1087
Biliary sludge:
more
than
a
curiosity
was first recognised Biliary sludge ultrasonographically, and was defined as an echogenic material that forms in layers in the most dependent portion of the gallbladder, varies with posture, and, unlike gallstones, does not cast an acoustic shadow.1 The composition of biliary sludge is now known, and,
increasingly recognised both as a precursor of gallstOnes2,3 and as an important cause of "idiopathic" it is
pancreatitis. people with sludge presenting with abdominal pain have no clear underlying cause or illness.4 However, several groups of patients are at considerably increased risk of sludge formation. Examples are recipients of total parenteral nutrition,5,6 patients immediately after abdominal surgery,7 pregnant women,and those who are critically ill in intensive care units.9 Bone marrow transplantation and AIDS likewise predispose to sludge."," The main components of biliary sludge are bile supersaturated with cholesterol, mucin glycoprotein in very high quantities, cholesterol monohydrate crystals, and calcium bilirubinate granules.12 The evidence that biliary sludge leads to gallstones is considerable. First, all groups of patients identified with sludge who have been followed-up have a very high incidence of subsequent gallstone formation, and gallstones can frequently be observed as developing within the biliary sludge.5-8.10,11 Second, bilirubin in biliary sludge is predominantly unconjugated, a pattern typical of that seen in the matrix of cholesterol gallstones, which is itself formed at the early stages of gallstone development.12,13 By contrast, bilirubin in normal bile is predominantly conjugated.l4 Third, sludge contains cholesterol crystals, a critical and essential early step in gallstone fonnation.12 Finally, the very high mucin glycoprotein content has also been noted in animal models of gallstone formation such as cholesterol-fed prairie dogs.13 Whether sludge is an essential intermediate step in formation of all gallstones is unknown, although Lee et al, using ultrasound, observed that sludge is often a recurrent event in subjects who have no clear predisposing factor. The concept that gallstones can form only at specific critical periods in the gallbladder is an attractive but largely unexplored hypothesis. Many researchers now believe that gallstones arise because of a triple hepatobiliary defect: (a) cholesterol-supersaturated gallbladder bile; (b) increased rate of cholesterol crystal nucleation; and (c) reduced gallbladder contractility.Several factors may be important in controlling the rate of cholesterol nucleation, and considerable evidence suggests that mucin glycoprotein is an important pronucleating agent.15,16 It seems that the triple hepatobiliary defect associated with gallstone formation may be present in subjects with biliary sludge. Sludge contains supersaturated bile and a very high concentration of Some
agent (mucin glycoprotein).12 We know about impairment of gallbladder little very in contractility subjects with biliary sludge. The only group of patients at risk of sludge formation to have been studied in this respect are recipients of total parenteral nutrition, in whom contractility is reduced.17 Regular administration of cholecystokinin (CCK) stimulates gallbladder contractility and prevents biliary sludge formation,18 which suggests that there is a contractility defect in some patients with sludge and that reversal of this defect will prevent sludge formation and presumably gallstone formation, as well. Two recent studies’9-20 have suggested that biliary tract disease, and specifically biliary sludge, may be responsible for most cases of "idiopathic" pancreatitis; many patients with this disorder subsequently get gallstones. Treatment with bile salts,
nucleating
endoscopic sphincterotomy, or cholecystectomy seems to be effective in preventing further attacks of pancreatitis in most cases.19,20 Significance of low level echoes within the gallbladder. Am J Roentgenol 1979; 132: 967-72. 2. Paumgartner G, Sauerbruch T. Gallstones: pathogenesis. Lancet 1991; 338: 1117-21. 3. Editorial. Gallstones, bile acids, and the liver. Lancet 1989; ii: 249-51. 4. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. 1. Conrad MR, Janes JO, Dietchy J.
5.
Gastroenterology 1988; 94: 170-76. Roslyn JL, Pitt HA, Mann LL, Ament ME, DenBesten L. Gallbladder disease in patients on long term parenteral nutrition. Gastroenterology 1983; 84: 148-54.
6.
Messing B, Bories C, Kunstlinger F, et al. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology
1983; 84: 1012-19. L, Gaini S, Testa S, et al. Gallbladder sludge formation during prolonged fasting after gastrointestinal surgery. Gut 1985; 26: 734-38. 8. Maringhini A, Marceno MP, Lanzarone F, et al. Sludge and stones in gallbladder after pregnancy. J Hepatol 1987; 5: 218-22. 7. Bolondi
9. 10.
Murray FE, Stinchcombe SJ, Hawkey CJ. High incidence of biliary sludge in patients on the intensive care unit. Clin Sci 1991; 81: 26S. Frick MP, Snover DC, Feinberg SB, et al. Sonography of the gallbladder in bone marrow transplant patients. Am J Gastroenterol 1984; 79:
122-27. 11. Grumbach K, Coleman BG, Gal AA, Arger PH, et al. Hepatic and biliary tract abnormalities in patients with AIDS. J Ultrasound Med 1989; 8: 247-54. 12. Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology 1986; 90: 677-86. 13. Smith BF, LaMont JT. Identification of a mucin bilirubin complex in the matrix of cholesterol gallstones. J Clin Invest 1985; 76: 439-45. 14. Fevary J, Blanckaert N, Pol L, et al. Analysis of bilirubins in biological fluids by extraction and thin layer chromatography: applications to patients with haemolysis, Gilbert’s syndrome and cholelithiasis. Hepatology 1983; 3: 177-83. 15. Lee SP, LaMont JT, Carey MC. Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J Clin Invest 1981; 67: 1712-23. 16. Levy P, Smith BF, LaMont JT. Human gallbladder mucin accelerates in vitro nucleation of cholesterol in artificial bile. Gastroenterology 1984; 87: 270-75. 17. Cano N, Cicero F, Ranier F, et al. Ultrasonographic study of gallbladder motility during total parenteral nutrition. Gastroenterology 1983; 84: 1012-19. 18. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 24-31. 19. Ros E, Navarro S, Bru C, Garcia-puges A, Valderrama R. Occult microlithiasis in ’idiopathic’ acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 1991; 101: 1701-09. 20. Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med 1992; 326: 589-93.
Biliary sludge:
more
than
a
curiosity
was first recognised Biliary sludge ultrasonographically, and was defined as an echogenic material that forms in layers in the most dependent portion of the gallbladder, varies with posture, and, unlike gallstones, does not cast an acoustic shadow.1 The composition of biliary sludge is now known, and,
increasingly recognised both as a precursor of gallstOnes2,3 and as an important cause of "idiopathic" it is
pancreatitis. people with sludge presenting with abdominal pain have no clear underlying cause or illness.4 However, several groups of patients are at considerably increased risk of sludge formation. Examples are recipients of total parenteral nutrition,5,6 patients immediately after abdominal surgery,7 pregnant women,and those who are critically ill in intensive care units.9 Bone marrow transplantation and AIDS likewise predispose to sludge."," The main components of biliary sludge are bile supersaturated with cholesterol, mucin glycoprotein in very high quantities, cholesterol monohydrate crystals, and calcium bilirubinate granules.12 The evidence that biliary sludge leads to gallstones is considerable. First, all groups of patients identified with sludge who have been followed-up have a very high incidence of subsequent gallstone formation, and gallstones can frequently be observed as developing within the biliary sludge.5-8.10,11 Second, bilirubin in biliary sludge is predominantly unconjugated, a pattern typical of that seen in the matrix of cholesterol gallstones, which is itself formed at the early stages of gallstone development.12,13 By contrast, bilirubin in normal bile is predominantly conjugated.l4 Third, sludge contains cholesterol crystals, a critical and essential early step in gallstone fonnation.12 Finally, the very high mucin glycoprotein content has also been noted in animal models of gallstone formation such as cholesterol-fed prairie dogs.13 Whether sludge is an essential intermediate step in formation of all gallstones is unknown, although Lee et al, using ultrasound, observed that sludge is often a recurrent event in subjects who have no clear predisposing factor. The concept that gallstones can form only at specific critical periods in the gallbladder is an attractive but largely unexplored hypothesis. Many researchers now believe that gallstones arise because of a triple hepatobiliary defect: (a) cholesterol-supersaturated gallbladder bile; (b) increased rate of cholesterol crystal nucleation; and (c) reduced gallbladder contractility.Several factors may be important in controlling the rate of cholesterol nucleation, and considerable evidence suggests that mucin glycoprotein is an important pronucleating agent.15,16 It seems that the triple hepatobiliary defect associated with gallstone formation may be present in subjects with biliary sludge. Sludge contains supersaturated bile and a very high concentration of Some
agent (mucin glycoprotein).12 We know about impairment of gallbladder little very in contractility subjects with biliary sludge. The only group of patients at risk of sludge formation to have been studied in this respect are recipients of total parenteral nutrition, in whom contractility is reduced.17 Regular administration of cholecystokinin (CCK) stimulates gallbladder contractility and prevents biliary sludge formation,18 which suggests that there is a contractility defect in some patients with sludge and that reversal of this defect will prevent sludge formation and presumably gallstone formation, as well. Two recent studies’9-20 have suggested that biliary tract disease, and specifically biliary sludge, may be responsible for most cases of "idiopathic" pancreatitis; many patients with this disorder subsequently get gallstones. Treatment with bile salts,
nucleating
endoscopic sphincterotomy, or cholecystectomy seems to be effective in preventing further attacks of pancreatitis in most cases.19,20 Significance of low level echoes within the gallbladder. Am J Roentgenol 1979; 132: 967-72. 2. Paumgartner G, Sauerbruch T. Gallstones: pathogenesis. Lancet 1991; 338: 1117-21. 3. Editorial. Gallstones, bile acids, and the liver. Lancet 1989; ii: 249-51. 4. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. 1. Conrad MR, Janes JO, Dietchy J.
5.
Gastroenterology 1988; 94: 170-76. Roslyn JL, Pitt HA, Mann LL, Ament ME, DenBesten L. Gallbladder disease in patients on long term parenteral nutrition. Gastroenterology 1983; 84: 148-54.
6.
Messing B, Bories C, Kunstlinger F, et al. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology
1983; 84: 1012-19. L, Gaini S, Testa S, et al. Gallbladder sludge formation during prolonged fasting after gastrointestinal surgery. Gut 1985; 26: 734-38. 8. Maringhini A, Marceno MP, Lanzarone F, et al. Sludge and stones in gallbladder after pregnancy. J Hepatol 1987; 5: 218-22. 7. Bolondi
9. 10.
Murray FE, Stinchcombe SJ, Hawkey CJ. High incidence of biliary sludge in patients on the intensive care unit. Clin Sci 1991; 81: 26S. Frick MP, Snover DC, Feinberg SB, et al. Sonography of the gallbladder in bone marrow transplant patients. Am J Gastroenterol 1984; 79:
122-27. 11. Grumbach K, Coleman BG, Gal AA, Arger PH, et al. Hepatic and biliary tract abnormalities in patients with AIDS. J Ultrasound Med 1989; 8: 247-54. 12. Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology 1986; 90: 677-86. 13. Smith BF, LaMont JT. Identification of a mucin bilirubin complex in the matrix of cholesterol gallstones. J Clin Invest 1985; 76: 439-45. 14. Fevary J, Blanckaert N, Pol L, et al. Analysis of bilirubins in biological fluids by extraction and thin layer chromatography: applications to patients with haemolysis, Gilbert’s syndrome and cholelithiasis. Hepatology 1983; 3: 177-83. 15. Lee SP, LaMont JT, Carey MC. Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J Clin Invest 1981; 67: 1712-23. 16. Levy P, Smith BF, LaMont JT. Human gallbladder mucin accelerates in vitro nucleation of cholesterol in artificial bile. Gastroenterology 1984; 87: 270-75. 17. Cano N, Cicero F, Ranier F, et al. Ultrasonographic study of gallbladder motility during total parenteral nutrition. Gastroenterology 1983; 84: 1012-19. 18. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 24-31. 19. Ros E, Navarro S, Bru C, Garcia-puges A, Valderrama R. Occult microlithiasis in ’idiopathic’ acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 1991; 101: 1701-09. 20. Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med 1992; 326: 589-93.
