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Insulin resistance, obesity, and related disorders among black adolescents
THE J O U R N A L OF
PEDIATRICS SEPTEMBER
1996
Volume 129
Number 3
EDITOR'S COLUMN Insulin resistance, obesity, and related disorders among black adolescents Obesity, hypertension, and non-insulin-dependent diabetes mellitus are increasing at an alarming rate among black Americans. NIDDM is approaching the high frequency found in the Pima Indians of Arizona (>40%), and is 60% more frequent than in the white population. 1 The incidence of hypertension among black Americans is 38%, compared with 29% among white Americans. 2 Of greatest concern, however, is the evidence that this "epidemic" is not restricted to the adult population--among children and adolescents there has been a dramatic increase in the prevalence of these disorders during the past two decades) Hyperinsulinemia, caused by insulin resistance, has been implicated in the pathogenesis of obesity, NIDDM, hypertension, polycystic ovarian disease, acanthosis nigricans, lipid abnormalities, and atherosclerosis, 4 as well as ischemic heart disease. 5 It has been suggested that insulin resistance per se may be the common underlying cause of these disorders. Studies done among populations with a high prevalence of NIDDM, such as American Indians, Mexican Americans, Pacific Islanders, and Austrafian aborigines, have demonstrated that an extended period of increasing insulin resistance precedes the decline in B-cell function heralding the onset of overt NIDDM. 6 Moreover, relatively high insulin levels have been found among children and young adults in populations with a high risk of NIDDM, as well as among the offspring of type II diabetic parents. 7 Longitudinal follow-up studies indicate that children with elevated insulin tevels are at an increased risk of having NIDDM later in life.6, 8 Because approximately 40% of adult patients with NIDDM have clinical macroangiopathy at the time of diagJ Pediatr 1996;129:319-21 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/75382
nosis, long-term insulin resistance and resulting hyperinsulinism may themselves promote the development of complications before the onset of the diabetic state. 9 Hyperinsulinemia and insulin resistance are also associated with essential hypertension in nonobese, nondiabetic young adults,l° and longitudinal studies suggest that glucose intolerance may antedate the onset of hypertension. 11 Impaired insulin sensitivity has been demonstrated in the nonobese normotensive children of patients with essential hypertension. 12 However, the mechanism underlying the association between hyperinsulinism and hypertension re-
See related article, p. 440.
NIDDM Non-insulin-dependentdiabetes mellims - - 7 mains controversial. It has been suggested that insulin may regulate blood pressure through the promotion of renal sodium retention, through a direct effect of insulin on the sympathetic nervous system, or through enhanced atherogenesis in resistance vessels. 13 It is interesting to consider the reason that this "epidemic" of disorders associated with insulin resistance is affecting black Americans disproportionately. The Bogalusa [Louisiana] Heart Study I4 demonstrated that black children had significantly higher insulin secretion in response to an oral glucose load than did white counterparts throughout all stages of puberty, suggesting lower insulin sensitivity among black children. In this issue of The Journal of Pediatrics, Arslanian and Suprasongsin t5 report their extension of these studies to investigate the differences in both insulin sensitivity and insulin secretion between black and white adolescents by using a hyperglycemic clamp. Of particular note is that these subjects were nonobese arid had no family history
319
320
Editor's column
of diabetes. Although basal levels of insulin were similar in the two groups, both the first and second phases of insulin secretion in response to an intravenous glucose load were significantly higher in black adolescents matched for age, sex, and pubertal staging. In addition, insulin sensitivity measured during the hyperglycemic clamp was 35% lower in the black adolescents. Thus this study demonstrates a significant racial difference in insulin physiology already present during adolescence and before the development of obesity. Therefore black Americans may be predisposed to insulin resistance and hyperinsulinism, which subsequently promote the development of obesity, NIDDM, hypertension, and other abnormalities. The apparent racial disparity in insulin sensitivity may be the result of different genetic backgrounds, differences in environmental or cultural factors, or a combination of both genetics and environment. According to the "thrifty genotype" theory, 16, 17a genotype that efficiently converts excess energy intake into depot fat under the influence of a robust insulin response would have a survival advantage under conditions of scarcity. However, with the availability of high-calorie foods and reduced physical activity, the previously advantageous "thrifty" genotype would promote insulin resistance, hyperinsulinism, obesity, and, in susceptible individuals, development of overt disease. The molecular basis of insulin resistance remains poorly understood, and attempts to define the exact loci of insulin resistance have met limited success, is Though defined genetic defects have been identified in rare syndromes of extreme insulin resistance, 19,2o the molecular and genetic mechanisms responsible for the development of insulin resistance in the majority of individuals are not known. However, the racial difference in insulin sensitivity present in adolescents before the development of obesity, as demonstrated by Arslanian and Suprasongsin,15 suggests an underlying genetic predisposition is responsible for at least part of this disparity. On the other hand, the rising frequency of NIDDM, hypertension, and obesity among black Americans points to an important change in the environmental context that is promoting increasing development of overt disorders in individuals genetically predisposed to insulin resistance. The contemporary "Western" diet is unique in human history in its availability and composition. 21 Furthermore, modern American civilization represents the first period in history in which regular physical activity is not an integral part of daily life for the majority of people. 22 Evidence indicates that the excessive energy intake, high-fat diets, and low levels of leisure-time physical activity that characterize the American 1990s lifestyle each independently promotes insulin resistance. 21 Thus environmental changes may be exacerbating underlying genetic differences, leading to increasing insulin
The Journal of Pediatrics September 1996
resistance in the American population in general but dispro= portionately among black Americans. NIDDM, obesity, and hypertension appear to represent the outcome of a process in which a genetic predisposition to insulin resistance and hyperinsulinism interact with the environment. Given the direction of lifestyle pressures in America in the 1990s, early intervention may be necessary to reverse the trend of increasing insulin resistance-related disorders surfacing among America's children, adolescents, and young adults. Furthermore, the studies of Arslanian and Suprasongsin indicate that a predisposition to insulin resistance and hyperinsulinism is present among black American teenagers before overt changes in body habitus, apparently placing them at an increased risk of having these' 'lifestyle" disorders and potentially accounting for the increased incidence of such disorders in the black population. To address this potential epidemic of obesity, NIDDM, and hypertension among American children, a concerted public health effort aimed at promoting dietary change and physical activity among the young is critical, with particular focus on those ethnic groups at greatest risk. Orit Pinhas-Hamiel, MD Maccabi, Pediatric Endocrine Unit Ramat-Hasharon, Israel
Philip Zeitler MD, PhD Division of Endocrinology The Children's Hospital Denver, CO 80218 REFERENCES
1. Douglas JG. Hypertension and diabetes in Blacks. Diabetes Care 1990;13:1191-5. 2. Hypertension prevalence and the status of awareness, treatment, and control in the United States. Final report of the Subcommittee on Definition and Prevalence of the 1984 Joint National Committee. Hypertension 1985;7:457-68. 3. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeifler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996; 128:608-15. 4. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 5. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:95-7. 6. Zimmet PZ, Collins VR, Dowse GK, Knight LT. Hyperinsulinemia in youth is a predictor of type. 2 diabetes mellitus. Diabetologia 1992;35:534-41. 7. Johnston C, Ward WK, Beard JC, McKnight B, Porter D. Islet function and insulin sensitivity in the non-diabetic offspring of conjugal type 2 diabetic patients. Diabet Med 1990; 7:119-25. 8. Martin BC, Warram J, Krolewski AS, Bergman RN, Soeldner JS, Kahn RC. Role of glucose intolerance and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992;340:925-9.
The Journal of Pediatrics Volume 129, Number 3
9. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states: sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 94:1714-21. 10. Ferranini E. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-7. 11. Reaven GM, Hoffman BB. A role for insulin in the etiology and course of hypertension. Lancet 1987;2:435-6. 12. Gmnfeld B, Balzareti M, Romo M, Gimenez M, Gutman R. Hyperinsulinemia in normotensive offspring of hypertensive patients. Hypertension 1994;23(1 Suppl):ll2-5. 13. Yudkin J. Hypertension and non-insulin-dependent diabetes. BMJ 1991;303:730-2. 14. Svec F, Nastasi K, Hilton C, Bao W, Srinivasan SR, Berenson GS. Black-white contrasts in insulin levels during pubertal development: the Bogalusa Heart Study. Diabetes 1992;41: 313-7.
Editor's column
321
15. Arslanian S, Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity in black versus white healthy adolescents. J Pediatr 1996;129:440-3. 16. Neel JV. Diabetes mellims: a "thrifty"genotype rendered detrimental by "progress" Am J Hum Genet 1962;14:353-62. i7. Coleman DI. Obesity genes: beneficial effects in heterozygous mice. Science 1979;203:663-5. 18. Kahn CR. Causes of insulin resistance. Nature 1995;373:384-5. 19. Moller DE, Flier JS. Insulin resistance: mechanisms, syndromes and implications. N Engl J Med 1991;325:938-48. 20. Taylor SI, Cama A, Accili D, et al. Mutations in the insulin receptor gene. Endocr Rev 1992;13:566-95. 21. Odea K. Obesity in the "Land of Milk and Honey." Diabetes Metab Rev 1992;8:373-88. 22. Saito I, Nishino M, Kawabe H, et al. Leisure time physical activity and insulin resistance in young obese students with hypertension. Am J Hypertens 1992;5:915-8.
Is biliary sludge a stone-in-waiting? Cholelithiasis, cholecystitis, and abdominal pain crises have long been recognized as common complications of sickle cell disease (SCD).I-4 Gallstones are present in between 10% and 55% of children with SCD, the incidence depending on age. In the individual patient, differentiation between an abdominal pain crisis and cholecystitis may be difficult. Most patients with SCD and symptomatic gallstones undergo cholecystectomy.5-s In these patients abdominal pain crises usually cease or decrease in frequency after cholecystectomy. Modem preoperative transfusion regimens have made this procedure safe in SCD patients. At many centers patients with SCD undergo screening ultrasonography and prophylactic cholecystectomy when gallstones are found. Biliary sludge is a mixture of bile and particulate matter, which consists of a variety of precipitates such as cholesterol monohydrate, calcium bilirubinate, and other calcium salts.9-1l Xenobiotics such as the third-generation cephalosporin ceftriaxone may also form precipitates. Though the sludge phase usually precedes the stone phase, sludge may disappear without forming stones. Biliary sludge is usually diagnosed at ultrasound evaluation by a finding of layered low-amplitude echoes without shadowing in the gallbladder. Sludge may also be detected by microscopic analysis of bile obtained at endoscopic retrograde cholangiopancreatography or duodenal intubation. Two recent studies that addressed the issue of biliary sludge in children with SCD obtained apparently different results. Winter et al., 12 at Duke University, retrospectively reviewed the charts of 75 children with SCD who had unJ Pediatr 1996;129:321-2 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/75980
dergone ultrasonography for hepatobiliary symptoms; 17 had evidence of sludge. Nine had both stones and sludge and received cholecystectomy. In the remaining eight patients with sludge alone, choMithiasis developed within 30 months and the patients underwent cholecystectomy. The authors concluded that children with SCD and sludge present on ultrasound should undergo cholecystectomy. In contrast, in this issue of The Journal, Walker and Serjeant 13 present a cohort of 429 Jamaican children with SCD who had serial annual ultrasonographic studies beginning at age 5 years. Sludge was found in 17 symptom-free children.
See related article, p. 443. Although stones developed in 12 of these 17 children, all remained free of symptoms. The sludge resolved in 4 of the 5 children without stones; asymptomatic sludge persisted in one patient, No patient subsequently had symptomatic hepatobiliary disease. Supporting the notion that the natural history of cholelithiasis in Jamaica may differ from that in the United States is the authors' observation that only 4 of 81 children less than 10 years of age with documented gallstones had symptoms requiring cholecystectomy. The key difference between these two reports is the study populations: symptoms in children from the United States versus no symptoms in Jamaican children. The presence of symptoms indicates that the American children already had stones that triggered episodes ofbiliary colic. In contrast, not only were the Jamaican children free of symptoms, but ultrasonographically defined gallstones were less frequent, and these stones infrequently led to symptoms. What may explain this apparent paradox? The use of ceftriaxone? The role of diet may be important. Children in the United States are
PEDIATRICS SEPTEMBER
1996
Volume 129
Number 3
EDITOR'S COLUMN Insulin resistance, obesity, and related disorders among black adolescents Obesity, hypertension, and non-insulin-dependent diabetes mellitus are increasing at an alarming rate among black Americans. NIDDM is approaching the high frequency found in the Pima Indians of Arizona (>40%), and is 60% more frequent than in the white population. 1 The incidence of hypertension among black Americans is 38%, compared with 29% among white Americans. 2 Of greatest concern, however, is the evidence that this "epidemic" is not restricted to the adult population--among children and adolescents there has been a dramatic increase in the prevalence of these disorders during the past two decades) Hyperinsulinemia, caused by insulin resistance, has been implicated in the pathogenesis of obesity, NIDDM, hypertension, polycystic ovarian disease, acanthosis nigricans, lipid abnormalities, and atherosclerosis, 4 as well as ischemic heart disease. 5 It has been suggested that insulin resistance per se may be the common underlying cause of these disorders. Studies done among populations with a high prevalence of NIDDM, such as American Indians, Mexican Americans, Pacific Islanders, and Austrafian aborigines, have demonstrated that an extended period of increasing insulin resistance precedes the decline in B-cell function heralding the onset of overt NIDDM. 6 Moreover, relatively high insulin levels have been found among children and young adults in populations with a high risk of NIDDM, as well as among the offspring of type II diabetic parents. 7 Longitudinal follow-up studies indicate that children with elevated insulin tevels are at an increased risk of having NIDDM later in life.6, 8 Because approximately 40% of adult patients with NIDDM have clinical macroangiopathy at the time of diagJ Pediatr 1996;129:319-21 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/75382
nosis, long-term insulin resistance and resulting hyperinsulinism may themselves promote the development of complications before the onset of the diabetic state. 9 Hyperinsulinemia and insulin resistance are also associated with essential hypertension in nonobese, nondiabetic young adults,l° and longitudinal studies suggest that glucose intolerance may antedate the onset of hypertension. 11 Impaired insulin sensitivity has been demonstrated in the nonobese normotensive children of patients with essential hypertension. 12 However, the mechanism underlying the association between hyperinsulinism and hypertension re-
See related article, p. 440.
NIDDM Non-insulin-dependentdiabetes mellims - - 7 mains controversial. It has been suggested that insulin may regulate blood pressure through the promotion of renal sodium retention, through a direct effect of insulin on the sympathetic nervous system, or through enhanced atherogenesis in resistance vessels. 13 It is interesting to consider the reason that this "epidemic" of disorders associated with insulin resistance is affecting black Americans disproportionately. The Bogalusa [Louisiana] Heart Study I4 demonstrated that black children had significantly higher insulin secretion in response to an oral glucose load than did white counterparts throughout all stages of puberty, suggesting lower insulin sensitivity among black children. In this issue of The Journal of Pediatrics, Arslanian and Suprasongsin t5 report their extension of these studies to investigate the differences in both insulin sensitivity and insulin secretion between black and white adolescents by using a hyperglycemic clamp. Of particular note is that these subjects were nonobese arid had no family history
319
320
Editor's column
of diabetes. Although basal levels of insulin were similar in the two groups, both the first and second phases of insulin secretion in response to an intravenous glucose load were significantly higher in black adolescents matched for age, sex, and pubertal staging. In addition, insulin sensitivity measured during the hyperglycemic clamp was 35% lower in the black adolescents. Thus this study demonstrates a significant racial difference in insulin physiology already present during adolescence and before the development of obesity. Therefore black Americans may be predisposed to insulin resistance and hyperinsulinism, which subsequently promote the development of obesity, NIDDM, hypertension, and other abnormalities. The apparent racial disparity in insulin sensitivity may be the result of different genetic backgrounds, differences in environmental or cultural factors, or a combination of both genetics and environment. According to the "thrifty genotype" theory, 16, 17a genotype that efficiently converts excess energy intake into depot fat under the influence of a robust insulin response would have a survival advantage under conditions of scarcity. However, with the availability of high-calorie foods and reduced physical activity, the previously advantageous "thrifty" genotype would promote insulin resistance, hyperinsulinism, obesity, and, in susceptible individuals, development of overt disease. The molecular basis of insulin resistance remains poorly understood, and attempts to define the exact loci of insulin resistance have met limited success, is Though defined genetic defects have been identified in rare syndromes of extreme insulin resistance, 19,2o the molecular and genetic mechanisms responsible for the development of insulin resistance in the majority of individuals are not known. However, the racial difference in insulin sensitivity present in adolescents before the development of obesity, as demonstrated by Arslanian and Suprasongsin,15 suggests an underlying genetic predisposition is responsible for at least part of this disparity. On the other hand, the rising frequency of NIDDM, hypertension, and obesity among black Americans points to an important change in the environmental context that is promoting increasing development of overt disorders in individuals genetically predisposed to insulin resistance. The contemporary "Western" diet is unique in human history in its availability and composition. 21 Furthermore, modern American civilization represents the first period in history in which regular physical activity is not an integral part of daily life for the majority of people. 22 Evidence indicates that the excessive energy intake, high-fat diets, and low levels of leisure-time physical activity that characterize the American 1990s lifestyle each independently promotes insulin resistance. 21 Thus environmental changes may be exacerbating underlying genetic differences, leading to increasing insulin
The Journal of Pediatrics September 1996
resistance in the American population in general but dispro= portionately among black Americans. NIDDM, obesity, and hypertension appear to represent the outcome of a process in which a genetic predisposition to insulin resistance and hyperinsulinism interact with the environment. Given the direction of lifestyle pressures in America in the 1990s, early intervention may be necessary to reverse the trend of increasing insulin resistance-related disorders surfacing among America's children, adolescents, and young adults. Furthermore, the studies of Arslanian and Suprasongsin indicate that a predisposition to insulin resistance and hyperinsulinism is present among black American teenagers before overt changes in body habitus, apparently placing them at an increased risk of having these' 'lifestyle" disorders and potentially accounting for the increased incidence of such disorders in the black population. To address this potential epidemic of obesity, NIDDM, and hypertension among American children, a concerted public health effort aimed at promoting dietary change and physical activity among the young is critical, with particular focus on those ethnic groups at greatest risk. Orit Pinhas-Hamiel, MD Maccabi, Pediatric Endocrine Unit Ramat-Hasharon, Israel
Philip Zeitler MD, PhD Division of Endocrinology The Children's Hospital Denver, CO 80218 REFERENCES
1. Douglas JG. Hypertension and diabetes in Blacks. Diabetes Care 1990;13:1191-5. 2. Hypertension prevalence and the status of awareness, treatment, and control in the United States. Final report of the Subcommittee on Definition and Prevalence of the 1984 Joint National Committee. Hypertension 1985;7:457-68. 3. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeifler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996; 128:608-15. 4. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 5. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:95-7. 6. Zimmet PZ, Collins VR, Dowse GK, Knight LT. Hyperinsulinemia in youth is a predictor of type. 2 diabetes mellitus. Diabetologia 1992;35:534-41. 7. Johnston C, Ward WK, Beard JC, McKnight B, Porter D. Islet function and insulin sensitivity in the non-diabetic offspring of conjugal type 2 diabetic patients. Diabet Med 1990; 7:119-25. 8. Martin BC, Warram J, Krolewski AS, Bergman RN, Soeldner JS, Kahn RC. Role of glucose intolerance and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992;340:925-9.
The Journal of Pediatrics Volume 129, Number 3
9. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states: sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 94:1714-21. 10. Ferranini E. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-7. 11. Reaven GM, Hoffman BB. A role for insulin in the etiology and course of hypertension. Lancet 1987;2:435-6. 12. Gmnfeld B, Balzareti M, Romo M, Gimenez M, Gutman R. Hyperinsulinemia in normotensive offspring of hypertensive patients. Hypertension 1994;23(1 Suppl):ll2-5. 13. Yudkin J. Hypertension and non-insulin-dependent diabetes. BMJ 1991;303:730-2. 14. Svec F, Nastasi K, Hilton C, Bao W, Srinivasan SR, Berenson GS. Black-white contrasts in insulin levels during pubertal development: the Bogalusa Heart Study. Diabetes 1992;41: 313-7.
Editor's column
321
15. Arslanian S, Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity in black versus white healthy adolescents. J Pediatr 1996;129:440-3. 16. Neel JV. Diabetes mellims: a "thrifty"genotype rendered detrimental by "progress" Am J Hum Genet 1962;14:353-62. i7. Coleman DI. Obesity genes: beneficial effects in heterozygous mice. Science 1979;203:663-5. 18. Kahn CR. Causes of insulin resistance. Nature 1995;373:384-5. 19. Moller DE, Flier JS. Insulin resistance: mechanisms, syndromes and implications. N Engl J Med 1991;325:938-48. 20. Taylor SI, Cama A, Accili D, et al. Mutations in the insulin receptor gene. Endocr Rev 1992;13:566-95. 21. Odea K. Obesity in the "Land of Milk and Honey." Diabetes Metab Rev 1992;8:373-88. 22. Saito I, Nishino M, Kawabe H, et al. Leisure time physical activity and insulin resistance in young obese students with hypertension. Am J Hypertens 1992;5:915-8.
Is biliary sludge a stone-in-waiting? Cholelithiasis, cholecystitis, and abdominal pain crises have long been recognized as common complications of sickle cell disease (SCD).I-4 Gallstones are present in between 10% and 55% of children with SCD, the incidence depending on age. In the individual patient, differentiation between an abdominal pain crisis and cholecystitis may be difficult. Most patients with SCD and symptomatic gallstones undergo cholecystectomy.5-s In these patients abdominal pain crises usually cease or decrease in frequency after cholecystectomy. Modem preoperative transfusion regimens have made this procedure safe in SCD patients. At many centers patients with SCD undergo screening ultrasonography and prophylactic cholecystectomy when gallstones are found. Biliary sludge is a mixture of bile and particulate matter, which consists of a variety of precipitates such as cholesterol monohydrate, calcium bilirubinate, and other calcium salts.9-1l Xenobiotics such as the third-generation cephalosporin ceftriaxone may also form precipitates. Though the sludge phase usually precedes the stone phase, sludge may disappear without forming stones. Biliary sludge is usually diagnosed at ultrasound evaluation by a finding of layered low-amplitude echoes without shadowing in the gallbladder. Sludge may also be detected by microscopic analysis of bile obtained at endoscopic retrograde cholangiopancreatography or duodenal intubation. Two recent studies that addressed the issue of biliary sludge in children with SCD obtained apparently different results. Winter et al., 12 at Duke University, retrospectively reviewed the charts of 75 children with SCD who had unJ Pediatr 1996;129:321-2 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/75980
dergone ultrasonography for hepatobiliary symptoms; 17 had evidence of sludge. Nine had both stones and sludge and received cholecystectomy. In the remaining eight patients with sludge alone, choMithiasis developed within 30 months and the patients underwent cholecystectomy. The authors concluded that children with SCD and sludge present on ultrasound should undergo cholecystectomy. In contrast, in this issue of The Journal, Walker and Serjeant 13 present a cohort of 429 Jamaican children with SCD who had serial annual ultrasonographic studies beginning at age 5 years. Sludge was found in 17 symptom-free children.
See related article, p. 443. Although stones developed in 12 of these 17 children, all remained free of symptoms. The sludge resolved in 4 of the 5 children without stones; asymptomatic sludge persisted in one patient, No patient subsequently had symptomatic hepatobiliary disease. Supporting the notion that the natural history of cholelithiasis in Jamaica may differ from that in the United States is the authors' observation that only 4 of 81 children less than 10 years of age with documented gallstones had symptoms requiring cholecystectomy. The key difference between these two reports is the study populations: symptoms in children from the United States versus no symptoms in Jamaican children. The presence of symptoms indicates that the American children already had stones that triggered episodes ofbiliary colic. In contrast, not only were the Jamaican children free of symptoms, but ultrasonographically defined gallstones were less frequent, and these stones infrequently led to symptoms. What may explain this apparent paradox? The use of ceftriaxone? The role of diet may be important. Children in the United States are