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Altered bile acid metabolism in primary biliary cirrhosis

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Abstract

Selected aspects of bile acid metabolism were assessed in six women with primary biliary cirrhosis and varying degrees of cholestasis. Urinary bile acid excretion was markedly increased and correlated highly with serum levels. In three patients in whom urinary bile acids were separated by chromatography, the majority of urinary bile acids were monosulfated (34%, 42%, 32%) or polysulfated and/or glucuronidated (30%, 20%, 38%). The monosulfates of chenodeoxycholic acid were conjugated at either the 3 position (67%, 68%, 73%) or the 7 position (33%, 32%, 27%); similarly, the monosulfates of cholic acid were conjugated at the 3 position (65%, 58%, 68%) or the 7 position (35%, 42%, 32%). The position of sulfation was not markedly influenced by the mode of amidation with glycine or taurine. Chenodeoxycholic exchangeable pool size, turnover rate, and synthesis were measured by isotope dilution and found to be well within normal limits, despite the cholestasis. The fraction of chenodeoxycholic acid synthesis excreted in urine ranged from 9 to 48%; 4–38% of chenodeoxycholic acid synthesis was sulfated. These data indicate that the major abnormalities in bile acid metabolism in patients with cholestasis secondary to primary biliary cirrhosis are formation of sulfated bile acids in greatly increased amounts, elevation of blood levels of primary bile acids, and a shift to renal excretion as a major mechanism for bile acid elimination. Chenodeoxycholic acid synthesis continues at its usual rate despite cholestasis. Whether these changes, including the formation of 7-monosulfated bile acids, occur in other forms of cholestasis and whether either the persistance of unchanged chenodeoxycholic acid synthesis or the formation of such novel conjugates has any pathophysiological significance remain to be investigated.

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Reverences

  1. Gregg JA. Urinary excretion of bile acids in patients with obstructive jaundice and hepatocellular diseases. Am J Clin Pathol 49:404, 1968

    Google Scholar 

  2. Stiehl A: Disturbances of bile acid metabolism in cholestasis. Clin Gastroenterol 6:45–67, 1977

    Google Scholar 

  3. Makino I, Hashimoto H, Shinozaki K, Yoshino K, Nakagawa S: Sulfated and nonsulfated bile acids in urine, serum and bile of patients with hepatobiliary diseases. Gastroenterology 68:545–553, 1975

    Google Scholar 

  4. Stiehl A: Bile salt sulphates in cholestasis. Eur J Clin Invest 4:59–63, 1972

    Google Scholar 

  5. van Berge Henegouwen GP, Brandt K-H, Eyssen H, Parmentier G: Sulfated and unsulfated bile acids in serum, bile and urine of patients with cholestasis. Gut 17:861–869, 1976

    Google Scholar 

  6. Stiehl A, Earnest DL, Admirand WH: Sulfation and renal excretion of bile salts in patients with cirrhosis of the liver. Gastroenterology 68:534–544, 1975

    Google Scholar 

  7. Back P, Gerok W: Differences in renal excretion between glycoconjugates, tauroconjugates, sulfoconjugates and glucuronoconjugates of bile acids in cholestasis.In Bile Acid Metabolism in Health and Disease, G Paumgartner, A Stiehl (eds). Lancaster, MTP Press, 1977, pp 93–100

    Google Scholar 

  8. Summerfield JA, Cullen J, Barnes S, Billing BH: Evidence for renal control of urinary excretion of bile acids and bile acid sulphates in the cholestatic syndrome. Clin Sci Mol Med 52:51–65, 1977

    Google Scholar 

  9. Stiehl A, Ast E, Czygan P, Frohling W, Raedsch R, Kommerell B: Pool size, synthesis, and turnover of sulfated and nonsulfated cholic acid and chenodeoxycholic acid in patients with cirrhosis of the liver. Gastroenterology 74:572–577, 1978

    Google Scholar 

  10. Williams CN, MacDonald IA, Park-Dincsov H: Primary bile acid kinetics in patients with primary biliary cirrhosis and in normal subjects. Clin Invest Med 2:29–40, 1979

    Google Scholar 

  11. Lauterburg BH, Pineda AA, Dickson ER, Baldus WP, Taswell HF: Plasma perfusion for the treatment of intractable pruritis of cholestasis. Mayo Clin Proc 53:403–407, 1978

    Google Scholar 

  12. Snel P, Tangerman A, van Berge Henegouwen GP, Geerdink P, Huybregts A, Van Tongeren JHM: Treatment of intractable pruritus in cholestatic jaundice: Removal of bile acids by plasma exchange and plasma perfusion.In Biological Effects of Bile Acids, G Paumgartner, A Stiehl, W. Gerok, (eds). Lancaster, MTP Press, 1979, pp 207–213

    Google Scholar 

  13. Raedsch R, Hofmann AF, Tserng K-Y: Separation of individual sulfated bile acid conjugates as calcium complexes using reversed-phase partition thin-layer chromatography. J Lipid Res 20:796–800, 1979

    Google Scholar 

  14. Lindstedt S: The turnover of cholic acid in man. Acta Physiol Scand 40:1–9, 1957

    Google Scholar 

  15. Hofmann AF, Hoffman NE: Measurement of bile acid kinetics by isotope dilution in man. Gastroenterology 67:314–323, 1974

    Google Scholar 

  16. Fleming CR, Ludwig J, Dickson ER: Asymptomatic primary biliary cirrhosis: Presentation, histology, and results withd-pencillamine. Mayo Clin Proc 53:587–593, 1978

    Google Scholar 

  17. van Berge Henegouwen GP, Hofmann AF: A simple batch adsorption procedure for the isolation of sulfated and nonsulfated bile acids from serum. Clin Chim Acta 73:469–474, 1976

    Google Scholar 

  18. Burstein S, Lieberman S: Hydrolysis of keto steroid hydrogen sulfates by solvolysis procedures. J Biol Chem 233:331–335, 1958

    Google Scholar 

  19. Roovers J, Evrard E, Vanderhaeghe H: An improved method for measuring human blood bile acids. Clin Chim Acta 19:449–457, 1968

    Google Scholar 

  20. Chavez MN, Krone CL: Silicic acid thin-layer chromatography of conjugated and free bile acids. J Lipid Res 17:545–547, 1976

    Google Scholar 

  21. Williams CN, Kaye R, Baker L, et al: Progressive familial cholestatic cirrhosis and bile acid metabolism. J Pediatr 81:493–500, 1972

    Google Scholar 

  22. Frohling W, Stiehl A: Bile salt glucuronides: Identification and quantitative analysis in the urine of patients with cholestasis. Eur J Clin Invest 6:67–74, 1976

    Google Scholar 

  23. Danzinger RG, Hofmann AF, Thistle JL, Schoenfield LJ: Effect of oral chenodeoxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis. J Clin Invest 52:2809–2821, 1973

    Google Scholar 

  24. Einarsson K, Hellstrom K, Kallner M: Influence of deoxycholic acid feeding on the elimination of cholesterol in normolipaemic subjects. Clin Sci Mol Med 47: 425–433, 1974

    Google Scholar 

  25. Alme B, Bremmelgaard A, Sjövall J, Thomassen P: Analysis of metabolic profiles of bile acids in urine using a lipophilic anion exchanger and computerized gas-liquid chromatography-mass spectrometry. J Lipid Res 18:338–362, 1977

    Google Scholar 

  26. Kirkpatrick RB, Lack L, Killenberg PG: Identification of the 3-sulfate isomer on the major product of enzymatic sulfation of chenodeoxycholate conjugate. J Biol Chem (in press)

  27. Tazawa Y, Konno T: Sulfated and nonsulfated bile acids in urine of infants with obstructive jaundice. Tohoku J Exp Med 129:55–63, 1979

    Google Scholar 

  28. Corbett CL, Bartholomew TC, Summerfield JA, Billing, BH: Is renal tubular secretion the major determinant of urinary bile acid composition in cholestasis? Gut 20:A956, 1979 (abstract)

    Google Scholar 

  29. Cowen AE, Korman MG, Hofmann AF, Cass OW: Metabolism of lithocholate in healthy man. I. Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine, and their sulfates. Gastroenterology 69:59–66, 1975

    Google Scholar 

  30. Schwenk M, Hofmann AF, Carlson GL, Carter JA, Coulston F, Greim H: Bile acid conjugation in the chimpanzee: Effective sulfation of lithocholic acid. Arch Toxicol 40:109–118, 1978

    Google Scholar 

  31. Miettinen TA: Lipid absorption, bile acids, and cholesterol metabolism in patients with chronic liver disease. Gut 13:682–689, 1972

    Google Scholar 

  32. Bremmelgaard A, Sjövall J: Bile acid profiles in urine of patients with liver disease. Eur J Clin Invest 9:341–348, 1979

    Google Scholar 

  33. Summerfield JA, Billing BH, Shackleton CHL: Identification of bile acids in the serum and urine in cholestasis. Biochem J 154:507–516, 1976

    Google Scholar 

  34. Thomassen PA: Urinary bile acids during development of recurrent cholestasis of pregnancy. Eur J Clin Invest 9:417–423, 1979

    Google Scholar 

  35. Thomassen PA: Urinary bile acids in late pregnancy and in recurrent cholestasis of pregnancy. Eur J Clin Invest 9:425–432, 1979

    Google Scholar 

  36. Vlahcevic ZR, Buhac I, Farrar JT, Bell CC, Jr, Swell L: Bile acid metabolism in patients with cirrhosis. I. Kinetic aspects of cholic acid metabolism. Gastroenterology 60:491–498, 1971

    Google Scholar 

  37. Vlahcevic ZR, Juttijudata P, Bell CC, Jr, Swell L; Bile acid metabolism in patients with cirrhosis. II. Cholic and chenodeoxycholic acid metabolism. Gastroenterology 62:1174–1181, 1972

    Google Scholar 

  38. Angelin B, Einarsson K, Hellstrom K: Effect of cholestyramine on bile acid kinetics in patients with portal cirrhosis of the liver. Am J Dig Dis 23:1115–1120, 1978

    Google Scholar 

  39. van Berge Henegouwen GP, Hofmann AF: Pharmacology of chenodeoxycholic acid. II. Absorption and metabolism in man. Gastroenterology 73:300–309, 1977

    Google Scholar 

  40. Hofmann AF, Milanese M, Belforte G, Molino G: A useful multicompartment model for the enterohepatic circulation of bile acids in man. Gastroenterology 77:A16, 1979 (abstract)

    Google Scholar 

  41. Tserng K-Y, Klein PD: Bile acid sulfates. III. Synthesis of 7- and 12-monosulfates of the bile acids and their conjugates using a sulfur trioxide-triethylamine complex. Steroids 33:167–182, 1979

    Google Scholar 

  42. Parmentier G, Eyssen H: Synthesis and characteristics of the specific monosulfates of chenodeoxycholate, deoxycholate and their taurine or glycine conjugates. Steroids 30:583–590, 1977

    Google Scholar 

  43. Cowen AE, Korman MG, Hofmann AF, Cass OW, Coffin SB: Metabolism of lithocholate in healthy man. II. Enterohepatic circulation. Gastroenterology 69:67–76, 1975

    Google Scholar 

  44. Cowen AE, Korman MG, Hofmann AF, Thomas PJ: Metabolism of lithocholate in man. III. Plasma disappearance of radioactivity after intravenous injection of labeled lithocholate and its derivatives. Gastroenterology 69:77–82, 1975

    Google Scholar 

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Author notes

  1. Richard Raedsch MD (postdoctoral fellow of the German Research)

    Present address: Division of Gastroenterology, Department of Medicine, University of Heidelberg, W. Germany

  2. Bernhard H. Lauterburg MD

    Present address: Institute for Lipid Research, Baylor College of Medicine, 77025, Houston, Texas

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, University of California at San Diego, Rochester, Minnesota

    Richard Raedsch MD (postdoctoral fellow of the German Research),  Bernhard H. Lauterburg MD &  Alan F. Hofmann MD

  2. Department of Internal Medicine and Gastroenterology Unit, Mayo Clinic & Mayo Foundation, Rochester, Minnesota

    Richard Raedsch MD (postdoctoral fellow of the German Research),  Bernhard H. Lauterburg MD &  Alan F. Hofmann MD

  3. General Clinical Research Center, Mayo Clinic & Mayo Foundation, Rochester, Minnesota

    Richard Raedsch MD (postdoctoral fellow of the German Research),  Bernhard H. Lauterburg MD &  Alan F. Hofmann MD

Authors
  1. Richard Raedsch MD
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  2. Bernhard H. Lauterburg MD
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  3. Alan F. Hofmann MD
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Additional information

Supported by NIH grant AM 21506 to the University of California and grant RR 00585 and NIH grants AM 19448 and AM 16770 to the Mayo Clinic and Mayo Foundation. In addition, research at the University of California was supported by grants-in-aid from the Rorer Company, the Eli Lilly Company, and the Canada Packers Limited Company.

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Raedsch, R., Lauterburg, B.H. & Hofmann, A.F. Altered bile acid metabolism in primary biliary cirrhosis. Digest Dis Sci 26, 394–401 (1981). https://doi.org/10.1007/BF01313580

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  • DOI: https://doi.org/10.1007/BF01313580

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