in order to cover Streptococcus pneumoniae. With this treatment the rapid progression of pneumococcal infection with circulatory collapse and shock can usually be prevented. Many children with SCD will visit areas where malaria may be contracted and they must receive appropriate malaria prophylaxis because they are at risk of developing severe haemolytic crises with profound anaemia and cardiac failure. Another medical emergency is splenic sequestration which results from trapping of sickled red blood cells in the spleen with massive organ enlargement and a fall of Hb _>2gd1-1. There is severe abdominal pain and anaemia, which may become so severe that circulatory collapse results with vomiting, diarrhoea and congestive cardiac failure leading to death. Progression is generally acute and rapid over the space of 1 to 2 hours. The aetiology is uncertain although pneumococcal infection has been implicated. The children should be admitted to hospital urgently, an intravenous infusion started immediately and a replacement blood transfusion is almost always required. The high mortality can be prevented by early recognition and intervention so parents should be taught to palpate the spleen. There is at least a 30% risk of recurrent sequestration and a 37% risk of hypersplenism following an initial episode of acute splenic sequestration (Topley, 1981). It is therefore, recommended that following the presenting episode children should undergo routine splenectomy. Painful vaso-occlusive crisis results from microvasculature obstruction causing hypoxia and pain most generally in the bones but also in joints, muscles and, on occasions, the soft tissues. In paediatric clinics we see the 'hand~foot' syndrome as the earliest presentation (Davies and Brozovic, 1989). In this there is dactylitis--that is, sickle vaso-occlusion of the metacarpals or metatarsals--with overlying soft tissue involvement. It is rare before the age of 6 months or after the age of 3 years. The pain can be very severe and in cases where the diagnosis of SCD has not already been made a variety of misdiagnoses have been entertained, including non-accidental injury and insect bites. It can affect one limb or all four at the same time; it can last only a day or 3 to 4 weeks. It is essential that the syndrome should be properly recognized and treated otherwise chronic damage may occur resulting in poor bone growth and subsequent deformity (Figure 3). The treatment, which is standard for all vaso-occlusive SCD crises, is rest, warmth, increased fluids to prevent dehydration, and adequate analgesia (initially paracetamol in standard doses). This management should be applied as a first-line for all complications of SCD at all ages. In our experience it is rarely necessary to admit infants with the 'hand/foot' syndrome, but it is important to advise parents that they should not force the child to use a limb or walk whilst the pain continues. Admission is usually based on either the need for parenteral analgesia or the coexistence of constitutional upset (see list above). Hospital treatment is with the standard regimen of rest, warmth, intravenous fluids (at 80 ml kg-124 h-1) and adequate analgesia under close

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Figure 3. Hand X-ray of an adult SS patient showing a markedly shortened right 3rd metacarpal as a result of a severe dactylitis in infancy.

observation. We use continuous infusions given intravenously of either pethidine at a starting dose of 2 mg kg- 1h - 1 or morphine at 10 btg kg- 1h - 1; the respiratory rate must be carefully monitored with these regimens while the dose is titrated against the pain relief. Pethidine is broken down into a stable metabolite, nor-pethidine, which is neuroexcitatory and on occasions causes fitting in SCD patients. It is therefore essential to monitor carefully the pain and clinical state of the patients during opiate therapy.

Preschool children (3-5 years) The most common problems in this age group are painful vaso-occlusive crisis, aplastic crisis and upper airways obstruction. Splenic sequestration and deaths related to infection occur, but rather less commonly than in the infants. The distribution of pain alters with age, most probably related to the recession of the red bone marrow. In this age group the pain is generally sited in the long bones and there may also be sympathetic joint effusions as a result of juxta-articular sickling. Septic arthritis is very rare, so aspiration of the joint effusions should only be undertaken in those rare cases where there is either no associated bone pain or there is proven septicaemia with one very severely affected joint. Mild painful vaso-occlusive crisis can be managed by the parents at home as above. Aplastic crises can occur at any age in SCD and are almost invariably associated with infection. The most common cause is with the parvovirus B 19

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strain which, while only causing 'fifth' disease in people with normal haemopoiesis, infects the developing erythroblasts causing a transient cessation of production (Pattison, 1987). The Hb can drop precipitously over a few days as the red cell life-span in SCD is reduced to 6 to 10 days. Patients are generally admitted with signs and symptoms of anaemia, absent bone pain and, in very severe cases, congestive cardiac failure. Reticulocytes are absent from the peripheral blood. Parvovirus-specific IGM may be tested for, and in early cases the parvovirus antigen will be seen on electron microscopy. A replacement blood transfusion should be given if Hb - 4 g dl- 1or the patient is clinically compromised. Adenotonsillar hypertrophy giving rise to upper airways obstruction (UAO) can become a problem from the age of 18 months. In severe cases this can give rise to hypoxaemia at night with consequent sickling. The marked hypertrophy is probably a compensation for the loss of lymphoid tissue in the spleen. UAO occurs in at least 18% of SS children and we have also documented adolescents with HbSC who have UAO (Davies et al, 1989). Children with UAO snore while asleep. They should have their tonsils and adenoids removed in order to prevent vaso-occlusive crisis at night. This may prevent neurological events. Transfusion is not required prior to operation.

Schoolchildren (5-15 years) In this age group the commonly encountered complications are the severe painful crisis and the 'chest' and 'girdle' syndromes. Splenic sequestration is rarely seen and infection occurs less commonly than in the infants. In the painful crisis the site of the pain moves more centrally in the body as the children grow older and is also generally more severe. The average hospital admission for a patient in this age group with limb pain is 4.9 days as compared with 8.3 days if the pain is situated in the trunk (Brozovic et al, 1987). Treatment is with the standard regimen as previously described. Visceral complications may occur when the pain is experienced in the trunk, shoulders, spine, ribs, pelvis and hips. The most important complications are the 'sickle chest syndrome' and the acute abdomen or 'girdle syndrome'. The sickle chest syndrome has now been well described (Davies et al, 1984; Yardumian and Davies, 1987). The term has been coined to describe a syndrome of pneumonic consolidation and associated hypoxaemia, which is presumed to result from vaso-occlusion of the pulmonary vasculature and in which no infective cause has been demonstrated. The clinical symptoms and signs precede the X-ray changes so it is essential to take action based on the clinical picture. Patients invariably have severe vaso-occlusive pain in the chest wall. They develop tachypnoea followed by the signs of consolidation, including crepitations on auscultation and dullness to percussion. As they become hypoxaemic central cyanosis can be seen in the mucous membranes. The best way of monitoring is by arterial blood gas estimations or transcutaneous oximetry; if the PaO2 falls to < 80 ml Hg on air, inspired oxygen is given and if it continues to fall to - 60 ml Hg then exchange transfusion is carried out (see below). X-ray changes are generally those of opacities which

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start at the lung bases and move to the mid-zones and then upper zones (Figure 4). A few very rapidly progressive cases never develop the classic X-ray features as described but instead have hilar shadowing. The sickle chest syndrome can develop slowly, over a period of days, or rapidly which can be fatal. A n y SCD patient with tachypnoea should be admitted as an emergency to hospital and monitored closely. Initial treatment is by the standard regimen but more active intervention should be considered. The chest syndrome may occur in complete isolation, or associated with abdominal distension and discomfort if not the full-blown picture of the sickle girdle syndrome. In the girdle syndrome an acute abdomen develops, presumably related to sickle vaso-occlusion of the mesenteric blood supply (Figure 5). If it is uncomplicated by other visceral involvement and treated appropriately it is generally self-limiting in 24 hours to 5 days. It is essential however, to look for and be aware of other causes of an acute abdomen; in particular the rarely encountered bowel ischaemia which can develop into bowel infarction when emergency surgical resection is life-saving. In general the only treatment required for the girdle syndrome is to stop oral intake and maintain hydration. Patients can be monitored by measuring their girth measurement around the umbilicus regularly (generally hourly) and

Figure 4. Chest X-ray demonstrating the lung consolidationseen in a severe sickle 'chest syndrome'.

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auscultating for bowel sounds. On occasions there may be involvement of the liver which can progress to hepatic sequestration. In this, as with splenic sequestration, the Hb drops by -> 2 g d1-1 due to the trapping of red blood cells in the liver. The liver distends and its function is impaired. It is generally associated with septicaemia (Hatton et al, 1985), and may occur at any age once the spleen has atrophied and fibrosed. A broad spectrum of neurological complications of SCD have now been described, including occlusive and haemorrhagic cerebrovascular accidents, transient ischaemic attacks, cranial nerve lesions, mental changes and spinal cord syndromes. The commonest presentation is an acute onset hemiplegia or hemiparesis due to cerebral infarction occurring in 7-29% of SS patients. A mean age of onset of 7.7 years and a modal age of 5 years has been reported (Hindmarsh et al, 1987). These occlusive strokes result from blockage of middle to large arteries in the brain as a result of a primary proliferation of smooth muscle and fibroblasts in the intima. The pathology

Figure 5. Abdominal X-ray during the sickle 'girdle syndrome' showing dilatation of the bowel.

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Neurological deficit immediate

Rehydration & treatment of fits I urgent

[ Exchangetransfusion ]

l

at 1-4weeks

Scan (CT/NMR) Doppler ultrasound (carotid artery) Angiogmm


vessel involved

>_2vessels involved I Regul/arcthe~na~ioElnSi°nI at3 years

same/ improved ~

deterioration Smoothluminal surfaces

1

\ = I No treatment[

. I~-~essl

No improvement

1 I Continuetransfusion [ I

I

Deterioration

Figure 6. Strategy for the investigation and treatment of neurological deficit in sickle cell disease.

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is therefore, quite unlike the sickle vaso-occlusion experienced in the small vessels elsewhere in the body. Once blockage has occurred many patients then develop a collateral circulation which is generally thin-walled and prone to rupture. The increased incidence of subarachnoid haemorrhage in late adolescence and adult life is related to these and also rupture of intracranial aneurysms in the Circle of Willis. Covert neurological damage related to SCD can also be demonstrated in patients with exhaustive investigation (Herold et al, 1986; Hindmarsh et al, 1987). Any child who has an acute neurological event should be admitted to hospital as an emergency and the strategy shown in Figure 6 followed. There is a greater than two thirds risk of a reoccurrence, with 80% of subsequent strokes occurring before 3 years (Powars et al, 1978). Recurrence can undoubtedly be prevented by a long-term transfusion regimen (see below). It is important, however, that this regimen is closely adhered to and that the sickle haemoglobin is kept below 25%. The most important issue to be resolved at present is how long transfusion therapy should be continued in order to remove the risk of recurrence. A reasonable compromise is to reassess at 3 years. However, as with other patients who undergo long-term transfusion therapy there is the problem of transfusion-induced haemosiderosis and compliance with chelation therapy to be considered (see thalassaemia). The proliferative sickle retinopathy (PSR) is now well recognized among patients with SCD and can be seen as early as 10 years. From this age monitoring on a regular yearly basis, where possible by a specialist ophthalmological clinic, should be performed because early intervention with laser or cryotherapy can prevent loss of sight. PSR is one of the more severe complications encountered in HbSC disease. Adolescence

Trunk pain often with associated visceral involvement is the main problem in this age group. Priapism can also occur. Patients in this age group often have an increased frequency of admissions with painful crisis. Treatment is the same regardless of age, but adolescents present particular psychological problems related to their development and altered home environment. They no longer see themselves as children and therefore find the paediatric ward irritating, yet few hospitals have the necessary dedicated adolescent wards and adult wards are totally unsuitable for them at times of illness. Chronic organ damage resulting from repeated sickling, in particular avascular necrosis of the head of the femur can be seen as early as 13 years of age in all types of SCD with up to 21% of young adults being affected (Taylor, 1985). When the femoral head is involved there is pain in the groin which may radiate to the knee. The patient limps and there is limitation of movement on external rotation. Without intervention this settles but many joints will eventually be destroyed. While hospital admission for parenteral opiates is rarely required it can interfere with daily life and work for many months or even years, requiring long-term oral opiate derivatives. The successful insertion of hip prostheses has been widely reported. In our view

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operation should be delayed as long as possible because of the high risk of complications postoperatively, both infective and later loosening of the joint, and the limited life-span of any prosthesis necessitating renewal anything from 5 to 20 years later. Longevity of the joint may well be improved by the insertion of non-cemented prostheses. Priapism may occur from childhood either as recurrent, short-lived (generally 2-6 hours) stuttering attacks, as have been reported in 42% of Jamaican SS patients, or as fulminant attacks (Serjeant et al, 1985). Antitestosterone hormones such as stilboestrol have been used to terminate attacks of stuttering priapism (Serjeant et al, 1985). Fulminant attacks must be treated as a medical emergency. If there is no improvement within a couple of hours then proceed to exchange transfusion. If there is no improvement at 24 hours following exchange transfusion then a surgical manoeuvre is probably necessary. The simplest approach is drainage and lavage using normal saline. Venous shunts should be held as a last resort. Active treatment is essential as prolonged priapism can lead to fibrosis within the corpora cavernosa and subsequent erectile impotence. Priapism becomes more frequent with age. The classic 'sickle habbitus' is rarely encountered in the SCD patients of the Western world, although it is still seen in some patients in their native surroundings. However, it is well documented that both sexes and all types of SCD have a reduced body weight and short stature (Platt et al, 1981), leading to delayed growth spurt and menarche. Boys are more severely affected than girls (Phebus et al, 1984). Nasogastric nutritional supplementation has been shown to produce rapid sustained increases in growth rate; unfortunately, neither simple oral nor mineral and vitamin supplementation have shown an effect (Heyman et al, 1985). BLOOD TRANSFUSION IN SCD

Table 5 lists indications for the use ofbtood transfusion in SCD. It is important to consider carefully before using transfusion in SCD because of the risks previously described of infection, iron overload and alloimmunization. Alloimmunization is particularly important in Northern Europe and North America where the donor population is predominantly Caucasian while the affected SCD population is predominantly AfroCaribbean and West African in origin. Red cell antibodies have been reported in 17.6% of transfused patients with rhesus and Kell antibodies accounting for two thirds (Davies et at, 1986; Vichinsky et al, 1990). We therefore recommend that prior to giving a blood transfusion to an SCD patient extended red cell phenotyping should be carried out, including ABO, full rhesus, Kell, MNSs, Jk, Lewis and Js a and Js b. All S - , s - individuals should be U-typed. All R0 individuals should be transfused with C negative, E negative blood (rr or R0). Kell-compatible blood should always be given. Blood for transfusion should be screened for the presence of HbS as donors with sickle cell trait often have Hb levels that are acceptable for blood donation. Other precautions, as for [3 thalassaemia, should be

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Table 5. Indications for blood transfusion in children with sickle cell disease.

Replacement Use when the Hb -----4g d1-1, or the child is clinicallycompromised Sequestration crises Aplastic crisis Haemolytic crises, e.g. malaria infection Bleeding Exchange transfusion Use to improve the oxygen carrying capacity of blood without altering the blood viscosity Neurological deficit 'Chest and girdle' syndromes Priapism Occasional patients with severe/protracted painful crisis Severelyaffected patients preoperatively Long-term transfusion Use to maintain the haemoglobin between 10.5 and 15 g d1-1, with -<25% HbS Neurological deficit Rarely to improve growth and development Occasionallyto prevent painful crisis

followed. Plasma reduced blood may be used but red cell concentrates should be avoided. H I V infection in SCD patients is now recognized in Europe. This results most often from blood transfusions received in the high-risk areas of Africa. H I V infections in SCD should be treated actively in the standard manner (see above). Table 5 shows the indications for exchange transfusion. The aim is to reduce HbS to less than 25% and to keep the haemoglobin level < 15 g d1-1 because of the risk of increasing the whole blood viscosity, while maintaining a steady blood volume. The total Hb and proportion of HbS should be measured prior to each exchange. In children, this is usually achieved by exchanging approximately one and a half times the total calculated blood volume over three exchanges: exchange volume (ml) = (35 x weight in kg) In very sick patients, exchange transfusion may be performed as a single, continuous procedure or as two separate exchanges. Long-term transfusion is best carried out by regular exchange transfusions. In patients with poor venous access it may be necessary to start with full exchange transfusion followed by top-up transfusions at regular intervals, generally 4-weekly, Iron chelation treatment may be required. SCD IN T H E COMMUNITY It is essential that children and their families should understand the pathophysiology sufficiently to be aware of situations and activities that they should avoid. They should be encouraged to be open with school teachers, and health professionals should be prepared to advise the schools. The

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teacher should recognize the manifestations of SCD and the problems associated with living with it. Most particularly the need for frequent drinks and the children's inability to concentrate their urine so that they must have easy access to toilets. Many of the children suffer from enuresis so school trips become a problem; fortunately, most children achieve control at or before puberty. Each child should find a level of physical activity that (s)he can undertake during that period of life. It has proved impossible to make blanket recommendations respecting sports. Most SS children cannot swim during the winter months but the few that find that swimming does not precipitate painful vaso-occlusive crisis and are prevented will be less inclined to respect other restrictions placed upon them. Unless there is overt neurological damage there is no indication for SCD children to receive special schooling apart from additional tuition to catch up on time that has been lost related to painful crisis or hospital admission. A multidisciplinary approach from the professionals is essential as every bodily system can be involved by the sickling phenomenon. This is generally best co-ordinated by the paediatrician or haematologist. CONCLUSION In the 1990s every couple in the developed world who is 'at risk' of having a child with a clinically-significant haemoglobinopathy, such as homozygous 13 thalassaemia or sickle cell disease, should now be screened and counselled preconceptuaUy or early in pregnancy. They should be counselled respecting the natural history, the problems of living with the disease, the improved therapies now available and the improved prognosis. Prenatal testing should be available and offered to these couples. The greatest clinical advances over the last decade have been in the thalassaemias with the introduction of 'optimal therapy' and bone marrow transplantation. In sickle cell disease the effect of prophylactic penicillin in reducing mortality has been proven and general guidelines for clinical management are now being agreed. In this article we have discussed the contemporary management of these diseases.

Acknowledgements The authors wouldlike to thank ProfessorG. B. Arden for ophthalmologicaladvice, Dr V. De Sanctis for help in compilingthe endocrinetables, Dr C. Borgne-Pignattifor Figure 1 and Brian Dugan for typing the manuscript.

REFERENCES Aldouri MA, Wonke B, Hoffbrand AV et al (1990) High incidence of cardiomyopathyin 13 thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation. Acta Haematologica 84(3): 113-117. Bartlett AN, Hoffbrand AV & KontoghiorghesGJ (1990)Long term trial with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one(L1). British Journal of Haematology 76: 301-304.

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Bond LR, Hatty SR, Horn MEC et al (1987) Gall stones in sickle cell disease in the United Kingdom. British Medical Journal 295: 234-236. Bronspiegel-Weintrob N, Olivieri NF, Tyler B et al (1990) Effect of age at the start of iron chelation therapy on gonadal function in 13thatassaemia major. New England Journal of Medicine 323: 713-719. Brozovic M, Davies SC & Brownell AI (1987) Acute admissions of patients with sickle cell disease who live in Britain. British Medical Journal 294: 1206-1208. Cao A, Pinto L, Lecca U et al (1984) Control of homozygous beta thalassaemia by carrier screening and antenatal diagnosis in Sardinians. Clinical Genetics 26: 12-22. Cumming P, Wallace E, Schorr J & Dodd R (1989) Exposure of patients to human immunodeficiency virus through the transfusion of blood components that test antibody negative. New England Journal of Medicine 321:941. Cummins D, Heuschel R & Davies SC (1991) An audit of penicillin prophylaxis in children with sickle cell disease resident in Brent. British Medical Journal (in press). Davies SC & Brozovic M (1989) The presentation, management and prophylaxis of sickle cell disease. Blood Reviews 3: 29-44. Davies SC, Luce PJ, Win A A et al (1984) Acute chest syndrome in sickle cell disease. Lanceti: 36-38. Davies SC, Stebbens VA, Samuels MP & Southall DP (1989) Upper airways obstruction and cerebrovascular accident in children with sickle cell anaemia. Lancet ii: 283-284. Donohue M, Wonke B, Hoffbrand AV & Dusheiko J (1990) Detection of antibodies to hepatitis C virus and the use of alpha 2b interferon in the treatment of chronic non-A, non-B hepatitis in multiply transfused thalassaemia patients. Blood 76(10): (abstract). Editorial (1986) Penicillin prophylaxis for babies with sickle cell disease. Lancet ii: 1432-1433. Feretis CB, Legakis NC, Apostolidis NS et al (1985) Prophylactic cholecystectomy during splenectomy for beta thalassaemia homozygous in Greece. Surgery, Gynaecology and Obstetrics 160: 9-12. Gaston MH, Verter JI, Woods G e t al (1986) Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. New England Journal of Medicine 314: 1593-1599. Girot R (1991) European Mediterranean WHO working group on haemoglobinopathies. Proceedings of the Cooley Care 1990 meeting, Athens, 14-15 June 1990, (in press). Gray A, Anionwu A, Davies SC & Brozovic M (1991) Mortality in sickle cell disease. Journal of Clinical Pathology (in press). Gutteridge J & Halliwell B (1989) Iron toxicity and iron radicals. Bailli~re's ClinicalHaematology 2: 195-256. Hatton CSR, Bunch C & Weatherall DJ (1985) Hepatic sequestration in sickle cell anaemia. British Medical Journal 290: 744-745. Herold S, Brozovic M, Gibbs J et al (1986) Measurement of regional cerebral blood flow, blood volume and oxygen metabolism in patients with sickle cell disease using positron emission tomography. Stroke 17: 692-698. Heyman MB, Vichinsky E, Katz R et al (1985) Growth retardation in sickle cell disease treated by nutritional support. Lancet i: 903-906. Higgs DR, Aldridge BE, Lamb J e t al (1978) The interaction of alpha thalassaemia and homozygous sickle cell disease. New England Journal of Medicine 306: 1441-1446. Hindmarsh PC, Brozovic M, Brook CGD & Davies SC (1987) Incidence of overt and covert neurological damage in children with sickle cell disease. Postgraduate Medical Journal 63: 751-753. Kazazian H H Jr (1990) The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Seminars in Hematology 27: 209-228. Leikin SL, Gallagher D, Kinney TR et al (1989) Mortality in children and adolescents with sickle cell disease. Pediatrics 84: 500-508. Lucarelli G, Galimberti M, Polchi P e t al (1990) Bone marrow transplantation in patients with thalassaemia. New England Journal of Medicine 322: 417-421. Marcus R, Davies S, Bantock H et al (1984) Desferrioxamine to improve cardiac function in iron overloaded patients with thalassaemia major. Lancet i: 392-393. Modell B & Berdouskas V (1984) The Clinical Approach to Thalassaemia, p 171. London: Grune & Stratton. Modell B, Petrou M, Ward R et al (1984) Effect of foetal diagnosis testing on birth rate of thalassaemia major in Britain. Lancet if: 1383-1387.

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