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Biliary Lipids and Gallstone Formation

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Clinical Hepatology

Abstract

In its role as an exocrine gland, the liver secretes bile, a solution of detergent-like molecules called bile salts2 and the membrane lipids lecithin (a phospholipid) and unesterified cholesterol (Fig. 1). Other components of bile are the glucuronide and glucose conjugates of bilirubin, the end-products of heme catabolism, and a mixture of proteins of diverse origin. This chapter highlights the biochemical origin and physical-chemical roles of biliary lipids in the formation of bile, and details our present understanding of their malfunction in the pathogenesis of cholesterol gallstones — one of the major diseases of western civilization [1]. In particular, I will discuss present concepts of the physical-chemical and pathophysiological basis of abnormal bile, the evolutionary sequence and stages in the formation of macroscopic stones, and how therapy with specific bile acids may reverse these abnormalities and culminate in the dissolution of stones.

The nomenclature bile salts and bile acids will be employed interchangeably in this chapter

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References

  1. Heaton KW (1973) The epidemiology of gallstones and suggested etiology. Clin Gastroenterol 2: 67–83

    PubMed  CAS  Google Scholar 

  2. Vlahcevic ZR, Schwartz CC, Gustafsson J et al. (1980) Biosynthesis of bile acids in man. Multiple pathways to cholic acid and chenodeoxycholic acid. J Biol Chem 255: 2925–2933

    PubMed  CAS  Google Scholar 

  3. Swell L, Gustafsson, J, Schwartz CC et al. (1980) An in vivo evaluation of the quantitative significance of several potential pathways to cholic and chenodeoxycholic acids from cholesterol in man. J Lipid Res 21: 455–466

    PubMed  CAS  Google Scholar 

  4. Swell L, Schwartz CC, Gustafsson J et al. (1981) A quantitative evaluation of the conversion of 25-hydroxycholesterol to bile acids in man. Biochim Biophys Acta 663: 163–168

    PubMed  CAS  Google Scholar 

  5. Salen G, Shefer S, Setoguchi T et al. (1975) Bile alcohol metabolism in man. Conversion of 5β-cholestane 3α,7 α,12α-25-tetrol to cholic acid. J Clin Invest 56: 226–231

    Article  PubMed  CAS  Google Scholar 

  6. Björkhem I, Gustafsson J, Johansson G et al. (1975) Biosynthesis of bile acids in man. Hydroxylation of the C-27 steroid side chain. J Clin Invest 55: 478–486

    Article  PubMed  Google Scholar 

  7. Nilsson S (1970) Synthesis and secretion of biliary phospholipids in man. Act Chir Scand Suppl 405: 6–38

    Google Scholar 

  8. Fears R (1981) The contribution of the cholesterol biosynthetic pathway to intermediary metabolism and cell function. Biochem J 199: 1–7

    PubMed  CAS  Google Scholar 

  9. Dietschy JM, Wilson JD (1970) Regulation of cholesterol metabolism. New Engl J Med 282:1128–1138; 1179–1183; 1261–1269

    Google Scholar 

  10. Carey MC (1982) The enterohepatic circulation. In: Arias I et al. (eds) The liver, biology and pathobiology. Raven Press, New York pp 429–465 I

    Google Scholar 

  11. Carey MC, Robins SJ (1982) Bile production and secretion. In: Stein JH et al. (eds) Internal medicine. Little Brown, Boston

    Google Scholar 

  12. Brown MS, Kovanen PT, Goldstein JL (1981) Regulation of plasma cholesterol by lipoprotein receptors. Science (Wash DC) 212:628–635

    Article  CAS  Google Scholar 

  13. Brown MS, Goldstein JL (1981) Lowering plasma cholesterol by raising LDL receptors. New Engl J Med 305: 515–517. (Editorial)

    Article  PubMed  CAS  Google Scholar 

  14. Danielsson H (1973) Mechanism of bile acid synthesis. In: Nair PP, Kritchevsky D (eds) The bile acids, vol 3. Plenum, New York, pp 1–32

    Google Scholar 

  15. Scherstén T (1970) Bile acid conjugation. In: Fishman WF (ed) Metabolic conjugation and metabolic hydrolysis, vol 2. Academic Press, New York, pp 75–121

    Google Scholar 

  16. Small DM (1971) The physical chemistry of cholanic acids. In: Nair PP, Kritchevsky D (eds) The bile acids, vol 1. Plenum, New York, pp 249–356

    Google Scholar 

  17. Carey MC, Small DM (1972) Micelle formation by bile salts: physical-chemical and thermodynamic considerations. Arch Int Med 130: 506–527

    Article  CAS  Google Scholar 

  18. Dietschy JM (1968) Mechanisms for the intestinal absorption of bile acids. J Lipid Res 9: 297–309

    PubMed  CAS  Google Scholar 

  19. Hofmann AF (1976) The enterohepatic circulation of bile acids in man. In: Stollerman GH (ed) Advances in internal medicine, vol 21. Year Book, Chicago, pp 501–534

    Google Scholar 

  20. Matern S, Gerok W (1979) Pathophysiology of the enterohepatic circulation. Rev Physiol Biochem Pharmacol 85: 126–204

    Google Scholar 

  21. Fromm H, Carlson GL, Hofmann AF et al. (1980) Metabolism in man of 7-ketolithocholic acid: Precursor of cheno- and ursodeoxycholic acids. Am J Physiol 239. G161–G166

    PubMed  CAS  Google Scholar 

  22. Cowen AE, Korman MG, Hofmann AF et al. (1980) Metabolism of lithocholate in healthy man. I. Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine and their sulfates. Gastroenterology 69: 59–66

    Google Scholar 

  23. Ahlberg J, Curstedt T, Einarsson K et al. (1981) Molecular species of biliary phosphatidylcholines in gallstone patients: The influence of treatment with cholic and chenodeoxycholic acids. J Lipid Res 22: 404–409

    PubMed  CAS  Google Scholar 

  24. Cantafora A, Angelico M, DiBase A et al. (1981) Structure of biliary phosphatidylcholine in cholesterol gallstone patients. Lipids 16: 589–592

    Article  PubMed  CAS  Google Scholar 

  25. Carey MC (1982) Role of lecithin in the absorption of dietary fat. In: Paaletti, R et al. (eds) Phospholipids and atherosclerosis. Raven Press, New York

    Google Scholar 

  26. Zeisel SH (1981) Dietary choline: Biochemistry, physiology and pharmacology. Ann Rev Nutr 1: 95–121

    Article  CAS  Google Scholar 

  27. Kawamoto T, Okano G, Akino T (1980) Biosynthesis and turnover of individual molecular species of phosphatidylcholine in liver and bile. Biochim Biophys Acta 619: 20–34

    PubMed  CAS  Google Scholar 

  28. Balint JA, Beeler DA, Kyriakides EC et al. (1971) The effects of bile salts upon lecithin synthesis. J Lab Clin Med 77: 122–133

    PubMed  CAS  Google Scholar 

  29. Kawamoto T, Akino T, Nakamura M et al. (1980) Metabolism of individual molecular species of phosphatidylcholine in the liver; subcellular membranes and bile. Origin of bile phosphatidylcholine. Biochim Biophys Acta 619: 35–47

    PubMed  CAS  Google Scholar 

  30. Turley SD, Dietschy JM (1979) Regulation of biliary cholesterol output in the rat: Dissociation from the rate of hepatic cholesterol synthesis, the size of the cholesteryl ester pool and the hepatic uptake of chylomicron cholesterol. J Lipid Res 20: 923–934

    PubMed  CAS  Google Scholar 

  31. Carey MC, Small DM (1978) Physical-chemistry of cholesterol solubility in bile: Relationship to gallstone formation and dissolution in man. J Clin Invest 61: 998–1026

    Article  PubMed  CAS  Google Scholar 

  32. Thornton JR, Heaton KW, MacFarlane DG (1981) A relation between high-density lipoprotein cholesterol and bile cholesterol saturation. Br Med J 283: 1352–1354

    Article  CAS  Google Scholar 

  33. Schwartz CC, Halloran LG, Vlahcevic ZR et al. (1978) Preferential utilization of free cholesterol from high-density lipoprotein for biliary cholesterol secretion in man. Science (Wash DC) 200: 62–64

    Article  CAS  Google Scholar 

  34. Schwartz CC, Berman M, Vlahcevic ZR et al. (1978) Multicompartmental analysis of cholesterol metabolism in man. Characterization of the hepatic bile acid and biliary cholesterol precursor sites. J Clin Invest 61: 408–423

    Article  PubMed  CAS  Google Scholar 

  35. Pangburn SH, Newton RS, Chang C-M et al. (1981) Receptor-mediator catabolism of homologous low-density lipoproteins in cultured pig hepatocytes. J Biol Chem 256: 3340–3347

    PubMed  CAS  Google Scholar 

  36. Sabesin SM (1982) Hepatocyte low-density lipoprotein catabolism. Gastroenterology 82: 386–388 (selected summaries)

    Google Scholar 

  37. DenBesten L, Connor WE, Bell S (1973) The effect of dietary cholesterol on the composition of human bile. Surgery 73: 266–273

    PubMed  CAS  Google Scholar 

  38. Bennion LJ, Grundy SM (1975) Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 56: 996–1011

    Article  PubMed  CAS  Google Scholar 

  39. Grundy SM, Ahrens EH Jr, Salen G et al. (1972) Mechanism of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J Lipid Res 13: 531–551

    PubMed  CAS  Google Scholar 

  40. Einarsson K, Grundy SM (1980) Effects of feeding cholic acid and chenodeoxycholic acid on cholesterol absorption and hepatic secretion of biliary lipids in man. J Lipid Res 21: 23–34

    PubMed  CAS  Google Scholar 

  41. Carella M, Dietschy JM (1977) Comparison of the effects of cholic acid and chenic acid feeding on rates of cholesterol synthesis in the liver of the rat. Am J Dig Dis 22: 318–326

    Article  Google Scholar 

  42. Coyne M J, Bonorris GG, Goldstein LI et al. (1976) Effects of chenodeoxycholic acid and phenobarbital on the rate-limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones. J Lab Clin Med 87: 281–291

    PubMed  CAS  Google Scholar 

  43. Angelin B, Mahley W (in preparation) Taurocholate down-regulates apolipoprotein E receptors on dog hepatocytes

    Google Scholar 

  44. Schoenfield LJ, Lachin JM et al. (1981) Chenodiol (chenodeoxycholic acid) for dissolution of gallstones. The National Cooperative Gallstone Study: A controlled trial of efficacy and safety. Ann Int Med 95: 257–282

    PubMed  CAS  Google Scholar 

  45. Carey MC, Small DM (1970) The characteristics of mixed micellar solutions with particular reference to bile. Am J Med 49: 590–608

    Article  PubMed  CAS  Google Scholar 

  46. Loomis CR, Shipley GG, Small DM (1979) The phase behavior of hydrated cholesterol. J Lipid Res 20: 525–535

    PubMed  CAS  Google Scholar 

  47. Small DM (1977) Liquid crystals in living and dying systems. J Colloid Interface Sci 58: 581–602

    Article  CAS  Google Scholar 

  48. 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: 3064–3075

    Article  PubMed  CAS  Google Scholar 

  49. 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: 601–615

    Article  PubMed  CAS  Google Scholar 

  50. Mazer MA, Carey MC (to be published) Quasielastic light scattering studies of aqueous biliary lipid systems. Cholesterol solubilization and precipitation in model bile solutions. Biochemistry

    Google Scholar 

  51. Carey MC, Montet J-C, Phillips MC et al (1981) Thermodynamic and molecular basis for dissimilar cholesterol solubilizing capacities by micellar solution of bile salts: Cases of sodium chenodeoxycholate and sodium ursodeoxycholate and their glycine and taurine conjugates. Biochemistry 20: 3637–3648

    Article  PubMed  CAS  Google Scholar 

  52. Shaffer EA, Small DM (1976) Gallstone disease: Pathogenesis and management. Curr Probl Surg 13: 1–72

    Article  Google Scholar 

  53. Ponz de Leon M, Carulli N (1980) How does bile acid feeding regulate cholesterol entry into bile ? Gastroenterology 78: 425–426

    Google Scholar 

  54. Bennion LJ, Drobny E, Knowler WC et al. (1978) Sex differences in the size of bile acid pools. Metabolism 26: 961–969

    Article  Google Scholar 

  55. Pomare EW, Heaton KW, Low-Beer TS et al. (1976) The effect of wheat bran upon bile salt metabolism and upon the lipid composition of bile in gallstone patients. Am J Dig Dis 21: 521–526

    Article  PubMed  CAS  Google Scholar 

  56. Low-Beer TS, Nutter S (1978) Colonic bacterial activity, biliary cholesterol saturation and pathogenesis of gallstones. 2: 1063–1064

    CAS  Google Scholar 

  57. Thornton JR, Heaton KW (1981) Effects of lactulose on bile composition. In: Paumgartner G et al. (eds) Bile acids and lipids. MTP Press, Lancaster, pp 181–188

    Google Scholar 

  58. Low-Beer TS, Pomare EW (1975) Can colonic bacterial metabolites predispose to cholesterol gallstones. Br Med J 1: 438–440

    Article  PubMed  CAS  Google Scholar 

  59. Angelin B, Einarsson K, Ewerth S et al. (1980) Biliary lipid composition in patients with portal cirrhosis of the liver. Scand J Gastroenterol 15: 849–852

    Article  PubMed  CAS  Google Scholar 

  60. Kern F, Everson GT, DeMark B et al. (1981) Biliary lipids, bile acids and gallbladder function in the human female. J Clin Invest 68: 1229–1242

    Article  PubMed  CAS  Google Scholar 

  61. Salvioli G, Carey MC (1982) A novel in vitro perfusion system to study membrane dissolution by bile salts: Different effects of taurochenodeoxycholate and tauro-ursodeoxycholate on lipid secretion and membrane resistance. Gastroenterology 82: 1168 (abstract)

    Google Scholar 

  62. Sarles H, Hauton J, Planche NE et al. (1970) Diet, cholesterol gallstones and the composition of bile. Am J Dig Dis 15: 251–260

    Article  PubMed  CAS  Google Scholar 

  63. Fridhandler TM, Davison JS, Kelly J et al. (1982) Depression of gallbladder contractility associated with early increases in bile lithogenicity. Gastroenterology 82: 1061 (abstract)

    Google Scholar 

  64. Roslyn AJ, Pitt HA, Kuchenbecker FL (1980) Alteration in biliary tract motility during cholesterol gallstone formation. Surg Forum 31: 205–206

    CAS  Google Scholar 

  65. Brotschi EA, LaMorte WW, Williams LF (1982) Dietary cholesterol and indomethacin alter gallbladder motility. Gastroenterology 82: 1026 (abstract)

    Google Scholar 

  66. Forgacs IC, Maisey MN, Dowling RH (1982) Reducing gallbladder contracting during ursodeoxycholic (UDCA) acid therapy — a possible explanation for relief of biliary pain during treatment. 7th Int Symp on Bile Acids, Cortina, Italy (Abstr )

    Google Scholar 

  67. Bouchier IAD, Cooperband SR, El Kodsi BM (1966) Mucous substances and viscosity of normal and pathological human bile. Gastroenterology 49: 343–353

    Google Scholar 

  68. Lee SP, 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: 1712–1723

    Article  PubMed  CAS  Google Scholar 

  69. Lee SP, Carey MC, LaMont JT (1981) Aspirin prevention of cholesterol gallstone formation in prairie dogs. Science (Wash DC) 211: 1429–1431

    Article  CAS  Google Scholar 

  70. DeBenedetto D, Turner B, Handin RI et al. (1981) Indomethacin inhibits gallbladder mucin secretion and prostaglandin release. Gastroenterology 80: 1133 (Abstr)

    Google Scholar 

  71. Rutledge FA, Hickman DM, Dunn JJ et al. (1981) Lysophosphatidylcholine acyltransferase activity during experimental cholelithiasis. Lipids 16: 714–720

    Article  PubMed  CAS  Google Scholar 

  72. Pitt HA, Roslyn JJ, Kuchenbecker SL et al. (1981) The role of cystic duct resistance in the pathogenesis of cholesterol gallstones. J Surg Res 30: 508–514

    Article  PubMed  CAS  Google Scholar 

  73. Pitt HA, Doty JE, DenBesten L et al. (1982) Stasis before gallstone formation: Altered gallbladder complicance or cystic duct resistance. Am J Surg 143: 144–149

    Article  PubMed  CAS  Google Scholar 

  74. Krejs GJ, Orci L, Conlon JM et al. (1979) Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med 301: 285–292

    Article  PubMed  CAS  Google Scholar 

  75. Tomkins R, Kraft AR, Zimmerman E et al. (1972) Clinical and biochemical evidence of increased gallstone formation after complete vagotomy. Surgery 71: 196–206

    Google Scholar 

  76. Holzbach RT, Marsh M (1974) Transient liquid crystals in human bile analogues. Mol Cryst Liq Cryst 28: 217–222

    Article  CAS  Google Scholar 

  77. Holzbach RT, Corbusier C, Marsh M et al. (1976) The process of cholesterol cholelithiasis induced by diet in the prairie dog: A physico-chemical characterization. J Lab Clin Med 87: 987–998

    PubMed  CAS  Google Scholar 

  78. Toor EW, Evans DF, Cussler EL (1978) Cholesterol monohydrate growth in model bile solutions. Proc Natl Acad Sci 75: 6230–6234

    Article  PubMed  CAS  Google Scholar 

  79. Holan KR, Holzbach RT, Hermann RE et al. (1979) Nucleation time: A key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 77: 611–617

    PubMed  CAS  Google Scholar 

  80. Womach NA, Zeppa R, Irvin GL III (1963) The anatomy of gallstones. Ann Surg 157: 670–686

    Article  Google Scholar 

  81. Womack NA (1971) The development of gallstones. Surg Gynecol Obstet 133: 937–945

    PubMed  CAS  Google Scholar 

  82. Nakayama F (1980) Oral cholelitholysis — cheno versus urso. Japanese experience. Dig Dis Sci 25: 129–134

    Article  PubMed  CAS  Google Scholar 

  83. Armstrong MJ, Carey MC (1982) The hydrophobic-hydrophilic balance of bile salts: Inverse correlation between reverse-phase, high-performance liquid chromatographic mobilities and mi- cellar cholesterol solubilizing capacities. J Lipid Res 23: 70–80

    PubMed  CAS  Google Scholar 

  84. Sama C, LaRusso NF, Lopez del Pino V et al. (1982) Effects of acute bile acid administration on biliary lipid secretion in healthy volunteers. Gastroenterology 82: 515–525

    PubMed  CAS  Google Scholar 

  85. Poupon RE, Poupon RY, Duval M et al. (1979) Chronic administration of chenodeoxycholic acid increases cholesterol saturation in bile in the dog. Eur J Clin Invest 9: 103–105

    Article  PubMed  CAS  Google Scholar 

  86. Pearlman BJ, Bonorris GG, Phillips MJ et al. (1979) Cholesterol gallstone formation and prevention by chenodeoxycholic and ursodeoxycholic acids. Gastroenterology 74: 634–641

    Google Scholar 

  87. Maton PN, Murphy GM, Dowling RH (1977) Ursodeoxycholic acid treatment of gallstones: Dose response study and possible mechanism of action. Lancet II: 1297–1301

    Article  Google Scholar 

  88. Tokyo Co-operative Gallstone Study Group (1980) Efficacy and indications of ursodeoxycholic acid treatment for dissolving gallstones. A multicenter double-blind trial. Gastroenterology 78: 542–548

    Google Scholar 

  89. Salvioli G, Igimi H, Carey MC (to be published) Cholesterol gallstone dissolution in bile. Dissolution kinetics of crystalline cholesterol monohydrate by conjugated chenodeoxycholate-lecithin and ursodeoxycholate-lecithin mixtures: Dissimilar phase equilibria and dissolution mechanisms. J Lipid Res

    Google Scholar 

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Authors and Affiliations

  1. Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA

    M. C. Carey

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  1. M. C. Carey
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Editors and Affiliations

  1. Department of Clinical Research, Heimhuder Straße 46, D-2000, Hamburg 13, Germany

    Géza Csomós M.D.

  2. School of Medicine, University of Vienna, Austria

    Heribert Thaler M.D. (Assoc. Professor, Head of the 4th Medical Department) (Assoc. Professor, Head of the 4th Medical Department)

  3. Wilhelminenspital of the City of Vienna, 16, Montlearstraße 37, A-1171, Vienna, Austria

    Heribert Thaler M.D. (Assoc. Professor, Head of the 4th Medical Department) (Assoc. Professor, Head of the 4th Medical Department)

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© 1983 Springer-Verlag Berlin Heidelberg

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Carey, M.C. (1983). Biliary Lipids and Gallstone Formation. In: Csomós, G., Thaler, H. (eds) Clinical Hepatology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68748-8_5

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  • DOI: https://doi.org/10.1007/978-3-642-68748-8_5

  • Publisher Name: Springer, Berlin, Heidelberg

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