Comment on biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis
Authors: Lucy J. Walker, Julia Newton, David E. J. Jones, Margaret F. Bassendine
Journal: Hepatology (2008)

We read with interest the article by Corpechot et al. in a recent issue of HEPATOLOGY.1 Corpechot et al. identify the absence of a biochemical response to ursodeoxycholic acid (UDCA) as an important predictive factor for death or liver transplantation in patients with primary biliary cirrhosis (PBC) and report that biochemical response was independent of baseline pretreatment serum bilirubin or histological stage.1 They have refined the biochemical criteria of nonresponse to UDCA identified by the Pares et al.,2 who reported that >40% reduction or fall to within the normal range of serum alkaline phosphatase (ALP) levels at 1 year upon UDCA treatment predicted similar life expectancy to that of an age-matched healthy population. These studies help to resolve the conflicting conclusions of two recent meta-analyses.3, 4 One systematic review to evaluate the benefits and harms of UDCA in patients with PBC did not demonstrate any benefit of UDCA on mortality or liver transplantation in patients with PBC.3 Another meta-analysis that was confined to trials using an appropriate dose of UDCA (>10 mg per kilogram of body weight per day) and with sufficient follow-up (at least 2 years) found that long-term treatment with UDCA can improve liver biochemistry and survival free of liver transplantation.4 UDCA remains the only drug licensed by the U.S. Food and Drug Administration to treat PBC and is recommended by the practice guidelines of the American Association for the Study of Liver Diseases for appropriately selected patients with PBC and abnormal liver biochemical values.5 Absence of a biochemical response to UDCA has, however, now been shown to have clear prognostic implications for those with PBC1, 2 and is a useful tool in identifying patients requiring further therapeutic intervention to cure or retard disease progression.6 We feel this is an appropriate opportunity to highlight the possible role of fibrates in this setting. The effects of bezafibrate and fenofibrate on the biochemical indices of patients with PBC has been described in several cohorts of Japanese patients. A number of studies report response to both bezafibrate7, 8 and fenofibrate9, 10 over 12-26 weeks in those who have previously failed to respond to UDCA. We have confirmed these findings in a retrospective analysis of a UK cohort of 16 patients with PBC who were based in the North East of England, the first such study outside of Japan. Fenofibrate (134-200 mg daily) was added to UDCA in patients with lack of biochemical response (no significant decrease in ALP, alanine aminotransferase or immunglobulin M) after a mean of 22.8 months UDCA monotherapy. We found there was a significant response to a combination of fenofibrate and UDCA after an equivalent period (23 months), with significant falls in ALP (P = 0.0016) (89% falling to within the normal range) and immunoglobulin M (P = 0.0015) (Fig. 1). Given that such biochemical indices are shown to be important in predicting long-term outcome in PBC, our experience emphasizes the need for a prospective trial of combination fibrate and UDCA therapy in patients who fail to respond to UDCA monotherapy. Fall in serum alkaline phosphatase (ALP) and immunoglobulin M (IgM) in patients with PBC after undergoing UDCA and fenofibrate combination therapy. (A) ALP levels at pre-UDCA therapy, pre-fenofibrate therapy after UDCA monotherapy, and after 23 months of combination UDCA fenofibrate therapy. * = Significant fall in ALP (P = 0.0016). (B) IgM levels at pre-UDCA therapy, pre-fenofibrate therapy after UDCA monotherapy, and after 23 months of combination UDCA fenofibrate therapy. * = Significant fall in IgM (P = 0.0015). Lucy J. Walker*, Julia Newton*, David E. J. Jones*, Margaret F. Bassendine*, * Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle Upon Tyne NE24HH UK.