A major step towards effective treatment evaluation in primary biliary cirrhosis
Authors: Ulrich Beuers, Keith D. Lindor
Journal: Journal of Hepatology (2011)

Early primary biliary cirrhosis: Biochemical response to treatment and prediction of long-term outcomeJournal of HepatologyVol. 55Issue 6PreviewThe biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) correlates with the long-term prognosis and thus could allow the identification of the patients needing new therapeutic approaches. Due to variation in both endpoints and studied populations, there is still no full agreement on the definition of the biochemical response. The aim of our study was to determine, in a population of patients with only early-stage disease, the best biochemical criteria of response to UDCA allowing to predict the absence of poor outcome, as defined by liver-related death, liver transplantation, complications of cirrhosis, or histological evidence of cirrhosis development. Full-Text PDF Primary biliary cirrhosis (PBC) is an immune-mediated chronic progressive inflammatory liver disease which affects up to one in a thousand middle-aged women (with a gender distribution of female:male of about 10:1) in the Northern hemisphere and leads, without medical treatment, to the destruction of small interlobular bile ducts, progressive cholestasis, fibrosis, and cirrhosis commonly necessitating liver transplantation. A diagnosis of PBC is made “with confidence” when biochemical markers of cholestasis in serum, particularly alkaline phosphatase (AP), are elevated persistently for more than 6 months in the presence of serum antimitochondrial antibodies (AMA) and in the absence of an alternative explanation [1EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237–267.Google Scholar, 2Lindor 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 (1020) Google Scholar]. Compatible histological findings confirm the diagnosis and allow staging (1: portal inflammation; 2: periportal inflammation; 3: fibrosis; 4: cirrhosis) before therapeutic intervention, but histological workup is usually not required to diagnose PBC [1EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237–267.Google Scholar, 2Lindor 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 (1020) Google Scholar]. The pathogenesis of PBC remains elusive [3Gershwin M.E. Mackay I.R. The causes of primary biliary cirrhosis: convenient and inconvenient truths.Hepatology. 2008; 47: 737-745Crossref PubMed Scopus (246) Google Scholar, 4Hohenester S. Oude-Elferink R.P. Beuers U. Primary biliary cirrhosis.Semin Immunopathol. 2009; 31: 283-307Crossref PubMed Scopus (149) Google Scholar] although increasing evidence suggests a concomitant role of (i) genetic factors as supported by sibling studies [[5]Invernizzi P. Gershwin M.E. The genetic basis of primary biliary cirrhosis: premises, not promises.Gastroenterology. 2008; 135: 1044-1047Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] and genome-wide association analyses [[6]Hirschfield G.M. Liu X. Xu C. Lu Y. Xie G. Gu X. et al.Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.N Engl J Med. 2009; 360: 2544-2555Crossref PubMed Scopus (512) Google Scholar], (ii) exogenous factors as suggested by immunoreactivity towards infectious agents [[7]Selmi C. Balkwill D.L. Invernizzi P. Ansari A.A. Coppel R.L. 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The biliary HCO(3)(−) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496Crossref PubMed Scopus (267) Google Scholar, 11Medina J.F. Martinez A. Vazquez J.J. Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis.Hepatology. 1997; 25: 12-17Crossref PubMed Google Scholar]. Today, the post-transcriptional secretagogue, ursodeoxycholic acid (UDCA) [[12]Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis.Nat Clin Pract Gastroenterol Hepatol. 2006; 3: 318-328Crossref PubMed Scopus (336) Google Scholar], at doses of 13–15 mg/kg/d is recommended as the standard treatment of PBC both by European [[1]EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237–267.Google Scholar] and American [[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 (1020) Google Scholar] Clinical Practice Guidelines as it improves serum biochemistry, delays development of liver fibrosis and portal hypertension, and may normalize life expectancy in up to two of the three patients treated – a major achievement for patients with PBC when compared to their fellow sufferers 25 years ago [13Pares A. Caballeria L. Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid.Gastroenterology. 2006; 130: 715-720Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar, 14Corpechot C. Abenavoli L. Rabahi N. Chretien Y. Andreani T. Johanet C. et al.Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis.Hepatology. 2008; 48: 871-877Crossref PubMed Scopus (474) Google Scholar, 15Kuiper E.M. Hansen B.E. de Vries R.A. den Ouden-Muller J.W. van Ditzhuijsen T.J. Haagsma E.B. et al.Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid.Gastroenterology. 2009; 136: 1281-1287Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar]. Liver transplantation is reserved for patients with advanced disease with signs and symptoms of decompensated cirrhosis not adequately responding to UDCA treatment [1EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237–267.Google Scholar, 2Lindor 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 (1020) Google Scholar]. Consequently, the search for additional therapeutic interventions in 35–40% of PBC patients who do not adequately respond to UDCA treatment is a focus of current research efforts. A number of promising drugs, such as the combined glucocorticoid receptor (GR)/pregnane X receptor (PXR) agonist, budesonide, the farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), the peroxisome proliferator-activated receptor α (PPARα) agonists, bezafibrate and fenofibrate, or the C23 UDCA homologue, norUDCA, are under evaluation as additive treatment options in combination with UDCA [[4]Hohenester S. Oude-Elferink R.P. Beuers U. Primary biliary cirrhosis.Semin Immunopathol. 2009; 31: 283-307Crossref PubMed Scopus (149) Google Scholar]. But how can treatment efficacy of novel agents in an orphan disease with an expected disease course of one to two decades effectively be evaluated? During the last 20 years – in the UDCA era – it has been impossible to organize a therapeutic trial in PBC which came close to the needs of an “ideal” trial with 1000 or more patients with PBC treated with UDCA or placebo over a period of five or more years in order to find a significant difference in transplantation-free survival, the primary endpoint which is regarded as the golden standard for therapeutic efficacy in chronic liver diseases. Today, the situation is even more difficult as it is common sense that any new drug for PBC should be tested in combination with UDCA against UDCA alone [[16]Silveira M.G. Brunt E.M. Heathcote J. Gores G.J. Lindor K.D. Mayo M.J. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis.Hepatology. 2010; 52: 349-359Crossref PubMed Scopus (70) Google Scholar]. This scenario would ask for even larger and longer trials than those needed to show efficacy of UDCA alone when transplantation-free survival was chosen as the primary endpoint. Surrogate markers of prognosis in PBC have been evaluated in large cohorts of PBC patients already in the 1970s, 1980s, and 1990s. Serum bilirubin was demonstrated to be the single most potent prognostic marker in PBC [[17]Shapiro J.M. Smith H. Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis.Gut. 1979; 20: 137-140Crossref PubMed Scopus (273) Google Scholar], but also serum albumin, age, prothrombin time, and cirrhosis have been unravelled and cross-validated as valuable surrogate markers to predict prognosis mainly of late stage disease. The PBC Mayo risk score is a composite of prognostic surrogate markers and a powerful tool to predict short-term prognosis of late stage PBC [[18]Dickson E.R. Grambsch P.M. Fleming T.R. Fisher L.D. Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making.Hepatology. 1989; 10: 1-7Crossref PubMed Scopus (681) Google Scholar]. The purpose of future trials, however, is to recognize early stage patients who are in need of combination therapy to hinder progression to cirrhosis and death. Pares and colleagues from Barcelona sought to determine the long-term prognosis of 192 Spanish patients with PBC of all stages under UDCA treatment in relation to their biochemical response to treatment. When they defined an “adequate response to UDCA” after 1 year of treatment by a decrease of serum AP by >40% or AP normalization (Barcelona criteria) [[13]Pares A. Caballeria L. Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid.Gastroenterology. 2006; 130: 715-720Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar], they found that patients adequately responding to UDCA had a survival similar to the normal population (Table 1). Corpechot and colleagues from Paris cross validated the Barcelona criteria in an independent cohort of 292 French patients with PBC (all stages) and found that a composite of AP ⩽3 × upper limit of normal (ULN), AST ⩽2 × ULN, and serum bilirubin ⩽1 mg/dl (Paris I criteria) were superior to the Barcelona criteria in order to predict normal life expectancy during long-term follow-up [[14]Corpechot C. Abenavoli L. Rabahi N. Chretien Y. Andreani T. Johanet C. et al.Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis.Hepatology. 2008; 48: 871-877Crossref PubMed Scopus (474) Google Scholar]. Kuiper and colleagues from the Netherlands cross validated the Barcelona and Paris I criteria in comparison to their own Rotterdam criteria (normalization of serum bilirubin and/or albumin after 1 year from elevated levels before start of UDCA treatment) in an independent cohort of 375 Dutch PBC patients for a period of 15 years and found that response to UDCA treatment according to Rotterdam criteria was associated with normal survival independent of the stage of disease before start of treatment [[15]Kuiper E.M. Hansen B.E. de Vries R.A. den Ouden-Muller J.W. van Ditzhuijsen T.J. Haagsma E.B. et al.Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid.Gastroenterology. 2009; 136: 1281-1287Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar]. They also confirmed that early stage patients under UDCA treatment had a survival comparable to the normal population after 15 years. In their cohort, the prognostic information as provided by the Paris I criteria was superior to that provided by the Barcelona criteria. This may have in part been due to the severity of disease in the Rotterdam cohort which was closer to the more advanced Paris cohort than the less advanced Barcelona cohort.Table 1Criteria of “adequate response to UDCA” in PBC. Open table in a new tab Recently, Kumagi and colleagues from Toronto studied a cohort of 69 patients with PBC with a follow-up liver biopsy about 10 years after first biopsy and start of UDCA treatment [[19]Kumagi T. Guindi M. Fischer S.E. Arenovich T. Abdalian R. Coltescu C. et al.Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis.Am J Gastroenterol. 2010; 105: 2186-2194Crossref PubMed Scopus (254) Google Scholar]. They found that an AP >1.67 × ULN after 2 years of UDCA treatment, along with ductopenia at first biopsy, predicted progression of disease by at least one stage after 10 years (Table 1). In the present issue of the Journal, Corpechot and colleagues from Paris re-evaluated their Paris I criteria in a cohort of 167 patients, all with early stage (1 or 2) PBC, and tested different threshold values for AP, AST, and bilirubin in order to predict long-term outcome under UDCA treatment [[20]Corpechot C. Chazouilleres O. Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome.J Hepatol. 2011; 55: 1361-1367Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar]. The revised definition of adverse outcomes included liver-related death, liver transplantation, or referral to a transplant unit, complications of cirrhosis, such as ascites, variceal bleeding, hepatic encephalopathy or hepatocellular carcinoma, or histological evidence of cirrhosis. The results of the present analysis allowed the conclusion that an AP and AST <1.5 × ULN and a normal serum bilirubin one year after start of UDCA treatment (Paris II criteria) predict outcome free of adverse events and help to identify those patients with early histological stage who do not need any treatment in addition to UDCA and thus are not eligible for future clinical trials [[20]Corpechot C. Chazouilleres O. Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome.J Hepatol. 2011; 55: 1361-1367Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar]. Corpechot et al., cross validated the former Barcelona, Paris I, Rotterdam and Toronto criteria in their cohort of patients with early stage PBC and found that the Toronto and Paris I criteria came closest to the Paris II criteria regarding specificity, positive predictive value, and positive likelihood ratio for predicting adverse outcome. This result was not unexpected for the Paris I criteria as there was some overlap between the Paris I and II cohorts. However, this cross validation further underlined the unique prognostic value of serum AP in early stage PBC as represented in the Toronto and Paris II cohorts. Thus, serum AP appears as an useful prognostic marker for prediction of adverse outcome in early stage PBC and deserves particular attention as a key surrogate inclusion marker for future therapeutic trials. The recent study of Drs. Corpechot, Chazouilleres, and Poupon is clearly a step forward in the search for criteria to identify patients with PBC in need of new therapies. However, as correctly stated by the authors, the limited number of patients and particularly of adverse events in this study prevent a definite conclusion and ask for extramural cross validation in an independent large cohort of early stage PBC patients before the Paris II criteria can be used as a “selection means” for future clinical trials [[20]Corpechot C. Chazouilleres O. Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome.J Hepatol. 2011; 55: 1361-1367Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar]. An inadequate response to UDCA as defined by the Paris II criteria also had a low negative predictive value of 13% and only a moderate sensitivity of 51% for the occurrence of adverse events [[20]Corpechot C. Chazouilleres O. Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome.J Hepatol. 2011; 55: 1361-1367Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar]. Thus, a considerable percentage of early stage patients selected by Paris II criteria would undergo additional treatment without real need, and only every second patient with an adverse outcome could be identified beforehand based on the Paris II criteria. These restrictions need to be kept in mind when the Paris II criteria are being cross validated in independent cohorts of early stage PBC patients in the near future. Their prognostic value in late stages 3–4 disease still remains to be determined. In summary, the Paris II criteria presented by Corpechot et al. in the present issue of the Journal appear as a promising selection tool for patients with early stage PBC in need of novel therapies in addition to UDCA. Extramural cross validation of Paris II criteria is urgently awaited. In the last two years U.B. has been a speaker for the Falk Foundation, Roche, and Gilead; acted as a consultant for Intercept; and received a research grant from Zambon.