Pediatric Annals

Sickle-Cell Disease: Pathophysiology and Diagnosis

William C Mentzer, JR, MD; Winfred C Wang, MD

Abstract

Sickle-cell disease is one of the most common inherited anemias of the hematopoietic system. In this article we plan to discuss the clinical features of the disorder and describe current concepts of diagnosis. * Prognosis and treatment will be considered in the article that follows.

INCIDENCE AND DISTRIBUTION

The sickle-cell gene occurs in the highest frequency in equatorial Africa, where an incidence of up to 40 per cent has been reported in some areas. As a result of the slave trade, the gene was distributed to the Caribbean and North and South America (Table 1 ). It is also found in several other areas, including southern Italy, Sicily, Greece, Turkey, Arabia, and southern India. Recent immigration has increased the frequency of the gene in Britain and other northern European countries.

About 25 years ago it was noted that there was a close geographic association between the distribution of falciparum malaria (the most serious form of malaria) and that of the sickle-cell gene. The diminished longevity and reproductive capability of the homozygous sickle-cell patient is apparently counterbalanced by a protective effect against falciparum infection (in both frequency and severity) in the heterozygote. This "balanced polymorphism" produces a stable gene frequency. In areas of the world where there is no endemic malaria, the incidence of the gene in blacks is slowly declining.

Several possible mechanisms for the resistanolo Plasmodium falciparum have been proposed. Perhaps the most satisfactory experimental evidence has been the demonstration that parasitized AS red cells sickle more readily than do unparasitized cells during in-vitro incubation under hypoxic conditions.1 In vivo, this may result in rapid removal from the circulation and destruction of the parasite.

PATHOPHYSIOLOGY

Sickle-cell anemia is the result of a mutation of the β-globin gene. Sickle β-globin chains differ from the normal in that valine is substituted for glutamic acid at the number six position. This structural alteration, which involves only one of the 146 amino acids that form the β-globin chain, allows the polymerization and gelation of Hb S on deoxygenation. Formation of long fibers of deoxygenated S is responsible for the distortion of the normally discoid red cell into a sickle cell, and the sickling of erythocytes is, in turn, responsible for the myriad clinical manifestations of sickle-cell anemia.

Although oxygenated blood from patients with sickle-cell disease has normal viscosity, deoxygenation, with resultant sickling, leads to a large increase in whole-blood viscosity, as a consequence of the increased rigidity of the sickled red cell. Such rigidity also impairs passage of individual sickled red cells through the microcirculation. The ensuing reduction in blood flow may lead to regional infarction - the so-called vaso-occlusive crisis.

Although the presence of sickled red cells is regarded to be of paramount importance in the initiation of a vaso-occlusive crisis, abnormal interactions between such cells and the vascular endothelium3 or the coagulation system4 have recently been suggested as additional contributing factors. The increased mechanical fragility of sickled red cells is thought to be responsible for the other major clinical manifestation of sickle-cell anemia - chronic hemolytic anemia.

Sickling is usually reversible on reoxygenation of sickled erythrocytes. However, after repeated cycles of sickling, some cells may become irreversibly sickled and fail to regain their normal shape, even after oxygénation. Irreversibly sickled cells make up 0-40 percent of the circulating red cells in patients with sickle-cell anemia3 and are the sickle cells noted on the air-dried peripheral blood smear. These cells have an unusually short survival and contribute to the hemolytic anemia of sickle-cell disease.6 Their possible role in the initiation of painful crises has been suspected but never defined.

Sickling requires deoxygenation…

Sickle-cell disease is one of the most common inherited anemias of the hematopoietic system. In this article we plan to discuss the clinical features of the disorder and describe current concepts of diagnosis. * Prognosis and treatment will be considered in the article that follows.

INCIDENCE AND DISTRIBUTION

The sickle-cell gene occurs in the highest frequency in equatorial Africa, where an incidence of up to 40 per cent has been reported in some areas. As a result of the slave trade, the gene was distributed to the Caribbean and North and South America (Table 1 ). It is also found in several other areas, including southern Italy, Sicily, Greece, Turkey, Arabia, and southern India. Recent immigration has increased the frequency of the gene in Britain and other northern European countries.

About 25 years ago it was noted that there was a close geographic association between the distribution of falciparum malaria (the most serious form of malaria) and that of the sickle-cell gene. The diminished longevity and reproductive capability of the homozygous sickle-cell patient is apparently counterbalanced by a protective effect against falciparum infection (in both frequency and severity) in the heterozygote. This "balanced polymorphism" produces a stable gene frequency. In areas of the world where there is no endemic malaria, the incidence of the gene in blacks is slowly declining.

Several possible mechanisms for the resistanolo Plasmodium falciparum have been proposed. Perhaps the most satisfactory experimental evidence has been the demonstration that parasitized AS red cells sickle more readily than do unparasitized cells during in-vitro incubation under hypoxic conditions.1 In vivo, this may result in rapid removal from the circulation and destruction of the parasite.

PATHOPHYSIOLOGY

Sickle-cell anemia is the result of a mutation of the β-globin gene. Sickle β-globin chains differ from the normal in that valine is substituted for glutamic acid at the number six position. This structural alteration, which involves only one of the 146 amino acids that form the β-globin chain, allows the polymerization and gelation of Hb S on deoxygenation. Formation of long fibers of deoxygenated S is responsible for the distortion of the normally discoid red cell into a sickle cell, and the sickling of erythocytes is, in turn, responsible for the myriad clinical manifestations of sickle-cell anemia.

Although oxygenated blood from patients with sickle-cell disease has normal viscosity, deoxygenation, with resultant sickling, leads to a large increase in whole-blood viscosity, as a consequence of the increased rigidity of the sickled red cell. Such rigidity also impairs passage of individual sickled red cells through the microcirculation. The ensuing reduction in blood flow may lead to regional infarction - the so-called vaso-occlusive crisis.

Although the presence of sickled red cells is regarded to be of paramount importance in the initiation of a vaso-occlusive crisis, abnormal interactions between such cells and the vascular endothelium3 or the coagulation system4 have recently been suggested as additional contributing factors. The increased mechanical fragility of sickled red cells is thought to be responsible for the other major clinical manifestation of sickle-cell anemia - chronic hemolytic anemia.

Sickling is usually reversible on reoxygenation of sickled erythrocytes. However, after repeated cycles of sickling, some cells may become irreversibly sickled and fail to regain their normal shape, even after oxygénation. Irreversibly sickled cells make up 0-40 percent of the circulating red cells in patients with sickle-cell anemia3 and are the sickle cells noted on the air-dried peripheral blood smear. These cells have an unusually short survival and contribute to the hemolytic anemia of sickle-cell disease.6 Their possible role in the initiation of painful crises has been suspected but never defined.

Sickling requires deoxygenation and, therefore, is most likely to occur in hypoxic regions of the body, such as the spleen. Because sickling is not instantaneous, red cells are usually able to pass through hypoxic regions of the venous circulation and return to the arterial circulation before sickling has occurred. Vascular stasis, by prolonging the period of hypoxia, will promote sickling. Acidosis, which diminishes hemoglobin oxygen affinity and, thus, increases the percentage of de-oxygenated Hb S at any given oxygen tension, will also promote sickling.

The intraerythrocytic concentration of Hb S is a major determinant of sickling. Thus, dehydration, which may lead to an increase in hemoglobin concentration, will increase the amount of sickling. On the other hand, the concurrent presence of iron deficiency or a-thalassemia, both conditions that diminish the intraerythrocytic concentration of hemoglobin, may diminish the propensity of red cells to sickle.

The presence of other, non-S, hemoglobins within the erythrocyte may also retard the sickling process. This is particularly true of fetal hemoglobin and, to a somewhat lesser extent, of Hb A. Still other hemoglobins, such as Hb C, retard gelation of hemoglobin S far less than do hemoglobins F or A. Thus, inheritance of 0-globin genes for Hb S and Hb C (Hb SC disease) results in a clinically significant sickling hemoglobinopathy, while the inheritance of genes for Hb S and Hb A (sickle-cell trait) does not.

DIAGNOSIS

The recommended initial screening test7 for a qualitative hemoglobin abnormality is electrophoresis on cellulose acetate at alkaline pH. This procedure is simply performed and rapid and results in few false positives and no false negatives. The "sickle-cell prep," which uses sodium metabisulfite to produce sickling, is an inadequate screening test because it is cumbersome, fails to identify nonsickling abnormal hemoglobins, and does not distinguish homozygotes for Hb S from hétérozygotes.

A solubility test (e.g., Sickledex) should be carried out on all specimens containing hemoglobin migrating in the position of Hb S, A positive solubility test confirms the presence of Hb S, while a negative test is consistent with presence of another hemoglobin, such as D or G. Solubility tests do not distinguish the homozygous from the heterozygous presence of Hb S, do not reveal the presence of doubly heterozygous conditions, such as SC disease, and do not detect Hb S in low concentrations, as seen in the newborn.

PRENATAL DIAGNOSIS

Within the past five years, techniques have been developed that make it possible to identify the presence of sickle-cell disease in the fetus. *·* Now, through amniocentesis, sickle-cell disease can be found by analyzing the fibroblasts in amniotic fluid. The technique is based on the fact that the sickle-cell gene is associated with a particular pattern of deoxyribonucleic acid cleavage fragments induced by certain restriction endonuclease enzymes. I0 The use of amniotic fluid eliminates the risk associated with fetal blood sampling and is applicable in about 80 percent of the cases in which the parents are at risk producing a child with sicklecell anemia (Figure 1).

Table

TABLE 1INCIDENCE OF HETEROZYGOUS HEMOGLOBIN CONDITIONS IN AMERICAN BLACKS*

TABLE 1

INCIDENCE OF HETEROZYGOUS HEMOGLOBIN CONDITIONS IN AMERICAN BLACKS*

Figure 1 . Results of a test of the amniotic fluid in a pregnancy at risk for the birth of a child with sickle-cell disease. Four left-hand lanes show various test patterns, fifth lane is that of the fetus at risk. Lane 1 (left): normal pregnancy. Lanes 2 and 3: parents are heterozygous carriers, have hemoglobin AS. Lane 4: a child with hemoglobin SS who has received the sickle-cell gene from each parent. Lane 5 (right): amniotic fluid cells indicate that this fetus will have the sickle trait. Numbers at right indicate size in kilobases of fragments containing the beta-globin genes. In this family, the presence of a /js-globin gene was associated with a 1 3.0-kilobase fragment while the BAgenes were associated with a 7.6-kilobase fragment. The fetus at risk had both 7.6- and 1 3.0-kilobase fragments and subsequently proved to have sickle trait, as expected. This is an autoradiogram of haptoglobin-A "-digested deoxyribonucleic acid hybridized with glob in-complementary DNA. Reproduced with permission from Kan, Y. W., and Dozy, A. M. 10

Figure 1 . Results of a test of the amniotic fluid in a pregnancy at risk for the birth of a child with sickle-cell disease. Four left-hand lanes show various test patterns, fifth lane is that of the fetus at risk. Lane 1 (left): normal pregnancy. Lanes 2 and 3: parents are heterozygous carriers, have hemoglobin AS. Lane 4: a child with hemoglobin SS who has received the sickle-cell gene from each parent. Lane 5 (right): amniotic fluid cells indicate that this fetus will have the sickle trait. Numbers at right indicate size in kilobases of fragments containing the beta-globin genes. In this family, the presence of a /js-globin gene was associated with a 1 3.0-kilobase fragment while the BAgenes were associated with a 7.6-kilobase fragment. The fetus at risk had both 7.6- and 1 3.0-kilobase fragments and subsequently proved to have sickle trait, as expected. This is an autoradiogram of haptoglobin-A "-digested deoxyribonucleic acid hybridized with glob in-complementary DNA. Reproduced with permission from Kan, Y. W., and Dozy, A. M. 10

SICKLE-CELL CRISES

Untoward episodic events in the lives of sicklecell patients are referred to as "crises," a somewhat inappropriate but firmly established term. There are two general types of crises, those that lead to anemia and those caused by vaso-occlusion.

Anemic crises. There are two principal types, aplastic and splenic-sequestration crises.

Aplastic crises are due to a temporary failure of bone-marrow erythroid production. Because of the extremely short life span of sickle red-blood cells (10-20 days), even a temporary failure of bonemarrow production leads to a rapid fall in hematocrit. Aplastic crises are not unique to sickle-cell disease but occur with other hemolytic anemias, such as hereditary spherocytosis or thalassemia. They are usually triggered by a viral or bacterial infection, may occur in several members of a family, and are much more common in childhood.' Clinical features are secondary to a rapid worsening of the anemia and include weakness, listlessness, pallor, tachypnea, tachycardia, hepatomegaly, and other evidence of congestive heart failure and decreased jaundice. The hemoglobin may fall to a level as low as 1 gm./100 ml.; the reticulocyte count is usually less than 1 percent. White-cell and platelet counts are usually unaffected. Aplasia may last 5-10 days; recovery is associated with a profound reticulocytosis.

Splenic-sequestration crises are characterized by an acute, massive enlargement of the spleen and a rapid fall in hemoglobin level." In hemoglobin SS disease, they occur between the ages of six months and five years - a period when the spleen may be enlarged before autoinfarction. They are also seen in sickle-thalassemia and hemoglobin SC disease - conditions in which there is often persistent splenomegaly. Sequestration is most commonly triggered by a viral infection and is manifested by the development over a few hours of weakness, listlessness, pallor, splenomegaly, tachypnea, tachycardia, and evidence of hypovolemic shock. The reason for the sudden pooling of a huge volume of blood in the spleen is unknown. The rapidity with which the syndrome develops is largely responsible for its being a leading cause of mortality in children with sickle-cell disease.

Hyperhemolytic crisis is a term that has been used to refer to a further increase in hemolysis superimposed on the normally rapid rate. Such crises are rare and occur primarily when there is concomitant G6PD deficiency.11 In these cases, an acute infection or exposure to an oxidant drug may result in a further lowering of the hematocrit and increase in jaundice.

Vaso-occlusive crises. The hallmark of sickle-cell disease is the painful crisis affecting the extremities, back, chest, or abdomen." Typically, these crises begin after the age of four or five years (with the exception of the hand-foot syndrome), occur frequently during later childhood, and decline in frequency during adulthood . There is a wide spectrum in frequency and severity. In some patients, painful crises occur almost every week, whereas others may go for years between crises. Occasional patients with hemoglobin SC disease or sickle-j3+thalassemia may escape them altogether.

Painful crises may be precipitated by a number of factors, such as exposure to high altitudes, flight in unpressurized airplanes, administration of a drug (such as ammonium chloride) that produces metabolic acidosis, or dehydration secondary to excessive fluid loss or inadequate intake. Perhaps the most frequently recognized precipitating factor is infection, either viral or bacterial. Exposure to cold is frequently reported by patients as a triggering event. Strenuous physical exertion, local trauma, long periods of inactivity (such as a long car or bus ride), alcohol intoxication, and pregnancy have been associated with pain crises. In many cases, a crisis will awaken a patient from sleep. Psychologic stresses are difficult to measure but are probably often significant. One study15 showed that 50 per cent of painful crises were preceded by severe depression.

Pain in the extremities, chest, and back probably results from small areas of infarction in the bone or bone marrow. The pain is usually severe and continuous, with a throbbing character. It may last from a few hours to weeks, but on the average lasts three or four days. Pain may be symmetric or asymmetric, may affect single or multiple sites, and may migrate. There is usually exquisite tenderness of the site; mild edema or effusion may be present. Fever is often present but generally low-grade (<102°F). Joint pain, particularly in the knees, shoulders, elbows, wrists, and ankles, may simulate rheumatoid arthritis or rheumatic fever. Localized redness or warmth is usually absent and, when present, should raise the question of osteomyelitis.

Laboratory documentation of 'a painful crisis and differentiation from bacterial infection or from factitious crisis may be difficult. Lactic dehydrogenase isoenzymes 1 and 2 are elevated in sickle-cell disease and even further elevated during a vasoocclusive crisis but not in an acute infection).16*17 The absolute band count18 and leukocyte alkaline phosphatase score19 are elevated above baseline values in sickle-cell patients during acute bacterial infection but not during vaso-occlusive crisis. In the early differentiation of vasco-occlusive bone pain from osteomyelitis, x-rays are of little value. However, bone-marrow scans have demonstrated decreased uptake of "Tc-sulfur colloid particles in infarction and may prove to be useful.20

Hand-foot syndrome, or dactylitis, presents as a painful, tender swelling of the dorsa of the hand and feet. 2 ' It occurs between the ages of six months and approximately five years and is often the initial manifestation of sickle-cell disease. In patients with SS disease, the frequency of this complication is about 10 percent in the United States. The condition is usually symmetric and may affect hands, feet, or both. The symptoms usually subside after one to two weeks but may recur. Radiologically, there are no changes initially, but after one to two weeks, periostitis, osteolysis, and bone reabsorption may appear in the metacarpale, metatarsals, or phalanges. This usually resolves completely, but occasionally premature fusion of epiphyses may lead to shortening of the affected bone.

Acute central-nervous-system manifestations of vaso-occlusion - cerebro vascular accidents, seizures, altered states of consciousness, and visual disturbances - occur in 13 to 26 percent of SS patients.12 The incidence in other forms of sickle-cell disease is considerably less. There is no sex predilection for these complications. However, 80 percent of cerebrovascular complications occur in patients less than 15 years old, with an average age of onset of six."

Cerebral angiography in stroke patients has, surprisingly, demonstrated partial or complete occlusion of large cerebral vessels such as the internal carotid artery or anterior and middle cerebral arteries, rather than involvement of small arteries.2*

Angiography may show an extensive collateral network, often with a moyamoya* pattern (Figure 2). It has been postulated that vaso-occlusion of vasa vasorum or sludging of erythrocytes may alter the nutrition of the inner portion of the wall of large cerebral vessels, leading to intimai edema, proliferation, and partial or complete occlusion.

Strokes are sometimes associated with an infection or painful crisis and are often accompanied by seizures. The resultant hemiplegia improves in 6070 percent of cases but in the majority leaves residual deficits. Death occurs in a small percentage. The frequency of recurrence is high - approximately 60 percent. Many patients with recurrent strokes develop a pseudobulbar palsy, with difficulty in speaking, swallowing, and ambulatibn.

Convulsions are more commonly generalized but may be focal. Visual disturbances include transient blindness, diplopia, and optic atrophy. Cranialnerve-lesions and transient ataxia have also been observed, as have often fatal subdural, subarachnoid, and intracerebral hemorrhage and cortical venous and/or sinus thrombosis.

Figure 2. Left carotid angiogram in a six-year-old girl with SS disease and right hemiparesis. Partial obstruction of anterior and middle cerebral arteries, abnormal arborization of peripheral vessels, and extensive moyamoya patterns are demonstrated.

Figure 2. Left carotid angiogram in a six-year-old girl with SS disease and right hemiparesis. Partial obstruction of anterior and middle cerebral arteries, abnormal arborization of peripheral vessels, and extensive moyamoya patterns are demonstrated.

Acute pulmonary crises often develop in sicklecell patients as a result of pneumonia or infarction.21 Sixty percent of acute pulmonary episodes occur in children under four; most of these are presumed to be due to pneumonia. However, whatever the initial event, local pulmonary capillary stasis and low oxygen tension presumably lead to sideling, pulmonary infarction, and delayed resolution of any infectious process.

Pulmonary episodes are associated with prolonged fever (12 days in one series) and a tendency to recurrence.16 Differentiation between infection and infarction is often impossible. Both are commonly associated with pleuritic pain, pleural effusion, dyspnea and fever, lower-lobe infiltrates, and increased leukocytosis. Infection is associated with age below five years, onset with a chill, upper-lobe infiltrates, purulent sputum, and a positive blood culture. Preceding symptoms of a painful crisis, episodes of unexplained dyspnea, new infiltrates or sites of chest pain after initiation of antibiotic therapy, and a serum bilirubin of greater than 5 mg./ 100 ml. suggest infarction.15 Most pulmonary infections of proved cause are due to pneumococcus, but Mycoplasma pneutnoniae, Hemophilus influenzae, Escherichia colt, Salmonella, and other gram-negative rods have been implicated. M. pneumoniae infection may be of unusual seventy in sickle-cell patients."

In older patients, pulmonary emboli, chronic pulmonary hypertension, and cor pulmonale may occur.

Abdominal crises, manifested by abdominal pain (particularly in the right upper quadrant), jaundice, leukocytosis, and elevated liver enzymes, are said to occur in 10 percent of patients with sicklecell anemia.1* It is frequently difficult to distinguish among hepatic crises, acute hepatitis, and cholecystitis secondary to cholelithiasis.

Intrahepatic sickling or sickle hepatopathy results in transient sickling within sinusoids or hepatic arteries, with resulting hepatocellular necrosis.19

Viral hepatitis in sickle-cell patients is relatively infrequently recognized, despite repeated exposure to blood products. It is characterized by marked and prolonged hyperbilirubinemia and high SGOT levels, but otherwise classic symptoms and signs.

Cholelithiasis has been reported to occur in 6.5 to 37 percent of patients with sickle-cell disease.'0 The incidence of cholelithiasis increases with age, and it is rare to see stones in children under 1 0 years of age. Approximately 55 percent of the stones are radiopaque.

Priapism can occur in patients with sickle-cell disease, resulting from obstruction of venous blood flow by sickled erythrocytes within the erectile tissue of the corpora cavernosa. The stasis leads to local hypoxia, actdosis, and further sickling, with production of a thick, dark, viscous fluid. The majority of cases occur in sickle-cell patients under age 12.3li3ï The incidence in hospitalized male patients has been reported to be 2.4 to 5 percent. Attacks may occur spontaneously, often during sleep, or may be precipitated by sexual activity, infection, or painful crises. They may last from a few hours to weeks. Impotence and megaphallus may result, particularly when attacks occur during adulthood. Treatment has included aspiration of the corpora cavernosa, shunts to drain the corpora, and transfusion therapy.

COMPLICATIONS OF SICKLE-CELL DISEASE

Complications of sickle-cell disease can be manifest in any organ system. As with any chronic illness, there are also significant psychosocial effects. Eye. Ocular manifestations of sickle-cell disease are common, particularly in hemoglobin SC disease and sickle-0 thalassemia."·" Sickle-cell lesions can occur in the conjunctiva, iris, optic disc, and retina. Conjunctival "commas" are small corkscrew vascular segments on the buibar conjunctiva. They have been correlated with the percentage of irreversibly sickled cells (ISCs) in the peripheral blood. Segmentai iris atrophy and neovascularization of the optic-nerve head are rare findings. By far the most significant abnormalities are seen in the retina and can be divided into nonproliferative and proliferative changes. Nonproliferative retinopathy includes retinal hemorrhages, increased venous tortuosity, black sunbursts, schisis cavities (atrophie, cystic areas), angioid streaks (red or gray jagged lines in the posterior pole), and whitening of the peripheral retina. Proliferative sickle retinopathy seems to evolve in the following sequence: peripheral arteriolar occlusion - arteriolar-venular -» anastomosis -»neovascularization ("sea-fan" appearance) -* vitreous hemorrhage-* retinal detachment. Many of these changes can be seen best by fluoroscein angiography. Retinitis proliferans, the end stage of this process, results from the organization and fibrosis associated with neovascularization and hemorrhage. It has been reported in as many as half of the hemoglobin-SC patients and as early as age six. Visual-field defects and blindness may result. Treatment has been through photo-coagulation of the nutrient arterioles supplying the sea fans or, at more advanced stages, vitrectomy and/or retinal detachment repair.

Ear. Relatively little is known regarding possible otologie complications of sickle-cell disease. A sensorineural hearing loss of at least 25 decibels was found in 22 percent of a series of Jamaican patients and was attributed to obstruction of the venous drainage of the cochlea." Although hearing loss is usually of gradual onset, sudden, reversible hearing loss related to painful crises has been reported in both SS and S-/3 thalassemia teenage patients.

Heart. The anemia of homozygous sickle-cell disease leads to an increase in cardiac output and cardiac enlargement from an early age." Pulmonary vascular occlusion may cause cor pulmonale in older sickle-cell patients. Surprisingly, myocardial ischemia and infarction are rarely seen, even in adult patients. A single case of angina pectoris in a seven-year-old has been described.37 Sinus arrhythmia is not uncommon. Cardiac abnormalities are much less prominent in hemoglobin-SC disease.

Physical examination usually reveals cardiomegaly, with lateral or downward displacement of the apex beat and often a left parasternal heave. Nearly always present is a systolic ejection murmur, loudest at the left sternal border and radiating widely over the precordium. An accentuated S and middiastolic rumble or S are often heard. Chest x-rays usually demonstrate generalized cardiomegaly. Electrocardiogram findings are nonspecific: evidence of left- ventricular hypertrophy is common; right-ventricular overload and a prolonged PR interval may be seen. Sonography has shown left- and right-ventricular dilatation, increased stroke volume, and abnormal septal motion.

Kidneys. Renal function in children with sickle-cell disease is characterized by increased renal blood flow, decreased ability to excrete acid and sodium, and inability to concentrate urine, even after fluid deprivation.38 This inability has been noted in children as young as six months of age but becomes more severe with increasing age. Enuresis and nocturia are extremely common effects of the large fluid intake and urine output of these patients.

Hyponatremia has been noted in children hospitalized for sickle-cell crisis or infection and treated with fluids intravenously.39 It appears to be due to excessive salt loss in the urine. Administration of sodium (6-11 mEq. /kg. /day) is recommended.

Leg ulcers. Leg ulcers are a physically and psychosocially debilitating complication of sickle-cell disease. They are uncommon under age 10 but often begin during adolescence.40

Ulcers characteristically heal slowly over months to years, leaving irregularly pigmented scars. There is often repeated breakdown at the same or adjacent sites. Treatment is inconsistently helpful and consists of bed rest, elevation of the leg, and frequent cleaning. Oral zinc sulfate, pinch-skin grafts, and chronic transfusion have sometimes been useful. Unfortunately, the chronic pain and the prolonged treatment regimen often lead to severe disruption of education and employment.

Skeleton. The common skeletal abnormalities seen in sickle-cell disease are caused by marrow expansion or bone infarction.41 (Osteomyelitis is discusssed in the section on Infection.) Marrow expansion is due to increased erythropoiesis and is, therefore, generally more prominent in SS disease than in SC disease and S-ß-thalassemia. Marrow expansion in the skull may result in frontal bossing anc* tne radiologie picture of widened diploic spaces and, rarely, a "hair-on-end" appearance. Overgrowth of the anterior portion of the maxilla may lead to gnathopathy (an exaggerated "bucktooth" appearance). Marrow expansion in the vertebrae, pelvis, and long bones may result in osteoporosis, cortical thinning, a coarse trabecular pattern, and large nutrient-vessel foramina on xray.

Infarctive changes in the long bones lead to cortical thickening, periosteal elevation, "bone-withinbone" appearance, and patchy sclerosis. The tubular bones of the hands and feet in young children are particularly susceptible to infarction (see "Hand-foot syndrome"). In the vertebral bodies, smooth biconcavities of the upper and lower surfaces or a steplike depression of the middle 60 percent of these surfaces ("step" sign) may be found. Of most clinical significance, however, is avascular necrosis affecting the articular surfaces of the femoral and humeral heads. Involvement of the head of the femur occurs in up to 15 percent of patients, increases with age, may be bilateral, and may necessitate total prosthetic replacement.

Physical and sexual development. The average weight of patients with sickle-cell anemia is normal at birth, is below the mean by six months of age, and remains low through childhood, adolescence, and adulthood.41 The height of hemoglobin-SS patients is slightly decreased through childhood and early adolescence but equal to or above that of adult controls. Bone age is retarded an average of one to two years, accounting, at least in part, for the delay in the attainment of normal height. Hemoglobin-SS patients have a lean body habitus, but this is not necessarily true for patients with hemoglobin-SC disease or sickle thalasserma. Adult siclde-cell-anemia patients have long legs and a relatively short trunk (resulting in a decreased upperto-lower-segment ratio), narrow shoulders and hips, and increased anteroposterior chest diameter and accentuation of normal vertebral curvatures.

Sexual maturation in sickle-cell-anemia patients is commonly delayed for several years. The etiology for this is unclear, but the finding of elevated luteinizing hormone and follicle-stimulating hormone levels for a given stage of sexual development is suggestive of transient gonada) impairment.4'

Pregnancy. Pregnancy in sickle-cell anemia is complicated by increased severity of anemia (sometimes exacerbated by folate deficiency), increased urinary-tract infections, and more frequent painful crises, particularly during the last trimester and in the postpartum period.44 There is an increased incidence of spontaneous abortion and stillbirth, which results in fetal loss as high as 50 percent.

Newborns are often born prematurely and/or small for gestational age; birth weights below 2,500 gm. have been reported in 16 to 58 percent. Exchange transfusion in the mother at the onset and end of the third trimester may markedly reduce maternal and neonatal morbidity and mortality.43 Infection. The sickle-cell-anemia patient is extraordinarily susceptible to overwhelming infection, particularly due to Streptococcus pneumoniae (pneumococcus) and, to a lesser extent, Hemopkilus influenzae type b. These infections take the form of sepsis, meningitis, and pneumonia and most commonly occur within the first five years of life. In a Los Angeles study, sepsis or meningitis occurred in approximately 1 0 percent of patients during the first five years of life, and the two conditions were responsible for the majority of deaths in this age group.46

The sickle-cell-anemia patient has a diminished ability to clear pneumococci from the bloodstream because of at least two abnormalities: defective splenic function and deficient pneumococcal serum-opsonizing activity.

The spleen in siclde-cell-anemia infants may become palpably enlarged after about six months of age but has usually "autoinfarcted" by age five. However, "functional asplenia" may be detected before autoinfarction, usually between six months and three years of age.47 Even though the spleen may be palpable, it fails to take up "Tc-sulfur coloid particles and to remove nuclear remnants (Howell-Jolly bodies) from circulating red blood cells.

Serum opsonins, proteins that bind to the pneumococcus and promote its ingestion by phagocytes, are also diminished.4' Hemoglobin-SC and sickle-thalassemia patients appear to have only a slightly increased risk for overwhelming infections.

A vaccine containing capsular polysaccharide antigen from 14 of the most common pathogenic pneumococcal serotypes (Pneumovax) is now available. This promises to afford 80-90 percent protection against overwhelming pneumococcal infection in sickle-cell patients older than age two. (Efficacy of the vaccine in younger patients has not yet been demonstrated.4")

Osteomyelitis in sickle-cell patients may be caused by a number of organisms, but more than half of the cases are due to Salmonella, an otherwise rare enologie agent. The reason for the increased incidence of Salmonella is unknown. Osteomyelitis most commonly affects the long bones and in about half the cases occurs in children under five. Differentiation of osteomyelitis from acute bony infarction may be difficult, since both can cause fever, pain, and localized tenderness and swelling. Radiographie changes of osteomyelitis are generally not noted at presentation. Bone scan with "Tc-sulfur colloid may be useful.

Psychosocial. Psychosocial effects of such a chronic disease as sickle-cell disease can be at least as significant to the patient and family as medical problems.'0 Adverse effects on family stability, education, employment, and self-esteem are obvious. Solutions to these problems are less obvious, but approaches can be made through individual counseling and education, patient and parent groups, vocational rehabilitation services, summer camps for children, community educational programs, and regular evaluations by a health-care team that addresses both medical and psychosocial needs.

SICKLING VARIANTS

A clinically significant hemoglobinopathy can result from the simultaneous inheritance of one sickle )3 globin gene and an allelic gene for another abnormal ß chain. For example, when sickle trait and Hb C trait are inherited together, the result is a milder form of sickle-cell disease, Hb SC disease, easily recognized by hemoglobin electrophoresis, which reveals approximately equal amounts of hemoglobins S and C. Although the anemia in SC disease is milder than that in sickle-cell anemia (Table 2), and although any of the vaso-occlusive manifestations of sickle-cell anemia may occur, they tend to be less frequent and less severe.51 A notable exception is the occurrence of sickle retinopathy, which is more common in SC disease than in sickle-cell anemia. The spleen usually does not atrophy with advancing age, and, in fact, hypersplenism, splenic infarction, and mild splenic sequestration crisis are occasional features of the disease in both children and adults. Although the frequency of infection is greater in SC disease than in the general population, there is no particular predilection for overwhelming pneumococcal infection, as is the case in sickle-cell anemia."

When sickle trait and /3-thalassemia trait are inherited together, the severity of the resulting disease is, to a great extent, dependent on the severity of the thalassemic lesion. In sickle-/? +thalassemia, where there is residual production of normal ßchains, some hemoglobin A is produced and the clinical course is often quite mild, with only minimal anemia and rare vaso-occlusive crises. In contrast, in sickle-^0 thalassemia, where there is complete absence of normal j3-globin synthesis, the intracellular concentration of sickle hemoglobin tends to be higher and the clinical severity often equals that of sickle-cell anemia itself. Sickle-|3 thalassemia should be suspected when microcytosis is present in association with an Hb S concentration greater than 50 percent. Hemoglobin Aj levels are elevated, and family studies confirm the presence of jS-thalassemia trait in one parent and sickle trait in the other.

A number of other abnormal hemoglobins may be found in combination with sickle hemoglobin. Accurate identification of such hemoglobins is essential, so that an appropriate prognosis can be made and genetic counseling offered to the affected individual and his family.

SICKLE TRAIT

Sickle-cell trait, which occurs in 8 percent of American blacks, is a condition frequently encountered in most general pediatrie practices." It is important that children with sickle trait and their families be provided with accurate information, with particular emphasis on the distinction between sickle trait and sickle-cell anemia. Sickle-cell trait is not a disease. There is no shortening of the life span and no known influence on athletic ability. Although one study has suggested an adverse effect on growth and mental ability," the findings of this study have been disputed by others. Under ordinary circumstances, sickle-trait erythrocytes do not sickle in vivo, and the clinical manifestations that accompany sickling are not seen. There is no anemia, and red-cell morphology is normal. Painful vaso-occlusive crises do not occur. On the other hand, under unusual circumstances (e.g., extreme hypoxia), sickling may occur. The hyperosmolarity, acidosis, and hypoxia found in the medulla of the kidney provide a uniquely favorable environment for the sickling of sickle-trait red cells; therefore, renal manifestations are frequent. Up to 70 percent of persons with sickle trait exhibit hyposthenuria, and approximately 4 percent will have at least one episode of gross hematuria during their lifetime." These abnormalities do not lead to any significant degree of impaired renal function. When present, hematuria must be fully assayed, as it may be due to a condition other than sickle trait. Bacteriuria and pyelonephritis occur more frequently during pregnancy in subjects with sickle trait than in controls.

Table

TABLE 2CLINICAL FEATURES OF COMMON SICKLING VARIANTS51

TABLE 2

CLINICAL FEATURES OF COMMON SICKLING VARIANTS51

Flight in pressurized aircraft poses no hazard for those with sickle trait. There is evidence suggesting that flight in unpressurized aircraft above 10,000 feet may precipitate a vaso-occlusive crisis; however, military combat pilots with sickle-cell trait have logged extensive time under similar circumstances without incident."

Occasional case reports of sudden death during or after anesthesia emphasize the need for adequate oxygénation of sickle-trait patients during any surgical procedure. On the other hand, such case reports have been infrequent and several large studies indicate that there is not any actual increased risk of anesthesia in sickle trait.

SCREENING

The primary goals of a sickle-cell screening program54 should be:

1. To detect patients with sickle-cell disease before the onset of complications in order to provide a program for comprehensive medical care, counseling, and education.

2. To incorporate screening into comprehensive medical care and include procedures that will identify other causes of anemia.

3. To detect carriers of hemoglobin traits who are at risk of having children with sickle-cell disease and to provide genetic counseling so that the significance of these traits can be fully understood.

4. To simultaneously provide educational programs that will increase awareness and understanding of sickle-cell disease and trait in the lay and professional community.

When screening is performed to identify patients with sickle-cell disease, the ideal target population is the black newborn. Approximately one out of 250 black newborns will have a clinically significant hemoglobinopathy. Early diagnosis through cord-blood screening alerts the physician and family before the onset of symptoms. Prompt, sensitive counseling helps the family cope with the disease. Education of physicians and families may be effective in preventing some of the early morbidity and mortality, particularly those due to overwhelming infection and splenic sequestration. Identification of sickle-cell trait in a newborn infant may lead to the discovery of families in which both parents are carriers and, therefore, are at risk of producing a homozygous offspring in subsequent pregnancies. In this situation, couples may wish to take advantage of newly developed procedures for prenatal diagnosis.

Other target populations include pregnant black women and black patients undergoing general anesthesia, since the milder forms of sickle-cell disease, such as SC disease or S-/3*-thalassemia, occasionally escape detection until late childhood or adult life.

When the goal is to detect "carriers" of an abnormal hemoglobin in order to provide genetic counseling, the optimal groups to screen are adolescents and adults of childbearing age. Screening procedures should be capable of detecting sickle-cell trait, hemoglobin-C trait, and /3-thalassemia trait, as any of these /3-chain abnormalities, when inherited in combination with sickle-cell trait, will result in a clinically significant sickling disorder. Programs initiated in secondary schools, adolescent clinics, and family-planning clinics have been the most successful. When an index case has been identified, screening should be offered to other family members.

Informed consent and confidentiality. Sickle-cell screening must be voluntary and preceded by written informed consent. The consent form must be couched in understandable terms and must indicate the purpose of testing, the potential benefits and risks, and the right to receive testing results. Persons with sickle-cell trait have, at times, received unjustified discrimination in employment and insurance. Thus, it is important to maintain the right to confidentiality of those screened.

REFERENCES

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44. Horger, E. O. Hemoglobinopathies in pregnancy. Clin. Obstet. Gynecoì. 17 (1974), 127-162.

45. Morrison, J. C.. and Wiser, W. L. The use of prophylaric partial exchange transfusion in pregnancies associated with sickle cell hemoglobinopathies. Obstet. Gynecoì, 48 (1976).

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49. Ammann, A. J-, et al. Polyvalent pneumococcal-polysaccharide immunization of patients with sickle-cell anemia and patients with sptenectomy. N. Engl. J. Med. 297 (1977), 897-900.

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53. Sears. D. A. The morbidity of sickle cell trait. Am, j. Med. 64 (1978). 1021-1036.

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55. Lubin, B. H., Mentzer, W. C., Jr.. Wang, W., andDavis, J. R., Jr. Sickle cell screening, counseling and education. Hemoglobinopathies in Children (Volume 3 of Progress in Pediatrie Hematology and Oncology. Littleton, Mass.: PSG Publishing Company, 1980, pp. 105-122.

TABLE 1

INCIDENCE OF HETEROZYGOUS HEMOGLOBIN CONDITIONS IN AMERICAN BLACKS*

TABLE 2

CLINICAL FEATURES OF COMMON SICKLING VARIANTS51

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