Gallstones were considered to be uncommon in infants and children but have been increasingly diagnosed in the recent years, mainly due to wide spread use of ultrasonography. There is not much information about cholelithiasis in children from India and there is no consensus among Indian pediatricians and pediatric surgeons regarding the management of gallstones in children. Hence, the purpose of this review is to increase awareness about the management of gallstones in children.

A detailed electronic (PubMed) literature search was made for this purpose and English language literature (original articles, clinical trials, case series, case report, letter, meta-analysis, practice guideline, randomized controlled trial) related to gallstones in children (key words used: gallstones, children, ceftriaxone, fetal gallstones) were reviewed. The period of search was from 1965 to December 2009. During this period a total of 372 articles were published of which relevant 61 articles were included in this review.

A unique subset is chronic hemolytic disease. In this condition, cholelithiasis is usually not seen before the age of five and thereafter, the incidence increases progressively with age. In sickle-cell disease, the prevalence of pigment gallstones was reported to be 10% to 15% in children under 10 years of age, it increased to 40% in those aged 10-18 years, and 50% in adults(17-19). The prevalence of gallstones in hereditary spherocytosis was 10% to 20% and in adult series it was 40%(20,21). In thalassemia, the reported figure is low (10% to 15%)(22,23). With longer survival of thalassemia patients, higher prevalence of gallstones (50%) has been reported(24). The highest prevalence of gallstones have been reported in thalassemics with Gilbert’s syndrome genotype(24,25). However, in a study on 64 patients with median age of 10 (range, 5 to 20) years with thalassemia major from Chandigarh, none had gallstones(26).

Gallstones are either cholesterol gallstones (pure and mixed) or pigment stones (black or brown). Cholesterol supersaturation of bile with stasis predisposes to cholesterol gallstone formation. Mixed cholesterol gallstones are the commonest stones in adults and in adolescent girls. However, pigment stones are more common in children. Black pigment stones are formed due to supersaturation of bile with calcium bilirubinate and are seen in hemolytic disorders and in association with total parenteral nutrition. Brown pigment stones are associated with infection and biliary stasis and form more often in the bile ducts than in the gallbladder(16).

Biliary sludge is composed of mucin, calcium bilirubinate and cholesterol crystals. It is commonly associated with prolonged fasting, total parenteral nutrition, pregnancy, sickle-cell disease, treatment with ceftriaxone or octreotide(27). The natural history of biliary sludge is variable; it may resolve spontaneously or may progress to gallstone develop-ment. Persistent sludge may give rise to biliary complications (such as obstruction or infection).

Etiologically cholelithiasis (Table I)(11,16) in children can be divided into three groups; hemolytic, other known etiology, and idiopathic. Almost 20% to 30% of all gallstones in children are due to hemolytic diseases such as sickle-cell disease, hereditary spherocytosis and thalassemia. In around 40% to 50% of cases, gallstones are due to another known etiology such as total parenteral nutrition, prolonged fasting, ileal disease or ileal resection, frusemide therapy, congenital biliary diseases such as choledochal cyst, chronic liver disease and progressive familial intrahepatic cholestasis (PFIC). Around 30% to 40% of cases are idiopathic. As in adults, gallstones in adolescent girls are more often idiopathic(16).

TABLE I



Etiology of Gallstones in Children(11,16)

Total parenteral nutrition (TPN) impairs entero-hepatic circulation and cholecystokinin induced gallbladder contraction resulting in biliary stasis, sludge and stones(28). The longer the duration of TPN therapy, the higher the risk of developing cholelithiasis(29). The risk of developing gallstones in children on prolonged TPN therapy is increased if there is concomitant ileal resection or disease. In a study of 21 children on prolonged TPN (more than 3 months), Roslyn, et al. have shown that 43% of children developed gallstones but this figure was 64% in children with ileal resection or disease(29). Sludge develops more rapidly in neonates than in adults after a mean time of TPN infusion in neonates of 10 days, as compared with more than 6 weeks in adults. In a prospective study of 41 neonates, Matos, et al. have shown that gallbladder sludge appeared in 18 (44%) of those infants who had received TPN infusion for a mean period of 10 days(30). In 12 infants, the sludge cleared within one week of resuming enteral feeding but two of the remaining infants went on to develop asymptomatic gallstones. Spontaneous resolution occurred in one of these two infants by 6 months while the calculi persisted in the other baby.

Ceftriaxone, a third-generation cephalosporin, is a popular drug among pediatricians as it has a broad spectrum of antimicrobial activity and good CSF penetration. Biliary sludge or biliary lithiasis has been reported as a potential complication of ceftri-axone treatment since 1986(31). Since ceftriaxone induced biliary lithiasis is reversible and disappears on discontinuation of therapy it is called ‘pseudoli-thiasis’. In a patient with normal renal function, 60% of the drug is excreted unchanged into the urine and 40% is excreted into the bile(32). Ceftriaxone is an anion, can concentrate in bile 20 to 150 times more than in serum and readily forms an insoluble salt with calcium (calcium-ceftriaxone) that precipitates in gallbladder(33). The risk factors for ceftriaxone pseudolithiasis are hypercalcemia, renal failure (leads to increase biliary concentration), high dose (>2g or >200mg/kg/day), long-term treatment and gallbladder stasis(34).

The incidence of ceftriaxone induced pseudolithiasis is 15% to 46% in various prospective studies(38-42). Usually pseudoliths appear after 6 (range, 3 to 22) days of therapy and disappear after 15 (range, 2-63) days of discontinuation of therapy(35,36). Most cases of ceftriaxone induced pseudolithiasis are asymptomatic and detected on sonography but rarely (0-19% of cases)(36), they can produce symptoms like pain abdomen, nausea, vomiting and biliary obstruction. In symptomatic cases, discontinuation of drug is recommended. However, cessation of drug therapy is unnecessary in incidentally detected asymptomatic cases of ceftri-axone induce pseudolithiasis.

Gallstones in the adolescent age group with a strong family history of gallstones under the age of 40 years, intrahepatic cholestasis of pregnancy or a cholestatic reaction to oral contraception should raise the suspicion of a rare condition called low phospholipid associated cholelithiasis (LPAC)(37). The underlying cause is a mutation in MDR3, a gene which encodes the ABCB4 transporter. This protein is responsible for the translocation of phosphatidyl-choline across the canalicular membrane of hepato-cytes which then solubilises cholesterol in bile. In the absence of phosphatidylcholine, bile becomes supersaturated with cholesterol and predisposes to gallstone formation. This condition is more frequent in females than in males (3:1). Apart from a family history of cholesterol gallstones amongst first degree relatives, intrahepatic hyperechoic foci (cholesterol crystal deposits in intrahepatic bile ducts) are a characteristic sign of the LPAC syndrome. The typical biliary symptoms experienced by these patients are probably due to cholesterol crystal deposits and bile duct inflammation as symptoms recur in more than half of the cases after cholecystectomy. Ursodeoxycholic acid (UDCA) appears to relieve biliary symptoms long before the dissolution of intrahepatic stones(38).

Table II summarizes the clinical presentations at different age of presentation.

TABLE II



Clinical Presentations of Gallstones in Children(46,47)

The prenatal diagnosis of fetal gallstones has been reported since 1983(39) but is a rare finding and little is known about the natural history and clinical significance. The most cases of fetal cholelithiasis reported in the literature are detected in the third trimester of pregnancy with no apparent sex predilection and all were identified as incidental findings. The echogenic material detected in fetal gallbladder is usually sludge as in most reported cases there was lack of acoustic shadowing. The prognosis of fetal gallstones is very good as complete spontaneous resolution has been documented in the majority of cases between 1 and 12 months after birth and those that persist are rarely symptomatic(40). There are several hypotheses put forward to explain the formation of fetal gallstones but none are conclusive. Brown, et al. have suggested that increased level of estrogen might predispose to the formation of stones by increasing the secretion of cholesterol and reducing the synthesis of bile acids(41). Other possible predisposing factors are: use of narcotics in pregnant women, hemolytic anemia, blood group incompatibility, structural abnormalities like choledochal cyst, pregnancy induced cholestasis, etc.(42,43).

Cholelithiasis is uncommon in infants but increasing numbers are reported in recent years mainly due to increasing use of ultrasonography (US). Gallstones in infancy are usually asymptomatic but occasionally can present with cholestatic jaundice, transient acholic stools, sepsis and abdominal pain. In symptomatic infants, gallstones are more often associated with stones in the common bile duct (CBD) than stones in the gallbladder alone(44,45). In a series of 13 cases of cholelithiasis in infants, St-Vil, et al. have reported that 11 were asymptomatic and detected by US done for unrelated problems(44). In another series of 40 cases of cholelithiasis in infancy, Debray, et al. have shown that 6 had isolated gallstones and were asymptomatic whereas 34 had bile duct obstruction and were symptomatic(45).

Children with gallstones can present with acute abdominal pain due to cholecystitis, cholangitis or pancreatitis. However, an acute presentation is uncommon (5% to 10% of cases only). Most commonly, children with cholelithiasis present with typical right upper quadrant pain (50%) or non-specific abdominal symptoms (25%) including poorly localized abdominal pain and nausea. Around 20% of cases are asymptomatic (incidentally detected stones)(11,46,47). Gallstones in children are more often (60%) symptomatic than in adults (20%)(46). The type of symptoms depend on the age of presentation, older children (6 years or more) often localize pain in the right upper quadrant whereas younger children (5 years or less) tend to present with nonspecific symptoms(11). Fatty food intolerance, a typical symptom of gallstone disease in adults, tends to be reported by older children(47).

In this age group, the symptoms are similar to those reported in adults. Fatty food intolerance, biliary colic and acute or chronic cholecystitis are usual presenting features of symptomatic patients(47).

The universally used and the most accurate diagnostic test in detecting the presence of gallstones is ultrasonography. Gallstones are usually mobile, single or multiple and characteristically cast an acoustic shadow. Biliary sludge though appearing echogenic on ultrasound, does not cast an acoustic shadow. A stone, as small as 1.5 mm, can be detected by ultrasonography. The sensitivity and specificity of ultrasonography exceeds 95% for gallbladder cholelithiasis, but this figure is only 50%-75% for choledocholithiasis. In children 20% to 50% gallstones are radiopaque(48).

Management of gallstones depends on the symptoms and the age of the patient. Symptomatic gallstones need cholecystectomy and same is true for complicated gallstones but there is no consensus about the management of asymptomatic gallstones in children. In a prospective study of children with non-pigmented gallstones, Bruch SW, et al. followed 41 children with non-specific or no symptoms for 21 months(51). Of these, 50% remained or became asymptomatic, 32% experienced definite improvement in symptoms, 18% had continued symptoms but none had any biliary complications. Wesdorp, et al.(11) have substantiated this observation in their study of 82 children with cholelithiasis who were followed up for a mean period of 4.6 years. The suggested treatment algorithm for gallstones in children is given in Fig.1. Children with gallstones should be divided into two groups. Those with typical symptoms (right upper quadrant or epigastric pain, nausea, vomiting and fatty food intolerance) should have their gallbladders removed. Asymptomatic children or children with nonspecific symptoms can undergo safe follow up. These children will require observation into adulthood to determine their lifetime risk of developing symptoms.

Fig. 1. Management algorithm for gallstones in children.

In recent years, laparoscopic cholecystectomy has become the treatment of choice in the surgical management of children with cholelithiasis. It has the advantage of being less invasive with lower morbidity and mortality and shorter hospital stay over conventional open cholecystectomy(52).

In this group of children, screening with US is recommended at around 5 years of age. Screening is also recommended before splenectomy as both splenectomy and cholecystectomy can be combined in presence of gallstones and it confers a survival benefit over splenectomy alone in hereditary spherocytosis(56). However, there is no advantage of doing cholecystectomy with splenectomy if there are no gallstones as these patients are not at an increased risk of cholelithiasis after splenec-tomy(57). In sickle-cell disease, prophylactic cholecystectomy is recommended even for asympto-matic gallstones as it is difficult to differentiate an acute abdominal crisis from acute cholecystitis, and the morbidity and mortality of emergency cholecystectomy in this setting is much higher than in elective cholecystectomy(58). To avoid sickling during the perioperative period it is recommended that hemoglobin S be decreased to at least 30% and total hemoglobin be increased to at least 11 g/dL. During the surgery and recovery period, hypotension, dehydration, hypoxia, hypothermia and acidosis should be prevented(47).

1. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). The Epidemiology of gallstone disease in Rome, Italy. Part I. Prevalence data in men. Hepatology 1988; 8: 904-906.

2. Bainton D, Davies GT, Evans KT, Gravelle IH. Gallbladder disease. Prevalence in a South Wales Industrial Town. N Engl J Med 1976; 294: 1147-1149.

3. Khuroo MS, Mahajan R, Zargar SA, Javid G, Sapru S. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kashmir. Gut 1989; 30: 2001-2005.

4. Singh V, Trikha B, Nain CK, Singh K, Bose SM. Epidemiology of gallstone disease in Chandigarh: A community-based study. J Gastroenterol Hepatol 2001; 16: 560-563.

5. Malhotra SL. Epidemiological study of cholelithiasis among railroad workers in India with special reference to causation. Gut 1968; 9: 290-295.

6. Kotwal MR, Rinchen CZ. Gallstone disease in the Himalayas (Sikkim and North Bengal): causation and stone analysis. Indian J Gastroenterol 1998; 17: 87-89.

7. Jayanthi V. Pattern of gallstone disease in Madras city, south India-a hospital based survey. J Assoc Physicians India 1996; 44: 461-464.

8. Khan HN. Asymptomatic gallstones in the laparo-scopic era. J R Coll Surg Edin Irel 2004; 2: 115.

9. Gracie WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Engl J Med 1982; 307: 798-800.

10. Schirmer WJ, Grisoni Er, Gauderer MWL. The spectrum of cholelithiasis in the first year of life. J Pediatr Surg 1989; 24: 1064-1067.

11. Wesdorp I, Bosman D, de Graaff A, Aronson D, van der Blij F, Taminiau J. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr 2000; 31: 411-417.

12. Palasciano G, Portincasa P, Vinciguerra V, Velardi A, Tardi S, Baldassarre G, et al. Gallstone prevalence and gallbladder volume in children and adolescents: an epidemiological ultrasonographic survey and relationship to body mass index. Am J Gastroenterol 1989; 84: 1378-1382.

13. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Ikematsu H, Noguchi A, et al. Prevalence of gallstone disease in a general population of Okinawa, Japan. Am J Epidemiol 1988; 128: 598-605.

14. Ganesh R, Muralinath S, Sankarnarayanan VS, Sathiyasekaran M. Prevalence of cholelithiasis in children – a hospital-based observation. Indian J Gastroenterol 2005; 24: 85.

15. Kaechele V, Wabitsch M, Thiere D, Kessler AL, Haenle MM, Mayer H, et al. Prevalence of gallbladder stone disease in obese children and adolescents: influence of the degree of obesity, sex and pubertal development. J Pediatr Gastroenterol Nutr 2008; 42: 66-70.

16. Schweizer P, Lenz MP, Kirschner HJ. Pathogenesis and symptomatology of cholelithiasis in childhood. Dig Surg 2000; 17: 459-467.

17. Webb DK, Darby JS, Dunn DT, Terry SI, Serjeant GR. Gallstones in Jamaican children with homozygous sickle-cell disease. Arch Dis Child 1989; 64: 693-696.

18. Tripathy D, Dash BP, Mohapatra BN, Kar BC. Cholelithiasis in sickle cell disease in India. J Assoc Physicians India 1997; 45: 287-289.

19. do Santos Gumiero AP, Bellomo-Brandao MA, Costa-Pinto EAL. Gallstones in children with sickle cell disease followed up at a Brazilian hematology center. Arq Gastroenterol 2008; 45: 313-318.

20. Croom RD 3rd, McMillan CW, Orringer EP, Sheldon GF. Hereditary spherocytosis. Recent experience and current concept of patho-physiology. Ann Surg 1986; 203: 34-39.

21. Kar R, Rao S, Srinivas UM, Mishra P, Pati HP. Clinico-hematological profile of hereditary spherocytosis: experience from a tertiary care center in North India. Hematology 2009; 14: 164-167.

22. Kalayci AG, Albayrak D, Gunes M, Incesu L, Agac R. The incidence of gallbladder stones and gallbladder function in beta-thalassemic children. Acta Radiol 1999; 40: 440-443.

23. Lotfi M, Keramati P, Assadsangabi R, Nabavizadeh SA, Karimi M. Ultrasonographic assessment of the prevalence of cholelithiasis and biliary sludge in beta-thalassemia patients in Iran. Med Sci Monit 2009; 15; CR398-402.

24. Origa R, Galanello R, Perseu L, Tavazzi D, Cappellini MD, Terenzani L, et al. Cholelithiasis in thalassemia major. Eur J Hematol 2008; 82: 22-25.

25. Galanello R, Piras S, Barella S, Leoni GB, Cipollina MD, Perseu L, et al. Cholelithiasis and Gilbert’s syndrome in homozygour beta-thalassemia. Br J Haematol 2001; 115: 926-928.

26. Chawla Y, Sarkar B, Marwaha RK, Dilawari JB. Multitransfused children with thalassemia major do not have gallstones. Trop Gastroenterol 1997; 18: 107-108.

27. Hussaini SH, Pereira SP, Veysey MJ, Kennedy C, Jenkins P, Murphy GM, et al. Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones. Gut 1996; 38: 775-783.

28. Jawaheer G, Pierro A, Lloyd DA, Shaw NJ. Gallbladder contractility in neonates: effects of parenteral and enteral feeding. Arch Dis Child Fetal Neonatal Ed 1995; 72: F200-202.

29. Roslyn JJ, Berquist WE, Pitt HA, Mann LL, Kangarloo H, DenBesten L, Ament ME. Increased risk of gallstones in children receiving total parenteral nutrition. Pediatrics 1983; 71: 784-789.

30. Matos C, Avni EF, Van Gansbeke D, Pardou A, Struyven J. Total parenteral nutrition (TPN) and gallbladder diseases in neonates - sonographic assessment. J Ultrasound Med 1987; 6: 243-248.

31. Schaad UB, Tschappeler H, Lentze MJ. Transient formation of precipitations in the gallbladder associated with ceftriaxone therapy. Pediatr Infect Dis 1986; 5: 708-710.

32. Richards DM, Heel RC, Brogden RN, Speight TM, Avery GS. Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 1984; 27: 469-527.

33. Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility. Gastroenterology 1990; 99: 1772-1778.

34. Lee SP, Lipsky BA, Teefey SA. Gallbladder sludge and antibiotics. Pediatr Infect Dis J 1990; 9: 422-423.

35. Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. Reversible ceftriaxone-associated biliary pseudolithiasis in children. Lancet 1988; 2: 1411-1413.

36. Schaad UB, Suter S, Gianella-Borradori A, Pfenninger J, Auckenthaler R, Bernath O, et al. A comparison of ceftriaxone and cefuroxome for the treatment of bacterial meningitis in children. N Engl J Med 1990; 322: 141-147.

37. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis 2007; 2: 29.

38. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastro-enterology 2001; 120: 1449-1467.

39. Beretsky I, Lankin DH. Diagnosis of fetal cholelithiasis using real-time high resolution imaging employing digital detection. J Ultrasound Med 1983; 2: 381-383.

40. Suma V, Marini A, Bucci N, Toffolutti T, Talenti E. Fetal gallstones: sonographic and clinical observations. Ultrasound Obstet Gynecol 1998; 12: 439-441.

41. Brown LD, Teele LR, Doubilet MP. Echogenic material in the fetal gallbladder: sonographic and clinical observations. Radiology 1992; 182: 73-76.

42. Abbitt LP, Mc Ilhenuy J. Prenatal detection of gallstones. J Clin Ultrasound 1990; 18: 202-204.

43. Stringer MD, Lim P, Cave M, Martinez D, Lilford RJ. Fetal gallstones. J Pediatr Surg 1996; 31: 1589-1591.

44. St-Vil D, Yazbeck S, Luks FI, Hancock BJ, Filiatrault D, Youssef S. Cholelithiasis in newborns and infants. J Pediatr Surg 1992; 27: 1305-1307.

45. Debray D, Pariente D, Gauthier F, Myara A, Bernard O. Cholelithiasis in infancy: A study of 40 cases. J Pediatr 1993; 122: 385-391.

46. Rief S, Sloven DG, Lebenthal E. Gallstones in children. Am J Dis Child 1991; 145: 105-108.

47. Holcomb GW Jr, Holcomb GW III. Cholelithiasis in infants, children and adolescents. Pediatric Rev 1990; 11: 268-274.

49. Poddar U, Thapa BR, Bhasin DK, Prasad A, Nagi B, Singh K. Endoscopic retrograde cholangio-pancreatography in the management of pancreatobiliary disorders in children. J Gastroenterol Hepatol 2001; 16: 927-931.

50. Prasad H, Poddar U, Thapa BR, Bhasin DK, Singh K. Endoscopic management of post laparoscopic cholecystectomy bile leak in a child. Gastrointest Endosc 2000; 51: 506-507.

51. Bruch SW, Ein SH, Rocchi C, Kim PCW. The management of nonpigmented gallstones in children. J Pediatr Surg 2000; 35: 729-732.

52. Chan S, Currie J, Malik AI, Mahomed AA. Pediatric cholecystectomy: shifting goalposts in the laparoscopic era. Surg Endosc 2008; 22: 1392-1395.

53. Gamba PG, Zancan L, Muraca M, Vilei MT, Talenti E, Guglielmi M. Is there a place of medical treatment in children with gallstones? J Pediatr Surg 1997; 32: 476-478.

54. Sokal EM, De Bilderling G, Clapuyt P, Opsomer RJ, Buts JP. Extracorporeal shock-wave lithotripsy for calcified lower choledocholithiasis in an 18-month-old boy. J Pediatr Gastroenterol Nutr 1994; 18: 391-394.

55. Miltenburg DM, Schaffer R, Breslin T, Brandt ML. Changing indications for pediatric cholecystec-tomy. Pediatrics 2000; 105: 1250-1253.

56. Marchetti M, Quaglini S, Barosi G. Prophylactic splenectomy and cholecystectomy in mild here-ditary spherocytosis: analyzing the decision in different clinical scenarios. J Intern Med 1998; 244: 217-226.

57. Sandler A, Winkel G, Kimura K, Soper R. The role of prophylactic cholecystectomy during splenec-tomy in children with hereditary spherocytosis. J Pediatr Surg 1999; 34: 1077-1078.

58. Al-Salem AH. Should cholecystectomy be performed concomitantly with splenectomy in children with sickle-cell disease? Pediatr Surg Int 2003; 19: 71-74.

59. Newman KD, Powell DM, Holcomb GW III. The management of choledocholithiasis in children in the era of laparoscopic cholecystectomy. J Pediatr Surg 1997; 32: 1116-1119.

60. Vrochides DV, Sorrells DL, Kurkchubasche AG, Wesselhoeft CW Jr, Tracy TF Jr, Luks FI. Is there a role for routine preoperative endoscopic retrograde cholangiopancreatography for suspected choledo-cholithiasis in children? Arch Surg 2005; 140: 359-361.