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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