Gallstone disease in children

Seminars in Pediatric Surgery (2012) 21, 255-265

Gallstone disease in children Jan Svensson, MD,a Erica Makin, MSc, FRCS (Paeds)b From the aDepartment of Paediatric Surgery, Astrid Lindgren Children’s Hospital, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; and b Department of Paediatric Surgery, Royal London Hospital, Whitechapel, London, United Kingdom. KEYWORDS Gallstones; Genetics; Pathology; Biliary dyskinesia; Laparoscopic cholecystectomy; Single-port cholecystectomy

Gallstone disease in children is evolving, and for the previous 3 decades, the frequency for surgery has increased greatly. This is in part because of improved diagnostic modalities, but also changing pathology, an increased awareness of emerging comorbidities, such as childhood obesity, and other associated risk factors. This article outlines the pathophysiology, genetics, and predisposing factors for developing gallstones and includes a review of the literature on the current and more novel medical and surgical techniques to treat this interesting disease. © 2012 Elsevier Inc. All rights reserved.

Gallstones, or cholelithiasis (latin: chole– bile, lithia– stone, sis–process), have been identified in Egyptian mummies dating from the eighteenth dynasty (1550-1292 BC) and have been with us ever since.1 In 1507, Antonio Benivenius, the Florentine pathologist, first described them in the medical literature.2 There is a somewhat false perception that this disease can only occur in adults, with a prevalence in modern Western societies of 15%-20%;3 however, children are by no means exempt. The prevalence of gallstones in the pediatric population has been reported infrequently and is known to vary between countries. Italy, for instance, has an estimated prevalence of 0.13%-0.2% in infants and children4 and Japans has been reported as about 0.13%.5 The highest prevalence has been reported from the Netherlands and is based on ultrasonography screening at 1.9%.6 There appears to be a bimodal distribution with a small peak in infancy, which increases throughout adolescence, acquiring a marked female preponderance.7-9 Most importantly, for the last 3 decades, there has been a consistent Address reprint requests and correspondence: Erica Makin, Msc, FRCS (Paeds), Department of Paediatric Surgery, The Royal London Hospital, Whitechapel, London E1 1BB, UK. E-mail: [email protected].

1055-8586/$ -see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sempedsurg.2012.05.008

increase in the incidence of gallstones requiring cholecystectomy along with a shift in the indications for surgery.9-13 Although this increase in diagnosed gallstones during childhood is multifactorial, almost certainly diagnostic improvements and the rise of childhood obesity have played a significant role.

Physiology The function of bile is largely 2-fold. It facilitates the absorption of lipids and fat-soluble vitamins (A, D, E, and K) from the gastrointestinal tract (nutritional role) and actively transports substances, such as bilirubin and cholesterol, from the hepatocyte to the gastrointestinal tract (excretory role). The latter is achieved by a mixture of bile acids and fatty acids, which solubilize cholesterol by formation of micelles, facilitating transport across the biliary canalicular membrane into the extrahepatic biliary tree and subsequently into the duodenum. Fat-soluble bilirubin is the chief metabolic by-product of the destruction and recycling of red cells and is transported by albumin to be actively taken up by hepatocytes. Thereafter, it is conjugated with

256 Table 1

Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 Solute concentration in bile

Solute

Main component

Percentage*

Bile acids Fatty acids Cholesterol Proteins Inorganic salts/metals Bilirubin Phospholipids

Primary bile acids (cholic and chenodeoxycholic acid)

61 12 9 7 5 3 3

Albumin, immunoglobulins, liver specific proteins, for example, 5’nucleotidase Na, K, HCO3, Cl, Cu Mono/diglucuronide Phosphotidylcholine

*Percentages represent ratio to solute concentration (mg/mL).

glucuronic acid before being excreted into biliary ductules as a soluble molecule.

4. ABCC2, previously known as multidrug resistance–associated protein 2, actively transports bilirubin into the biliary canaliculus.

Formation of bile and the enterohepatic circulation

Bile acids form simple micelles within the biliary lumen and activate ABCB4 and ABCG5 and ABCG8 to secrete phospholipids and cholesterol (Figure 1). Cholesterol in its native form is only mildly soluble in aqueous bile. Therefore, it forms mixed micelles with bile salts (ionized form of bile acids) and phospholipids (mainly phosphatidylcholine), thus enabling the secretion of cholesterol into the intestine.

Bile composition varies with the nutritional state of the patient and where it is within the extrahepatic biliary tree.14 It is mainly water (⬎90%),15 with the remaining solutes and their respective concentrations listed in Table 1.16 Bile acids are produced by the hepatocytes within the liver from the oxidation of cholesterol and are, therefore, the main pathway for cholesterol excretion. In humans, the 2 main bile acids are cholic and chenodeoxycholic acid. These are then conjugated with taurine and glycine to produce taurocholic, glycocholic, taurochenodeoxycholic, and glycochenodeoxycholic acid, respectively. Conjugated bile acids are more soluble at acidic pH and are more resistant to precipitation by calcium ions, thereby enabling high concentrations of bile acids to be maintained in the lumen of the biliary tract and the intestine. The gallbladder itself concentrates bile 5- to 10-fold by actively absorbing water, bicarbonate, and chloride ions, leaving a supersaturated solution ready for postprandial injection into the duodenum. Secondary bile acids are produced in the intestine by bacterial 7 ␣-dehydroxylation. These bile acids are then reabsorbed by the enterocytes in the terminal ileum and colon and subsequently transported back to the liver via the portal venous system as an enterohepatic recirculation.17

Molecular mechanisms of bile formation The biliary canalicular membrane of the hepatocyte contains numerous transport proteins termed ATP-binding cassette (ABC) transporters, of which 4 are essential to the formation of bile. 1. ABCB4 (ie, ABC, subfamily B, member 4), previously known as multidrug resistant 3 P-glycoprotein, transports phospholipids, predominantly phosphatidylcholine. 2. ABCB11 transporter, previously bile salt export pump, is the major canalicular exporter of bile salts. 3. ABCG5 and ABCG8 form obligate heterodimers to export cholesterol.

Pathophysiology Classification of gallstones Four types of gallstones have been described in children: cholesterol, black pigment, brown pigment, and calcium carbonate stones.18,19 Cholesterol stones contain between 70% and 100% cholesterol, the remaining constituents being bilirubin, protein, and calcium carbonate. Black pigment stones are composed of calcium bilirubinate (calcium salt of unconjugated bilirubin) and are associated with hemolysis20 and parenteral nutrition.21 Brown pigment stones are much rarer, associated with biliary tract infections (bacterial and helminthic) and are composed of calcium bilirubinate and fatty acids.19 Calcium carbonate stones seem to be relatively exclusive to this age-group and may be related to transient cystic duct obstruction, which encourages excess mucin to be secreted from the gallbladder and thus increasing the acid buffering capacity allowing calcium salts to precipitate out.19

Cholesterol gallstones Cholesterol supersaturated bile contains a higher proportion of cholesterol than can be solubilized by micelles. The cholesterol saturation index (CSI) is defined as “the ratio of the actual biliary cholesterol concentration and the maximal concentration that would be soluble at phase equilibrium in model bile with equal lipid composition.”22,23 In supersaturated bile (CSI ⬎1), monohydrate crystals of cholesterol

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Gallstone Disease in Children Hepatocyte

257 Biliary Canaliculus

ABCB4 MDR3 Phospholipid

Mixed micelle

ABCB11 BSEP Bile Acid

Simple micelle ABCG5 ABCG8

Cholesterol

Figure 1 Schematic showing biliary canalicular membrane, with 4 ATP-binding cassette transporters essential for the secretion of phospholipids, bile acids, and cholesterol into the biliary tract lumen. Step 1: simple micelles of bile acids activate phospholipids and cholesterol ATP-binding cassette transporters. Step 2: phospholipids, bile acids, and cholesterol form protective “mixed micelle.”

aggregate and ultimately form biliary sludge and microliths and can progress to gallstones both intra- and extrahepatically. A high CSI can be the result of either hypersecretion of cholesterol or hyposecretion of bile salts/phospholipids. Hypersecretion being the commonest,24 usually results from increased hepatic uptake of cholesterol derived from excess dietary intake mediated by the scavenger receptor B-1 for high-density lipoproteins, the apolipoprotein B/E receptor for low-density lipoproteins, and the low-density lipoproteins receptorrelated protein for chylomicron remnants.

Black pigment stones Black pigment stones are due to excess unconjugated bilirubin and ionized calcium in the form of calcium bilirubinate ⫾ calcium carbonate. Supersaturation may be due to reduced activity of the enzyme bilirubindiphosphate-glucuronyltransferase (UGT1-A1), which conjugates bilirubin (Gilbert syndrome) or overloading of hepatocyte bilirubin conjugation (hemolytic anemia), an increased endogenous ␤-glucuronidase activity, or a reduction in the bile salt pool. Sickle cell anemia, thalassemia, and hereditary spherocytosis are the commonest hemolytic disorders associated with pigment gallstones.25-29 Stones (and sludge) can be detected ultrasonographically in up to 45% of children with sickle cell anemia, and a third of these are in children ⬍10 years of age.29 In contrast, a smaller proportion (5%) of children with hereditary spherocytosis will develop gallstones by 10 years of age.30

The highest prevalence is observed in patients with Gilbert syndrome with a 4-fold increased risk because of the combined effect of increased bilirubin production and reduced bilirubin diphosphate-glucuronyltransferase activity mediated by the gene UGT1-A1.31,32 Another pathway for black pigment stone formation is ileal disease (eg, Crohn disease or after surgical resection). This reduces the absorption of bile salts resulting in solubilization and absorption of excess unconjugated bilirubin by the colon and subsequently entering the enterohepatic circulation.33 Overall, 20%-40% of all pediatric gallstone disease can be attributable to hemolytic disease. Traditionally, this proportion was believed to be as high as 50%, but because of the increasing prevalence of other risk factors (ie, obesity), the proportion has now fallen in many studies.8,9,34

Brown pigment stones In children, these contain large amounts of fatty acids and calcium bilirubinate. Bacterial or helminthic infection of the biliary tract is the prerequisite for brown pigment stone formation. Microbial ␤-glucuronidase, in contrast to the human enzyme, deconjugates bilirubin conjugates, thereby affecting the solubility of calcium bilirubinate, which precipitates out to form stones. Their formation is also associated with biliary duct dilatation, biliary stasis, and they are much more common in the Far East. Nonetheless, they can also be found in the common bile duct (CBD) years after a cholecystectomy.35,36

258

Microlithiasis and sludge Microliths are defined as gallstones ⬍3 mm in size. They can form within the intra- and extrahepatic biliary tree, can give rise to biliary colic, cholecystitis, and pancreatitis, and may persist after cholecystectomy, giving rise to ongoing symptoms.37 They can be notoriously difficult to diagnose, particularly in children, because they are often missed by standard transabdominal ultrasonography. Other methods of detection include endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP) and nasobiliary aspiration.38 Magnetic retrograde cholangiopancreatography has a lesser role, especially in younger children, because of its poor sensitivity. Biliary sludge is composed of precipitates of cholesterol monohydrate crystals, calcium bilirubinate, calcium phosphate, calcium carbonate, and calcium salts of fatty acids. These crystals are embed into biliary mucin to form “sludge.”39 The commonest predisposing factors in children are parenteral nutrition, systemic infection, any state of prolonged fasting or rapid weight loss, biliary stasis, and poor gallbladder contractility.6 Additionally, prolonged use of ceftriaxone, a third generation cephalosporin, which is partly secreted in an unmetabolized form, complexes with calcium to form an insoluble salt precipitating out in bile.40 The formation of sludge is a fluctuating condition. Early series show that sludge forms within 3 weeks of parenteral nutrition in about 6% of patients,21 although more recent studies show that sludge can develop and dissipate within days. Treatment is usually conservative. In rare cases of recurrent symptoms or persistent obstruction causing duct dilatation, consideration should be given to commencing ursodeoxycholic acid (UDCA), ERCP, and sphincterotomy to relieve obstruction in the older child. Occasionally, in neonates where persistent obstruction and duct dilatation persists, a percutaneous transhepatic cholangiogram to flush the biliary tract may be considered.

Risk factors for development of cholelithiasis Gallstone disease in children is evolving and can be attributed to multiple conditions and physiological stresses that predispose to the development of all types of gallstones (Table 2). Firstly, there is increasing survival of a cohort of critically ill neonates that have had lithogenic interventions, such as long-term parenteral nutrition after bowel resections for necrotizing enterocolitis or congenital short bowel because of gastroschisis or intestinal atresias. Secondly, there has been a marked increase in obesity and associated lipid dysregulation in children throughout the developed world. Finally, we have improved our ability to detect gallstones with an increasingly liberal use of ultrasonography. Some of the more currently emerging risk factors will now be discussed in further detail.

Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 Table 2 Risk factors for development of gallstone disease in children Subgroup

Risk factor

Hemolytic disease

Sickle cell disease Thalassemia Hereditary spherocytosis Gilbert syndrome Prematurity Parenteral nutrition Congenital: choledochal malformation ABCB4 ABCBG5/G8 PFIC Cystic fibrosis Obesity Insulin resistance Sepsis Crohn disease Cephalosporins Diuretics: furosemide Cardiac surgery: hemolysis on bypass Bowel resection (terminal ileum) Crohn disease Neonatal bowel resection (atresia, volvulus, gastroschisis) Biliary dyskinesia

Neonatal/congenital Genetic

Dietary Systemic Medications Surgery

Miscellaneous

ABC, ATP-binding cassette; PFIC, progressive familial intrahepatic cholestasis.

Genetics of gallstone formation Cholesterol gallstone formation is multifactorial. However, there appears to be a spectrum of emerging conditions with genetic associations being linked with the propensity to form gallstones. For instance, progressive familial intrahepatic cholestasis (PFIC) describes a group of autosomal recessive liver diseases often presenting in the neonatal period with a range of phenotypes from mild cholestasis to end-stage liver failure necessitating liver transplantation.41 Of particular interest is PFIC type 3 (formerly known as multidrug resistant 3 deficiency), caused by a mutation in the ABCB4 gene responsible for the transport of phospholipids across the biliary canalicular membrane.42-45 Heterozygous mutations of ABCB4 are found in up to 30% of patients with unexplained recurrent cholestasis, cholesterol gallstones, or biliary sludge in adults, and this entity has been termed “low phospholipid associated cholelithiasis.”46-49 A pediatric study analyzing 19 patients with cholesterol gallstones found that 1 patient had a heterozygous mutation in ABCB4, 7 patients had single-nucleotide polymorphisms, resulting in amino acid substitutions in 2, which may contribute to the formation of gallstones.50 The biochemical hallmark of all these PFIC/low phospholipid–associated cholelithiasis is low serum ␥-glutamyl transpeptidase (GGT) (often ⬍10 IU/L). Numerous candidate gallstone genes (LITH genes) have been identified. At least 23 have been described in mouse models, all contributing to the regulation of synthesis, uptake, and secretion of hepatobiliary lipids. Of these, 15 have

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Gallstone Disease in Children

been identified in humans,51 including ABCB4 and polymorphisms of the ABCG5/G8 gene, which encodes the cholesterol hemitransporter.52

Obesity There is a well recognized link between obesity and gallstone formation in the adult population,53,54 and this is becoming recognized in children.6,55 Childhood and adolescent obesity (age 2-19 years) has increased by 3% in 4 years (from 2000 to 2004) to a level of 17% as documented by the NHANES (National Health and Nutrition Examination survey) data in the United States.56 More concerning is the increase in number of children with severe obesity (body mass index [BMI] percentile ⬎99%), which has increased by ⬎300% from 0.8% in the years between 1976 and 2000 to 3.8% in years 2000-2004.54 The United States is not alone in their rising obesity rates; China reports an increase from 1.5% to 13% between 1989 and 1997.57 This trend is further supported by a recent study by Mehta et al9 who presented a series of 404 children/adolescents (0-18 years), where 53% of nonhemolytic cholelithiasis were classified as occurring in overweight or obese children/adolescents. Conversely, Bogue et al8 reported an obesity rate of ⬍1% in their series of 382 children/adolescents. However, accurate documentation of childhood BMI/obesity levels is poor and this may reflect this particularly low finding.58 Hispanic ethnicity and by inference genetic linkage strongly correlate with gallbladder disease in children. Obesity in these individuals seems to compound the presence of symptomatic cholelithiasis.9,59 The pathogenesis of cholelithiasis in the context of obesity is multifactorial and is linked to hypersecretion of cholesterol and its subsequent precipitation into bile along with gallbladder dysmotility.60-62 Insulin resistance may also be involved63 because it stimulates cholesterol production and inhibits 7␣-hydroxylase activity in hyperinsulinemic patients. Increased amounts of free fatty acids are taken up by the liver, and thus more very-low-density lipoprotein and cholesterol are secreted in overweight patients with insulin resistance.64

Biliary dyskinesia Biliary dyskinesia (poor gallbladder contractility) is defined as a gallbladder ejection fraction of ⬍35% with a cholecystokinin (CCK) analogue infusion at a radioisotope liver scan.65-68 When this is combined clinically with vague right upper quadrant or epigastric pain, nausea, or vomiting in the absence of gallstones on ultrasonography, then a diagnosis of biliary dyskinesia can be made.69 The changing trends in pediatric gallstone disease have resulted in an increase in the number of cholecystectomies performed for biliary dyskinesia, from never being performed in a 15-year series (1980-1996) reported by Miltenberg et al13 to the third most popular indication for surgery reported by the same institu-

259 tion between the years 2005 and 2008.9 Other pediatric series report a range of incidences for biliary dyskinesia from 14% to 68%.66,70,71 This most probably reflects an increased awareness and ability to diagnose the condition rather than a true increase in incidence. However, the resolution of symptoms postcholecystectomy has been disappointing,70-72 although, in some series, symptom resolution is as high as 95%.66,73 A particularly low ejection fraction ⬍15% and a lower than average BMI may correlate with resolution of symptoms postoperatively.69,70,74 There appears to be no correlation between pathology and postoperative outcome,72,75 although, the gallbladder in these patients is often not histologically normal. Brownie et al70 describe histological evidence of acute or chronic inflammation or sludging in 63% of patients with good symptom relief in this group. Although cholecystectomy is the accepted method for treating biliary dyskinesia, the natural history of the condition is not known. For instance, Scott Nelson et al76 described a symptom resolution rate of 75% in patients who were managed conservatively for a 2-year follow-up. Poor gallbladder contractility and biliary stasis observed during parenteral nutrition, rapid weight loss, and diabetes have been linked to increased cholesterol gallstone formation, secondary to the impaired function or release of CCK and more recently discovered, the inappropriate and excessive release of fibroblast growth factor 19 from ileal enterocytes, which suppresses bile acid synthesis within the hepatocyte.24,77-79 Further evidence to support the role of CCK in gallstone formation is the genetic deletion of CCK-1 receptors in murine models and single mutations in the cholesterol 7-alpha hydroxylase gene encoding the CCK receptor A, which is associated with hypercholesterolemic states and obesity.80,81

Clinical features Gallstones in children present in a similar way to that of adults, although there seems to be a delay from onset of symptoms to diagnosis/definitive treatment. For instance, the median time from onset of symptoms to surgical treatment in children operated at the Astrid Lindgren Children’s Hospital in Sweden during 2006-2008 was 3.5 years (unpublished observation). Gallstones may present in a variety of ways: ●

●

Asymptomatic (17%-50%): these are usually detected on ultrasonography while assessing for other abdominal pathology. A large proportion of asymptomatic gallstones will never cause problems, and indeed 16% and 34% have been shown to completely resolve in children and infants, respectively.8 Biliary colic/cholecystitis: pain is the commonest symptom, predominantly in the right upper quadrant (85%94%), less so epigastrically (⬃34%).6,8 This may be accompanied by nausea and vomiting in up to 60%.

260 ●

●

Cholangitis/choledocholithiasis/pancreatitis (7%-20% of symptomatic patients): this is usually associated with pain, fever, and jaundice.6,8 Nonspecific abdominal pain and irritability (24%-46%): typically seen in patients ⬍5 years of age and in hemolytic disease.6,8

Gallstones can be found in up to 0.5% of unselected newborns without apparent predisposing factors, but unlike older age-groups, spontaneous resolution may occur in up to 50%.82-85

Investigations Initially, liver biochemistry should be assessed, including the hepatic aminotransferases, alanine aminotransferase, and aspartate aminotransferase, which are elevated early in the course of biliary obstruction. Later, development of a more cholestatic picture brings about an elevation of serum bilirubin, alkaline phosphatase, and GGT. Bogue et al8 reported abnormal hepatic aminotransferases in 51% and an elevated GGT in 45% of patients with symptomatic disease. Interestingly, in the cohort of patients with nonspecific abdominal pain, elevated GGT was also seen in 41% of patients. Leukocytosis is very nonspecific, but may be raised particularly in cholangitis or pancreatitis. A raised amylase level is diagnostic of pancreatitis and is useful as a marker for disease resolution. Transabdominal ultrasonography is the initial investigation of choice because it is simple and readily available. Gallstones within the gallbladder demonstrate a typical echogenic acoustic shadow, although gallstones in the CBD may be difficult to detect because of overlying bowel gas. An assessment of hepatobiliary duct dilatation and pancreatitis can also be made. Endoscopic ultrasonography may be helpful to diagnose stones in the CBD, and for detection of microlithiasis,38 although its use is restricted to the older child because of size constraints. Magnetic retrograde cholangiopancreatography is useful particularly in the context of pancreatitis to assess any underlying congenital ductal anomalies (choledochal malformation, pancreas divisum) that may be compounding gallstone formation and also to assess the degree of pancreatic damage, potential pseudocyst formation once the acute inflammation has resolved. ERCP has both diagnostic and therapeutic advantages and has been used in children with a success rate for resolution of CBD stones in up to 95% of cases86,87 and remains the preferred modality for the diagnosis of congenital pancreaticobiliary ductal anomalies.

Management The aim of treatment is to provide long-term relief from the symptoms of gallstones and to minimize the possibility of complications and recurrence. A number of strategies have evolved, largely from adult experience.

Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 There have been no prospective randomized controlled trials that compare medical and surgical treatment of gallstone disease in children. An Italian multicenter study has shown that there is a difference in treatment depending on the specialty of the center. If patients are treated within a medical gastroenterology unit then they are more likely to receive oral dissolution therapy than patients treated in a surgical unit.88

Nonsurgical options Ursodeoxycholic acid Medical dissolution of gallstones obviates the need for surgery principally by increasing the concentration of compounds tending to keep cholesterol in solution. Currently, the most commonly used agent is the bile acid UDCA. This is a secondary bile acid found at low concentration in human bile,89 but is the predominant bile acid in the Chinese black bear (Ursus thibetanus). Indeed, raw black bear bile has been used in traditional Chinese medicine for centuries. Published experience in children is small. Gamba et al90 described 15 children with symptomatic radiolucent gallstones who were treated with UDCA for 1 year. All children became asymptomatic but actual resolution of stones occurred only in 2. In both of these patients, the stones recurred within 6 month after finishing the UCDA therapy. A larger series of 180 Italian children with gallstones was reported recently by Della Corte et al.88 Again, 65% of UDCA-treated children (n ⫽ 117) became asymptomatic with actual dissolution occurring only in 8 and recurring in 3 by the end of treatment. Of course, only those gallstones with a high proportion of cholesterol can be affected by UDCA therapy; so, it is important both to exclude those with potential pigment stones from treatment and confirm that they are radiolucent.

Extracorporeal shock-wave lithotripsy Extracorporeal shock-wave lithotripsy (ESWL) was first reported by Sauerbruch et al91 in 1986 and has been widely reported as an alternative method of gallstone clearance in adults.92,93 The initial report was based on 9 patients with functioning gallbladders containing 1-3 symptomatic radiolucent stones of ⬍25 mm in diameter with complete resolution of all stones. Two patients suffered colicky pain and 1 had mild pancreatitis after treatment. Five patients with CBD stones were also treated. However, 4 patients required ERCP, one of which required a sphincterotomy. Janssen et al92 in 2001 reported 120 consecutive patients that became stone free after a combination of ESWL and oral bile acids. However, long-term results are disappointing with a 60% recurrence rate at 10 years. Rabenstein et al93 presented a clearance rate of 42%-85%, but again reports a high recurrence rate of 43% after 5 years. There is a single report of ESWL in a child.94 This was a 12-year-old girl who was successfully treated with ESWL

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Gallstone Disease in Children

and oral dissolution treatment and remained free of stones and clinically asymptomatic 18 month after her intervention.

Cholecystolithotomy This refers to simple removal of stones, leaving the gallbladder in situ. The first cases of percutaneous cholecystolithotomy were reported in 1985.95 In 1988, Kellett et al96 described a technique of transperitoneal endoscopic percutaneous cholelithotomy as an alternative treatment for symptomatic gallstones in patients with an open cystic duct that wanted to keep their gallbladder. A more recent article presented a 10-year follow-up of 439 adult patients treated successfully with percutaneous cholecystolithotomy.97 Unfortunately, the recurrence rate was ⬎40% at 10-year follow-up, and 38 patients went on to have a cholecystectomy. A number of risk factors were described for recurrence, including heredity, fat-rich food intake, liver disease, multiple gallstones, and gall bladder dysfunction. The largest pediatric experience was reported from Dublin, Ireland, where 10 children were treated by cholelithotomy.98 At a median follow-up of 9.5 months, 30% had demonstrable recurrence of their stones. All nonsurgical treatments of gallstone disease in adults and children are associated with a high proportion of recurrence. The literature does not support this method of treatment for pediatric gallstone disease.

Surgical treatment Open versus laparoscopic cholecystectomy in children The first elective open cholecystectomy (OC) was performed by Carl Langenbuch, a surgeon working in Berlin, Germany in 1882.99 Although there is still some dispute in the literature, the first laparoscopic cholecystectomy (LC) is now also credited to a German surgeon, Erich Mühe in 1985.100 The first laparoscopic cholecystectomies in children were reported in 1991.101,102 Two retrospective cohort studies have shown that LC in children results in a shorter hospital stay, reduced analgesia requirement, and a lower ultimate cost of treatment.103,104 Other studies have confirmed small benefits of LC in children.105,106 A series of 21 consecutive patients treated with an LC were compared with 29 consecutive open cholecystectomies.105 Five patients in the laparoscopic group had CBD stones, which were treated successfully, and all benefited from a shorter hospital stay. However, there are no prospective randomized trials comparing OC and LC in the pediatric population. A recent Cochrane review from 2010 on adult patients concludes that there is no difference between mortality, complications, or operating times between OC, small-inci-

261 sion cholecystectomy, and LC, but there is a shorter hospital stay and a quicker convalescence in the minimally invasive group. In this review, the small-incision cholecystectomy and LC are comparable, but the former is associated with shorter operation time.107 Many series of LC have also been reported in children, and this technique has become the preferred technique.88,108-114 A series of 224 LC (185 performed for gallstones) over 6-years report no conversions, ductal injuries, bile leaks, or mortality. Imaging of the biliary tree was performed selectively with preoperative ERCP in 17 patients of which 8 had stones retrieved endoscopically. Intraoperative cholangiogram was performed in 38 patients; CBD stones were identified in 9. Two patients underwent a postoperative ERCP because of a rise in bilirubin, but none of these had retained gallstones.115 In 2008, Della Corte et al88 reported a large series of 181 children with gallstone disease. 64 underwent a cholecystectomy and the remaining patients were treated by UDCA. Fifty patients (78%) underwent LC and the remainder a traditional open operation. One child developed an incisional hernia in the open group. Three patients developed postcholecystectomy syndrome. There were no other perior postoperative complications.

Laparoscopic cholecystectomy This is similar to adult practice with most surgeons using 4 ports (umbilicus, epigastrium, and 2 in the right lower quadrant or flank). Although all ports can be 3 or 5 mm, a 10-mm port at the umbilicus facilitates the final removal of the gallbladder. Initial port placement in children and certainly infants should always be by an open (Hasson) approach as opposed to using a guarded Verres needle. A recent Cochrane review presented a meta-analysis on laparoscopic entry techniques.116 There was no advantage in any particular technique in terms of preventing major vascular or visceral complications. However, the open-entry technique demonstrated a reduction in incidence of failed entry, extraperitoneal insufflation, and omental injury. Ontable cholangiography, although more difficult in children simply because of size constraints, should be considered if there is any suspicion of choledocholithiasis. If patients have no clinical or radiological abnormalities to raise concerns about an obstructed biliary tract then no pre- or intraoperative cholangiography is necessary as long as the anatomy is completely clear during the dissection.117 Single-incision laparoscopic surgery (SILS) has evolved in adults since the first report in 1995118 and is a feasible alternative to traditional 4-port LC in adults and may be cosmetically superior.119 A recent review of 38 articles, including 1180 patients, was assessed for the complications of singleincision laparoscopic (SIL) cholecystectomy in adults.120 One or more extra ports were needed in 4% of cases. Laparoscopic cholangiography was attempted in only 4% of cases. There was no mortality, and the rate of major complications requiring surgical intervention or ERCP with stenting was 1.7%. A

262 recent trial has been published comparing the cosmetic outcome between SILS and 4-port LC (52 patients, 25 SILS, were assessed via a validated “Patient Scar Assessment Questionnaire”). There were no significant difference between the 2 methods in regard of “appearance,” “symptoms,” “scar consciousness,” or “satisfaction with appearance.”121 On the subject of children, the literature is limited.122-126 A comprehensive review on SIL cholecystectomy was presented by Holcomb127 in a previous edition of Seminars of Pediatric Surgery. He presents the development from open surgery to standard 4-port laparoscopy through 3-port technique to SIL and natural orifice endoscopic surgery (NOTES). This review also details the surgical technique and presents an ongoing prospective randomized trial comparing the operating time between SIL cholecystectomy and LC in children. NOTES has been described for cholecystectomy in adults.128,129 There are no reports on NOTES in the pediatric population, but animal trials in piglets to mimic the pediatric patient have been conducted.130,131 Thus, a group from Hannover, Germany, performed 8 transurethral nephroureterectomies and 4 bilateral tuboovariectomies.130,131 All procedures were successful. They conclude that any NOTES instruments and procedures must be tested in animal models before being used in children. To access the abdominal cavity and the gallbladder through the stomach, rectum, or vagina requires special skills and instruments that will preclude this technique to be used in children on a larger scale in the foreseeable future.

Postcholecystectomy syndrome Postcholecystectomy syndrome can be defined as the persistence or recurrence of symptoms similar to those experienced before the cholecystectomy,132 but can also involve new symptoms like intolerance to fasting. Colicky or noncolicky pain is most often present, but there may also be intolerance of fatty foods, bloating, flatulence, nausea, and vomiting.133 There have been no reports about the incidence of postcholecystectomy syndrome in children. Ure et al133 put forward an algorithm suggesting that those with gallstones caused by nonidiopathic factors, such as sepsis, TPN, and hemolytic disorders, would benefit from a cholecystostomy instead of a cholecystectomy because the risk of recurrence of gallstones is less likely in this group. However, there has been no trial evaluating the outcome of cholecystostomy versus cholecystectomy in children and it has not gained strong support.

Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 acids seem to have a carcinogenic effect on colonic mucosa. There have been numerous epidemiological studies trying to estimate the scale of this increased risk.134-136 The largest has been reported by Lagergren et al134 who identified 278,460 cholecystectomized patients. They found an increased risk of intestinal cancer, highest in small bowel carcinoma (relative risk [RR] ⫽ 1.77; 95% confidence interval [CI]: 1.37-2.24) and to a lesser extent small bowel carcinoid (RR ⫽ 1.71; 95% CI: 1.39-2.08) and right-sided colon cancer (RR ⫽ 1.16; 95% CI: 1.08-1.24). They found no difference with gender or any association with more distal intestinal cancer. There are 3 meta-analyses on this subject.137-139 Giovannucci et al137 reported a meta-analysis based on 33 casecontrol studies and found an association between cholecystectomy and risk of colorectal cancer (RR ⫽ 1.34; 95% CI: 1.14-1.57), particularly when limited to the proximal colon (RR ⫽ 1.88; 95% CI: 1.54-2.30). Reid et al138 pooled data on 33 trials and found a fairly weak association between cholecystectomy and colorectal cancer overall (RR ⫽ 1.11; 95% CI: 1.02-1.27) with a somewhat stronger association with right colon cancer and particularly in females. Xu et al139 presented a meta-analysis of 26 case-control studies in the Chinese population with a total of 11,502 cases and 15,565 controls. They reported a positive correlation between both cholecystectomy (RR ⫽ 2.85; 95% CI: 2.133.81) and cholelithiasis (RR ⫽ 2.68; 95% CI: 1.93-3.72). The correlation was stronger on the right side of the colon and only apparent in women on a subgroup analysis. A recent study from Sweden looked at the association between cholelithiasis, cholecystectomy, and cholangiocarcinoma.140 In this nationwide population-based cohort study, a total of 538,211 patients with gallstone disease with or without cholecystectomy from 1968 to 2008 were included. They found a 2-fold increase in both intra- and extrahepatic cholangiocarcinoma in patients with gallstone disease without cholecystectomy. The same was true in patients with gallstone disease and cholecystectomy, but only for the first years after cholecystectomy. After 10 years of follow-up, this risk declined to the level of the background population. In conclusion, there is evidence to suggest an increased risk of intestinal cancer after cholecystectomy. The risk may be higher the closer to the duodenum and perhaps more so in women. There is also a similarly increased risk of colon cancer in those with cholelithiasis who have not had cholecystectomy. There have been no studies addressing the association between cholecystectomy or cholelithiasis and intestinal cancer in children—who because of their potentially longer lives might seem to be even more at risk.

Association with malignancy After cholecystectomy, bile flows continually to the duodenum. This leads to an increased formation of secondary bile acids (deoxycholic and lithocholic acid) because of an increase of the enterohepatic circulation and degradation of primary bile acids by intestinal flora. Such secondary bile

Conclusions The prevalence of gallstone disease in children appears to be increasing. The etiology behind this is certainly multi-

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factorial, but there is good evidence to support that a rise in childhood obesity, awareness of emerging genetic factors, and improved diagnostic modalities certainly play a role. Asymptomatic or incidental gallstones do not require surgical intervention, but if indicated, the laparoscopic approach is the preferred approach. There appears to be a minimal role for the use of chemical dissolution, using UDCA for example, because although it may abolish symptoms in the short-term, long-term freedom from stones is rare.

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