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The Secretory Defect

  • K. Einarsson
  • B. Angelin

Abstract

Most patients with cholesterol gallstone disease have supersaturated gallbladder bile, i.e. the amount of cholesterol is in excess of what can theoretically be kept in solution. Saturated bile is also more common among races and populations with a high frequency of gallstones1, 2. The development of supersaturated bile appears to be a necessary step for the subsequent precipitation of cholesterol, and may thus be considered a major risk factor for cholesterol gallstones. Many individuals without gallstone disease, however, also have supersaturated bile3, 4 (Figure 1). It has therefore become evident that other factors are required for crystallisation of cholesterol and aggregation of the crystals to occur. This chapter summarises and discusses recent studies of the mechanisms leading to the supersaturation of bile in situations where cholesterol gallstones are common.

Keywords

Bile Acid Gallstone Disease Cholesterol Gallstone Bile Acid Synthesis Gallbladder Bile 
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.

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References

  1. 1.
    Bennion, L.J. and Grundy, S.M. (1978). Risk factors for the development of cholelithiasis in man. N. Engl. I. Med., 299, 1161–7, 1221–7CrossRefGoogle Scholar
  2. 2.
    Oviedo, M.A., Ho, KJ., Biss, K., Soong, SJ., Mikkelson, B. and Taylor, C.B. (1977). Gallbladder bile composition in different ethnic groups. Arch. Pathol. Lab. Med., 101, 208–12PubMedGoogle Scholar
  3. 3.
    Holzbach, R.T., Marsh, M., Olszewski, M. and Holan, K. (1973). Cholesterol solubility in bile: Evidence that supersaturated bile is frequent in healthy man. J. Clin. Invest, 52, 1467–79PubMedCrossRefGoogle Scholar
  4. 4.
    Ahlberg, J., Angelin, B. and Einarsson, K. (1981). Hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity and biliary lipid composition in man: Relation to cholesterol gallstone disease and effects of cholic acid and chenodeoxycholic acid treatment. Lipid. Res., 22, 410–22PubMedGoogle Scholar
  5. 5.
    Lindstrom, C.G. (1977). Frequency of gallstone disease in a welldefined Swedish population: A prospective necropsy study in Malmo Scand. J. Gastroenterol, 12, 341–6PubMedCrossRefGoogle Scholar
  6. 6.
    Einarsson, K., Nilsell, K., Leijd, B. and Angelin, B. (1985). Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N. Engl. Med., 313, 277–82CrossRefGoogle Scholar
  7. 7.
    Angelin, B., Einarsson, K., Ewerth, S. and Leijd, B. (1981). Biliary lipid composition in obesity. Scand. I. Gastroenterol, 16, 1015–9PubMedCrossRefGoogle Scholar
  8. 8.
    Bennion, LJ. and Grundy, S.M. (1975). Effects of obesity and caloric intake on biliary lipid metabolism in man./. Clin. Invest., 56, 996–1011CrossRefGoogle Scholar
  9. 9.
    Whiting, M.J. and Watts, J.McK. (1984). Supersaturated bile from obese patients without gallstones supports cholesterol crystal growth but not nucleation. Gastroenterology, 86, 243–8PubMedGoogle Scholar
  10. 10.
    Einarsson, K., Hellstrom, K. and Kallner, M. (1975). Gallbladder disease in hyperlipoproteinemia. Lancet, 1, 484–7PubMedCrossRefGoogle Scholar
  11. 11.
    Einarsson, K. and Angelin, B. (1986). Hyperlipoproteinemia, hypolipidemic treatment and gallstone disease. In Grundy, S.M. (ed.) Bile Acids and Atherosclerosis, pp. 66–97, (New York: Raven Press)Google Scholar
  12. 12.
    Angelico, M. and the GREPCO Group (1984). Relationships between serum lipids and cholelithiasis: Observations in the GREPCO study. In Capocaccia, L., Ricci, G., Angelico, F., Angelico, M. and Attili, A.F. (eds)Epidemiology and Prevention of Gallstone Disease, pp. 77–84 (Lancaster: MTP Press)Google Scholar
  13. 13.
    Angelico, M. and the GREPCO Group (1984). Factors associated with gallstone disease: Observations in the GREPCO study. In Capocaccia, L., Ricci, G., Angelico, F., Angelico, M. and Attili, A.F. (eds) Epidemiology and Prevention of Gallstone Disease, pp. 185–192 (Lancaster: MTP Press)Google Scholar
  14. 14.
    Roda, E., “for the Progetto Sirmione”. (1984). Factors associated with gallstone disease: Observations in the “Sirmione Study”. In Capocaccia, L., Ricci, G., Angelico, F., Angelico, M. and Attili, A.F. (eds)Epidemiology and Prevention of Gallstone Disease, pp. 207–9 (Lancaster: MTP Press)Google Scholar
  15. 15.
    Scragg, R.K., Calvert, G.D. and Oliver, J.R. (1984). Plasma lipids and insulin in gallstone disease: A case-control study. Br. Med.J., 289, 523–5Google Scholar
  16. 16.
    Kadziolka, R., Nilsson, S. and Schersten, T. (1977). Prevalence of hyper-lipoproteinaemia in men with gallstone disease. Scand. J. Gastroenterol 12, 353–5PubMedCrossRefGoogle Scholar
  17. 17.
    Ahlberg, J. (1979). Serum lipid levels and hyperlipoproteinemia in gallstone patients. Acta Chir. Scand., 145, 373–7PubMedGoogle Scholar
  18. 18.
    Ahlberg, J., Angelin, B., Einarsson, K., Hellström, K. and Leijd, B. (1980). Biliary lipid composition in normo- and hyperlipoproteinemia. Gastroenterology, 79, 90–4PubMedGoogle Scholar
  19. 19.
    Cooper, J., Ceizerova, H. and Oliver, M.F. (1975). Clofibrate and gallstones. Lancet, 1, 1083PubMedCrossRefGoogle Scholar
  20. 20.
    Coronary Drug Project Research Group (1977). Gallbladder disease as a side effect of drugs influencing lipid metabolism. N. Engl. I. Med., 296 1185–90CrossRefGoogle Scholar
  21. 21.
    Thistle, J.L. and Schoenfield, LJ. (1971). Induced alterations in composition of bile of persons having cholelithiasis. Gastroenterology, 61, 488–96PubMedGoogle Scholar
  22. 22.
    Grundy, S.M., Ahrens, E.H., Jr., Salen, G., Schreibman, P.H. and Nestel, P.J. (1972). Mechanisms of action of Clofibrate on cholesterol metabolism in patients with hyper lipidemia. J. Lipid. Res., 13, 531–51Google Scholar
  23. 23.
    Pertsemlidis, D., Panveliwalla, D. and Ahrens, E.H., Jr. (1974). Effects of Clofibrate and of an ostrogen-progestin combination on fasting biliary lipids and cholic acid kinetics in man. Gastroenterology, 66, 565–73PubMedGoogle Scholar
  24. 24.
    Bateson, M.C., Maclean, D. Ross, P.E. and Bouchier, I.A.D. (1978). Clofibrate therapy and gallstone induction. Dig. Dis., 23, 623–8CrossRefGoogle Scholar
  25. 25.
    Grundy, S.M. and Mok, H.Y.I. (1979). Effects of diets and drugs on biliary cholesterol secretion in man. In Fisher, M.M., Goresky, C.A., Shaffer, E.A. and Strasberg, S.M. (eds.) Gallstones, pp. 283–98 (New York: Plenum Press)Google Scholar
  26. 26.
    Angelin, B., Einarsson, K. and Leijd, B. (1979). Biliary lipid composition during treament with different hypolipidaemic drugs. Eur. J. Clin. Invest., 9, 185–90PubMedCrossRefGoogle Scholar
  27. 27.
    Angelin, B., Einarsson, K. and Leijd, B. (1981). Clofibrate treatment and bile cholesterol saturation: Short-term and long-term effects and influence of combination with ehenodeoxycholic acid. Eur. I. Clin. Invest., 11, 185–9CrossRefGoogle Scholar
  28. 28.
    Kesäniemi, Y.A. and Grundy, S.M. (1983). Clofibrate, caloric restriction, supersatura- tion of bile, and cholesterol crystals. Scand. J. Gastroenterol., 18, 897–902PubMedCrossRefGoogle Scholar
  29. 29.
    Von Bergmann, K. and Leiss, O. (1984). Effects of short-term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in patients with hyperlipidaemia. Eur. I. Clin. Invest., 14, 150–4CrossRefGoogle Scholar
  30. 29.
    Eriksson, M. and Angelin, B. (1987). Bezefibrate therapy and biliary lipids : effects of short-term and long-term treatment in patients with various forms of hyperlipoproteinemia. Eur. J. Clin. Invest., 17, 396–401PubMedCrossRefGoogle Scholar
  31. 31.
    Leiss, O., von Bergmann, K., Gnasso, A. and Augustin, J. (1985). Effect of gemofibrozil on biliary lipid metabolism in normolipidaemic subjects. Metabolism, 34, 74–82PubMedCrossRefGoogle Scholar
  32. 32.
    Angelin, B., Einarsson, K. and Leijd, B. (1984). Effects of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia. Eur. J. Clin. Invest., 14, 73–8PubMedCrossRefGoogle Scholar
  33. 33.
    Boston Collaborative Drug Surveillance Program. (1974). Surgically confirmed gallbladder disease, venous thrombo-embolism, and breast tumors in relation to postmenopausal oestrogen therapy. N. Engl. J. Med., 290, 15–9CrossRefGoogle Scholar
  34. 34.
    Stolley, P.D., Tonascia, J.A., Tockman, M.S., Sartwell, P.E., Rutledge, A.H. and Jacobs, M.P. (1975). Thrombosis with low-oestrogen oral contraceptives. Am. J. Epidemiol., 102, 197–208PubMedGoogle Scholar
  35. 35.
    Bennion, L.J., Ginsberg, R.L., Garnick, M.B. and Bennet, P.H. (1976). Effects of oral contraceptives on the gallbladder bile of normal women. N. Engl. J. Med., 294, 189–92PubMedCrossRefGoogle Scholar
  36. 36.
    Andersson, A., James, O.F.W., MacDonald, H.S., Snowball, S. and Taylor, W. (1980). The effects of ethinyloestradiol on biliary lipid composition in young men. Eur. J. Clin. Invest., 10, 77–80CrossRefGoogle Scholar
  37. 37.
    Holzbach, R.T. and Kibe, A. (1985). Pathogenesis of cholesterol gallstones. In Cohen, S. and Soloway, R.D. (eds) Gallstones, pp. 73–100, (New York: Churchill Livingstone)Google Scholar
  38. 38.
    Shaffer, E.A. and Small, D.M. (1977). Biliary lipid secretion in cholesterol gallstone disease: The effect of cholecystectomy and obesity./. Clin. Invest., 59, 828–40CrossRefGoogle Scholar
  39. 39.
    Reuben, A., Maton, P.N., Murphy, G.M. and Dowling, R.H. (1985). Bile lipid secretion in obese and non-obese individuals with and without gallstones. Clin. Sci., 69, 71–9PubMedGoogle Scholar
  40. 40.
    Nilsell, K., Angelin, B., Liljeqvist, L. and Einarsson, K. (1985). Biliary lipid output and bile acid kinetics in cholesterol gallstone disease: Evidence for an increased hepatic secretion of cholesterol in Swedish patients. Gastroenterology, 89, 287–93PubMedGoogle Scholar
  41. 41.
    Leiss, O. and von Bergmann, K. (1985). Comparison of biliary lipid secretion in non- obese cholesterol gallstone patients with normal, young, male volunteers. Klin. Wochensehr., 63, 1163–9CrossRefGoogle Scholar
  42. 42.
    Valdivieso, V.D., Palma, R., Nervi, F., Covarrubias, C., Severin, C. and Antezana, C. (1979). Secretion of biliary lipids in young Chilean women with cholesterol gallstones. Gut, 20, 997–1000PubMedCrossRefGoogle Scholar
  43. 43.
    Sampliner, R.E., Bennett, P.H., Commess, L.J., Rose, F.A. and Burch, T.A. (1970). Gallbladder disease in Pima Indians: Demonstration of high prevalence and early onset by cholecystography. N. Engl. J. Med., 283, 1358–64PubMedCrossRefGoogle Scholar
  44. 44.
    Bennion, L.J., Knowler, W.C., Mott, D.M., Spagnola, A.M. and Bennett, P.H. (1979). Development of lithogenic bile during puberty in Pima Indians. N. Engl. J. Med., 300, 873–6PubMedCrossRefGoogle Scholar
  45. 45.
    Angelin, B. (1984). Regulation of hepatic lipoprotein receptor expression. In Calandra, S., Carulli, N. and Salvioli, G. (eds.) Liver and Lipid Metabolism, pp. 187–201 (Amsterdam: Elsevier)Google Scholar
  46. 46.
    Grundy, S.M., Metzger, A.L. and Adler, R.D. (1972). Mechanisms of lithogenic bile formation in American Indian women with cholesterol gallstones. J.Clin. Invest., 51, 3026–43PubMedCrossRefGoogle Scholar
  47. 47.
    Angelin, B. and Einarsson, K. (1985). Regulation of HMG Co A reductase in human liver. In Preiss, B. (ed.) Regidation of HMG CoA Reductase, pp. 281–320 (New York: Academic Press)Google Scholar
  48. 48.
    Suckling, K.E. and Stange, E.F. (1985). Role of acyl-CoA: cholesterol acyltransferase in cellular cholesterol metabolism. J.Lipid. Res., 26, 647–71PubMedGoogle Scholar
  49. 49.
    Bjorkhem, I. (1985). Mechanism of bile acid synthesis in mammalian liver. In Danielsson, H. and Sjovall, J. (eds.)Sterols and Bile Acids, pp. 231–278, (Amsterdam: Elsevier Scientific Publishing Company)CrossRefGoogle Scholar
  50. 50.
    Einarsson, K., Angelin, B,., Ewerth, S., Nilsell, K. and Bjorkhem, I. (1986). Bile acid synthesis in man: Assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by isotope dilution-mass spectrometry. J.Lipid. Res.., 21, 82–8CrossRefGoogle Scholar
  51. 51.
    Lindstedt, S. (1957). The turnover of cholic acid in man Acta Physiol Scand 40, 1–9PubMedCrossRefGoogle Scholar
  52. 52.
    Angelin, B. and Einarsson, K. (1986). Bile acids and lipoprotein metabolism. In Grundy, S.M. (ed.) Bile Acids and Atherosclerosis, pp. 41–66 (New York: Raven Press)Google Scholar
  53. 53.
    Miettinen, T.A. (1970). Cholesterol production in obesity. Circulation, 44, 842–50Google Scholar
  54. 54.
    Nestel, P.J., Schreibman, P.H. and Ahrens, E.H. Jr. (1973). Cholesterol metabolism in human obesity. J.Clin. Invest., 52, 2389–97PubMedCrossRefGoogle Scholar
  55. 55.
    Angelin, B., Backman, L., Einarsson, K., Eriksson, L. and Ewerth, S. (1981). Hepatic cholesterol metabolism in obesity: Activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase. J.Lipid. Res., 23, 770–3Google Scholar
  56. 56.
    Leijd, B. (1980). Cholesterol and bile acid metabolism in obesity. Clin. Sci., 59, 203–6PubMedGoogle Scholar
  57. 57.
    Angelin, B., Hershon, K.S. and Brunzell, J.D. (1987). Bile acid metabolism in hereditary forms of hypertriglyceridemia: Evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc. Natl Acad. Sci. USA., 84, 5434–8PubMedCrossRefGoogle Scholar
  58. 58.
    Ahlberg, J., Angelin, B., Bjorkhem, I., Einarsson, K. and Leijd, B. (1979). Hepatic cholesterol metabolism in normo- and hyperlipidemic patients with cholesterol gallstones J.Lipid. Res., 20, 107–15PubMedGoogle Scholar
  59. 59.
    Einarsson, K., Hellstrom, K. and Kallner, M. (1973). The effect of clofibrate on the elimination of cholesterol as bile acids in patients with hyperlipoproteinaemia type II and IV. Eur. J. Clin. Invest., 3, 345–51PubMedCrossRefGoogle Scholar
  60. 60.
    Angelin, B. (1984). Effects of hypolipidemic treatment on bile acid and cholesterol metabolism in man. In Carlson, L.A. and Olsson, A.G. (eds.) Treatment of Hyperlipoproteinemia pp. 121–4 (New York: Raven Press)Google Scholar
  61. 61.
    Kesäniemi, Y.A. and Grundy, S.M. (1984). Influence of gemfibrozil and Clofibrate on metabolism of cholesterol and plasma triglycerides in man. J. Am. Med. Assoc., 251, 2241–6CrossRefGoogle Scholar
  62. 62.
    Kovanen, P.T., Brown, M.S. and Goldstein, J.L. (1979). Increased binding of low density lipoprotein to liver membranes from rats treated with 17a-ethinyl estradiol. J. Biol Chem., 254, 11367–73PubMedGoogle Scholar
  63. 63.
    Windler, E.E., Kovanen, P.T., Chao, Y.S., Brown, M.S., Havel, R J. and Goldstein, J.L. (1980). The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that mediates the uptake of rat lipoproteins containing apoproteins B and E. J. Biol Chem., 255, 10464–71Google Scholar

Copyright information

© Kluwer Academic Publishers 1988

Authors and Affiliations

  • K. Einarsson
    • 1
  • B. Angelin
    • 1
  1. 1.Department of Medicine, Division of Gastroenterology and Metabolism UnitKarolinska Institutet at Huddinge University HospitalHuddingeSweden

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