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Therapeutics

Ursodiol improved the clinical parameters and reduced disease progression in primary biliary cirrhosis

ACP J Club. 1991 Sept-Oct;115:48. doi:10.7326/ACPJC-1991-115-2-048


Source Citation

Poupon RE, Balkau B, Eschwège E, Poupon R, and the UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991 May 30;324:1548-54. [PubMed ID: 1674105]


Abstract

Objective

To evaluate treatment with ursodiol for patients with primary biliary cirrhosis.

Design

Randomized, double-blind, placebo-controlled trial of 2 years duration.

Setting

21 centers in France and 1 in Canada.

Patients

Patients with primary biliary cirrhosis (all clinical and histologic stages), serum alkaline phosphatase activity > twice normal, and positive antimitochondrial antibodies (titer > 1:100) were included. Patients who had taken ursodiol or immunosuppressive agents within 6 months and those with serum bilirubin > 150 mmol/L, serum albumin < 25 g/L, past or active esophageal gastrointestinal bleeding from varices, extrahepatic biliary obstruction, or consumption of > 50 g/d alcohol were excluded. 116 (79.4%) of 146 patients randomized completed the trial; 11 patients (7.5%) were withdrawn for another serious illness or noncompliance.

Intervention

Patients were randomized to receive oral ursodiol, 13 to 15 mg/kg of body weight/d (n = 73) or placebo (n = 73). Percutaneous liver biopsy was done at baseline (146 patients) and at 2 years (n = 95).

Main outcome measures

Failure of treatment (doubling of bilirubin levels to more than 70 mmol/L, ascites, gastrointestinal bleeding from esophageal varices, or side effects {unspecified}); decrease in clinically overt disease, defined as disappearance of jaundice, fatigue, pruritus, hepatomegaly, or splenomegaly; histologic features (scored on fibrosis, inflammation, necrosis, ductular proliferation, and cholestasis).

Main results

There were 6 treatment failures in the ursodiol group and 13 in the placebo group (relative risk for failure for ursodiol treatment, 0.32; 95% CI 0.11 to 0.88, P < 0.01). In an intention-to-treat analysis, the proportion of patients with clinically overt disease was reduced by 15%, from 48 to 37 patients assigned to ursodiol, compared with no reduction for placebo (P < 0.02). In an intention-to-treat analysis at the end of the trial, significantly fewer patients in the ursodiol group had jaundice (P < 0.006) but not pruritus, fatigue, hepatomegaly, or splenomegaly. The mean histologic score decreased from 11.0 to 9.5 in the ursodiol group and increased from 10.0 to 11.4 in the placebo group (P < 0.002 for the difference), but there was no difference in fibrosis. Patients treated with ursodiol had significant improvement in alkaline phosphatase, alanine aminotransferase, cholesterol, and IgM levels, and stabilization of serum bilirubin (P < 0.001 for all).

Conclusion

Treatment with ursodiol for 2 years improved the clinical status and prognosis for patients with primary biliary cirrhosis.

Sources of funding: In part, Synthelabo-Recherche; Jouveinal; Interfalk; Medical Research Council of Canada.

Address for article reprint: Dr. R.E. Poupon, INSERM U 21, 16 Avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France.


Commentary

This well-done, multicenter study confirms and extends the findings of a previous trial that included fewer patients who were studied for shorter periods. For the first time, ursodiol was shown to slow the progression of primary biliary cirrhosis. Ursodiol relieved itching in 44% of patients compared with 29% in the placebo group, but did not improve fatigue or substantially lower the serum bilirubin, although the bilirubin was stabilized. Ursodiol has no known immunosuppressive activity; therefore the significant decreases in serum IgM levels and antimitochondrial antibody titer are surprising. The effect of ursodiol on liver histologic features was statistically significant but less dramatic than its effects on biochemical test results. Primary biliary cirrhosis is typically progressive and irreversible. Thus, the histologic improvement in 13 patients receiving placebo highlights the problem with sampling variation in liver biopsies in this disease.

Several questions were not answered by this study. First, will the beneficial effects of ursodiol be sustainable? A report (1) has been published on the 2-year follow-up of this original study. All patients received ursodiol after 2 years. The authors found that long-term ursodiol therapy slowed the progression of primary biliary cirrhosis and reduced the need for liver transplantation.

Primary biliary cirrhosis is a lifelong disease characterized by immunologically mediated destruction of small bile ducts. It is unclear whether ursodiol ameliorates the underlying immunologic disorder. Longer observation periods are clearly needed. Second, which patients are most likely to benefit from ursodiol? Patients with clinically advanced disease were excluded from the study, but patients with all histologic stages were included. Do patients with histologically advanced disease respond as well as those in earlier stages? Third, should ursodiol be used with other drugs, such as colchicine, cyclosporin, or methotrexate, which are currently being evaluated? Probably, but controlled trials are needed to evaluate this.

Despite these questions, the results of this trial are impressive—the more so because ursodiol is free of side effects. Given its efficacy and safety, it is difficult not to recommend ursodiol for most patients with primary biliary cirrhosis.

Marshall M. Kaplan, MD
Tufts UniversityBoston, Massachusetts, USA


Updated Commentary

Recent studies have confirmed upsodiol to be the only therapy shown to improve survival (1). A meta-analysis by Goulis (2) questions the utility of ursodiol.


References

1. Poupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994;330:1342-7.

2. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999;354:1053-60.