Gallbladder disease in children can arise from a number of underlying conditions, but the disease is due to cholelithiasis in most cases. Cholelithiasis is usually classified as being either hemolytic or nonhemolytic in etiology. Hemolytic disease results in consumption of red blood cells leading to increased hepatic metabolism of bilirubin, which precipitates as stone formation. Nonhemolytic disease includes a variety of causes for stone development or symptomatic gallbladder disease without stones.
The major chemical components of bile that contribute to its lithogenic potential are bile salts, phospholipids, cholesterol, bilirubin, and electrolyte–water balance. The phospholipid component is mostly lethicin, which, along with bile salts, serve as detergents in the bile. With polar and nonpolar portions to these molecules, they form lecithin–bile acid– cholesterol micelles that keep the cholesterol soluble within the hydrophobic center of the micelle. An imbalance in the concentration of these substances is almost always due to an increase in cholesterol secretion, which results in cholesterol crystal precipitation. These crystals serve as the nidus for further precipitation, resulting in macroscopically detectable gallstones. The addition of physiologic components such as poor gallbladder emptying, inflammation, and bacterial colonization can further precipitate stone formation. This pathway accounts for the majority of adult gallstones, but is less common in children. In addition, cholesterol gallstones are extremely rare in prepubertal children. As in adults, obesity is a common risk factor for cholesterol stone formation in children. Obese children have been found to have an overall 2% incidence of gallstones. Finally, the composition of gallstones in children may be different than that found in adults. Whereas stones in adults are primarily cholesterol in composition, calcium carbonate and black pigment stones are often found in pediatric patients, especially those younger than 10 years of age.
Red blood cells are composed of a plasma membrane, the hemoglobin moiety, and a few cytoplasmic enzymes. These 3 basic components provide a functional outline for the major hereditary hemolytic diseases (Table 55-1). Their constant turnover by the reticuloendothelial system leads to the breakdown of hemoglobin to bilirubin. A nearly insoluble molecule, bilirubin requires conjugation by glucuronyl transferase to produce bilirubin diglucuronide, the molecule measured as “direct” bilirubin, which is more soluble. Because the enzymatic process of conjugation is saturable, the hemolytic states may cause an abnormal level of unconjugated (indirect) bilirubin in the bile. This results in the formation of calcium bilirubinate, which polymerizes with bilirubin to form black gallstones. Currently, research suggests that excessive unconjugated hyperbilirubinemia alone is not sufficient to produce pigment gallstones, but it is hypothesized that stasis as a result of incomplete emptying leads to sludge and later to gallstone formation. Because gallbladder sludge is frequently documented in patients with sickle-cell anemia, elective cholecystectomy has been recommended when evidence suggests the presence of sludge, with or without stones. In one study of 35 patients with sickle-cell disease (SCD) and biliary sludge, 23 (65.7%) went on to develop gallstones.
The Major Hereditary Hemolytic Diseases
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Table 55-1 The Major Hereditary Hemolytic Diseases
|Membrane Defects ||Hemoglobin Defects ||Enzyme Defects |
|Spherocytosis ||Sickle-cell disease ||Glucose-6-phosphate deficiency |
|Eliptocytosis ||α Thallasemia ||Pyruvate kinase deficiency |
|Pyropoikilocytosis ||β Thallasemia || |
|Hydrocytosis || || |
|Xerocytosis || || |
Hereditary Hemolytic Diseases
Hemolytic cholelithiasis secondary to SCD remains the most common cause of gallstones in children at many institutions. Fifty percent of patients with sickle-cell anemia develop gallstones by 20 years of age. These patients also represent the largest group of patients who develop postoperative complications after cholecystectomy. The total postoperative complication rate reported in the national SCD study group was 39% with sickle events representing 19% of complications; intraoperative or recovery room problems, 11%; transfusion complications, 10%; postoperative surgical events, 4%; and death, 1%. The open operation was performed in 58% of the patients and the laparoscopic route was used in 42%. The complication rates were similar between the 2 groups. The same study also reported that the incidence of sickle cell events may be higher in patients who were not preoperatively transfused. Meticulous attention and close coordinated efforts with hematologists regarding the perioperative management, transfusion guidelines, and pulmonary care may reduce the incidence of sickle-cell-related complications. Currently, it is now recommended that the laparoscopic approach be utilized for this patient population. Of note, the acute chest syndrome can be seen in up to 20% of sickle-cell patients undergoing abdominal surgery. One study has suggested that the laparoscopic approach does not decrease the incidence of this complication.
Two other hemolytic conditions associated with gallstones are hereditary spherocytosis and thalassemia. The incidence of cholelithiasis in patients with hereditary spherocytosis ranges from 43% to 63% and is slightly more common in girls than in boys. US is recommended before elective splenectomy to determine whether concomitant cholecystectomy should be performed at the time of the splenectomy. The incidence of cholelithiasis in thalassemia has markedly decreased due to more aggressive transfusion management, which prevents the production and release of native red cells containing defective hemoglobin.
In patients without hereditary hemolytic disease, changes to the enterohepatic circulation, whether directly or indirectly, are believed to contribute to stone formation. The most common cause of nonhemolytic cholelithiasis in neonates and infants is the use of total parenteral nutrition (TPN). While many patients requiring long-term TPN have gastrointestinal disease, the complete picture of TPN-associated cholestasis, liver disease, and gallstone formation is not completely understood. Decreased bile flow and gallbladder emptying from a lack of enteral stimulation has been postulated to be an important contribution to TPN-associated gallstones. However, in one study, the use of cholecystikinin (CCK) to prevent stone development in TPN-dependent children had no effect, implying that the role of CCK-mediated bile flow may be less important than previously thought in gallstone formation in these patients. Others postulate that the amino acid infusion from TPN alters bile composition. The administration of fat is believed to ameliorate the deleterious effects of the amino acids in the TPN. TPN has a primary lithogenic effect on bile causing increased bilirubin and calcium concentration. These effects have been shown to be prevented with glutamine supplementation, suggesting there are intermediary steps that still need to be clarified.
A large population of infants and neonates require TPN, but it has been noted that only 43% of children receiving long-term TPN will eventually develop cholelithiasis. This suggests that there are other factors necessary for the development of cholelithiasis in this patient population. Septicemia, dehydration, chronic furosemide therapy, cystic fibrosis, short-bowel syndrome, and ileal resection for necrotizing enterocolitis also are known contributing factors. Cystic fibrosis, the phenotype for defective epithelial chloride channels, results in decreased transport of water and chloride, which increases the viscosity of the bile and contributes to stone formation. Cystic fibrosis can also lead to obstruction of the biliary ductules resulting in liver failure. Similarly, patients with bowel dysmotility or dysfunction may have altered bacterial flora, which also affects the enterohepatic circulation. Neonates and premature infants are susceptible to the cholestatic effects of TPN because of the immaturity of their enterohepatic circulation of bile salts.
Possible causes of gallstones in older children include the use of oral contraceptives, cystic fibrosis, pregnancy, obesity, and ileal resection. Cholelithiasis has also been reported in children undergoing cardiac transplantation who are receiving cyclosporine and in patients who have previously required extracorporeal membrane oxygenation as a newborn.
The gallbladder can be a source of symptoms in patients without gallstones. Hydrops of the gallbladder, acalculous cholecystitis, biliary dyskinesia, and gallbladder polyps are being seen more frequently.
Acute inflammatory attacks of the gallbladder, called acute acalculous cholecystitis, occur more commonly in association with severe illness such as sepsis, burns, or trauma. This is much less common in children than in adults, but can be seen in critically ill children. In this setting, TPN is often used and, if prolonged, may result in decreased gallbladder contractility with progressive distention, stasis, and possible infection. In a small report of 12 patients, daily US criteria was used to assess the need for cholecystectomy. In the 3 patients who eventually underwent cholecystectomy, progressively increasing gallbladder wall thickness and distention along with pericholecystic fluid were found. In the other patients, the daily US examinations showed progressive improvement. These patients all recovered uneventfully.
Hydrops is characterized by massive distention of the gallbladder in the absence of stones, infection, or congenital anomalies. It has been most frequently reported in association with the Kawasaki disease and is usually due to a transient obstruction of the cystic duct or to increased mucus secretion by the gallbladder resulting in poor emptying. With additional gallbladder distention, further angulation of the cystic duct may increase the obstruction. Conservative treatment consisting of appropriate antibiotics and early initiation of enteral feedings to stimulate gallbladder emptying often leads to resolution of this condition. If serial US examinations show progressive gallbladder distention with increasing pain, or if the gallbladder appears gangrenous, cholecystectomy is recommended.
Biliary dyskinesia is becoming a common diagnosis in children. In some centers, it has become the most common reason for cholecystectomy. While the etiology of the symptoms is felt to be gallbladder distension secondary to poor emptying, bile stasis can also promote sludge, microscopic bile crystallization, and subsequent mucosal irritation. Chronic cholecystitis is often documented on histologic examination of the gallbladder specimen.
Gallbladder contractility and emptying can be assessed with radionuclide scanning during CCK injection. Most surgeons utilize a gallbladder ejection fraction of less than 35% as an indicator for cholecystectomy in a symptomatic patient. Laparoscopic cholecystectomy has been shown to be an effective treatment for this disorder, with expected resolution of symptoms in over 80%. One study examining predictors of successful outcomes after cholecystectomy for biliary dyskinesia found gallbladder ejection fractions of less than 15% most reliably predicted which children would have postoperative symptom relief following cholecystectomy. In that study, children with an ejection fraction greater than 15% did not have predictable resolution of symptoms. Biologic credibility for cholecystectomy in patients with stone disease and dyskinesia has been supported by a recent report from our institution, which found that children with biliary dyskinesia have a marked increased number of mucosal mast cells in the gallbladder mucosa. In a follow-up study, a moderate to high degree of mast cell activation was also found in children with both biliary dyskinesia and gallstones.
Gallbladder polyps are also being seen more frequently in children. Due to the inability to assure life-long follow-up combined with the extremely poor prognosis when gallbladder cancer develops, laparoscopic cholecystectomy is a reasonable option for symptomatic children with gallbladder polyps or for patients with a polyp >1 cm.