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Cited by 755Liver Diseases and ImmunityPediatric Hepatobiliary Diseases and TreatmentsDrug Transport and Resistance Mechanisms

A Multicenter, Controlled Trial of Ursodiol for the Treatment of Primary Biliary Cirrhosis

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Poupon, Renée E., Balkau, Beverley, Eschwège, Eveline, Poupon, Raoul, the UDCA–PBC Study Group*·1991·New England Journal of Medicine
DOI 10.1056/nejm199105303242204
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Abstract

BACKGROUND: In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis. METHODS: We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction. RESULTS: Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, cholesterol, and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol. CONCLUSIONS: Ursodiol is a safe and effective treatment for primary biliary cirrhosis.

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Crossref · 10.1056/nejm199105303242204

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  • IgM reduction with UDCA and experimental second-line therapies has been reported, but the prognostic significance of such change has yet to be established and IgM response does not currently feature in any response assessment paradigms.

    “IgM reduction with UDCA and experimental second-line therapies has been reported, but the prognostic significance of such change has yet to be established and IgM response does not currently feature in any response assessment paradigms.90 91”

    From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [90]

    The Changes in Clinical and Biochemical Variables section (p. 3) reports that IgM fell after two years of ursodiol treatment relative to placebo. The Discussion (p. 6) also reports improved IgM concentrations with chlorambucil, another treatment. The paper does not establish whether an IgM reduction has prognostic significance or address whether IgM features in response-assessment paradigms. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • There is no good evidence that the AMA titre correlates with the course of PBC.

    “There is no good evidence that the AMA titre correlates with the course of PBC (although it can fall with treatment),90”

    From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [90]

    The trial reports that antimitochondrial-antibody (AMA) titres improved with ursodiol treatment (Results, p. 1), supporting the parenthetical statement that they can fall with treatment. It does not assess whether AMA titre correlates with the course of primary biliary cirrhosis, so it does not establish the sentence’s main claim. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Treatment with ursodeoxycholic acid decreases the levels of biochemical markers of cholestasis and extends the time to liver transplantation.

    “Treatment with ursodeoxycholic acid decreases the levels of the biochemical markers of cholestasis and extends the time to liver transplantation.4,5”

    From A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis (2018) · cites this paper as [4]

    The trial reports significant improvements in bilirubin, alkaline phosphatase, and γ-glutamyltransferase levels with ursodiol (p. 1), supporting the biochemical-marker claim in patients with primary biliary cirrhosis. The Methods (p. 1) and Treatment Failures and Withdrawals (p. 3) assess biochemical deterioration and complications, not time to liver transplantation; that part is not established by this trial. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 8

  1. [3]3. Triger DR, Manifold IH, Cloke P, Underwood JCE. D-penicillamine in primary biliary cirrhosis: two year results of a single centre, double-blind controlled trial. Gut 1980; 21:A919-A920. abstract.
  2. [4]4. Bassendine MF, Macklon AF, Mulcahy R, James OFW. Controlled trial of high and low dose D-penicillamine in primary biliary cirrhosis: results at three years. Gut 1982; 23:A909. abstract.
  3. [31]31. Dixon WJ, ed. BMDP statistical software. Berkeley: University of California Press, 1988.
  4. [33]33. Batta AK, Arora R, Salen G, Katz S. Ursodeoxycholic acid improves liver function and reduces serum and urinary endogenous bile acids in primary biliary cirrhosis. Hepatology 1988; 8:1221. abstract.
  5. [32]32. Podda M, Battezzati PM, Bertolini E, et al. Effects of ursodeoxycholic acid (UDCA) on liver function tests and bile acid metabolism in anicteric primary biliary cirrhosis (PBC): a dose-response study. Hepatology 1988; 8:1266. abstract.
  6. [34]34. Hadziyannis S, Hadziyannis E. A randomised controlled trial of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC). Hepatology 1988; 8:1421. abstract.
  7. [42]42. Poupon R, Calmus Y. Bile acids and the immune system. In: Paumgartner G. Štiehl A, Gerok W, eds. Bile acids as therapeutic agents. Dordrecht, the Netherlands: Kluwer Academic (in press).
  8. [44]44. Leuschner U, Dienes HP, Güldütuna S, Birfkenfeld G, Leuschner M. Ursodeoxycholic acid (UDCA) inftuences immune parameters in patients with primary biliary cirrhosis (PBC). Hepatology 1990; 12:957. abstract.

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Authors
Poupon, R. E., Balkau, B., Eschwège, E., Poupon, R., & the UDCA–PBC Study Group*
Affiliations
  • Inserm (FR)
  • From Unit 21, Institut National de la Santé et de la Recherche Médicale, Villejuif, France (R.E.P., B.B., E.E.), and the Service d'Hépatologie, Hôpital Saint-Antoine, Paris (R.P.). Address reprint requests to Dr. R.E. Poupon, INSERM U 21, 16 Ave. Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France.
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1991-05-30
Volume
324
Issue
22
Pages
1548-1554
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199105303242204
OpenAlex
W2316970164
Semantic Scholar
015570573db8373a83f5637b7237cb6e0c7c4b55
Cited by
755
References
37
Citations by year
2026: 7 · 2025: 28 · 2024: 17 · 2023: 13 · 2022: 18 · 2021: 9 · 2020: 15 · 2019: 25 · 2018: 21 · 2017: 23 · 2016: 7 · 2015: 14 · 2014: 20 · 2013: 15 · 2012: 22
FWCI
26.09
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
ursodeoxycholic acid, primary biliary cirrhosis, bile acid accumulation, antimitochondrial antibodies, liver histopathology, serum enzymes, bilirubin, Mayo risk score, treatment efficacy, placebo comparison
MeSH terms
Alkaline Phosphatase, Aspartate Aminotransferases, Bilirubin, Cholesterol, Double-Blind Method, Drug Evaluation, Drug Tolerance, Female, gamma-Glutamyltransferase, Humans, Immunoglobulin M, Liver, Liver Cirrhosis, Biliary, Male, Middle Aged, Patient Compliance, Ursodeoxycholic Acid

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