Abstract
Recent clinical studies have indicated that ursodeoxycholic acid (ursodiol), administered at dosages ranging between 10 and 15 mg/kg/day, improves liver function indices in both cholestatic and inflammatory chronic liver diseases. These dosages would be considered high for the use of ursodiol in gallstone dissolution therapy. To investigate the dose-response relationship to ursodiol administration, we planned a few studies in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and chronic hepatitis (CH). Patients with PBC were subdivided into two groups on the basis of their serum bilirubin values, with 2 mg/dl as the dividing line. Ursodiol was given at dosages of 250, 500, and 750 mg/day for consecutive periods of two months, the order of treatment being randomly assigned to each patient. The enrichment with ursodiol of biliary bile acids was similar in both PBC and CH and, within the PBC group, in both anicteric and icteric patients. Highly significant decreases in serum enzyme levels were observed in all groups with the 250 mg/day dose, corresponding to about 4–5 mg/kg/day. The two higher doses induced further improvements in serum enzyme levels, especially in patients with PBC, but no significant differences were found between the 500 and the 750 mg/day doses. The improvements were roughly proportional to the enrichment of conjugated biliary bile acids with ursodiol. Serum bilirubin levels, an important prognostic factor in PBC, were also significantly reduced by ursodiol administration in patients with initial serum levels higher than 2 mg/dl. The present study indicated that ursodiol is a potentially useful drug for chronic liver disease. Controlled trials on adequate numbers of patients assuming clinically meaningful endpoints are needed. The present investigation suggests that daily doses of 500–600 mg/day, corresponding to about 8 mg/kg/day, should be employed for such studies.
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Miyazaki K, Nakayama F, Koga F, Koga A: Effect of chenodeoxycholic and ursodeoxycholic acids on isolated adult human hepatocytes. Dig Dis Sci 29:1123–1130, 1984
Koga Y: Anti-cholestatic and cytoprotective properties of ursodeoxycholic acid. Studies in vivo and in vitro. Acta Hepatol Jpn 28:1597–1604, 1987
Scholmerich J, Kitamura S, Baumgartner U, Miyai K: Prevention of taurolithocholate induced cholestasis with different tri- and dihydroxylated bile acids. Xth International Bile Acid Meeting: Trends in Bile Acid Research, Freiburg/Br., West Germany, June 9–11, 1988
Sarva RP, Fromm H, Farivar S, et al: Comparison of the effects between ursodeoxycholic and chenodeoxycholic acids on liver function and structure and on bile acid composition in the rhesus monkey. Gastroenterology 79:629–636, 1980
Shefer S, Zaki FG, Salen G: Early morphologic and enzymatic changes in livers of rats treated with chenodeoxycholic and ursodeoxycholic acids. Hepatology 3:201–208, 1983
Ward A, Brogden RN, Heel RC, et al: Ursodeoxycholic acid: A review of its pharmacological property and therapeutic efficacy. Drugs 27:95–131, 1984
Cohen BI, Hofmann AF, Mosbach EH, et al: Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit. Gastroenterology 91:189–197, 1986
Krol T, Kitamura T, Miyai K, Hardison W: Tauroursodeoxycholate reduces ductular proliferation and portal inflammation in bile duct-ligated hamsters. Hepatology 80:881, 1983
Zimmermann HJ: Chenodeoxycholic acid and the liver: Good news—bad news. Hepatology 2:288–289, 1982 (editorial)
Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hubner K: Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 30:642–649, 1985
Poupon R, Chretien Y, Poupon RE, Ballet F, Calmus Y, Darnis F: Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1:834–836, 1987
David A, Kurtz W, Strohm WD, Leuschner U: Die Wirkung von Ursodesoxycholsaure bei chronischen Lebererkrankungen: Eine Pilotstudie. Z Gastroenterol 23:420, 1985
Fisher MM, Paradine ME: Influence of ursodeoxycholic acid on biochemical parameters in cholestatic liver disease. Gastroenterology 90:1725, 1986
Raedsch R, Stiehl A, Kommereil B: Effects of ursodeoxycholic acid in primary biliary cirrhosis and primary sclerosing cholangitis. Xth International Bile Acid Meeting: Trends in Bile Acid Research, Freiburg/Br., West Germany, June 9–11, 1988
Bachrach WH, Hofmann AF: Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Dig Dis Sci 27:833–856, 1982
Ohya T: Long-term administration of ursodeoxycholic acid in patients with chronic hepatitis. A comparison of the effect of two doses on liver function. Jpn Pharmacol Ther 13:271, 1985
Podda M, Ghezzi C, Bettezzati PM, Bertolini E, Crosignani A, Petroni ML, Zuin M: Ursodeoxycholic acid for chronic liver diseases. J Clin Gastroenterol 10:S25-S31, 1988
Snedecor GW, Cochran WG: Statistical Methods. Ames, Iowa, The Iowa State University Press, 1980
Scholmerich J, Becher MS, Schmidt K, et al: Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties. Studies on isolated hepatocytes and lipid membrane vesicles. Hepatology 4:661–666, 1984
Tanikawa K, Kawahara T, Kumashiro R, et al: Effects of bile acids on the cultured hepatocyte and Kupffer cell. Hepatology 6:779, 1986
Allan RN, Gadacz TR, Mack E, et al: Impaired lithocholate sulfation in the rhesus monkey: A mechanism for chenodeoxycholate toxicity. Gastroenterology 69:802, 1975
Schoenfield LJ, Lachin JM, The Steering Committee, and the National Cooperative Gallstone Study: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. A controlled trial of efficacy and safety. Ann Intern Med 95:257–282, 1981
La Russo NF, Szczepanik PA, Hofmann AF: Effect of deoxycholic acid ingestion on bile acid metabolism and biliary lipid secretion in normal subjects. Gastroenterology 72:132, 1977
Scholmerich J, Baumgartner U, Leible P, Gerok W: Cholestatic effect of different bile salts in the isolated perfused rat liver—effect of number and of hydroxyl groups. Xth International Bile Acid Meeting: Trends in Bile Acid Research, Freiburg/Br., West Germany, June 9–11, 1988
Schaffner F, Popper H: Clinical-pathologic relations in primary biliary cirrhosis.In Progress in Liver Diseases, Vol VII. H Popper, F Schaffner (eds). New York, Grune and Stratton, 1982, pp 529–545.
Kurtz W, Guldutuna S, Leuschner U: Elevated liver tissue bile acids in steatosis and chronic hepatitis. Xth International Bile Acid Meeting: Trends in Bile Acid Research, Freiburg/Br., West Germany, June 9–11, 1988
Armstrong MJ, Carey MC: The hydrophobic-hydrophilic balance of bile salts. Inverse correlation between reversephase high performance liquid chromatographic mobilities and micellar cholesterol-solubilizing capacities. J Lipid Res 23:70–80, 1982
Attili AF, Angelico M, Cantafora A et al: Bile acid-induced liver toxicity: Relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 19:57–68, 1986
Shapiro JM, Smith H, Schaffner F: Serum bilirubin: A prognostic factor in primary biliary cirrhosis. Gut 20:137–140, 1979
Christensen E, Neuberger J, Crowe J, et al: Beneficial effects of azathioprine and prediction of prognosis in primary biliary cirrhosis. Gastroenterology 89:1084–1091, 1985
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Podda, M., Ghezzi, C., Battezzati, P.M. et al. Effect of different doses of ursodeoxycholic acid in chronic liver disease. Digest Dis Sci 34 (Suppl 12), S59–S65 (1989). https://doi.org/10.1007/BF01536665
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DOI: https://doi.org/10.1007/BF01536665