Diseases of the Gallbladder

Table 366-1 lists the conditions associated with hydrops of the gallbladder.

Acute noncalculous, noninflammatory distention of the gallbladder can occur in infants and children. It is defined by the absence of calculi, bacterial infection, or congenital anomalies of the biliary system. The disorder may complicate acute infections and Kawasaki disease, but the cause is often not identified. Hydrops of the gallbladder may also develop in patients receiving long-term parenteral nutrition, presumably as a result of gallbladder stasis during the period of enteral fasting. Hydrops is distinguished from acalculous cholecystitis by the absence of a significant inflammatory process and a generally benign prognosis.

Affected patients usually have right upper quadrant pain with a palpable mass. Fever, vomiting, and jaundice may be present and are usually associated with a systemic illness such as streptococcal infection. Ultrasonography shows a markedly distended, echo-free gallbladder, without dilation of the biliary tree. Acute hydrops is usually treated conservatively with a focus on supportive care and managing the intercurrent illness; cholecystostomy and drainage are rarely needed. Spontaneous resolution and return of normal gallbladder function usually occur over a period of several wk. If a laparotomy is required, a large, edematous gallbladder is found to contain white, yellow, or green bile. Obstruction of the cystic duct by mesenteric adenopathy is occasionally observed. Cholecystectomy is required if the gallbladder is gangrenous. Pathologic examination of the gallbladder wall shows edema and mild inflammation. Cultures of bile are usually sterile.

Cholecystitis and Cholelithiasis

Acute acalculous cholecystitis is uncommon in children and is usually caused by infection. Pathogens include streptococci (groups A and B), Gram-negative organisms, particularly Salmonella and Leptospira interrogans. Parasitic infestation with Ascaris or Giardia lamblia may be found. Calculous cholecystitis may rarely follow abdominal trauma or burn injury or is associated with a systemic vasculitis, such as periarteritis nodosa.

Clinical features include right upper quadrant or epigastric pain, nausea, vomiting, fever, and jaundice. Right upper quadrant guarding and tenderness are present. Ultrasonography discloses an enlarged, thick-walled gallbladder, without calculi. Serum alkaline phosphatase activity and direct-reacting bilirubin levels are elevated. Leukocytosis is usual.

Patients may recover with treatment of systemic and biliary infection. Because the gallbladder can become gangrenous, daily ultrasonography is useful in monitoring gallbladder distention and wall thickness. Cholecystectomy is required in patients who fail to improve with conservative management. Cholecystostomy drainage is an alternative approach in a critically ill patient.

Cholelithiasis is relatively rare in otherwise healthy children, occurring more commonly in patients with various predisposing disorders (Table 366-2). In an ultrasonographic survey of 1570 children (ages 6-19 yr) the overall prevalence of gallstone disease was 0.13% (0.27% in female subjects). In children, >70% of gallstones are the pigment type, 15-20% are cholesterol stones, and the remainder are composed of a mixture of cholesterol, organic matrix, and calcium bilirubinate. Black pigment gallstones, composed mostly of calcium bilirubinate and glycoprotein matrix, are a frequent complication of chronic hemolytic anemias. Brown pigment stones form mostly in infants as a result of biliary tract infection. Unconjugated bilirubin is the predominant component, formed by the high β-glucuronidase activity of infected bile. Cholesterol gallstones are composed purely of cholesterol or contain >50% cholesterol along with a mucin glycoprotein matrix and calcium bilirubinate. Calcium carbonate stones have also been described in children.

Patients with hemolytic disease (including sickle cell anemia, the thalassemias, and red blood cell enzymopathies) and Wilson disease are at increased risk for black pigment cholelithiasis. In sickle cell disease, pigment gallstones can develop before age 4 yr and have been reported in 17-33% of patients 2-18 yr of age. Genetic variation in the promoter of uridine diphosphate-glucuronosyltransferase 1A1 (the [TA]7/[TA]7 and [TA]7/[TA]8 genotypes) underlies Gilbert syndrome, a relatively common, chronic form of unconjugated hyperbilirubinemia, and is a risk factor for pigment gallstone formation in sickle cell disease.

Cirrhosis and chronic cholestasis also increase the risk for pigment gallstones. Sick premature infants may also have gallstones; their treatment is often complicated by such factors as bowel resection, necrotizing enterocolitis, prolonged parenteral nutrition without enteral feeding, cholestasis, frequent blood transfusions, and use of diuretics. Cholelithiasis in premature infants is often asymptomatic and may resolve spontaneously. Brown pigment stones are found in infants with obstructive jaundice and infected intra- and extrahepatic bile ducts. These stones are usually radiolucent, owing to a lower content of calcium phosphate and carbonate and a higher amount of cholesterol than in black pigment stones. MDR3 deficiency caused by ABCB4 mutations) is a cholestatic syndrome related to impaired biliary phospholipid excretion. It is associated with symptomatic and recurring cholelithiasis. Patients may show intrahepatic lithiasis, sludge, or microlithiasis along the biliary tree.

Obesity has assumed an increasingly important role as a risk factor for cholesterol cholelithiasis in children, particularly in adolescent girls. Cholesterol gallstones are also found in children with disturbances of the enterohepatic circulation of bile acids, including patients with ileal disease and bile acid malabsorption, such as those with ileal resection, ileal Crohn disease, and cystic fibrosis. Pigment stones can also occur in these patients.

Cholesterol gallstone formation seems to result from an excess of cholesterol in relation to the cholesterol-carrying capacity of micelles in bile. Supersaturation of bile with cholesterol, leading to crystal and stone formation, could result from decreased bile acid or from an increased cholesterol concentration in bile. Other initiating factors that may be important in stone formation include gallbladder stasis or the presence in bile of abnormal mucoproteins or bile pigments that may serve as a nidus for cholesterol crystallization.

Prolonged use of high-dose ceftriaxone, a third-generation cephalosporin, has been associated with the formation of calcium-ceftriaxone salt precipitates (biliary pseudolithiasis) in the gallbladder. Biliary sludge or cholelithiasis can be detected in >40% of children who are treated with ceftriaxone for at least 10 days. In rare cases, children become jaundiced and develop abdominal pain; precipitates usually resolve spontaneously within several months after discontinuation of the drug.

Acute or chronic cholecystitis is often associated with gallstones. The acute form may be precipitated by impaction of a stone in the cystic duct. Proliferation of bacteria within the obstructed gallbladder lumen can contribute to the process and lead to biliary sepsis. Chronic calculous cholecystitis is more common. It can develop insidiously or follow several attacks of acute cholecystitis. The gallbladder epithelium commonly becomes ulcerated and scarred.

More than 50% of patients with gallstones have symptoms, and 18% present with a complication as the first indication of cholelithiasis, such as pancreatitis, choledocholithiasis or acute calculous cholecystitis. The most important clinical feature of cholelithiasis is recurrent abdominal pain, which is often colicky and localized to the right upper quadrant. An older child may have intolerance for fatty foods. Acute cholecystitis is characterized by fever, pain in the right upper quadrant, and often a palpable mass. Jaundice occurs more commonly in children than adults. Pain may radiate to an area just below the right scapula. A plain x-ray of the abdomen may reveal opaque calculi, but radiolucent (cholesterol) stones are not visualized. Accordingly, ultrasonography is the method of choice for gallstone detection. Hepatobiliary scintography is a valuable adjunct in that failure to visualize the gallbladder provides evidence of cholecystitis.

Cholecystectomy is curative. Laparoscopic cholecystectomy is routinely performed in symptomatic infants and children with cholelithiasis. Common bile duct stones are unusual in children, occurring in 2-6% of cases with cholelithiasis, often in association with obstructive jaundice and pancreatitis. Operative cholangiography should be done at the time of surgery, however, to detect unsuspected common duct calculi. Endoscopic retrograde cholangiography with extraction of common duct stones is an option before laparoscopic cholecystectomy in older children and adolescents.

Asymptomatic patients with cholelithiasis pose a more difficult management problem. Studies in adults indicate a lag time of more than a decade between initial formation of a gallstone and development of symptoms. Spontaneous resolution of cholelithiasis has been reported in infants and children. If surgery is deferred for any patient, however, parents should be counseled about signs and symptoms consistent with cholecystitis or obstruction of the common bile duct by a gallstone. In patients with chronic hemolysis or ileal disease, cholecystectomy can be carried out at the same time as another surgical procedure. Because laparoscopic surgery can safely be performed in children with sickle cell disease, elective cholecystectomy is being done more frequently at the time of gallstone diagnosis, before symptoms or complications develop. In cases associated with liver disease, severe obesity, or cystic fibrosis, the surgical risk of cholecystectomy may be substantial so that the risks and benefits of the operation need to be carefully considered.

Biliary Dyskinesia

Biliary dyskinesia is a motility disorder of the biliary tract that may cause acalculous biliary colic in children, often in association with nausea and fatty food intolerance. There are usually no gallstones on imaging. Sphincter of Oddi dysfunction may be a variant that can present with chronic abdominal pain and recurrent pancreatitis. The diagnosis is based on a cholecystokinin–diisopropyl iminodiacetic acid scan demonstrating a gallbladder ejection fraction of less than 35%. Reproduction of pain on cholecystokinin administration may also be seen, as well as the absence of gallbladder filling on an otherwise normal ultrasound examination. In several recent reports, laparoscopic cholecystectomy was effective in providing both short-term and long-term improvement of symptoms in most children with biliary dyskinesia.