A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

Burton Combes, Robert L. Carithers, Willis C. Maddrey, Danyu Lin, Mary F. Mcdonald, Donald E. Wheeler, Edwin H. Eigenbrodt, Santiago J. Muñoz, Raphael Rubin, Guadalupe Garcia-tsao, Gregory F. Bonner, Alexander B. West, James L. Boyer, Velimir A. Luketic, Mitchell L. Shiffman, A. Scott Mills, Marion G. Peters, Heather M. White, Rowen K Zetterman, Stephen S. RossiAlan F. Hofmann, Rodney Smith Markin

Research output: Contribution to journalArticle

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Abstract

One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin (<2 mg/dL vs. 2 mg/dL or greater) and liver histology (stages I, II vs. stages III, IV-Ludwig criteria) were randomized within each stratum to ursodiol or placebo given in a single dose of 10 to 12 mg/kg at bedtime for 2 years. Placebo- (n = 74) and ursodioltreated (n = 77) patients were well matched at baseline for demographic and prognostic factors. Ursodiol induced major improvements in biochemical tests of the liver in strata 1 and 2 (entry bilirubin <2), but had less effect on laboratory tests in patients with entry serum bilirubin of ≥2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trial was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated with ursodiol tended to develop a treatment failure less frequently than those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients. Major complications of liver disease, progression to liver transplantation or death, occurred in 10.5% and 76.6%, respectively, in patients who had an entry serum bilirubin of <2 or ≥2 mg/dL. The incidence of these complications was comparable in ursodiol- and placebo-treated patients. Treatment failure occurred sooner in placebo than in ursodiol-treated patients in strata 1 and 2 but at the same rate in similarly treated patients in strata 3 and 4. Patients with advanced disease are unlikely to benefit from ursodiol. Trials longer than 2 years will likely be needed to determine whether ursodiol reduces major complications of liver disease in patients with milder disease.

Original languageEnglish (US)
Pages (from-to)759-766
Number of pages8
JournalHepatology
Volume22
Issue number3
DOIs
StatePublished - Sep 1995

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Ursodeoxycholic Acid
Biliary Liver Cirrhosis
Placebos
Bilirubin
Histology
Treatment Failure
Serum
Liver Diseases
Liver
Pruritus
Bile Acids and Salts
Bile
Liver Transplantation
Fatigue
Disease Progression
Fasting

ASJC Scopus subject areas

  • Hepatology

Cite this

A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. / Combes, Burton; Carithers, Robert L.; Maddrey, Willis C.; Lin, Danyu; Mcdonald, Mary F.; Wheeler, Donald E.; Eigenbrodt, Edwin H.; Muñoz, Santiago J.; Rubin, Raphael; Garcia-tsao, Guadalupe; Bonner, Gregory F.; West, Alexander B.; Boyer, James L.; Luketic, Velimir A.; Shiffman, Mitchell L.; Mills, A. Scott; Peters, Marion G.; White, Heather M.; Zetterman, Rowen K; Rossi, Stephen S.; Hofmann, Alan F.; Markin, Rodney Smith.

In: Hepatology, Vol. 22, No. 3, 09.1995, p. 759-766.

Research output: Contribution to journalArticle

Combes, B, Carithers, RL, Maddrey, WC, Lin, D, Mcdonald, MF, Wheeler, DE, Eigenbrodt, EH, Muñoz, SJ, Rubin, R, Garcia-tsao, G, Bonner, GF, West, AB, Boyer, JL, Luketic, VA, Shiffman, ML, Mills, AS, Peters, MG, White, HM, Zetterman, RK, Rossi, SS, Hofmann, AF & Markin, RS 1995, 'A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis', Hepatology, vol. 22, no. 3, pp. 759-766. https://doi.org/10.1016/0270-9139(95)90294-5
Combes, Burton ; Carithers, Robert L. ; Maddrey, Willis C. ; Lin, Danyu ; Mcdonald, Mary F. ; Wheeler, Donald E. ; Eigenbrodt, Edwin H. ; Muñoz, Santiago J. ; Rubin, Raphael ; Garcia-tsao, Guadalupe ; Bonner, Gregory F. ; West, Alexander B. ; Boyer, James L. ; Luketic, Velimir A. ; Shiffman, Mitchell L. ; Mills, A. Scott ; Peters, Marion G. ; White, Heather M. ; Zetterman, Rowen K ; Rossi, Stephen S. ; Hofmann, Alan F. ; Markin, Rodney Smith. / A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. In: Hepatology. 1995 ; Vol. 22, No. 3. pp. 759-766.
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T1 - A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

AU - Combes, Burton

AU - Carithers, Robert L.

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AU - Lin, Danyu

AU - Mcdonald, Mary F.

AU - Wheeler, Donald E.

AU - Eigenbrodt, Edwin H.

AU - Muñoz, Santiago J.

AU - Rubin, Raphael

AU - Garcia-tsao, Guadalupe

AU - Bonner, Gregory F.

AU - West, Alexander B.

AU - Boyer, James L.

AU - Luketic, Velimir A.

AU - Shiffman, Mitchell L.

AU - Mills, A. Scott

AU - Peters, Marion G.

AU - White, Heather M.

AU - Zetterman, Rowen K

AU - Rossi, Stephen S.

AU - Hofmann, Alan F.

AU - Markin, Rodney Smith

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N2 - One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin (<2 mg/dL vs. 2 mg/dL or greater) and liver histology (stages I, II vs. stages III, IV-Ludwig criteria) were randomized within each stratum to ursodiol or placebo given in a single dose of 10 to 12 mg/kg at bedtime for 2 years. Placebo- (n = 74) and ursodioltreated (n = 77) patients were well matched at baseline for demographic and prognostic factors. Ursodiol induced major improvements in biochemical tests of the liver in strata 1 and 2 (entry bilirubin <2), but had less effect on laboratory tests in patients with entry serum bilirubin of ≥2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trial was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated with ursodiol tended to develop a treatment failure less frequently than those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients. Major complications of liver disease, progression to liver transplantation or death, occurred in 10.5% and 76.6%, respectively, in patients who had an entry serum bilirubin of <2 or ≥2 mg/dL. The incidence of these complications was comparable in ursodiol- and placebo-treated patients. Treatment failure occurred sooner in placebo than in ursodiol-treated patients in strata 1 and 2 but at the same rate in similarly treated patients in strata 3 and 4. Patients with advanced disease are unlikely to benefit from ursodiol. Trials longer than 2 years will likely be needed to determine whether ursodiol reduces major complications of liver disease in patients with milder disease.

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