Ursodeoxycholic acid and primary biliary cirrhosis: EASL and AASLD guidelines

We read with interest the recent EASL Clinical Practice Guidelines on management of cholestatic liver disease [[1]EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67.Google Scholar]. We would like to congratulate the authors on the correct grading of evidence for the use of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) but at the same time we would like to challenge them about the interpretation of data. Levels of evidence are designed as objective tools based on widely accepted defined criteria. The authors correctly used a grade II-2/B1 recommendation for use of UDCA in PBC, as data to support this are only available from “cohort or case–control analytical studies”. In contrast, the recent AASLD clinical practice guidelines [[2]Lindor K.D. Gershwin M.E. Poupon R. Kaplan M. Bergasa N.V. Heathcote E.J. Primary biliary cirrhosis.Hepatology. 2009; 50: 291-308Crossref PubMed Scopus (963) Google Scholar] give a different level of evidence for use of UDCA, which is Class I, level A i.e. data to support this are “derived from multiple randomized clinical trials or meta-analyses”. This grading is methodologically incorrect and probably reflects opinion rather than evidence. In fact, no single randomized controlled trial to date has demonstrated a significant effect of UDCA in terms of survival or liver transplantation, and neither have a meta-analysis nor a Cochrane review, which evaluated all randomized trials [3Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar, 4Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. Although the authors of the EASL guidelines criticize the published meta-analyses [3Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar, 4Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar] for including studies with short duration or with use of inadequate doses of UDCA, this criticism is not justified. The Cochrane review with updated and longer follow-up data still failed to find benefit of UDCA [[3]Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar], and sensitivity analyses regarding UDCA dose in both meta-analyses showed no difference between standard doses (>13 mg/kg) versus lower doses with respect to major outcome measures [3Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar, 4Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. Even a selective analysis of raw data from the French, Canadian and Mayo cohorts showed a possible benefit of UDCA only in patients with moderate and severe disease [[5]Poupon R.E. Lindor K.D. Cauch-Dudek K. Dickson E.R. Poupon R. Heathcote E.J. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.Gastroenterology. 1997; 113: 884-890Abstract Full Text PDF PubMed Scopus (544) Google Scholar], in whom currently even those clinicians who feel UDCA is effective, acknowledge that it is less likely to exert a beneficial therapeutic effect. As regards the interpretation of evidence, the crucial issue is the fact that in those studies in which cross-over from placebo or no treatment to UDCA occurred, (after approximately 2 years) the cross-over patients deteriorated despite using UDCA [[4]Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. A potential solution to evaluate this paradox was given in correspondence from us [[6]Burroughs A. Goulis J. Leandro G. Ursodeoxycholic acid for primary biliary cirrhosis – authors’ reply.Lancet. 2000; 355: 658Abstract Full Text Full Text PDF Google Scholar]. Nevertheless, our suggestions for analysis have never been taken up. However, we acknowledge that in early stage and/or asymptomatic PBC, UDCA may have benefit – but conclusive evidence is lacking. Data to support the use of UDCA in early asymptomatic PBC needs strengthening. Indeed, the “Paris” and “Barcelona” criteria mentioned by the authors, refer to cohorts with no control groups and thus data interpretation should be made with great caution [[1]EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67.Google Scholar]. In the asymptomatic PBC cohort described by Prince et al. (only 7% of patients were taking UDCA), 45% did not develop a liver-related symptom during a median follow-up of 7.4 years [[7]Prince M.I. Chetwynd A. Craig W.L. Metcalf J.V. James O.F. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort.Gut. 2004; 53: 865-870Crossref PubMed Scopus (199) Google Scholar]. These could be the same patients who “respond” to UDCA. Moreover, the emphasis in the guidelines for evidence of histological improvement is misplaced, as we have previously pointed out [[8]Chan C.W. Papatheodoridis G.V. Goulis J. Burroughs A.K. Ursodeoxycholic acid and histological progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 1094-1095Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Notably, in the original trials there were patients in the non-fibrotic stages of PBC progressing to fibrosis, despite an improvement in inflammation [3Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar, 4Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. This dichotomy between improvement in inflammation but worsening of fibrosis is difficult to interpret as an improvement in histological stage. In conclusion, the absence of best-level evidence confirms that UDCA for all PBC patients remains an unresolved issue. Currently, the highest level of evidence (meta-analysis of randomized trials) suggests that UDCA does not influence patients’ survival, time to transplantation, or any other patient-important clinical outcome [3Gong Y. Huang Z.B. Christensen E. Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis.Cochrane Database Syst Rev. 2008; : CD000551PubMed Google Scholar, 4Goulis J. Leandro G. Burroughs A.K. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.Lancet. 1999; 354: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar].