Original Article

Ursodiol for the Long-Term Treatment of Primary Biliary Cirrhosis

List of authors.
  • Renee E. Poupon,
  • Raoul Poupon,
  • Beverley Balkau,
  • and the UDCA-PBC Study Group

Abstract

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.

Introduction

Primary biliary cirrhosis is a chronic cholestatic liver disease that progresses slowly toward a terminal phase characterized by hyperbilirubinemia, signs of decompensated cirrhosis, ascites, and variceal bleeding. The survival of patients with end-stage primary biliary cirrhosis is usually very short1. Orthotopic liver transplantation is now considered the treatment of choice. Medications to treat primary biliary cirrhosis that have been assessed in controlled trials include immunosuppressive agents, penicillamine, and colchicine2-21. None of these medications, however, have proved totally effective or safe.

Given that ursodiol (ursodeoxycholic acid) has no apparent hepatotoxicity in humans, we postulated that long-term treatment with this drug might displace endogenous bile acids and thus reverse their suspected cytotoxicity in primary biliary cirrhosis. In a pilot study, ursodiol produced sustained improvement in liver-function tests22. We then conducted a two-year multicenter, double-blind, controlled trial in which patients with primary biliary cirrhosis were randomly assigned to receive either ursodiol or placebo23. At the end of the trial, the risk of treatment failure (as defined by the onset of hyperbilirubinemia, ascites, or bleeding) was significantly (about three times) higher in the placebo group than in the ursodiol group. However, with the criteria used for patient selection and the short follow-up, there were few liver transplantations or referrals for it. Because of the benefit of ursodiol, all the patients completing the study received ursodiol in an open trial and were monitored for two more years.

In this overview of the four years, we compare the course of primary biliary cirrhosis in the patients assigned to ursodiol and those assigned to placebo. We sought to determine whether long-term administration of ursodiol provides sustained protection to the liver and reduces the incidence of liver failure and the need for liver transplantation. We also defined factors predictive of treatment failure.

Methods

Study Design

The study protocol was approved by the ethics committee of the Hopital Saint-Antoine. Informed consent was obtained from each patient before the study. The trial included 146 patients randomly assigned in double-blind fashion to ursodiol or an identical placebo (13 to 15 mg per kilogram of body weight per day in two doses). A patient described previously23 who did not meet the eligibility requirements (because of a bilirubin value of 9.6 mg per deciliter [165 μmol per liter]) has been omitted from this analysis. The criteria for entry were biopsy-proved primary biliary cirrhosis, serum alkaline phosphatase activity more than twice the upper limit of normal, and a positive test for antimitochondrial antibodies. Patients were admitted to the trial regardless of the duration of the disease or the histologic stage. The principal criteria for exclusion were drug therapy (including use of ursodiol) during the previous six months, a serum bilirubin concentration above 8.8 mg per deciliter (150 μmol per liter), a serum albumin concentration below 2.5 g per deciliter, past or active variceal bleeding, ascites, and features suggestive of intercurrent liver or biliary diseases. At the end of the double-blind period, the investigators were encouraged to treat all their patients with ursodiol. Patients who agreed to this treatment were followed in an open study for two years, according to the same protocol. Six patients were lost to follow-up during the open phase of the trial (four had been in the ursodiol group, and two in the placebo group). Compliance with treatment was assessed by comparing serum levels of ursodiol with those of total bile acids. In the ursodiol group, patients were considered to have stopped treatment if the proportion of ursodiol was less than 30 percent. Two patients originally assigned to placebo who did not receive ursodiol after the double-blind period (in a joint decision by the patient and the physician) were also monitored for two more years. In the placebo group, patients were considered to have taken ursodiol if the proportion of the drug was higher than 30 percent during the double-blind period. Five patients had evidence of episodic ingestion of ursodiol.

The main end point in the assessment of efficacy was treatment failure, defined, as previously,23 by the presence of at least one of the following criteria: hyperbilirubinemia, a clinical complication (variceal bleeding, ascites, or encephalopathy), and adverse effects of treatment. Two additional end points were used during the open phase of the trial: liver transplantation (or referral for it) and liver transplantation or death. The distinction between actual transplantation and referral for it was made to avoid bias related to the availability of organs and eligibility criteria for transplantation. These criteria were the presence of at least two of the following complications: a serum bilirubin concentration above 8.8 mg per deciliter, ascites, or variceal bleeding; the absence of intercurrent diseases; and age under 65 years.

Statistical Analysis

Quantitative data are expressed as means ±SE. Enzyme activity and immunoglobulin concentrations were standardized according to the reference values of each laboratory and expressed as multiples of the upper limit of the normal values. Clinically overt liver disease was defined by the presence of at least one of the following signs or symptoms: jaundice, fatigue, pruritus, hepatomegaly, and splenomegaly. The Mayo risk score, based on a combination of five variables (bilirubinemia, age, albuminemia, prothrombin time, and severity of edema), was calculated as described elsewhere24. Histologic stages were defined as follows: stage I (portal inflammation mainly confined to portal triads), stage II (diffuse portal and periportal inflammation and fibrosis), stage III (lobular fibrosis and bridging), and stage IV (cirrhosis)25.

Data were analyzed with BMDP software, version 1990 (University of California Press, Berkeley). All analyses were performed according to the intention-to-treat principle. The analysis of efficacy at four years included the combined data from the double-blind trial and the open trial, beginning at the time of randomization. The rates of treatment failure, liver transplantation (or referral for it), and liver transplantation (or referral for it) or death were estimated from Kaplan-Meier survival curves26 and compared by the Cox proportional-hazards model,27 with adjustment for possible differences in prognostic factors (age, bilirubin and albumin levels, and the presence of cirrhosis) between the two groups at entry. All variables were checked with a time-dependent variable to see whether the proportional-hazards assumption was followed.

Factors predictive of treatment failure were analyzed in the combined data on the 129 patients treated with ursodiol -- i.e., the 72 patients initially assigned to ursodiol (who were treated for four years) plus the 57 patients assigned to placebo (who were treated with ursodiol during years 3 and 4). The values for the potentially prognostic variables were those recorded at entry into the double-blind trial in the case of the patients assigned to ursodiol and those recorded at the end of the double-blind trial in the case of the patients assigned to placebo. All the Cox models were adjusted for age and for time since diagnosis to account for the fact that treatment with ursodiol was started two years later in the placebo group. The univariate associations between potentially predictive variables and the three end points were tested with the Cox model. The independent predictive value of each characteristic was defined with stepwise multivariate Cox models. When appropriate, logarithms of the quantitative variables were used, except for the prothrombin time, which was expressed as either >80 percent or ≤ 80 percent of the value obtained with a reference serum. All reported P values are two-sided, and a P value ≤ 0.05 was considered to indicate statistical significance.

Results

Characteristics of the Patients

Table 1. Table 1. Base-Line Characteristics of the Patients in the Original Study Groups.

The characteristics of the patients at the time of randomization are shown in Table 1.

Data on all 129 patients treated with ursodiol were combined to identify the factors predictive of treatment failure. The characteristics of this combined group were similar to those of the two original groups at the time of randomization: age, 57 ±1 years; bilirubin, 1.2 ±0.1 mg per deciliter (19.8 ±1.4 μmol per liter); alkaline phosphatase, 4.9 ±0.3 times the upper limit of normal; alanine aminotransferase, 2.5 ±0.1 times the upper limit of normal; albumin, 3.93 ±0.04 g per deciliter; serum bile acid, 10.3 ±1.0 μg per milliliter (26.3 ±2.5 μmol per liter); prothrombin time, 95.6 ±0.6 percent of the reference value; proportion with clinically overt disease, 60 percent; Mayo risk score, 4.84 ±0.08; and proportion with histologic stage III or IV, 48 percent. The time elapsed since diagnosis was, however, longer in the combined group than in the original groups: 49 ±4 months (range, 1 to 264).

Effect of Treatment on Course of Disease

Figure 1. Figure 1. Probability of a Response to Treatment with Ursodiol.

During the first 24 months (shaded area), patients were randomly assigned to receive ursodiol or placebo; thereafter, all patients were treated with ursodiol. The probability of a response was significantly higher in the patients treated for four years with ursodiol than in those who first received placebo (P<0.002; relative risk, 0.28; 95 percent confidence interval, 0.12 to 0.63).

Figure 1 shows the probability of a response to treatment over the four-year study period in the groups as initially randomized. At the end of the two-year double-blind period, there were 13 treatment failures in the placebo group and 5 in the ursodiol group; at the end of the four-year study period, there were 20 and 9 treatment failures, respectively. The probability of a response to treatment was significantly higher in the patients treated with ursodiol for four years than in those who initially received placebo (P<0.002; relative risk, 0.28; 95 percent confidence interval, 0.12 to 0.63).

Side effects were recorded in two patients during the double-blind period: one patient in the ursodiol group had a transient increase in the severity of pruritus at the outset of treatment, and one patient in the placebo group had abdominal pain.

Figure 2. Figure 2. Probability of Liver Transplantation (Upper Panel) and Liver Transplantation or Death (Lower Panel) in Patients Treated with Ursodiol.

These probabilities were significantly lower in the patients treated for four years with ursodiol than in those who first received 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). The shaded area indicates the period of the double-blind trial. Data on transplantation include referrals for liver transplantation.

Figure 2 shows the Kaplan-Meier curves for liver transplantation or referral for it. There were 4 transplantations (or referrals) in the group assigned to ursodiol, as compared with 13 in the group assigned to placebo. Fifteen of the 17 patients who were referred for liver transplantation actually underwent the procedure. One patient originally assigned to placebo died while awaiting a donor. In another patient from that group, transplantation was not performed because the patient had a psychiatric disorder. The probability of liver transplantation was significantly lower in the patients who received four years of ursodiol treatment than in those who initially received placebo (P = 0.003; relative risk, 0.21; 95 percent confidence interval, 0.07 to 0.66). The incidence of liver transplantation or death was significantly lower in the group assigned to ursodiol than in the group assigned to placebo (P = 0.005; relative risk, 0.32; 95 percent confidence interval, 0.14 to 0.74) (Figure 2).

In the group assigned to ursodiol, five of the six deaths were related to liver disease (one each from variceal bleeding, liver failure, and the effects of portacaval shunting, and two after liver transplantation) and one to intercurrent disease (bone metastases of unknown origin). In the group assigned to placebo, 8 of the 10 deaths were related to liver disease (variceal bleeding in 2 and liver failure and effects of liver transplantation in 3 each) and 2 to intercurrent diseases (meningeal hemorrhage and liver cancer).

Factors Predictive of Treatment Failure

Table 2. Table 2. Univariate Analysis of Potential Prognostic Variables for Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients. Table 3. Table 3. Multivariate Analysis of Factors Predictive of Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients.

In the univariate analysis, the factors found to be predictive of treatment failure were high bilirubin level, low albumin level, high level of total bile acids, hepatomegaly, splenomegaly, advanced histologic stage, and a high Mayo risk score (Table 2). The multivariate analysis identified two independent predictive factors: high bilirubin level and hepatomegaly (Table 3).

In the univariate analysis, the factors significantly associated with liver transplantation or referral for liver transplantation were high bilirubin level, low albumin level, high level of total bile acids, hepatomegaly, splenomegaly, advanced histologic stage, a high Mayo risk score, and a prothrombin time of 80 percent of the reference value or less (Table 2). The multivariate analysis identified two independent predictive factors: low albumin level and splenomegaly (Table 3). In the univariate analysis, the same factors that predicted liver transplantation also predicted liver transplantation or death (Table 2). The multivariate analysis identified three independent predictive factors for this combined outcome: high bilirubin level, low albumin level, and splenomegaly (Table 3).

Discussion

We found that ursodiol slows the progression of primary biliary cirrhosis and reduces the need for liver transplantation. After two years, the risk of hyperbilirubinemia or clinical complications was approximately three times higher in the placebo group than in the ursodiol group. Analysis of the combined data showed that the rate of treatment failure was the same at four years as at two years: the risk of major complications was three times higher in the patients originally assigned to placebo than in those originally assigned to ursodiol. The double-blind trial was stopped for ethical reasons after two years, when the benefit of ursodiol had been established.

During the study period, other trials of ursodiol in primary biliary cirrhosis began28-31. The results to date consistently show an improvement in biochemical indexes associated with the medication, sometimes accompanied by improvement in clinical and histologic findings. We believe that these trials28-31 have insufficient power to allow the conclusion that ursodiol has no influence on clinical and histologic measures. We await the results of three larger trials of about 200 patients each, in which the patients are being followed for at least two years32-34.

In our study, the difference in the need for liver transplantation between the original study groups shows that ursodiol slows the progression of primary biliary cirrhosis. The effect of changes in laboratory measures or histologic scores is debatable35. The need for liver transplantation clearly reflects major deterioration. Most of the transplantations were carried out more than two years after the study began, for several reasons. First, patients requiring liver transplantation were excluded from the two-year trial. Thus, there was a longer observation period before end-stage primary biliary cirrhosis developed in the patients who were included. Second, in most instances liver transplantation was performed in patients who had treatment failure in the initial two years of the trial. Progression of disease was most evident in the placebo group and was not the consequence of introducing ursodiol. Nevertheless, some patients had treatment failure while taking ursodiol. This may in part reflect a poorer response in patients with more advanced disease. It is noteworthy that the proportion of patients who underwent transplantation was similar in the different centers. This argues against a bias related to differences in eligibility criteria.

The results were analyzed on an intention-to-treat basis, regardless of compliance with treatment and minor violations of protocol. Two of the four patients assigned to ursodiol who underwent liver transplantation stopped taking the drug at least six months before the decision was made to perform transplantation. The indication for liver transplantation in the third patient (histologic evidence of cirrhosis) was unconventional. The fourth patient, who complied with treatment (with serum ursodiol levels ranging from 43 to 66 percent of total bile acids), had gradual deterioration. In this patient, the bilirubin value increased from 2.2 mg per deciliter (38 μmol per liter) at entry to 4.9 mg per deciliter (84 μmol per liter) after 42 months of treatment. In the group assigned to placebo, 12 of the 13 patients who were referred for liver transplantation followed the assigned placebo and ursodiol regimens, as shown by analysis of serum bile acids. The remaining patient did not take ursodiol for a period of one year during years 3 and 4 of the study. In eight of these patients, treatment failure occurred during the double-blind period.

The rate of liver transplantation (or a referral for it) or death was significantly higher in the placebo group than in the ursodiol group. Most deaths were due to complications of either liver disease or liver transplantation. We did not study survival as such, because successful transplantation means one fewer death and it is difficult to distinguish the effects of ursodiol from those of liver transplantation in a survival analysis. In addition, our study was not designed to address this issue and did not include enough patients to do so. When the available survival data23,33,34 are examined (for a total of 550 patients monitored for two to four years), the mortality rate is about 6 percent for the patients treated with ursodiol and 12 percent for the patients receiving placebo.

The measures most strongly associated with treatment failure were three laboratory values (high levels of bilirubin and bile acids and low levels of albumin) and two clinical indexes (hepatomegaly and splenomegaly). The Mayo score, in the calculation of which bilirubinemia has a preponderant influence, was also strongly related to treatment failure. The multifactorial analysis identified bilirubinemia and hepatomegaly as independent predictive variables. As was true in untreated patients, a high bilirubin level was the factor most strongly associated with poor outcome12,24,36,37. Although the level of circulating bile acids was strongly associated with disease progression, it had no independent predictive role; this is partly explained by the strong correlation between bile acids and bilirubin. Histologic stage had no independent predictive value. The prognostic value of histologic stage in the natural course of primary biliary cirrhosis is controversial12,36-39.

Among the 129 patients treated with ursodiol, bilirubinemia and signs of cirrhosis were independent predictive factors for liver transplantation (or referral for it) and the combined outcome of liver transplantation or death. The minor differences in the values obtained with the different end points could be explained by the strong associations between the various measures and the small differences in the number of patients in each category (11 liver transplantations and 16 liver transplantations or deaths).

In conclusion, long-term ursodiol therapy is well tolerated. It slows the progression of primary biliary cirrhosis and reduces the need for liver transplantation. Further studies are required to assess the additional benefit of combined medical treatments, such as ursodiol plus immunosuppressive agents.

Funding and Disclosures

Presented in part at the 43rd annual meeting of the American Society for the Study of Liver Diseases, Chicago, October 31-November 3, 1992.

Supported in part by grants from Synthelabo-Recherche and Interfalk Canada.

We are indebted to the Association Francaise pour l'Etude du Foie, under whose auspices the study was conducted; and to D. Young for his assistance in the preparation of the manuscript.

Author Affiliations

From INSERM Unite 21, Villejuif, France (R.E.P., B.B.), and the Service d'Hepatologie, Hopital Saint-Antoine, Paris (R.P.).

Address reprint requests to Dr. R.E. Poupon, INSERM Unite 21, 16 Ave. Paul-Vaillant-Couturier, 94807 Villejuif CEDEX, France.

The Ursodeoxycholic Acid-Primary Biliary Cirrhosis (UDCA-PBC) Study Group consisted of the following investigators: P.M. Huet and B. Willems (Montreal); C. Mathieu-Chandelier and J.C. Paris (Lille); H. Mathiex-Fortunet (Rouen); J.P. Capron and D. Capron (Amiens); D. Dhumeaux and J.M. Metreau (Creteil); R. Poupon (Paris); Y. Deugnier (Rennes); P. Opolon and O. Bousquet (Paris); J.L. Payen (Toulouse); S. Bresson-Hadni and J.P. Miguet (Besancon); F. Degos (Clichy); M. Beaugrand and J.C. Trinchet (Bondy); F. Blanc (Montpellier); P. Cassan, J.L. Gineston, and T. Morin (Rodez); G. Parelon and H. Michel (Montpellier); J.P. Etienne and C. Buffet (Kremlin-Bicetre); P. Couzigou (Bordeaux); A. Levy-Bruhl and E.A. Pariente (Orleans); A. Valla and J.C. Verwaerde (Caen); J.C. Chaput and T. Poynard (Clamart); A. Gauthier (Marseilles); and V.-G. Levy (Paris). Bile acid analysis: G. Paumgartner (Munich, Germany). Statistical analysis: B. Balkau and A.-M. Niard (INSERM, Villejuif). Study coordinators: R.E. Poupon and E. Eschwege (INSERM, Villejuif); P. Atlan and P. Attali (Synthelabo-Recherche, Bagneux); and R. Poupon (Hopital Saint-Antoine, Paris).

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Citing Articles (350)

    Figures/Media

    1. Table 1. Base-Line Characteristics of the Patients in the Original Study Groups.
      Table 1. Base-Line Characteristics of the Patients in the Original Study Groups.
    2. Figure 1. Probability of a Response to Treatment with Ursodiol.
      Figure 1. Probability of a Response to Treatment with Ursodiol.

      During the first 24 months (shaded area), patients were randomly assigned to receive ursodiol or placebo; thereafter, all patients were treated with ursodiol. The probability of a response was significantly higher in the patients treated for four years with ursodiol than in those who first received placebo (P<0.002; relative risk, 0.28; 95 percent confidence interval, 0.12 to 0.63).

    3. Figure 2. Probability of Liver Transplantation (Upper Panel) and Liver Transplantation or Death (Lower Panel) in Patients Treated with Ursodiol.
      Figure 2. Probability of Liver Transplantation (Upper Panel) and Liver Transplantation or Death (Lower Panel) in Patients Treated with Ursodiol.

      These probabilities were significantly lower in the patients treated for four years with ursodiol than in those who first received 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). The shaded area indicates the period of the double-blind trial. Data on transplantation include referrals for liver transplantation.

    4. Table 2. Univariate Analysis of Potential Prognostic Variables for Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients.
      Table 2. Univariate Analysis of Potential Prognostic Variables for Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients.
    5. Table 3. Multivariate Analysis of Factors Predictive of Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients.
      Table 3. Multivariate Analysis of Factors Predictive of Treatment Failure, Liver Transplantation, and Liver Transplantation or Death in the Ursodiol-Treated Patients.