Gallstone disease is a major cause of morbidity in adult patients (1). The link between gallstone disease and obesity is well established in adult study populations (2). As the prevalence of obesity in children in industrialized nations is increasing, pediatricians are more and more often confronted with obesity-related disease (3,4). The role of obesity as a risk factor for the development of gallbladder stones in children and adolescents has not yet been conclusively defined.
Large, prospective, ultrasound investigations have demonstrated a correlation between increasing age and the prevalence of gallbladder stone disease (GD) (2,5,6). Although even the prenatal occurrence of gallbladder stones has been described (7), prevalence rates of GD in children and adolescents given in the literature are approximately 0.1% to 0.6% (8-10). This is because of, on one hand, a presumably low frequency of gallbladder stones in this age group but also, on the other hand, to the very small number of routine diagnostic ultrasound examinations performed in children and adolescents, which permits asymptomatic stones to remain undetected. Recently published studies, however, suggest that the prevalence of cholecystolithiasis may be increasing in childhood and adolescence (3,4,11).
Possible risk factors for the development of gallbladder stones in childhood include increased hemolysis (e.g., in sickle-cell anemia) (12), immunoglobulin deficiency (13), therapeutic administration of opioids, ceftriaxone and furosemide (14,15), parenteral nutrition (15,16), premature birth (17), and certain rare metabolic disorders (18-21). There is a paucity of data with regard to other potential risk factors, such as hereditary predisposition or pubertal development stage (22).
The objective of the present study was to perform diagnostic upper abdominal ultrasound examinations, the accepted method of choice for diagnosis of GD (23), in a large cohort of obese children and adolescents to determine the prevalence of cholecystolithiasis as well as to assess the effects of risk factors such as degree of obesity, sex, age, and Tanner stage on the occurrence of GD.
MATERIALS AND METHODS
The present clinical cross-sectional study was conducted between February 2000 and May 2001 at the Hochried Clinic for Children and Adolescents in Murnau, Bavaria, Germany. Children and adolescents were admitted to the hospital to reduce body weight. Inclusion criteria for the present study included the following:
- Age 8.0 to 18.0 years;
- Body mass index (BMI) ≥2.0 standard deviation score (SDS) according to the new German reference values;(24)
- Informed consent of the patient and the parents.
Of a total 637 patients admitted during the study period, 493 fulfilled the inclusion criteria (218 males [44.2%] and 275 females [55.8%]). A total of 144 children and adolescents were excluded from the study. Reasons were departure ahead of time were acute illness, impossibility to take blood samples, missing informed consent, no fasting period before ultrasound examination, or impossibility to evaluate the gallbladder. Patients' average age was 13.9 ± 2.0 (males, 13.6 ± 2.0; females, 14.2 ± 1.9) years; median age was 13.9 (males, 13.5; females, 14.2) years (Table 1).
History and Physical Examination
Data on patients' family history were obtained by means of a questionnaire mailed to parents before admission. Particular attention was paid to metabolic disorders. At the time of initial examination, children and adolescents were interviewed regarding both general medical history and specific factors affecting lithogenesis, including dietary habits, alcohol and nicotine abuse, and medication.
At initial examination, body weight, body height, and arterial blood pressure were documented. Patients' BMI (body weight [kg]/height2 [m2]) was calculated. The recruitment criteria for the study required that patients' BMI be at least two SD above normal values. Normal values were based on new references values for the German population (24). BMI-SDS was calculated. Because it considers the child's age, this score is more useful than BMI alone and is comparable with sex-specific BMI percentiles (25).
To ensure the comparability of the inclusion criteria (BMI ≥ 2.0 SDS) with other international studies, the BMI cut-off values according to Cole (26) were used to divide the participants into overweight and obese individuals.
Pubertal development was also evaluated at the initial examination according to Tanner (27,28). Four hundred ninety of 493 patients were assigned to one of three groups: prepubertal (Tanner 1), intrapubertal (Tanner 2-3), and late pubertal (Tanner 4-5). This division according to stages was maintained throughout the period of the study (Table 2).
Ultrasound examination of the upper abdomen was performed in all children and adolescents within 10 (average 6.3) days of admission. All ultrasound examinations were conducted by the same experienced sonographer. Examinations were performed using a Versa Plus ultrasound unit (Siemens, Erlangen, Germany) with a 3.5 MHz multiconvex transducer head for examination of the abdomen. Patients fasted for at least 5 hours before the examination. The fasting period was self-reported and documented before the examination.
The ultrasound examination was performed with patients in supine position. To achieve optimum access to both the liver and gallbladder, patients were instructed to place their right arm over their head to maximize the distance between the lower costal margin and the iliac crest. If any structures were detected within the gallbladder lumen, an additional examination was conducted with the patient standing to ascertain whether the structures were mobile (gallbladder stones) or adhered to the gallbladder wall (e.g., gallbladder polyps).
The diagnosis of cholecystolithiasis was made on the basis of the following criteria:
- One or more hyperechoic structures with distal shadow within the gallbladder lumen;
- One or more hyperechoic structures without distal shadow within the gallbladder lumen, which, upon visualization in several planes, demonstrated mobility can be definitively differentiated from gallbladder polyps or septum;
- A hyperechoic structure with distal shadow occupying the gallbladder bed with no visualization of residual gallbladder lumen (“stone-packed gallbladder”);
- Failure to visualize gallbladder after cholecystectomy with corresponding abdominal scar(s).
Visualization of the gallbladder was successful in 491 (99.6%) patients. Failure to visualize the gallbladder was limited to two subjects (0.4%) who had undergone prior cholecystectomy.
Statistics and Ethics
Because of the low frequency of gallbladder stones in children, the data obtained in the present study have been evaluated descriptively. The Wilcoxon test (Mann-Whitney test) was only used to calculate the differences in age and degree of adiposity. The study was conducted in accordance with the principles of the Helsinki Declaration and was approved by the ethics commission of the Faculty of Medicine of the University of Ulm. Informed consent was obtained from all parents or guardians of the children or, where appropriate, directly from the adolescents.
According to the international standard of Cole (26), 91.6% of the female patients and 99.1% of the male patients were obese (corresponding to BMI > 30 in adults). The others were overweight (corresponding to BMI > 25 in adults). All of the patients with gallstones were obese (Table 3).
Gallbladder stones were detected in 8 of 493 (1.6%) patients. In taking into consideration the two children who had undergone cholecystectomy, GD affected 10 children and adolescents in the study group (2.0%). Of these 10 patients, 8 were females and 2 were males (Table 2).
We did not detect gallbladder stones in any prepubertal children. Two intrapubertal males and three intrapubertal females were found to have gallbladder stones (n = 4) or had undergone prior cholecystectomy (n = 1). In the late pubertal group, four girls were found to suffer from gallbladder stones, whereas one further girl had already undergone cholecystectomy (Table 4).
The average age of the 10 children with gallbladder stones was higher than that of the remaining children with normal gallbladder status (16.1 ± 1.5 years, range 14-19 vs. 13.9 ± 2.0 years; range 9-19; P < 0.001). Compared with children without gallbladder stones, the age-independent BMI-SDS was obviously higher in children with gallbladder stones (3.4 ± 0.5, range 2.6-4.1 vs. 2.7 ± 0.4, range 2.0-4.6; P < 0.001).
Of the 10 children with gallbladder stones, 9 had reported participating in weight-reducing diets, in 3 cases immediately before in-patient admission. In the group of children without gallbladder stones, 392 of 483 (81%) children reported having attempted at least one diet, 165 admission (42%) of them immediately before in-patient. The nine children with gallbladder stones lost an average of 10.1 ± 7.0 (range 2-25) kg compared with only 5.8 ± 5.0 (range 0-35) kg in the group not suffering from cholecystolithiasis.
Three of the children suffering from gallbladder stones in the present collective had a family history positive for gallbladder stones in their parents (the mother was affected in all 3 cases) (Table 4). In the remaining 483 children, reports of GD affecting the parents were returned in 481 cases. In 48 of 481 (10%) patients, there was a positive family history for the mother; in 13 of 481 (2.7%) patients, there was a positive family history for the father.
In none of the 10 children with pathologic gallbladder status (Table 4) could we identify by medical history or physical examination any special risk factors for cholecystolithiasis in childhood such as sickle cell anemia, spherocytosis, thalassemia, cystic fibrosis, Wilson's disease, pyloric stenosis, short-bowel syndrome, cirrhosis of the liver, chronic diarrhea, congenital bile duct anomalies, malabsorption, drug intake of furosemide, methadone, or ceftriaxone, or a history of parenteral nutrition, umbilical catheter, and immunoglobulin deficiency, with the exception of obesity.
Until recently, cholecystolithiasis in children and adolescents was considered rare; the prevalence rates are reported between 0.1% and 0.6% in unselected populations (8,9). It was observed primarily in patients with underlying diseases characterized by increased hemolysis (12,29) and in cases of certain metabolic disorders such as Wilson's disease or cystic fibrosis (19-21) or long-term parenteral nutrition (15,16) (Table 1). In recent years, however, an increase in the number of children affected by GD has been reported (3,4,11). The proportion of idiopathic cholecystolithiasis in children and adolescents has been estimated at 20% to 65% (19,29-31), and this proportion appears to increase in relation to children's age.
Risk factors for the development of cholecystolithiasis in adults living in Western industrial nations include advanced age, obesity, positive family history for gallbladder stones, and female sex (5,6,32). Because of the low prevalence of gallbladder stones in the unselected study collectives published to date (8,9), it remains unclear whether these same risk factors also play an important role in children and adolescents.
Compared with earlier sonographic surveys (8-10), the prevalence of gallbladder stones in the present study at 2.0% is high, particularly in comparison with our own recently conducted study of an unselected cohort of 482 children and adolescents, in whom only 0.6% were diagnosed with cholecystolithiasis (8). In unselected cohorts, despite similar age and sex distribution, the proportion of overweight subjects was 14.5%, whereas in the present study, all participants were obese by definition (BMI-SDS > 2.0). When we compared obese children and adolescents in the present collective with (n = 10) and without (n = 483) GD, the average BMI-SDS was 3.4 ± 0.5 and 2.7 ± 0.4, respectively. Although the small number of cases precludes meaningful testing of statistical significance, these data, together with the overall higher prevalence of gallbladder stones in this “high-risk collective,” suggest that obesity may play an important role in the development of gallbladder stones in children and adolescents. In a study of girls who had undergone cholecystectomy, obesity was given as the cause of cholecystolithiasis in up to 50% of cases (33). Studies of obese individuals have demonstrated an increased cholesterol saturation of bile (34). Finally, the serious increase in SD paralleling the increase in obesity in children and adolescents over the past years (11) underscores the importance of obesity as a risk factor in this disorder.
Rapid weight reduction is another known risk factor for lithogenesis (35). During fasting, the saturation index of the bile and the gallbladder volume both increase (15,16,36-38), whereas gallbladder motility is reduced in persons consuming low-fat diets (39). Because of the relatively low number of participants found to suffer from gallbladder stones (n = 10) in the present study, it is not possible to draw more wide-ranging conclusions from our data.
Because the higher prevalence of gallbladder stones in adult females has been ascribed to the increased cholesterol saturation of the bile secondary to the effects of estrogens (40), female sex appears not to play a significant role as a risk factor in prepubertal children (30). In our study, in the intra- and latepubertal groups, however, the proportion of subjects suffering from gallbladder stones was obviously higher in girls (2.9%, 8/275 subjects) than in boys (0.9%, 2/218 subjects). In contrast with our data, other retrospective analyses have found a more balanced distribution between the sexes, with female to male ratios in the range of 1.4:1 to 2:3 (19,30,31). These retrospective analyses, however, considered cases drawn from a single institution or a single country but based on very nonuniform collectives. There were also differences in the composition of the gallbladder stones in relation to the age of the children (22,41), which may reflect the influence of different types of risk factors.
Three of the 10 subjects suffering from gallbladder stones had a family history positive for gallbladder stones in the parents' generation. Numerous studies have described a high proportion of persons with cholecystolithiasis with positive family histories (22,32). Because we had to rely on patients' histories with regard to the parents' gallbladder status, the strength of these data obtained in a relatively young patient group is limited by the probable high proportion of asymptomatic and undiagnosed gallbladder stones in the parents' generation.
The indication for cholecystectomy in children is based on criteria similar to those applied to adults. Therefore, asymptomatic patients do not necessarily require surgical treatment of GD (22,29). At the time of examination, all eight children with cholecystolithiasis were asymptomatic, and no therapy was initiated.
Compared with an unselected collective, the prevalence of GD found in our collective of obese children and adolescents, previously treated with diet for obesity, is high at 2.0%. Because the BMI-SDS in the group of obese children and adolescents with GD was much higher than that calculated in subjects with normal gallbladder status, extreme obesity does appear to be a relevant risk factor promoting the development of gallbladder stones in children and adolescents. In addition, the risk factors known to favor the development of GD in adults such as female sex should also be considered in obese children and adolescents.
1. Kang JY, Ellis C, Majeed A, et al. Gallstones: an increasing problem: a study of hospital admissions in England between 1989/1990 and 1999/2000. Aliment Pharmacol Ther
2. Kratzer W, Mason RA, Kaechele V. World distribution of gallstones in sonographic surveys. J Clin Ultrasound
3. Wang G, Dietz WH. Economic burden of obesity in youths aged 6 to 17 years: 1979-1999. Pediatrics
4. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense, cure. Lancet
5. Attili AF, Carulli N, Roda E, et al. Epidemiology of gallstone disease in Italy: prevalence data of the Multicenter Italian Study on Cholecystolithiasis (M.I.COL.). Am J Epidemiol
6. Jørgensen T. Prevalence of gallstones in a Danish population. Am J Epidemiol
7. Wendtland-Born A, Wiewrodt B, Bender SW, et al. Prävalenz von gallensteinen in der neugeborenenperiode. Ultraschall Med
8. Kaechele V, Wabitsch M, Hay B, et al. Cholezystolithiasis bei kindern und jugendlichen. Monatsschr Kinderheilkd
9. Palasciano G, Portincasa P, Vinciguerra V, et al. Gallstone prevalence and gallbladder volume in adolescents: an epidemiological ultrasonic survey and relationship to body mass index. Am J Gastroenterol
10. Trygstad O. Cholelithiasis in children. Tidsskr Nor Laegeforen
11. Waldhausen JH, Benjamin DR. Cholecystectomy is becoming an increasingly common operation in children. Am J Surg
12. Al-Salem AH, Quaisruddin S. The significance of biliary sludge in children with sickle cell disease. Pediatr Surg Int
13. Danon YL, Dinari G, Garty BZ, et al. Cholelithiasis in children with immunoglobulin A deficiency: a new gastroenterologic syndrome. J Pediatr Gastroenterol Nutr
14. Stabile A, Ferrara P, Marietti G, et al. Ceftriaxone-associated gallbladder lithiasis in children. Eur J Pediatr
15. Whitington PF, Black DD. Cholelithiasis in premature infants treated with parenteral nutrition and furosemide. J Pediatrics
16. Roslyn JJ, Berquist WE, Pitt HA, et al. Increased risk of gallstones in children receiving total parenteral nutrition. Pediatrics
17. Müller H, Greiner P, Brandis M. Gallensteine im säuglingsalter. Monatsschr Kinderheilkd
18. Anagnostopopoulos D, Tsagari N, Noussia-Arvanitaki S, et al. Gallbladder disease in patients with cystic fibrosis. Eur J Pediatr Surg
19. Henschke CI, Littlewood Teele R. Cholelithiasis in children. J Ultrasound Med
20. Rosenfield N, Grand RJ, Watkinns JB, et al. Cholelithiasis and Wilson disease. J Pediatr
21. Stern RC, Rothstein FC, Doershuk CF. Treatment and prognosis of symptomatic gallbladder disease in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr
22. Holcomb GW, Holcomb GW. Cholelithiasis in infants, children and adolescents. Pediatr Rev
23. Bortoff GA, Chen MY, Ott DJ, et al. Gallbladder stones: imaging and intervention. Radiographics
24. Kronmeyer-Hauschild K, Wabitsch M, Kunze D, et al. Perzentile für den body mass index für das kindes- und jugendalter unter heranziehung verschiedener deutscher stichproben. Monatsschr Kinderheilkd
25. Sheehy A, Gasser T, Largo R, et al. Short-term and long-term variability of standard deviation scores for size in children. Ann Hum Biol
26. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ
27. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child
28. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child
29. Wesdorp I, Bosman D, de Graaff A. Clinical presentation and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr
30. Reif S, Sloven DG, Lebenthal E. Gallstones in children. AJDC
31. Kumar R, Nguyen K, Shun A. Gallstones and common bile duct calculi in infancy and childhood. Aust NZ J Surg
32. Gilat T, Feldmann C, Halpern Z, et al. An increased familial frequency of gallstones. Gastroenterology
33. Honore LH. Cholesterol cholelithiasis in adolescent females. Arch Surg
34. Bennion LJ, Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest
35. Wudel LJ, Wright JK, Debelak JP, et al. Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study. J Surg Res
36. Bloch HM, Thornton JR, Heaton KW. Effect of fasting on the composition of gallbladder bile. Gut
37. Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight reduction dieting. Arch Intern Med
38. Das JB, Poulos ND, Ansari GG. Biliary lipid composition and bile acid profiles during and after enteral fast of total parenteral nutrition in the rabbit. J Pediatr Gastroenterol Nutr
39. Festi D, Colecchia A, Orsini M, et al. Gallbladder motility and gallstone formation in obese patients following very low calorie diets. Use it to lose it. Int J Obes Relat Metab Discord
40. Von Bergmann K, Becker M, Leiss O. Biliary cholesterol saturation in nonobese women and nonobese men before and after puberty. Eur J Clin Inv
41. Schweizer P, Lenz MP, Kirschner HJ. Pathogenesis of cholelithiasis in childhood. A prospective study. Dig Surg