Ursodeoxycholic acid, when used for treatment of PSC, was associated with poorer clinical outcomes when compared to placebo. More patients developed varices, died, or became eligible for liver transplantation in the group receiving UDCA compared to the placebo group despite improvement in liver tests. The likelihood of developing these adverse events was not predicted by a biochemical response, and as expected was predicted irrespective of treatment by higher Mayo risk score or presence of cirrhosis on entry biopsy (data not shown).
A statistically significant biochemical response was observed for alkaline phosphatase and AST (). However, response at six months was not associated with development of primary endpoints.
Previous studies led us to believe that UDCA would be safe and beneficial (9
). Patients with primary biliary cirrhosis, in whom a dose of 13–15 mg/kg/day has been approved by the Food and Drug Administration have not had more adverse events when treated with higher doses up to 25 or 30 mg/kg/day (14
). Pilot studies in patients with PSC using doses ranging from 17–25 mg/kg/day did not have an increased risk of adverse events. Reassessment of the initial UDCA study which used a dose 13–15 mg/kg/day in 105 patients showed a trend towards improved survival free of transplant in the treated group. Hence, the findings in this study were quite unanticipated.
The surprising results in this study led us to examine the data in several ways. The primary analysis is represented in the first row of (assessing all primary endpoints and adjusting for baseline stratification variables). However, we were concerned that the study groups differed in followup visits, and that some endpoints could only be observed through particular tests. Therefore in addition to assessing primary endpoints, we also assessed transplantation, meeting minimal listing criteria, and death alone. Both these models, as well as the adjusted models, provided hazard ratios that were not only in the same, unexpected direction, but represented a clinically relevant increase in worse outcomes for patients on UDCA as compared to placebo.
It is unclear how a drug that has a reputation for such safety would have these paradoxical effects in this condition. Analysis of the actual drug supply for contaminants failed to disclose any unusual compounds within the study supply of the drug. It is unclear whether higher doses of UDCA allowed unabsorbed drug to enter the colon and be modified into hepatotoxic bile acids. The possibility of hepatotoxic bile acids being produced from unabsorbed UDCA remains a potential explanation and deserves further evaluation (15
). In an animal model, UDCA aggravated bile infarcts and hepatocyte necroses in the setting of biliary obstruction and this may also explain why the results in PSC, where biliary obstruction occurs, were different than in PBC (16
Ursodeoxycholic acid may also modulate apoptosis (17
). It is possible that the high dose of UDCA used in this study prevented apoptosis of activated stellate cells which continued to be active in fibrogenesis leading to the advanced liver disease found in this study.
At this time, UDCA in a dose 25–30 mg/kg/day for patients with PSC should not be used because of the increased risk of clinically important adverse endpoints. There is no treatment that can be recommended at this time and only therapy in the context of prospective trials should be considered. Continued testing of drugs in pilot studies is reasonable, but the findings of this study mandate that any positive biochemical response be confirmed within a randomized controlled trial. In the absence of such randomized controlled data, it is likely that the adverse events detected in this study would have been attributed to the progressive nature of the liver disease and not recognized as related to the drug. It is hoped that in the near future that a safe and effective therapy for patients with PSC will be developed, but high-dose UDCA cannot be recommended despite findings in a recent, small pilot study (18
). The results of this study caution against empiric therapy for patients with PSC and highlight the need for confirmation of promising pilot studies by adequate controlled trials.