Ursodeoxycholic acid therapy in primary biliary cirrhosis

Background/Aims: A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. Methods: Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. Results: In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects or toxicity. Conclusions: UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC. Background. Ursodiol (ursodeoxycholic acid) therapy leads to major improvements in patients with primary biliary cirrhosis. The benefit of long-term treatment is uncertain. Methods. We randomly assigned 145 patients with biopsy-proved primary biliary cirrhosis to receive ursodiol (13 to 15 mg per kilogram of body weight per day) (72 patients) or placebo (73 patients). After two years of follow-up, because of the benefit from ursodiol, all patients completing the study received ursodiol in an open trial and were monitored for two more years. The end points in the assessment of efficacy were as follows: progression of disease, as defined by the presence of hyperbilirubinemia, variceal bleeding, ascites, or encephalopathy; liver transplantation or a referral for that procedure; and liver transplantation (or a referral) or death. Results. Disease progressed significantly less frequently in the ursodiol group than in the placebo group (P < 0.002; relative risk, 0.28;95 percent confidence interval, 0.12 to 0.63). The probability of liver transplantation or a referral for that procedure and the probability of transplantation or death were significantly lower in the group assigned to ursodiol than in the group assigned to placebo (for transplantation alone, P = 0.003; relative risk, 0.21;95 percent confidence interval, 0.07 to 0.66; for transplantation or death, P = 0.005; relative risk, 0.32;95 percent confidence interval, 0.14 to 0.74). High bilirubin levels and, to a lesser extent, signs of cirrhosis at entry into the trial were predictive of disease progression, liver transplantation or a referral, and transplantation or death. Conclusions. Long-term ursodiol therapy slows the progression of primary biliary cirrhosis and reduces the need for liver transplantation. (N Engl J Med 1994;330:1342-7). Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the leastknown hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (P < 0.001). Significant falls in serum alkaline phosphatase, amino-transferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with primary biliary cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with primary biliary cirrhosis. (HEPATOLOGY 1994;19:1149-1156).