Gallbladder disease is one of the most common and costly digestive diseases that requires hospitalization in the United States. Gallbladder calculi are more common in the adult population and remain relatively uncommon in children; however, the incidence of cholelithiasis in children has increased. The ultrasonogram below reveals multiple stones in a gallbladder.[1]
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Transverse view of the gallbladder reveals multiple stones, without gallbladder wall thickening, edema, or surrounding fluid accumulation.
Children may present with black pigment, cholesterol, calcium carbonate, protein-dominant, or brown pigment stones. Typically, only 1 type of stone forms at any given time.
Pain in the right upper quadrant (RUQ) of the abdomen is common. A Murphy sign (expiratory arrest with palpation in the RUQ) is thought to be pathognomonic (see Clinical Presentation). Ultrasonography of the RUQ is the study of choice in patients with uncomplicated cholelithiasis (see Workup).
As in adults, treatment for simple cholelithiasis is largely symptomatic, and laparoscopic cholecystectomy remains the criterion standard in treatment for symptomatic cholelithiasis (see Treatment and Management).[2]
Gallstone distribution
The distribution of gallstone types in children differs from the adult population, with cholesterol stones being the most common type of stone in adults and black pigment stones being the most common type in children.
Black pigment stones make up 48% of gallstones in children. They are formed when bile becomes supersaturated with calcium bilirubinate, the calcium salt of unconjugated bilirubin. Black pigment stones are commonly formed in hemolytic disorders and can also develop with parenteral nutrition.
Calcium carbonate stones, which are rare in adults, are more common in children, accounting for 24% of gallstones in children.[3]
Cholesterol stones are formed from cholesterol supersaturation of bile and are composed of 70-100% cholesterol with an admixture of protein, bilirubin, and carbonate. These account for most gallstones in adults but make up only about 21% of stones in children.[4, 5]
Brown pigment stones are rare, accounting for only 3% of gallstones in children, and form in the presence of biliary stasis and bacterial infection. They are composed of calcium bilirubinate and the calcium salts of fatty acids and occur more often in the bile ducts than in the gallbladder.
The remaining portion of gallstones in children consists of protein-dominant stones, which make up about 5% of gallstones in these patients.
Microliths are gallstones smaller than 3 mm; can form within the intrahepatic and extrahepatic biliary tree; may lead to biliary colic, cholecystitis, and pancreatitis; can persist after cholecystectomy; and are difficult to diagnose as they are often missed on ultrasonography. Biliary sludge is made up of precipitates of cholesterol monohydrate crystals, calcium bilirubinate, calcium phosphate, calcium carbonate, and calcium salts of fatty acids, which are embedded in biliary mucin to form sludge.[6]
Go to Cholelithiasis for more complete information on this topic.
The complications of cholelithiasis in children are similar to those in adults. Cholelithiasis primarily affects the gallbladder and may cause irritation of the gallbladder mucosa, resulting in chronic calculous cholecystitis and symptoms of biliary colic.
If a gallstone obstructs the cystic duct, acute cholecystitis can occur, with distension of the gallbladder wall and possible necrosis and spillage of bile. If gallstones migrate from the gallbladder into the cystic duct and main biliary ductal system, further complications can occur, such as choledocholithiasis, biliary obstruction with or without cholangitis, and gallstone pancreatitis.
Cholelithiasis in children has various causes related to predisposing factors. Hemolytic disease, hepatobiliary disease, obesity,[7] prolonged parenteral nutrition, abdominal surgery, trauma, ileal resection, Crohn disease, sepsis, and pregnancy all may lead to an increased incidence of gallstones in the pediatric population.
Less prominent risk factors include acute renal failure, prolonged fasting, low-calorie diets, and rapid weight loss. Biliary pseudolithiasis, or reversible cholelithiasis, has been identified with the use of certain medications, primarily ceftriaxone.[8]
Genetic conditions, such as progressive familial intrahepatic cholestasis type 3, can also predispose to gallstone formation. Defects in the in the ABCB4 gene have been increasingly recognized in both adults and children with recurrent cholestasis and cholesterol gallstones.[9]
Although gallbladder disease had traditionally been considered an adult condition, the prevalence has been rising in the pediatric population. A population-based study estimated the prevalence of gallstones and biliary sludge in children at 1.9% and 1.46%, respectively.[10] The true number of affected children may have previously been underestimated because patients with cholelithiasis can present with nonspecific abdominal pain.
The morbidity and mortality associated with gallstones are more commonly associated with cholecystitis or ascending cholangitis. The primary morbidity associated with uncomplicated cholelithiasis is chronic abdominal pain, which can be incapacitating.
Although no racial predilection is noted, individuals of certain ethnic heritage have been identified to be at higher risk for developing gallstones, particularly the Pima Indians of North America and Scandinavians.
Prior to puberty, the sex ratio of cholelithiasis in children appears to be equal. However, after puberty, the frequency of cholelithiasis is significantly greater in females than in males and is comparable to the adult ratio of 4:1 female predominance.
Factors in the incidence of pediatric cholelithiasis
Factors affecting the increasing incidence of cholelithiasis in children include increased detection with increased use of ultrasonography, as well as the growing obesity epidemic.[11] The increasing incidence of pediatric gallbladder disease parallels the rise in obesity in children.[11]
The frequency of cholelithiasis in children with sickle cell disease is almost double that of the general population.[12, 13] Pigmented gallstones occur in approximately 50% of children with sickle cell disease by age 22 years. Approximately 20-40% of all pediatric gallstone disease can be attributable to hemolytic disease.[14]
For patient education information, see eMedicineHealth's Digestive Disorders Center and Cholesterol Center, as well as Gallstones, High Cholesterol, and Cholesterol FAQs.
Although approximately 80% of adults with gallstones were historically believed to be asymptomatic, retrospective studies have found that only 33-40% of children are asymptomatic.
In symptomatic patients, pain, primarily in the right upper quadrant, is the most common presenting symptom and may be accompanied by nausea and vomiting.[6]
Gallstones should be considered in the workup of nonspecific, intermittent abdominal pain in children with risk factors. Risk factors include chronic hemolysis, obesity, ileal disease, a family history of childhood gallstones, parity, and parenteral nutrition.
Cholelithiasis should be considered in any symptomatic child with sickle cell or other hemolytic disease. Also, consider cholelithiasis in children with jaundice and low-grade elevations of transaminases. Older children may be able to localize their pain to the RUQ.
Perform a complete physical examination in children. Include auscultation, visualization, and, lastly, palpation of the abdomen in the examination. Pain in the RUQ is common. A Murphy sign (expiratory arrest with palpation in the RUQ) is thought to be pathognomonic. Also, note hepatomegaly and splenomegaly, because they may be a clue to venous congestion or a hemolytic process that may be a predisposing factor for cholelithiasis.
Obesity should also be noted on physical examination, because this can be a risk factor for the development of cholesterol gallstones.
The workup of cholelithiasis in pediatric patients is similar to that in adults. The goal is to demonstrate evidence of gall bladder or biliary tract disease. Laboratory tests should include a complete blood count, gamma-glutamyltransferase (GGT), amylase, urinalysis, direct and indirect bilirubin, alkaline phosphatase, and transaminase levels.
All laboratory results in simple cholelithiasis should be within reference ranges. They are of use in identifying more complex disease processes, including biliary obstruction and cholecystitis. Abnormal results on liver function tests or CBC count suggest infection, obstruction, or both.
Ultrasonography of the RUQ is the study of choice in patients with uncomplicated cholelithiasis. Plain radiography, radionuclide scanning, and cholangiopancreatography can also play a role in the assessment of cholelithiasis.
Go to Imaging in Cholelithiasis for more complete information on this topic.
Ultrasonography can be used to identify the location of the stone (as demonstrated in the image below, gallbladder wall thickening, the presence of gallbladder sludge, and pericholecystic fluid. Furthermore, an ultrasonographic Murphy sign (expiratory arrest with pressure from the sonographic probe in the RUQ) aids in the diagnosis of cholelithiasis.
View Image
Transverse view of the gallbladder reveals multiple stones, without gallbladder wall thickening, edema, or surrounding fluid accumulation.
Abdominal plain radiography in pediatric patients with cholelithiasis is seldom useful, because gallstones, with the exception of calcium carbonate stones, are not radio-opaque. However, radiography may be beneficial in identifying small-bowel obstruction or free air under the diaphragm.
Radionuclide scanning, such as with iminodiacetic acid (IDA) derivatives (eg, hepatoiminodiacetic acid [HIDA], diisopropyl iminodiacetic acid [DISIDA], and para-isopropyliminodiacetic acid [PIPIDA] scanning), is also used to assess gallbladder filling and bile excretion, particularly in response to cholecystokinin or a fatty meal.
In children with suspected hepatobiliary complications, magnetic resonance cholangiopancreatography (MRCP)[15] or endoscopic retrograde cholangiopancreatography (ERCP) can help delineate the anatomy of the extrahepatic and intrahepatic biliary tract, identify the presence of ductal stones, and provide a therapeutic mode of removing a stone or decompressing the biliary tract.[16, 17]
ERCP in the pediatric population has been associated with the same frequency of success and complications as in adults. As a noninvasive alternative, the MRCP has demonstrated promise in the evaluation of choledocholithiasis.
Expectant management with periodic clinical and ultrasonographic surveillance is appropriate for asymptomatic cholelithiasis.
An exception is in children with sickle cell anemia, in whom laparoscopic cholecystectomy is currently recommended for asymptomatic gallstones, in order to prevent potential complications of cholelithiasis, which tend to be more common in children with sickle cell anemia.[18]
Ursodeoxycholic acid therapy
Ursodeoxycholic acid can be useful in the medical management of cholelithiasis.[19] One study in which pediatric patients received 25 mg/kg/d of ursodeoxycholic acid for a median period of 13 months demonstrated resolution of clinical discomfort in 83.7% of patients. However, complete disappearance of gallstones was observed in only 7.2%, and the cholelithiasis recurred in 50% of these patients. All children did complete the therapy with no adverse effects.
Ursodeoxycholic acid has not been approved by the US Food and Drug Administration for use in pediatric patients. Nevertheless, it has a long history of use as adjunctive therapy in the management of adolescents with cystic fibrosis and in infants and children with hereditary cholestasis syndromes, biliary atresia, and cholestasis associated with parenteral nutrition.
The primary disadvantage with ursodeoxycholic acid therapy is the high incidence of gallstone recurrence. Therefore, this treatment is not recommended in patients with symptomatic cholelithiasis and is indicated only for patients either unfit or unwilling to undergo surgical intervention.
Laparoscopic cholecystectomy is currently the criterion standard in the treatment of symptomatic cholelithiasis. It has been proven to be safe and effective in children, with a low rate of postoperative complications.[2, 20, 21]
One multicenter study reported recurrence of symptoms after cholecystectomy (postcholecystectomy syndrome) in only 4.7% of patients.
Indications for laparoscopic cholecystectomy in cholelithiasis include symptoms of biliary colic or chronic abdominal pain or the presence of cholecystitis.
Removal of the gallbladder in asymptomatic children with cholelithiasis is not standard practice, with the exception of those with sickle cell anemia. Laparoscopic cholecystectomy has also been demonstrated to be safe and effective in patients with sickle cell disease.[13] In addition, because gallbladder sludge is frequently documented in patients with sickle cell anemia and most patients with sickle cell disease who have biliary sludge go on to develop gallstones, elective cholecystectomy has been recommended for those patients with evidence of biliary sludge, with or without stones.
Surgical complications of laparoscopic cholecystectomy include common bile duct injury and bile leaks, as well as complications of hemolytic disease in patients who are at risk. Postoperative complications such as biliary tract obstruction tend to be more common in patients with sickle cell disease.[22]
Laparoscopic cholecystectomy with intraoperative cholangiography has demonstrated promise as an alternative to endoscopic retrograde cholangiopancreatography (ERCP) in patients with obstructive common bile duct stones (choledocholithiasis).[23]
A decrease in the consumption of fatty foods and controlled weight reduction in patients with obesity may be effective in preventing the development of cholesterol stones.[7]
In prospective cohort studies, Leitzmann et al found that an increase in exercise reduced symptomatic gallstones in women and men by approximately 20%.[24, 25] This reduction may be extrapolated to the pediatric population.
Complications of concern include cholecystitis and ascending cholangitis.
With migration of gallstones from the gallbladder, through the cystic duct, and into the main biliary ductal system, more ominous complications may occur, including choledocholithiasis, biliary obstruction with or without cholangitis, gallstone ileus, biliary hepatitis, and biliary pancreatitis.
Postcholecystectomy syndrome involves the persistence or recurrence of symptoms experienced prior to surgery and may include new symptoms. The incidence of postcholecystectomy syndrome in children is not currently known.[6]
Spontaneous resolution without specific treatment is most commonly observed in asymptomatic cholelithiasis, however some medications may be beneficial.
Clinical Context:
Also called ursodeoxycholic acid, this drug is indicated for radiolucent, noncalcified gallbladder stones less than 20 mm in diameter, when conditions preclude cholecystectomy. Ursodiol suppresses hepatic cholesterol synthesis and secretion and also inhibits intestinal absorption. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids and does not appear to affect secretion of phospholipids into bile. After repeated doses, ursodiol reaches steady-state bile concentrations in about 3 weeks.
Cholesterol is insoluble in aqueous media but can be solubilized in at least 2 different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by dispersing cholesterol as liquid crystals in aqueous media. The overall effect of ursodiol is to increase the concentration level at which the saturation of cholesterol occurs. The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing bile, thus resulting in bile conducive to the dissolution of cholesterol stones.
Ursodiol is used in combination with chenodeoxycholic acid and in conjunction with extracorporeal shock-wave lithotripsy for the dissolution of gallstones. It is also indicated for gallstone prevention. Ursodiol is not FDA-approved for children, but data are emerging.
Ursodiol is available in 250-mg and 500-mg tabs and in 300-mg caps. It is also available as an orphan drug (Ursofalk) in 60 mg/mL suspension. An extemporaneous liquid formulation may be compounded for pediatric use.
Melissa Kennedy, MD, Attending Physician, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia
Disclosure: Nothing to disclose.
Coauthor(s)
Joshua R Friedman, MD, PhD, Director and Head of Disease Biology, Janssen Research and Development
Disclosure: Received salary from Johnson & Johnson for employment.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
B UK Li, MD, Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin; Attending Gastroenterologist, Director, Cyclic Vomiting Program, Children’s Hospital of Wisconsin
Disclosure: Nothing to disclose.
Chief Editor
Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.
Additional Contributors
Jorge H Vargas, MD, Professor of Pediatrics and Clinical Professor of Pediatric Gastroenterology, University of California, Los Angeles, David Geffen School of Medicine; Consulting Physician, Department of Pediatrics, University of California at Los Angeles Health System
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Alexandre F Migala, DO, Hildegardo Costa, MD, and Richard D Warren, MD, to the development and writing of the source article.
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