Pathophysiology of Cholesterol Gallstone Disease

  • Piero Portincasa
  • Antonio Moschetta
  • Agostino Di Ciaula
  • Daniela Pontrelli
  • Rosa C. Sasso
  • Helen H. Wang
  • David Q. -H. Wang


Gallstone disease is one of the most costly digestive diseases requiring hospitalization in westernized countries, and its prevalence ranges from 10% to 15% in adults in Europe and the USA [1, 2, 3, 4]. The burden of disease is summarized by the prevalence of patients with gallstones, by its incidence (over a million new diagnoses of gallstones a year), and by the number of cholecystectomies performed yearly in the USA (approaching 700,000) [5]. Similar trends in gallstone disease have been confirmed in large epidemiological surveys carried out in Italy [6, 7, 8, 9, 10]. In Western societies approximately 80% of gallstones are cholesterol gallstones [11], either pure cholesterol or mixed cholesterol stones (containing more than 50% cholesterol by weight).


Bile Salt Gallstone Formation Cholesterol Gallstone Biliary Lipid Gallstone Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Portincasa P, Moschetta A, Palasciano G (2006) Cholesterol gallstone disease. Lancet 368:230–239PubMedCrossRefGoogle Scholar
  2. 2.
    Wang DQH, Afdhal NH (2004) Genetic analysis of cholesterol gallstone formation: searching for Lith (gallstone) genes. Curr Gastroenterol Rep 6:140–150PubMedCrossRefGoogle Scholar
  3. 3.
    Everhart JE, Khare M, Hill M et al (1999) Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 117:632–639PubMedCrossRefGoogle Scholar
  4. 4.
    Sandler RS, Everhart JE, Donowitz M et al (2002) The burden of selected digestive diseases in the United States. Gastroenterology 122:1500–1511PubMedCrossRefGoogle Scholar
  5. 5.
    National Institutes of Health (1993) Consensus Development Conference Statement on Gallstones and Laparoscopic Cholecystectomy. Am J Surg 165:390–398CrossRefGoogle Scholar
  6. 6.
    Attili AF, De Santis A, Capri R et al (1995) The natural history of gallstones: the GREPCO experience. Hepatology 21:656–660CrossRefGoogle Scholar
  7. 7.
    Attili AF, Carulli N, Roda E et al (1995) Epidemiology of gallstone disease in Italy: prevalence data of the Multicepter Italian Study on Cholelithiasis (M.I.C.O.L.). Am J Epidemiol 141:158–165PubMedGoogle Scholar
  8. 8.
    Attili AF, Capocaccia R, Carulli N et al (1997) Factors associated with gallstone disease in the MICOL experience. Hepatology 26:809–818PubMedCrossRefGoogle Scholar
  9. 9.
    Attili AF, Scafato E, Marchioli R et al (1998) Diet and gallstones in Italy: the cross-sectional MICOL results. Hepatology 27:1492–1498PubMedCrossRefGoogle Scholar
  10. 10.
    Festi D, Sottili S, Colecchia A et al (1999) Clinical manifestations of gallstone disease: evidence from the multicenter Italian study on cholelithiasis (MICOL). Hepatology 30:839–846PubMedCrossRefGoogle Scholar
  11. 11.
    Diehl AK (1991) Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 20:1–19PubMedGoogle Scholar
  12. 12.
    Grundy SM (2004) Cholesterol gallstones: a fellow traveler with metabolic syndrome? Am J Clin Nutr 80:1–2PubMedGoogle Scholar
  13. 13.
    Wang DQH, Zhang L, Wang HH (2005) High cholesterol absorption efficiency and rapid biliary secretion of chylomicron remnant cholesterol enhance cholelithogenesis in gallstone-susceptible mice. Biochim Biophys Acta 1733:90–99PubMedGoogle Scholar
  14. 14.
    Lammert F, Sauerbruch T (2005) Mechanisms of disease: the genetic epidemiology of gallbladder stones. Nat Clin Pract Gastroenterol Hepatol 2:423–433PubMedCrossRefGoogle Scholar
  15. 15.
    Sherlock S, Dooley J (2002) Diseases of the liver and biliary system. Blackwell Science, OxfordGoogle Scholar
  16. 16.
    Portincasa P, Moschetta A, Mazzone A et al (2003) Water handling and aquaporins in bile formation: recent advances and research trends. J Hepatol 39:864–874PubMedCrossRefGoogle Scholar
  17. 17.
    Groen AK, Bloks VW, Bandsma RH et al (2001) Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL. J Clin Invest 108:843–850PubMedGoogle Scholar
  18. 18.
    Grunhage F, Lammert F (2006) Gallstone disease. Pathogenesis of gallstones: a genetic perspective. Best Pract Res Clin Gastroenterol 20:997–1015PubMedCrossRefGoogle Scholar
  19. 19.
    Berge KE, Tian H, Graf GA et al (2000) Accumulation of dietary cholesterol in cytosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775PubMedCrossRefGoogle Scholar
  20. 20.
    Lee MH, Lu K, Hazard S et al (2001) Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27:79–83PubMedCrossRefGoogle Scholar
  21. 21.
    Smit JJM, Schinkel AH, Oude Elferink RPJ et al (1993) Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462PubMedCrossRefGoogle Scholar
  22. 22.
    Bodzioch M, Orso E, Klucken J et al (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351PubMedCrossRefGoogle Scholar
  23. 23.
    Rust S, Rosier M, Funke H et al (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355PubMedCrossRefGoogle Scholar
  24. 24.
    Brooks-Wilson A, Marcil M, Clee SM et al (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–345PubMedCrossRefGoogle Scholar
  25. 25.
    de Vree JM, Jacquemin E, Sturm E et al (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95:282–287PubMedCrossRefGoogle Scholar
  26. 26.
    Deleuze JF, Jacquemin E, Dubuisson C et al (1996) Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 23:904–908PubMedCrossRefGoogle Scholar
  27. 27.
    Dixon PH, Weerasekera N, Linton KJ et al (2000) Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 9:1209–1217PubMedCrossRefGoogle Scholar
  28. 28.
    Strautnieks SS, Bull LN, Knisely AS et al (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20:233–238PubMedCrossRefGoogle Scholar
  29. 29.
    Lee MH, Lu K, Hazard S et al (2001) Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27:79–83PubMedCrossRefGoogle Scholar
  30. 30.
    Graf GA, Yu L, Li WP et al (2003) ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem 278:48275–48282PubMedCrossRefGoogle Scholar
  31. 31.
    Kosters A, Kunne C, Looije N et al (2006) The mechanism of ABCG5/ABCG8 in biliary cholesterol secretion in mice. J Lipid Res 47:1959–1966PubMedCrossRefGoogle Scholar
  32. 32.
    Wang HH, Patel SB, Carey MC et al (2007) Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8(-l-) mice. Hepatology 45:998–1006PubMedCrossRefGoogle Scholar
  33. 33.
    Yu L, Li-Hawkins J, Hammer RE et al (2002) Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 110:671–680PubMedGoogle Scholar
  34. 34.
    Yu L, Hammer RE, Li-Hawkins J et al (2002) Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA 99:16237–16242PubMedCrossRefGoogle Scholar
  35. 35.
    Gerloff T, Stieger B, Hagenbuch B et al (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050PubMedCrossRefGoogle Scholar
  36. 36.
    Wang R, Salem M, Yousef IM et al (2001) Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci USA 98:2011–2016PubMedCrossRefGoogle Scholar
  37. 37.
    Wang R, Lam P, Liu L et al (2003) Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38:1489–1499PubMedGoogle Scholar
  38. 38.
    de Vree JM, Jacquemin E, Sturm E et al (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95:282–287PubMedCrossRefGoogle Scholar
  39. 39.
    van Erpecum KJ, Carey MC (1997) Influence of bile salts on molecular interactions between sphingomyelin and cholesterol: relevance to bile formation and stability. Biochim Biophys Acta 1345:269–282PubMedGoogle Scholar
  40. 40.
    Wang H, Chen J, Hollister K et al (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553PubMedCrossRefGoogle Scholar
  41. 41.
    Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365PubMedCrossRefGoogle Scholar
  42. 42.
    Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368PubMedCrossRefGoogle Scholar
  43. 43.
    Janowski BA, Willy PJ, Devi TR et al (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383:728–731PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang Z, Li D, Blanchard DE et al (2001) Key regulatory oxysterols in liver: analysis as delta4-3-ketone derivatives by HPLC and response to physiological perturbations. J Lipid Res 42:649–658PubMedGoogle Scholar
  45. 45.
    Ananthanarayanan M, Balasubramanian N, Makishima M et al (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865PubMedCrossRefGoogle Scholar
  46. 46.
    Huang L, Zhao A, Lew JL et al (2003) Farnesoid X-receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 278:51085–51090PubMedCrossRefGoogle Scholar
  47. 47.
    Repa JJ, Berge KE, Pomajzl C et al (2002) Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 277:18793–18800PubMedCrossRefGoogle Scholar
  48. 48.
    Modica S, Moschetta A (2006) Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett 580:5492–5499PubMedCrossRefGoogle Scholar
  49. 49.
    Willy PJ, Mangelsdorf DJ () Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. Genes Dev 11:289–298Google Scholar
  50. 50.
    del Castillo-Olivares A, Gil G (2000) Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription. Nucl Acids Res 28:3587–3593PubMedCrossRefGoogle Scholar
  51. 51.
    Lu TT, Makishima M, Repa JJ et al (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515PubMedCrossRefGoogle Scholar
  52. 52.
    Peet DJ, Turley SD, Ma W et al (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704PubMedCrossRefGoogle Scholar
  53. 53.
    Carey MC, Small DM (1978) The physical chemistry of cholesterol solubility in bile. Relation to gallstone formation and dissolution in man. J Clin Invest 61:998–1026PubMedCrossRefGoogle Scholar
  54. 54.
    Holzbach RT, Marsh M, Olszewski M et al (1973) Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 52:1467–1479PubMedCrossRefGoogle Scholar
  55. 55.
    Mazer NA, Carey MC, Kwasnick RF et al (1979) Quasielastic light scattering studies of aqueous biliary lipid systems. Size, shape, and thermodynamics of bile salt micelles. Biochemistry 18:3064–3075PubMedCrossRefGoogle Scholar
  56. 56.
    Mazer NA, Benedek GB, Carey MC (1980) Quasielastic light-scattering studies of aqueous biliary lipid systems. Mixed micelle formation in bile salt-lecithin solutions. Biochemistry 19:601–615PubMedCrossRefGoogle Scholar
  57. 57.
    Mazer NA, Carey MC (1983) Quasi-elastic light-scattering studies of aqueous biliary lipid systems. Cholesterol solubilization and precipitation in model bile solutions. Biochemistry 22:426–442PubMedCrossRefGoogle Scholar
  58. 58.
    Mazer NA, Schurtenberg P, Carey MC et al (1984) Quasi-elastic light scattering studies of native hepatic bile from the dog: comparison with aggregative behavior of model biliary lipid systems. Biochemistry 23:1994–2005PubMedCrossRefGoogle Scholar
  59. 59.
    Somjen GJ, Gilat T (1983) A non-micellar mode of cholesterol transport in human bile. FEBS Lett 156:265–268PubMedCrossRefGoogle Scholar
  60. 60.
    Somjen GJ, Gilat T (1985) Contribution of vesicular and micellar carriers to cholesterol transport in human bile. J Lipid Res 26:699–704PubMedGoogle Scholar
  61. 61.
    Somjen GJ, Marikovsky Y, Lelkes P et al (1986) Cholesterol-phospholipid vesicles in human bile: an ultrastructural study. Biochim Biophys Acta 879:14–21PubMedGoogle Scholar
  62. 62.
    Halpern Z, Dudley MA, Kibe A et al (1986) Rapid vesicle formation and aggregation in abnormal human biles: a time-lapse video-enhanced contrast microscopy study. Gastroenterology 90:875–885PubMedGoogle Scholar
  63. 63.
    Halpern Z, Dudley MA, Lynn MP et al (1986) Vesicle aggregation in model systems of supersaturated bile: relation to crystal nucleation and lipid composition of the vesicular phase. J Lipid Res 27:295–306PubMedGoogle Scholar
  64. 64.
    Holan KR, Holzbach RT, Hermann RE et al (1979) Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 77:611–617PubMedGoogle Scholar
  65. 65.
    Holzbach RT, Corbusier C (1978) Liquid crystals and cholesterol nucleation during equilibration in supersaturated bile analogs. Biochim Biophys Acta 528:436–444PubMedGoogle Scholar
  66. 66.
    Olszewski MF, Holzbach RT, Saupe A et al (1973) Liquid crystals in human bile. Nature 242:336–337PubMedCrossRefGoogle Scholar
  67. 67.
    Wang DQH, Carey MC (1996) Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing system. J Lipid Res 37:606–630PubMedGoogle Scholar
  68. 68.
    Admirand WH, Small DM (1968) The physicochemical basis of cholesterol gallstone formation in man. J Clin Invest 47:1043–1052PubMedGoogle Scholar
  69. 69.
    Wang DQH, Carey MC (1996) Characterization of crystallization pathways during cholesterol precipitation from human gallbladder biles: identical pathways to corresponding model biles with three predominating sequences. J Lipid Res 37:2539–2549PubMedGoogle Scholar
  70. 70.
    Small DM, Bourges M, Dervichian DG (1966) Ternary and quaternary aqueous systems containing bile salt, lecithin, and cholesterol. Nature 211:816–818PubMedCrossRefGoogle Scholar
  71. 71.
    Small DM, Bourges MC, Dervichian DG (1966) The biophysics of lipidic associations. I. The ternary systems: lecithin-bile salt-water. Biochim Biophys Acta 125:563–580PubMedGoogle Scholar
  72. 72.
    Small DM (1968) A classification of biologic lipids based upon their interaction in aqueous systems. J Am Oil Chem Soc 45:108–119PubMedCrossRefGoogle Scholar
  73. 73.
    Small DM, Admirand W (1969) Solubility of bile salts. Nature 221:265–267PubMedCrossRefGoogle Scholar
  74. 74.
    Hofmann AF, Amelsberg A, Vansonnenberg E (1993) Pathogenesis and treatment of gallstones. N Engl J Med 328:1854–1855PubMedCrossRefGoogle Scholar
  75. 75.
    LaMont JT, Carey MC (1992) Cholesterol gallstone formation. 2. Pathobiology and pathomechanics. Prog Liver Dis 10:165–191PubMedGoogle Scholar
  76. 76.
    Wang DQH, Cohen DE, Lammert F et al (1999) No pathophysiologic relationship of soluble biliary proteins to cholesterol crystallization in human bile. J Lipid Res 40:415–425PubMedGoogle Scholar
  77. 77.
    Carey MC (1978) Critical tables for calculating the cholesterol saturation of native bile. J Lipid Res 19:945–955PubMedGoogle Scholar
  78. 78.
    Gollish SH, Burnstein MJ, Ilson RG et al (1983) Nucleation of cholesterol monohydrate crystals from hepatic and gallbladder bile of patients with cholesterol gallstones. Gut 24:836–844PubMedCrossRefGoogle Scholar
  79. 79.
    Harvey PRC, Sömjen G, Lichtenberg MS et al (1987) Nucleation of cholesterol from vesicles isolated from bile of patients with and without cholesterol gallstones. Biochim Biophys Acta 921:198–204PubMedGoogle Scholar
  80. 80.
    Holzbach RT (1990) Current concepts of cholesterol transport and crystal formation in human bile. Hepatology 12:26S–31SPubMedCrossRefGoogle Scholar
  81. 81.
    Holzbach RT (1990) Nucleation of cholesterol crystals in native bile. Hepatology 12:155S–161SPubMedCrossRefGoogle Scholar
  82. 82.
    Wang DQH, Paigen B, Carey MC (1997) Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J Lipid Res 38:1395–1411PubMedGoogle Scholar
  83. 83.
    Wang HH, Afdhal NH, Gendler SJ et al (2006) Evidence that gallbladder epithelial mucin enhances cholesterol cholelithogenesis in MUC1 transgenic mice. Gastroenterology 131:210–222PubMedCrossRefGoogle Scholar
  84. 84.
    Konikoff FM, Chung DS, Donovan JM et al (1992) Filamentous, helical and tubular microstructures during cholesterol crystallization from bile. Evidence that biliary cholesterol does not nucleate classic monohydrate plates. J Clin Invest 90:1156–1161CrossRefGoogle Scholar
  85. 85.
    Konikoff FM, Cohen DE, Carey MC (1994) Phospholipid molecular species influence crystal habits and transition sequences of metastable intermediates during cholesterol crystallization from bile salt-rich model bile. J Lipid Res 35:60–70PubMedGoogle Scholar
  86. 86.
    Konikoff FM, Laufer H, Messer G et al (1997) Monitoring cholesterol crystallization from lithogenic model bile by time-lapse density gradient ultracentrifugation. J Hepatol 26:703–710PubMedCrossRefGoogle Scholar
  87. 87.
    Lammert F, Wang DQH, Hillebrandt S et al (2004) Spontaneous cholecysto-and hepatolithiasis in Mdr2-/-mice: a model for low phospholipid-associated cholelithiasis. Hepatology 39:117–128PubMedCrossRefGoogle Scholar
  88. 88.
    Holzbach RT (1995) Cholesterol nucleation in bile. Ital J Gastroenterol Hepatol 27:101–105Google Scholar
  89. 89.
    Holzbach RT (1997) Newer pathogenetic concepts in cholesterol gallstone formation: a unitary hypothesis. Digestion 58 Suppl 1:29–32PubMedCrossRefGoogle Scholar
  90. 90.
    Busch N, Matiuck N, Sahlin S et al (1991) Inhibition and promotion of cholesterol crystallization by protein factors from normal human gallbladder bile. J Lipid Res 32:695–702PubMedGoogle Scholar
  91. 91.
    Lee SM, LaMont JT, Carey MC (1981) Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. Studies in the prairie dog. J Clin Invest 67:1712–1723PubMedCrossRefGoogle Scholar
  92. 92.
    Afdhal NH, Gong D, Niu N et al (1993) Cholesterol cholelithiasis in the prairie dog: role of mucin and nonmucin glycoproteins. Hepatology 17:693–700PubMedCrossRefGoogle Scholar
  93. 93.
    LaMont JT (1982) Gallbladder mucin glycoprotein hypersecretion in experimental cholelithiasis: role of mucin gel in nucleation of cholesterol gallstones. Adv Exp Med Biol 144:231–234PubMedGoogle Scholar
  94. 94.
    Levy PF, Smith BF, LaMont JT (1984) Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology 87:270–275PubMedGoogle Scholar
  95. 95.
    Lee SP, Nicholls JF (1986) Nature and composition of biliary sludge. Gastroenterology 90:677–686PubMedGoogle Scholar
  96. 96.
    Lee SP, Maher K, Nicholls JF (1988) Origin and fate of biliary sludge. Gastroenterology 94:170–176.PubMedGoogle Scholar
  97. 97.
    Carey MC, Cahalane MJ (1988) Whither biliary sludge. Gastroenterology 95:508–523PubMedGoogle Scholar
  98. 98.
    Wang HH, Afdhal NH, Gendler SJ et al (2004) Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation. J Lipid Res 45:438–447PubMedCrossRefGoogle Scholar
  99. 99.
    Wittenburg H, Lammert F, Wang DQH et al (2002) Interacting QTLs for cholesterol gallstones and gallbladder mucin in AKR and SWR strains of mice. Physiol Genomics 8:67–77PubMedGoogle Scholar
  100. 100.
    Groen AK, Noordam C, Drapers JAG et al (1990) Isolation of a potent cholesterol nucleation-promoting activity from human gallbladder bile of patients with solitary or multiple cholesterol gallstones. Hepatology 11:525–533PubMedCrossRefGoogle Scholar
  101. 101.
    Hussaini SH, Pereira SP, Murphy GM et al (1995) Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile. Hepatology 22:1735–1744PubMedGoogle Scholar
  102. 102.
    Miquel JF, Nunez L, Amigo L et al (1998) Cholesterol saturation, not proteins or cholecystitis, is critical for crystal formation in human gallbladder bile. Gastroenterology 114:1016–1023PubMedCrossRefGoogle Scholar
  103. 103.
    Holzbach RT, Kibe A, Thiel E et al (1984) Biliary proteins: unique inhibitors of cholesterol crystal nucleation in human gallbladder bile. J Clin Invest 73:35–45PubMedCrossRefGoogle Scholar
  104. 104.
    Kibe A, Holzbach RT (1984) Inhibition of cholesterol crystal formation by apolipoproteins in supersaturated model bile. Science 255:514–516CrossRefGoogle Scholar
  105. 105.
    Secknus R, Darby GH, Chernosky A et al (1999) Apolipoprotein A-I in bile inhibits cholesterol crystallization and modifies transcellular lipid transfer through cultured human gall-bladder epithelial cells. J Gastroenterol Hepatol 14:446–456PubMedCrossRefGoogle Scholar
  106. 106.
    Stolk MFJ, van de Heijning BJM, van Erpecum KJ et al (1994) The effect of bile acid hydrophobicity on nucleation of several types of cholesterol crystals from model bile vesicles. J Hepatol 20:802–810PubMedCrossRefGoogle Scholar
  107. 107.
    van de Heijning BJM, Stolk MFJ, van Erpecum KJ et al (1994) The effects of bile salt hydrophobicity on model bile vesicle morphology. Biochim Biophys Acta 1212:203–210PubMedGoogle Scholar
  108. 108.
    van Erpecum KJ, Portincasa P, Stolk MFJ et al (1994) Effects of bile salt and phospholipid hydrophobicity on lithogenicity of human gallblader bile. Eur J Clin Invest 24:744–750PubMedCrossRefGoogle Scholar
  109. 109.
    Portincasa P, Di Ciaula A, van Berge-Henegouwen GP (2004) Smooth muscle function and dysfunction in gallbladder disease. Curr Gastroenterol Rep 6:151–162PubMedCrossRefGoogle Scholar
  110. 110.
    Portincasa P, Di Ciaula A, Baldassarre G et al (1994) Gallbladder motor function in gallstone patients: sonographic and in vitro studies on the role of gallstones, smooth muscle function and gallbladder wall inflammation. J Hepatol 21:430–440PubMedCrossRefGoogle Scholar
  111. 111.
    Moschetta A, Stolk MF, Rehfeld JF et al (2001) Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Aliment Pharmacol Ther 15:181–185PubMedCrossRefGoogle Scholar
  112. 112.
    Wang DQH, Schmitz F, Kopin AS et al (2004) Targeted disruption of the murine cholecystokinin-1 recept or promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J Clin Invest 114:521–528PubMedGoogle Scholar
  113. 113.
    Sitzmann JV, Pitt HA, Steinborn PA et al (1990) Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 170:25–31PubMedGoogle Scholar
  114. 114.
    Gebhard RL, Prigge WF, Ansel HJ et al (1996) The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology 24:544–548PubMedCrossRefGoogle Scholar
  115. 115.
    Colecchia A, Sandri L, Bacchi-Reggiani ML et al (2003) Is it possible to predict the clinical course of gallstone disease? Usefulness of gallbladder motility evaluation in a clinical setting. Am J Gastroenterol 101:2576–2581Google Scholar
  116. 116.
    Portincasa P, Moschetta A, Baldassarre G et al (2003) Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting the Rome II criteria for irritable bowel. World J Gastroenterol 9:2293–2299PubMedGoogle Scholar
  117. 117.
    Portincasa P, Moschetta A, Berardino M et al (2004) Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in beta-thalassemia major adults. world J Gastroenterol 10:2383–2390PubMedGoogle Scholar
  118. 118.
    Portincasa P, Moschetta A, Colecchia A et al (2003) Measurement of gallbladder motor function by ultrasonography: towards standardization. Dig Liver Dis (già Ital J Gastroenterol Hepatol) 35 (Suppl 3): S56–S61Google Scholar
  119. 119.
    Portincasa P, Di Ciaula A, Palmieri VO et al (1994) Sonographic evaluation of gallstone burden in humans. Ital J Gastroenterol Hepatol 26:141–144Google Scholar
  120. 120.
    Portincasa P, Di Ciaula A, Palmieri VO et al (1994) Enhancement of gallbladder emptying in gallstone patients after oral cholestyramine. Am J Gastroenterol 89:909–914PubMedGoogle Scholar
  121. 121.
    Portincasa P, Di Ciaula A, Palmieri VO et al (1995) Effects of cholestyramine on gallbladder and gastric emptying in obese and lean subjects. Eur J Clin Invest 25:746–753PubMedCrossRefGoogle Scholar
  122. 122.
    Portincasa P, van Erpecum KJ, van de Meeberg PC et al (1996) Apolipoprotein (Apo) E4 genotype and gallbladder motility influence speed of gallstone clearance and risk of recurrence after extracorporeal shock-wave lithotripsy. Hepatology 24:580–587PubMedCrossRefGoogle Scholar
  123. 123.
    Portincasa P, Di Ciaula A, Palmieri VO et al (1996) Tauroursodeoxycholic acid, ursodeoxycholic acid and gallbladder motility in gallstone patients and healthy subjects. Ital J Gastroenterol Hepatol 28:111–113Google Scholar
  124. 124.
    Portincasa P, Di Ciaula A, Palmieri VO et al (1997) Impaired gallbladder and gastric motility and pathological gastro-esophageal reflux in gallstone patients. Eur J Clin Invest 8:653–661CrossRefGoogle Scholar
  125. 125.
    Portincasa P, Altomare DF, Moschetta A et al (2000) The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, place bocontrolled ultrasonographic study. Am J Gastroenterol 95:3444–3451PubMedCrossRefGoogle Scholar
  126. 126.
    Portincasa P, Di Ciaula A, Vendemiale G et al (2000) Gallbladder motility and cholesterol crystallization in bile from patients with pigment and cholesterol gallstones. Eur J Clin Invest 30:317–324PubMedCrossRefGoogle Scholar
  127. 127.
    Portincasa P, Colecchia A, Di Ciaula A et al (2000) Standards for diagnosis of gastrointestinal motility disorders. Section: ultrasonography. A position statement from the Gruppo Italiano di Studio Motilita Apparato Digerente. Dig Liver Dis 32:160–172PubMedCrossRefGoogle Scholar
  128. 128.
    Portincasa P, Moschetta A, Di Ciaula A et al (2001) Changes of gallbladder and gastric dynamics in patients with acute hepatitis A. Eur J Clin Invest 31:617–622PubMedCrossRefGoogle Scholar
  129. 129.
    Stolk MFJ, van Erpecum KJ, Renooij W et al (1995) Gallbladder emptying in vivo, bile composition and nucleation of cholesterol crystals in patients with cholesterol gallstones. Gastroenterology 108:1882–1888PubMedCrossRefGoogle Scholar
  130. 130.
    van Erpecum KJ, van Berge-Henegouwen GP, Stolk MFJ et al (1992) Fasting gallbladder volume, postprandial emptying and cholecystokinin release in gallstone patients and normal subjects. J Hepatol 14:194–202PubMedCrossRefGoogle Scholar
  131. 131.
    Xiao ZL, Amaral J, Bianeani P et al (2005) Impaired cytoprotective function of muscle in human gallbladders with cholesterol stones. Am. J Physiol Gastrointest Liver Physiol 288:G525–G532PubMedCrossRefGoogle Scholar
  132. 132.
    Di Magno EP, Hendricks JC, Go VLW et al (1979) (Relationships among canine fasting pancreatic and biliary secretions, pancreatic duct pressure, and duodenal phase III motor activity-Boldireff revisited. Dig Dis Sci 24:689–693CrossRefGoogle Scholar
  133. 133.
    Stolk MFJ, van Erpecum KJ, Smout AJPM et al (1993) Motor cycles with phase III in antrum are associated with high motilin levels and prolonged galibladder emptying. Am J Physiol 264:G596–G600.PubMedGoogle Scholar
  134. 134.
    Stolk MF, van Erpecum KJ, Peeters TL et al (2001) Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients. Dig Dis Sci 46:1328–1334PubMedCrossRefGoogle Scholar
  135. 135.
    van Erpecum KJ, Venneman NG, Portincasa P et al (2000) Agents affecting gall-bladder motility—role in treatment and prevention of gallstones (review). Aliment Pharmacol Ther 14 Suppl 2:66–70PubMedCrossRefGoogle Scholar
  136. 136.
    Pauletzki JG, Althaus R, Holl J et al (1996) Gallbladder emptying and gallstone formation: a prospective study on gallstone recurrence. Gastroenterology 111:765–771PubMedCrossRefGoogle Scholar
  137. 137.
    Yu P, Chen Q, Biancani P et al (1996) Membrane cholesterol alters gallbladder muscle contractility in prairie dogs. Am J Physiol 271:G56–61PubMedGoogle Scholar
  138. 138.
    Xiao ZL, Chen Q, Amaral J et al (1999) CCK receptor dysfunction in muscle membranes from human gallbladders with cholesterol stones. Am J Physiol 276:G1401–G1407PubMedGoogle Scholar
  139. 139.
    Yu P, De Petris G, Biancani P et al (1994) Cholecystokinin-coupled intracellular signaling in human gallbladder muscle. Gastroenterology 106:763–770PubMedGoogle Scholar
  140. 140.
    Yu P, Harnett KM, Biancani P et al (1994) Interaction between signal transduction pathways contributing to gallbladder tonic contraction. Am J Physiol 265:1082–1089Google Scholar
  141. 141.
    Yu P, Chen Q, Harnett KM et al (1995) Direct G protein activation reverses impaired CCK signaling in human gallbladders with cholesterol stones. Am J Physiol 269:G659–665PubMedGoogle Scholar
  142. 142.
    Yu P, Chen Q, Xiao Z et al (1998) Signal transduction pathways mediating CCK-induced gallbladder muscle contraction. Am J Physiol 275:G203–211PubMedGoogle Scholar
  143. 143.
    Portincasa P, Stolk MF, van Erpecum KJ et al (1995) Cholesterol gallstone formation in man and potential treatments of the gallbladder motility defect. Scand J Gastroenterol Suppl 212:63–78PubMedCrossRefGoogle Scholar
  144. 144.
    van Erpecum KJ, Stolk MFJ, van den Broek AMWC et al (1993) Bile concentration promotes nucleation of cholesterol monobydrate crystals by increasing the cholesterol concentration in the vesicles. Eur J Clin Invest 23:283–288PubMedCrossRefGoogle Scholar
  145. 145.
    Magnuson TH, Lillemoe KD, Zarkin BA et al (1992) Patients with uncomplicated cholelithiasis acidify bile normally. Dig Dis Sci 37:1517–1522PubMedCrossRefGoogle Scholar
  146. 146.
    Calamita G, Ferri D, Bazzini C et al (2005) Expression and subcellular localization of the AQP8 and AQP1 water channels in the mouse gall-bladder epithelium. Biol Cell 97:415–423PubMedCrossRefGoogle Scholar
  147. 147.
    Conter RL, Roslyn JJ, Porter-Fink V et al (1986) Gallbladder absorption increases during early cholesterol gallstone formation. Am J Surg 151:184–192PubMedCrossRefGoogle Scholar
  148. 148.
    Ginanni Corradini S, Elisei W, Giovannelli L et al (2000) Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile. Gastroenterology 118:912–920CrossRefGoogle Scholar
  149. 149.
    Einarsson C (1999) Lipid absorption by the human gallbladder. Ital J Gastroenterol Hepatol 31:571–573PubMedGoogle Scholar
  150. 150.
    Booker ML, Scott TE, LaMorte WW (1989) Effect of dietary cholesterol on phosphatidylcholines and phosphatidylethanolamines in bile and gallbladder mucosa in the prairie dog. Gastroenterology 97:1261–1267PubMedGoogle Scholar
  151. 151.
    Heaton KW, Emmett PM, Symes CL et al (1993) An explanation for gallstones in normal-weight women: slow intestinal transit. Lancet 341:8–10PubMedCrossRefGoogle Scholar
  152. 152.
    van Erpecum KJ, van Berge-Henegouwen GP (1999) Gallstones: an intestinal disease? Gut 44:435–438PubMedCrossRefGoogle Scholar
  153. 153.
    van Erpecum KJ, Wang DQH, Lammert F et al (2001) Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: soluble pronucleating proteins in gallbladder and hepatic biles. J Hepatol 35:444–451PubMedCrossRefGoogle Scholar
  154. 154.
    Portincasa P, van Erpecum KJ, Jansen A et al (1996) Behavior of various cholesterol crystals in bile from gallstone patients. Hepatology 23:738–748PubMedCrossRefGoogle Scholar
  155. 155.
    Shoda J, He BF, Tanaka N et al (1995) Increase of deoxycholate in supersaturated bile of patients with cholesterol gallstones disease and its correlation with de novo syntheses of cholesterol and bile acids in liver, gallbladder emptying, and small intestinal transit. Hepatology 21:1291–1302PubMedGoogle Scholar
  156. 156.
    Thomas LA, Veysey MJ, Murphy GM et al (2005) Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut 54:630–635PubMedCrossRefGoogle Scholar
  157. 157.
    Thomas LA, Veysey MJ, Bathgate T et al (2000) Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis. Gastroenterology 119:806–815PubMedCrossRefGoogle Scholar
  158. 158.
    Berr F, Kullak-Ublick GA, Paumgartner G et al (1996) Alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology 111:1611–1620PubMedCrossRefGoogle Scholar
  159. 159.
    Pereira SP, Bain IM, Kumar D et al (2003) Bile composition in inflammatory bowel disease: ileal disease and colectomy, but not colitis, induce lithogenic bile. Aliment Pharmacol Ther 17:923–933PubMedCrossRefGoogle Scholar
  160. 160.
    Brink MA, Slors JF, Keulemans YC et al (1999) Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone formation in ileal Crohn’s disease. Gastroenterology 116:1420–1427PubMedCrossRefGoogle Scholar
  161. 161.
    Maurer KJ, Rogers AB, Ge Z et al (2006) Helicobacter pylori and cholesterol gallstone formation in C57L/J mice: a prospective study. Am J Physiol Gastrointest Liver Physiol 290:G175–G182PubMedCrossRefGoogle Scholar
  162. 162.
    Maurer KJ, Ihrig MM, Rogers AB et al (2005) Identification of cholelithogenic enterohepatic helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology 128:1023–1033PubMedCrossRefGoogle Scholar
  163. 163.
    Fox JG, Dewhirst FE, Shen Z et al (1998) Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. Gastroenterology 114:755–763PubMedCrossRefGoogle Scholar
  164. 164.
    Moschetta A, Bookout AL, Mangelsdorf DJ (2004) Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 10:1352–1358PubMedCrossRefGoogle Scholar
  165. 165.
    Wang HH, Wang DQH (2004) Overexpression of liver X receptor a (LXRa) enhance cholesterol (Ch) cholelithogenesis in gallstone-resistant AKR mice (abstract). Gastroenterology 126[4, Suppl. 2]: A15–110Google Scholar

Copyright information

© Springer-Verlag Italia 2008

Authors and Affiliations

  • Piero Portincasa
    • 1
  • Antonio Moschetta
    • 1
    • 2
  • Agostino Di Ciaula
    • 3
  • Daniela Pontrelli
    • 1
  • Rosa C. Sasso
    • 1
  • Helen H. Wang
    • 4
  • David Q. -H. Wang
    • 4
  1. 1.Department of Internal Medicine and Public Medicine Clinica Medica A. MurriUniversity of Bari Medical SchoolBariItaly
  2. 2.Department of Translational PharmacologyConsorzio Mario Negri SudSanta Maria Imbaro (Chieti)Italy
  3. 3.Division of Internal MedicineHospital of BisceglieBisceglie (Bari)Italy
  4. 4.Gastroenterology Division Beth Israel Deaconess Medical Center Department of MedicineHarvard Medical SchoolBostonUSA

Personalised recommendations