Epidemiology of Gallstone Disease

More than 20 million adults in the United States have gallstones, and approximately 300,000 cholecystectomies are performed annually, with an estimated 1.8 million ambulatory visits. Recent data suggest that gallstone disease in adults is associated with increased mortality from cardiovascular disease and cancer in adults. Predominantly a disease of adulthood, gallstone disease ranges in prevalence from 4% to 11% in developed countries, with wide variations along racial and ethnic lines. The incidence in adults is approximately 1% to 3%. The incidence and prevalence of gallstone disease is influenced by age, sex, culture, ethnicity, and a variety of medical factors, and it varies geographically. For instance, members of the Masai tribe of East Africa, whose bile is only half saturated with cholesterol, do not develop gallstones, whereas the Pima Indians of Arizona have an 80% prevalence. Furthermore, epidemiologic studies suggest that there is a strong heritable effect in gallstone formation. Puppala et al. demonstrated a genome-wide link on chromosome 1p in a Mexican American cohort with gallstones.

Investigations using a mouse model suggest that the Lith family of genes, such as Lith1 and Lith2 , may determine susceptibility to cholesterol gallstone formation. Apobec-1, an RNA-specific enzyme of apoprotein B (apoB), is linked to Lith6 , and when down-regulated, there is decreased expression of 7-α-hydroxylase and increase in gallstones. The nuclear receptor FXR, encoded by NR1H4, has been linked to Lith7 as a genetic factor in gallstone development. MDR3/ABCB4 is the physiologic translocator of phospholipids across the canalicular membrane of the hepatocyte, and ABCB11is responsible for bile salt export. Mutations of the gene ABCB4 have been described in adults with cholesterol gallstones and less often in young adults. Patients with mutations in ABCB11 are also at risk for gallstone development. Recent murine data suggest that overexpression of ABCB11 enhances biliary excretion, but does not affect lithogenesis in bile. Other genes with strong associations to gallstone formation include ABCG5, ABCG8, CYP7A1, and CCK1R . Alterations in protein kinase Cbeta, lack of adiponectin, and deletion of SIRT1, have all been shown in mice to induce gallstone formation. Overexpression of sterol carrier protein 2 (SCP2) and elevated levels of retinol-binding protein 4 (RBP4) have recently been shown in patients with cholesterol gallstones. Polymorphisms in hepatic uridine diphosphate (UDP)–glucuronosyltransferase (UGT1A1) have also been described in patients with hemolytic disease that predispose to increased gallstone formation rates.

The earliest reported case of cholelithiasis in a child was by Gibson in 1737. Attempts to estimate the frequency of childhood gallstones included an extensive review of 5037 cases in 1959, in which a prevalence of 0.15% in children younger than 16 years of age was noted. The prevalence of gallbladder disease in children since the 1960s appears to be increasing. For example, in a review in 1984, of 708 infants referred for cholestasis between 1970 and 1981, an incidence of 1.4% was found, whereas a review in 2000 of 4200 children who underwent abdominal ultrasound between 1988 and 1998 estimated a prevalence of gallstones at 1.9%. Other reports have noted that 4% of all cholecystectomies are performed in patients younger than 20 years of age. In a review of 693 cases of childhood gallstones reported since 1968, early infancy, and adolescence were the most common ages for diagnosis. Infants younger than 6 months of age represented 10% of all cases in which the age was known. Children from 6 months to 10 years of age accounted for 21%, and adolescents (mostly female) 11 to 21 years of age represented 69% of all cases. Most gallstones in children have an underlying predisposing condition, such as hemolytic disease, pregnancy, and TPN. Gallstones in infancy are typically found in those with short bowel syndrome; TPN, diuretic, and cephalosporin use; and after cardiac surgery. Stones found in children from the ages of 1 to 5 years are usually secondary to hemolysis, and stones found in adolescents are most likely associated with obesity, menarche, pregnancy, and the use of oral contraceptives. In one of the largest series to date, obesity and Hispanic ethnicity were strongly correlated with symptomatic gallbladder disease in a group of more than 400 children at Texas Children’s Hospital in Houston. Obesity was also identified as a major risk factor in a study by Walker et al. in a 9-year study period in Louisville, Kentucky. However, there appears to be regional variation, given that at the Hospital for Sick Children in Toronto, morbid gallbladder disease requiring cholecystectomy was more common in those with sickle cell disease and other hemolytic or oncologic disease. In the current era, cholecystectomy is being performed at increasing frequency for indications of biliary dyskinesia and nonhemolytic stones, rather than for hemolytic disease. Morbid obesity linked with gallbladder disease increased from 6% to 15% in one series, and an adjusted odds ratio of 3.1 in an electronic medical record of 766 patients with gallstones.

Pathophysiology of Gallstone Disease

Bile is composed of five major components: water, bilirubin, cholesterol, bile pigments, and phospholipids. The primary phospholipid is lecithin. Calcium salts and some proteins are minor components of bile. Stone formation occurs, owing to the precipitation of the insoluble constituents of bile, which are cholesterol, bile pigments, and calcium salts. Gallstones are classically divided into cholesterol stones or pigment stones ( Table 79-1 ). Chemically pure gallstones are rare, and in any single stone, the composition varies from the core to the crust. Most stones are “mixed” in composition, and the formation patterns of both cholesterol and pigment stones share many characteristics.

Cholesterol, the major sterol in bile, is nearly insoluble in water. It is made soluble in aqueous bile by aggregation with bile salts or lecithin. When cholesterol is no longer soluble, cholesterol monohydrate crystals precipitate from solution, a process known as nucleation .

The interplay among the major bile components cholesterol, lecithin, and bile salts is depicted in Figure 79-1 . When the composition of bile lies in the micellar zone, the bile can solubilize additional cholesterol. As the cholesterol concentration continues to increase, the likelihood of cholesterol crystallization and, hence, gallstone formation, increases. A decrease in bile salt concentration or lecithin also predisposes to gallstones.

(A) Triangular phase diagram showing phases present at equilibrium in biles of different compositions. In the micellar zone (the area in the lower left of the triangle), all the cholesterol is held in solution as micelles. Biles with a composition outside the micellar zone, if allowed to come to equilibrium, would form liquid and/or solid cholesterol crystals (as depicted schematically in each of the zones). The micellar zone is larger for gallbladder bile (a 10% lipid solution shown here) than for hepatic bile (a 3% lipid solution not shown). (B) Triangular phase diagram with schematic representations of ranges of lipid compositions found in gallbladder biles of normals and gallstone patients. Bile with a composition that falls in the metastable zone takes a prolonged period to come to equilibrium and thus appears to be stable. Excess cholesterol is “carried” in the metastable zone by cholesterol-rich unilamellar vesicles. The boundaries of the physiologically relevant metastable zone are approximate.

(From Carey MC, Cohen DE. Biliary transport of cholesterol in micelles and liquid crystals. In: Paumgartner G, Stiehl A, Gerak W, editors. Bile Acids and the Liver . Lancaster: MTP Press; 1987. p. 287–300, with permission. )

The pathophysiology of gallstone formation is multifactorial. Three primary conditions must be met to permit the formation of cholesterol gallstones. First, the bile must be supersaturated with cholesterol, which then acts as the driving force behind crystal precipitation. ABCG5 and ABCG8 are important regulators in this pathway, and overexpression of these transporters promotes biliary sterol secretion and decreases absorption of dietary cholesterol. Single nucleotide polymorphisms in ABCG8 have been shown to have strong association with gallstone disease. Biliary cancer was also identified at an increased rate in patients with ABCG8 mutations in D19H .

Second, bile kinetics must be such as to allow nucleation, the transition to solid cholesterol crystals. Finally, gallbladder stasis must exist to allow agglomeration of cholesterol crystals into stones. Genetic factors as well as gallbladder hypersecretion of mucus and excess arachidonyl lecithin appear to be critical in lithogenesis ( Figure 79-2 ).

Current understanding of cholesterol gallstone formation. Cholesterol supersaturation is an essential prerequisite, which combined with a more rapid nucleation time and gallbladder stasis allows crystal formation. Excess biliary mucus provides a structural nidus for crystal growth, driven by increased dietary arachidonyl lecithins.

(Adapted from Hay DW, Carey MC. Pathophysiology and pathogenesis of cholesterol gallstone formation. Semin Liver Dis 1990; 10 :159–170, with permission. )

Cholesterol supersaturation can result from the following conditions:

• 1.
  

  An increased delivery of cholesterol to the liver via increased lipoprotein (low-density lipoprotein [LDL] and chylomicrons). Very low-density lipoprotein (VLDL) production and trafficking of bile acids are increased in gallstone patients and may be caused by increased activity of hepatic microsomal triglyceride transfer protein (MTTP). This can occur in women secondary to estrogen or oral contraceptive use or with increased dietary cholesterol intake.

  
  
• 2.
  

  An increased endogenous cholesterol synthesis secondary to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. Both obesity and hypertriglyceridemia are causes of increased HMG-CoA reductase activity.

  
  
• 3.
  

  A decrease in 7-α-hydroxylase activity, which decreases the conversion of cholesterol to bile acids. This defect occurs most commonly with increasing age.

  
  
• 4.
  

  A decrease in the conversion of cholesterol to cholesterol esters from inhibited acyl-CoA cholesterol acyltransferase activity (ACAT). Progesterone, either pregnancy induced or exogenous, and clofibrate are examples of ACAT inhibitors.

The potential defects leading to cholesterol supersaturation are thus numerous and overlapping.

Figure 79-2 summarizes the current understanding of the formation of cholesterol gallstones and, perhaps, of any gallstone. The process must have a supersaturated solution (either cholesterol or bilirubin pigment); a “still” environment, or gallbladder stasis; and crystal agglomeration or nucleation. The initial nucleating event creates the core of the stone, from which a self-perpetuating process ensues. Nucleation is not as well understood as cholesterol supersaturation. Nucleation times are strikingly different between gallstone patients and control subjects. Gallbladder hypomotility seems to be involved in the crystallization process, because agitation prevents aggregation. Animal studies support hypomotility as an important causative factor. Technetium-99m-dimethyl iminodiacetic acid–gallbladder-emptying studies in adult gallstone patients have documented diminished gallbladder emptying after meals.

Biliary sludge, or tumefacient sludge, a collection of mucus, calcium bilirubinate, and cholesterol crystals, appears to precede the formation of gallstones in animal models. However, some clinical studies in children do not support sludge as being a precursor of gallstones. Mucin hypersecretion appears to be a primary event in sludge formation, and evidence suggests that prostanoids, such as arachidonyl lecithin, mediate the hypersecretion. Mucin may serve as the nidus for nucleation and subsequent sludge formation owing to its hydrophobic domain, which binds phospholipid and cholesterol. Recent analysis of the microbiota in a mouse model implicates a role in cholesterol gallstone formation and may be related to changes in mucin.

Cholesterol Stones

Cholesterol gallstones are yellowish-white in appearance, hard, crystalline, and layered. They frequently have a brownish core, with a variety of substances found there, including calcium salts. “Rings” of protein (glycoproteins) and calcium salts (calcium bilirubinate, calcium hydroxyapatite, and calcium carbonate) form around the core, resulting in the layered appearance. The cholesterol content is higher than 50%, with minimal calcium salt content. This composition is not radiopaque; thus, the stones are rarely seen on plain film radiographs. Cholesterol stones form within the gallbladder and are frequently multiple, ranging in size from approximately 2 to 25 mm in diameter. The presence of cholesterol stones in the biliary tree is the result of migration. Cholesterol gallstones account for approximately 70% of all stones found in developed countries.

There clearly are genetic influences, with high prevalence rates seen in both children and adult Native Americans. Studies of the Pimas of Arizona have demonstrated the development of lithogenic bile-containing excess cholesterol during adolescence. The prevalence of cholesterol gallstones in children is unknown, but increases slowly with age in both sexes. Pubertal changes, in particular early menarche, cause a dramatic increase in the incidence of cholesterol gallstones. This phenomenon has been attributed to the effect of estrogen and progesterone surges that occur during puberty; it has also been seen in pregnancy and with the use of oral contraceptives, although investigation suggests no relationship between oral contraceptives and gallstones. Sex hormones appear to induce biliary stasis and cause cholesterol hypersecretion by the liver. It remains unclear whether estrogen, the progestins, or a combination of both, are responsible. Data from a high-risk Chilean population also suggest that insulin resistance plays a major role in gallstone formation. Insulin resistance has also been shown to be a risk factor for gallstones and sludge during pregnancy, independent of BMI.

The metabolic syndrome, a constellation of disorders linked to obesity and insulin dysregulation, now includes cholesterol gallstone disease. In a mouse model, hepatic insulin resistance was found to directly promote cholesterol formation, when a liver-specific insulin receptor (Fox01) was downregulated. In addition, high dietary carbohydrates have also been linked to diminished gallbladder volume and increased cholesterol crystal formation. Obesity has also been shown to increase the likelihood of cholesterol gallstone formation, likely from excessive hepatic cholesterol secretion secondary to increased cholesterol synthesis.

Pigment Stones

Pigment stones account for a much higher percentage of stones in prepubertal children, whereas cholesterol stones are predominant in adolescence and adulthood. Two types of pigment gallstones are found in children and are referred to as black and brown . In both black and brown stones, the pigment present is calcium bilirubinate, which interacts with mucin glycoproteins to form stones (see Table 79-1 ).

Black pigment stones are black to dark brown in color and small (usually less than 5 mm), occur multiply, and are typically hard, shiny, and crystalline. They are composed primarily of highly crosslinked polymers of bilirubin with mucin glycoproteins and calcium salts of phosphate and carbonate. The high concentration of calcium salts (as compared with brown and cholesterol stones) accounts for the 50% to 75% radiopacity seen on plain radiographs. Black stones typically form within the gallbladder and do not recur after resection. They are usually associated with hemolytic diseases, of which sickle cell disease and hereditary spherocytosis are the most common. The duration of the hemolytic disease appears to be a significant risk factor for stone formation. Children younger than 10 years of age with sickle cell disease have a 14% prevalence of stones, whereas children 11 to 20 years of age have a 36% prevalence. Older adults with sickle cell disease have more than a 50% prevalence. In a study from Houston, Texas, the median age of detecting gallstones in 458 patients with sickle cell disease was 10.5 years. Other disease states, such as thalassemia, Wilson’s disease, and mechanical shearing of erythrocytes associated with artificial heart valves, have been associated with black pigment stones. Black pigment stones form within the gallbladder, and their presence in the common bile duct is the result of migration. Black stones are found in sterile bile and are not associated with infection.

The formation of black stones results from altered gallbladder bile homeostasis and supersaturation of the bile. This process could occur by at least three mechanisms: an increase in bilirubin anions, an increase in unbound Ca ²⁺ , and a decrease in factors that solubilize bilirubin and calcium. An increase in bilirubin anions has been shown to occur secondary to hemolysis. Increased unbound calcium could occur secondary to increased plasma ionized calcium or to a decrease in calcium-binding agents, such as micellar bile salts and lecithin-cholesterol vesicles. The decrease in the bile salt pool secondary to an interruption of the enterohepatic circulation as seen in ileal resection or the nil per os (NPO) status accompanying TPN could result in this phenomenon.

Brown pigment stones are brown to orange in color, soft, soaplike or greasy in texture, and commonly assume the shape of their origin, the common bile duct. The stone color is derived from calcium bilirubinate, and the greasy texture results from a significant component of fat (calcium palmitate or stearate derived from lecithin). The scarcity of calcium carbonate and phosphate accounts for their lack of opacity on radiography. The cholesterol content ranges from 2% to 28%, which is higher than in black stones and allows in part for their increased solubility. The most distinct clinical feature of brown gallstones in both adults and children is the association with infection. These stones are a major public health problem in rural areas of Asian countries, where they are found secondary to parasitic infestation with such organisms as Opisthorchis sinensis and Ascaris lumbricoides . They are an uncommon type of stone in Western society and are typically found in the common bile duct after cholecystectomy when the bile is infected. Urinary tract infections may predispose to stone formation in early childhood. In some 85% of cases, the bile grows Escherichia coli . In children, especially infants, these stones can be seen in association with other organisms such as Staphylococcus , Enterobacter , Citrobacter , and Salmonella enterica serotype Virchow. Infection with stasis results in excessive secretion of mucin, which may serve as the glycoprotein nidus for stone formation. Bacteria also release beta-glucuronidase, phospholipase A1, and conjugated bile salt hydrolase, which hydrolyze bilirubin glucuronides, lecithin, and conjugated bile salts, producing unconjugated bilirubin, free saturated fatty acids, lysolecithin, and free bile acids. With the exception of lysolecithin, these products precipitate with calcium to form stones. Duodenal diverticula and biliary tree abnormalities, such as stenosis, also may predispose to brown stone formation.

Gallstones in Infants

Infants younger than 12 months of age may be predisposed to gallstone formation, as compared with older children ( Table 79-2 ). For example, the bile of infants is more dilute than that of older children, with a lower bile salt concentration, a shorter nucleation time, and a higher cholesterol saturation index. These factors may help explain the increased tendency of infants to produce sludge and gallstones. Table 79-2 demonstrates the likelihood (nearly one-half of reported cases) for spontaneous resolution of gallstones during infancy. Such information deserves special consideration concerning therapeutic intervention in infants and suggests that, unless symptomatic, gallstones during infancy do not require surgical intervention and often resolve without treatment.

Total Parenteral Nutrition—Associated Stones

The association between TPN and cholelithiasis is clearly established. Gallstone formation in premature infants and neonates receiving TPN appears to have four stages: decreased hepatobiliary flow due to immaturity, stasis within the biliary tree, sludge formation, and finally, stone formation. Cholestasis, which increases with decreasing gestational age, is found in at least 50% of infants with a birth weight less than 1000 g. After 2 months on TPN, 80% of infants have cholestasis. This predisposition to cholestasis in infancy is multifactorial. Bile acid transport, bile secretion, and basal and stimulated bile salt flow rates all are immature. Bile salt flow (dependent and independent) is decreased, approximating only 50% of that in adults. The absence of oral feeding reduces the enterohepatic circulation of bile acids. Fasting also inhibits the release of gut and biliary tree hormones, such as cholecystokinin, gastrin, secretin, motilin, and glucagon. The formation of echogenic, thick, “molasses-like” biliary sludge within the gallbladder has been documented in both adults and children receiving TPN. Serial ultrasound examinations of adults receiving continuous TPN infusion show sludge formation, increasing from 6% of patients in the first week to 50% in the fourth week and 100% after 6 weeks. Gallbladder enlargement may be the first physical sign of sludge formation in infants. Stagnant bile in a dilated gallbladder provides an ideal milieu for the development of both acalculous cholecystitis and cholelithiasis. TPN-induced gallstones are pigment stones, typically black, and usually found in the gallbladder. They often have a high calcium phosphate or carbonate content; however, stone analysis indicates that they are of a mixed bilirubin-cholesterol composition and perhaps belong to a special group of TPN-induced pigment stones.

Cystic Fibrosis-Associated Gallstones

Gallstones, gallbladder, and biliary tract abnormalities are frequently found in patients with cystic fibrosis, and they increase with age. “Microgallbladders” have been identified radiologically in up to 16% of adult patients with cystic fibrosis and in 30% of patients at autopsy. Common bile duct stenosis has been identified in 96% of cystic fibrosis patients with liver disease, resulting in enlarged gallbladders and elevated serum bile acid levels, which may predispose to gallstone formation. Gallstones in patients with cystic fibrosis appear secondary to excessive bile acid loss resulting in a reduced bile acid pool. The bile composition becomes abnormal, with a relative excess of cholesterol associated with the decrease in bile salts, thus making the bile lithogenic. The bile acid malabsorption and reduced bile salt pool respond to pancreatic enzyme therapy. Gallstones have not been found without pancreatic insufficiency.

Ileal Disease and Ileal Resection-Associated Stones

The enterohepatic circulation constantly replenishes the bile acid pool, which in turn governs the rate of bile salt secretion. The terminal ileum serves as the site of nearly 98% of bile acid resorption. Terminal ileal disease, typically Crohn’s disease, or surgical resection of the ileum can result in an interruption of this bile acid recycling. The bile salt pool is subsequently reduced, thus altering the balance of bile components and favoring cholesterol supersaturation and increased bile lithogenicity. The formation of gallstones secondary to ileal disease has been reported in both adults and children. However, it appears that ileal resection only increases the tendency to gallstone formation after puberty. After puberty, cholesterol secretion increases, whereas bile salt secretion declines, predisposing to cholesterol supersaturation and, hence, stone formation.

Drug-Associated Stones

The use of furosemide, octreotide, ceftriaxone, cyclosporine, and tacrolimus has been associated with an increased tendency to form gallstones. In reported cases associated with furosemide administration, numerous other contributing factors, such as prematurity, sepsis, and small bowel disease, were also noted. Whether furos­emide alone contributes to gallstone formation remains unclear.

Octreotide has a wide range of biologic activities, including several clinically useful applications such as treatment of upper gastrointestinal bleeding, secretory diarrhea, acromegaly, and gastroenteropancreatic endocrine tumors. Gallstone formation has been found in about half of patients who receive chronic octreotide therapy. It is thought that this may be related to octreotide-induced gallbladder stasis or a direct effect of octreotide on gallbladder absorption.

Ceftriaxone can induce gallbladder concretions. Ceftriaxone is excreted in bile and can displace bilirubin from albumin-binding sites. Reports in both adults and children have noted biliary echo densities or sludge often causing symptoms of cholecystitis with right upper quadrant pain, nausea, and vomiting. Analysis of the sludge reveals high concentrations of a calcium salt of ceftriaxone, with traces of bilirubinate and cholesterol, thus resembling pigment stone composition. Fasting, dehydration, and age older than 24 months are risk factors associated with this so-called pseudolithiasis. The process of bile concretion and the related symptoms are reversible when the drug is discontinued. However, in a series of patients followed in Israel, other cephalosporins were also lithogenic, and 38% of patients had biliary disease related to this class of medications.

Cyclosporine use in children undergoing bone marrow and solid organ transplantation has been implicated in gallstone formation, possibly related to elevated drug levels and hepatic toxicity. However, underlying sepsis, total parenteral nutrition, and NPO status are also likely contributors. Heart transplantation in infants younger than 3 months of age appears to confer the greatest risk of cholelithiasis, substantially higher than that seen in kidney or liver graft recipients. Children undergoing bone marrow transplantation also have been reported to have a higher likelihood of cholelithiasis.

Diagnosis of Gallstone Disease

The classic symptom complex of right upper quadrant pain and vomiting is usually associated with stones only in older children and adolescents. Younger children tend to present with nonspecific symptoms. Jaundice is frequently encountered in “symptomatic” infants. The most likely age for silent stones is infancy through the preschool years. Intolerance to fatty food is rarely reported in children. Fever is an unusual finding at any age and, if present, indicates associated cholecystitis. Complications of gallstone disease include cholecystitis, choledocholithiasis, cholangitis, and gallbladder perforation, but these occur rarely in children. Pancreatitis has been identified in 8% to 27% of children with gallstone disease and may represent the most common complication in children. Obstructive biliary disease has been demonstrated in up to 58% of patients with gallbladder disease.

Laboratory evaluation is typically nondiagnostic. Occasional patients will have a leukocytosis as well as mildly elevated aminotransaminase levels and γ-glutamyl transferase (GGT). Because black pigmented stones are more common in children than in adults, plain-film radiography may be helpful and demonstrate radiopaque stones. Ultrasonography is the diagnostic procedure of choice, because it is noninvasive, sensitive, and specific. Ultrasonography also allows examination of the surrounding abdominal viscera, such as the pancreas and the biliary tree. Annual biliary ultrasonography has been suggested in children with known predisposition to gallstones, such as those with hereditary spherocytosis and sickle cell anemia. Oral cholecystography has been largely replaced by ultrasound, but it can occasionally be useful in the evaluation of gallbladder function. Endoscopic retrograde cholangiopancreatography (ERCP) is particularly useful in the evaluation of ductal stones. Percutaneous cholangiograms offer another approach, but are seldom used in children for this purpose.

Treatment of Gallstone Disease

Observation may be the most prudent treatment in infants with asymptomatic gallstone disease (see Table 79-2 ). As the infant ages, the hepatobiliary enzyme systems mature and the potential for spontaneous stone dissolution exists. Spontaneous stone resolution also has been observed in TPN-induced gallstones. In children for whom the duration of TPN is expected to be limited and the stones are asymptomatic, observation is indicated. However, in children who are chronically dependent on TPN, such as those with pseudo-obstruction syndrome or short bowel syndrome, stones should be removed.

Gallstones in older children should be removed, because spontaneous resolution seldom occurs. Cholecystostomy is indicated for acute drainage of the gallbladder and perhaps in seriously ill patients for whom only simple stone extraction is needed. Laparoscopic cholecystectomy has become the surgical procedure of choice, in both adults and children.

Options for nonsurgical treatment of gallstone disease continue to proliferate. Despite the growing popularity of medical therapy for adults, there is no such approved medical treatment for gallstones in children ( Table 79-3 ). Two bile acids currently exist for oral gallstone dissolution: chenodeoxycholic acid (chenodiol) and ursodeoxycholic acid (ursodiol). Both agents occur naturally and are present in bile. Chenodiol works by inhibiting HMG-CoA reductase, which suppresses hepatic cholesterol synthesis. Side effects such as diarrhea and hepatotoxicity have limited its widespread use. The mechanism of action of ursodiol is similar to chenodiol, inhibiting HMG-CoA reductase and additionally, blocking intestinal absorption of cholesterol. Ursodeoxycholic acid also reduces lipid peroxidation and mucin secretagogue activity. Diarrhea and hepatotoxicity are rare. Combination use of both chenodiol and ursodiol appears more effective and allows a 50% reduction in dosage with fewer side effects. Drawbacks to the use of such therapy include the long duration of therapy, recurrence after stopping, low success rate, and high cost. However, only cholesterol stones are amenable to this therapy. Animal studies may provide future treatment modalities. For example, ezetimibe, a cholesterol-lowering agent, has recently been shown in mice to prevent gallstone formation. Another mouse model has demonstrated reduction of cholesterol gallstones using garlic and onion!

TABLE 79-3

TREATMENT ALTERNATIVES FOR GALLSTONES IN CHILDREN AND ADULTS

Type	Comments
Cholecystectomy	Method of choice in most cases
Cholecystostomy	Effective for acute gallbladder drainage (i.e., acalculous cholecystitis)
Laparoscopic cholecystectomy	Effective with severely ill patients, shortens hospitalization (e.g., cystic fibrosis)
ERCP
Basket removal	Bile duct stone removal
Mechanical basket lithotripsy	Stone crushing within bile ducts
Electrohydraulic lithotripsy	Stone destruction within bile ducts
Laser lithotripsy	Stone destruction within bile ducts
ESWL	Limited experience (unpublished), only for cholesterol stones currently
Dissolution
Oral	Ursodeoxycholic acid and chenodeoxycholic acid
	Blocks HMG-CoA reductase, decreases cholesterol synthesis
Contact	Methyl tert -butyl-ether (for cholesterol stones only)
	Bile acid EDTA (for pigment stones; experimental)
Preventive
Enteral feeds	Even small amounts during TPN decrease stone risk
Weight loss	For obesity—gradual weight loss
Lovastatin and simvastatin	Block HMG-CoA reductase, decrease cholesterol synthesis (experimental)
Cholecystokinin	Stimulates gallbladder contraction while NPO (experimental)

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