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Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression

2003; Elsevier BV; Volume: 39; Issue: 1 Linguagem: Inglês

10.1016/s0168-8278(03)00243-5

1600-0641

G. Paumgartner,

Drug Transport and Resistance Mechanisms

Ursodeoxycholic acid (UDCA) is widely used for the treatment of primary biliary cirrhosis (PBC) [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar]. At present, it is the only drug approved by the US Food and Drug Administration (FDA) for this disease. UDCA is a hydrophilic, dihydroxy bile acid (3α,7β-dihydroxy-5β-cholanic acid) which is normally present in human bile albeit in a low concentration of only about 3% of total bile acids. It is the major bile acid of the bile of black bears which has been used since centuries in Chinese traditional medicine as a remedy for liver diseases [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar]. Multiple mechanisms of action of UDCA have been described, including protection of injured cholangiocytes against toxic effects of hydrophobic bile acids, stimulation of impaired biliary secretion, inhibition of apoptosis of hepatocytes and, possibly, stimulation of detoxification of hydrophobic bile acids [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar].Although early trials clearly showed that UDCA improves serum liver tests including bilirubin and other markers of cholestasis [2Leuschner U. Fischer H. Kurtz W. Guldutuna S. Hubner K. Hellstern A. et al.Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial.Gastroenterology. 1989; 97: 1268-1274Abstract PubMed Google Scholar, 3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 4Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar], evidence that UDCA inhibits the progression of the disease has come slowly and in pieces. An analysis of the combined data of three large trials showed that therapy with UDCA at daily doses of 13–15 mg/kg for up to 4 years increases the time taken to liver transplantation or death [[6]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 (547) Google Scholar] and another study in which patients with PBC were treated with UDCA for up to 6 years suggested that UDCA prolonged transplant-free survival [[7]Lindor K.D. Therneau T.M. Jorgensen R.A. Malinchoc M. Dickson E.R. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis.Gastroenterology. 1996; 110: 1515-1518Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. Proof that UDCA delays histologic progression of the disease has not been very strong. Three studies [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar] reported an effect of UDCA on the histologic progression of PBC, but two of them are limited by a small number of patients [[8]Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar] or variable duration of therapy [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar].Those who only believe in meta-analysis maintain that adequate proof for an effect of UDCA on disease progression in PBC is lacking. A meta-analysis of eight randomized trials showed no difference between UDCA and placebo in the effects on incidence of death, liver transplantation and death or liver transplantation [[11]Goulis J. Leandro G. Burroughs A. 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 (264) Google Scholar]. It must, however, be considered that six of the trials included in this meta-analysis evaluated treatment given up to 24 months only and that two of the trials used daily doses of UDCA (7.7 and 10 mg/kg) which are now generally considered to be too low. Similarly, another meta-analysis of 16 randomized trials which included studies with UDCA doses as low as 8 mg/kg per day (8–15 mg/kg per day) and follow-up as short as 3 months (3 months–5 years) did not detect a survival benefit for patients treated with UDCA [[12]Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis (Cochrane Review). In: The Cochrane Library, Issue 1. 2003. Oxford: Update Software.Google Scholar]. Additional trials with longer duration and sufficient dosage of UDCA would be desirable, but are difficult to perform since on the basis of available evidence UDCA therapy has been recommended in the guide lines of large medical associations such as the American Association for the Study of Liver Diseases [[13]Heathcote E.J. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.Hepatology. 2000; 31: 1005-1013Crossref PubMed Scopus (388) Google Scholar] and UDCA has been approved for treatment of PBC by the US FDA. In this situation, studies of the effect of UDCA on histologic progression of PBC are of considerable importance.The authors of four large controlled trials [3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 4Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] of UDCA treatment of PBC have put together their data to analyze the effect of treatment with UDCA on histologic progression of PBC. The results of this analysis are published in the present issue of the Journal [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. From the French [[3]Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar], the Mayo [[5]Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar], the Canadian [[4]Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar] and the Spanish [[9]Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] trials they selected patients in whom paired liver biopsy specimens were available. The medium time interval between the pretreatment and posttreatment biopsy was 25 months (range: 7–48 months). A total of 367 patients (200 treated with UDCA and 167 with placebo) was selected. Histologic staging was performed according to the Ludwig criteria in three studies [3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] or according to a method very similar to the Ludwig system in one study [[4]Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar]. The baseline characteristics (age, gender, liver biochemical tests, Mayo risk score) and histologic stages (UDCA group: 19% stage I, 30% stage II, 32% stage III, 21% stage IV; Placebo group: 23% stage I, 25% stage II, 34% stage III, 20% stage IV) were similar in the UDCA and the placebo group. Most interestingly, there was no significant difference in histologic progression between the two treatment groups when all patients (histologic stages I–IV) were included. In contrast, a trend to a lower progression rate was found in the non-cirrhotic patients (stages I–III) of the UDCA group and a significantly (P<0.03) lower progression rate in the patients of the UDCA group having histologic stages I–II. The benefit of UDCA was mainly due to a higher percentage of patients with ‘no change’ of histologic stage rather than to an improvement of histology. One is disappointed not to find statistically significant differences in terms of progression of the degree of fibrosis, portal inflammation, and bile duct paucity between the UDCA and the placebo group not only in the whole group (histologic stages I–IV) but also in the subgroups, but this may result from too small numbers of patients in the subgroups. Only a significant delay in the progression of periportal necroinflammatory lesions (P=0.03) and an improvement in the degree of ductular proliferation (P<0.02) was found under UCDA treatment in the whole group of patients.What do we learn from these findings? First, UDCA has little, if any effect on the progression of the disease in the late stages (stages III and IV) of PBC. Second, once extensive fibrosis or cirrhosis is present, the major targets of UDCA therapy namely the small interlobular bile ducts have largely vanished. Protection of the biliary epithelium of small interlobular bile ducts against toxic effects of hydrophobic bile acids appears to be one of the major mechanism of action of UDCA. Third, and most importantly, if treatment is initiated early, the progression of the disease may be delayed.In the light of the findings of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] the results of a recent randomized, controlled trial of Papatheodoridis and colleagues [[15]Papatheodoridis G.V. Hadziyannis E.S. Deutsch M. Hadziyannis S.J. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial.Am J Gastroenterol. 2002; 97: 2063-2070Crossref PubMed Google Scholar] can be better understood. This trial has a long follow up (7.3±3 years) but a relatively small number of patients (n=86) and the rather serious limitation that it is not placebo controlled. It compared UDCA treatment (12–15 mg/kg per day) against no treatment and did not detect an effect of UDCA on the development of liver decompensation or on liver death or transplantation. It must, however, be recognized that, because of the relatively small number of patients, a difference of less than 30% between the UDCA and the no treatment group could not be excluded. In the 86 patients who were randomized to receive UDCA or no treatment, a liver biopsy was performed before entry into the study or within the previous 12 months and the histological lesions were classified according to the Ludwig criteria. In the UDCA group 9.3% of the patients had histologic stage I, 25.6% stage II, 25.6% stage III and 39.5% stage IV. The respective figures in the group of patients receiving no treatment were 11.6, 25.6, 32.6 and 30.2%. It is important to note that more than 25% of the treated patients had extensive fibrosis and nearly 40% had cirrhosis at baseline. Follow-up liver biopsies were performed in 82% of patients with histologic stages I–III after a medium time interval of 5.0 years (range: 2.0–10.1) in the UDCA group and 5.1 years (range: 1.8–10.3) in the no treatment group. According to the findings of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] one would not expect to see a slowing of histologic progression of the disease by UDCA in this subgroup with a large proportion of stage III patients. Exactly, this was the case. The study did not find an effect of UDCA on histologic progression of the disease. To detect a beneficial effect of UDCA in patients with stages I–II, the number of patients in the trial of Papatheodoridis et al. [[15]Papatheodoridis G.V. Hadziyannis E.S. Deutsch M. Hadziyannis S.J. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial.Am J Gastroenterol. 2002; 97: 2063-2070Crossref PubMed Google Scholar]obviously is to small for a valid statistical analysis.The study of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] in the present issue of the Journal is important because it confirms previous reports [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar] that UDCA can delay the progression of PBC from early stages of the disease to severe fibrosis or cirrhosis. It reminds us that, to reach this goal, we should start UDCA treatment of our patients with PBC early. Ursodeoxycholic acid (UDCA) is widely used for the treatment of primary biliary cirrhosis (PBC) [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar]. At present, it is the only drug approved by the US Food and Drug Administration (FDA) for this disease. UDCA is a hydrophilic, dihydroxy bile acid (3α,7β-dihydroxy-5β-cholanic acid) which is normally present in human bile albeit in a low concentration of only about 3% of total bile acids. It is the major bile acid of the bile of black bears which has been used since centuries in Chinese traditional medicine as a remedy for liver diseases [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar]. Multiple mechanisms of action of UDCA have been described, including protection of injured cholangiocytes against toxic effects of hydrophobic bile acids, stimulation of impaired biliary secretion, inhibition of apoptosis of hepatocytes and, possibly, stimulation of detoxification of hydrophobic bile acids [[1]Paumgartner G. Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.Hepatology. 2002; 36: 525-531Crossref PubMed Scopus (530) Google Scholar]. Although early trials clearly showed that UDCA improves serum liver tests including bilirubin and other markers of cholestasis [2Leuschner U. Fischer H. Kurtz W. Guldutuna S. Hubner K. Hellstern A. et al.Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial.Gastroenterology. 1989; 97: 1268-1274Abstract PubMed Google Scholar, 3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 4Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar], evidence that UDCA inhibits the progression of the disease has come slowly and in pieces. An analysis of the combined data of three large trials showed that therapy with UDCA at daily doses of 13–15 mg/kg for up to 4 years increases the time taken to liver transplantation or death [[6]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 (547) Google Scholar] and another study in which patients with PBC were treated with UDCA for up to 6 years suggested that UDCA prolonged transplant-free survival [[7]Lindor K.D. Therneau T.M. Jorgensen R.A. Malinchoc M. Dickson E.R. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis.Gastroenterology. 1996; 110: 1515-1518Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. Proof that UDCA delays histologic progression of the disease has not been very strong. Three studies [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar] reported an effect of UDCA on the histologic progression of PBC, but two of them are limited by a small number of patients [[8]Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar] or variable duration of therapy [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar]. Those who only believe in meta-analysis maintain that adequate proof for an effect of UDCA on disease progression in PBC is lacking. A meta-analysis of eight randomized trials showed no difference between UDCA and placebo in the effects on incidence of death, liver transplantation and death or liver transplantation [[11]Goulis J. Leandro G. Burroughs A. 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 (264) Google Scholar]. It must, however, be considered that six of the trials included in this meta-analysis evaluated treatment given up to 24 months only and that two of the trials used daily doses of UDCA (7.7 and 10 mg/kg) which are now generally considered to be too low. Similarly, another meta-analysis of 16 randomized trials which included studies with UDCA doses as low as 8 mg/kg per day (8–15 mg/kg per day) and follow-up as short as 3 months (3 months–5 years) did not detect a survival benefit for patients treated with UDCA [[12]Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis (Cochrane Review). In: The Cochrane Library, Issue 1. 2003. Oxford: Update Software.Google Scholar]. Additional trials with longer duration and sufficient dosage of UDCA would be desirable, but are difficult to perform since on the basis of available evidence UDCA therapy has been recommended in the guide lines of large medical associations such as the American Association for the Study of Liver Diseases [[13]Heathcote E.J. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.Hepatology. 2000; 31: 1005-1013Crossref PubMed Scopus (388) Google Scholar] and UDCA has been approved for treatment of PBC by the US FDA. In this situation, studies of the effect of UDCA on histologic progression of PBC are of considerable importance. The authors of four large controlled trials [3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 4Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] of UDCA treatment of PBC have put together their data to analyze the effect of treatment with UDCA on histologic progression of PBC. The results of this analysis are published in the present issue of the Journal [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. From the French [[3]Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar], the Mayo [[5]Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar], the Canadian [[4]Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar] and the Spanish [[9]Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] trials they selected patients in whom paired liver biopsy specimens were available. The medium time interval between the pretreatment and posttreatment biopsy was 25 months (range: 7–48 months). A total of 367 patients (200 treated with UDCA and 167 with placebo) was selected. Histologic staging was performed according to the Ludwig criteria in three studies [3Poupon R.E. Balkau B. Eschwege E. Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.N Engl J Med. 1991; 324: 1548-1554Crossref PubMed Scopus (667) Google Scholar, 5Lindor K.D. Dickson E.R. Baldus W.P. Jorgensen R.A. Ludwig J. Murtaugh P.A. et al.Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.Gastroenterology. 1994; 106: 1284-1290PubMed Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar] or according to a method very similar to the Ludwig system in one study [[4]Heathcote E.J. Cauch-Dudek K. Walker V. Bailey R.J. Blendis L.M. Ghent C.N. et al.The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.Hepatology. 1994; 19: 1149-1156Crossref PubMed Scopus (397) Google Scholar]. The baseline characteristics (age, gender, liver biochemical tests, Mayo risk score) and histologic stages (UDCA group: 19% stage I, 30% stage II, 32% stage III, 21% stage IV; Placebo group: 23% stage I, 25% stage II, 34% stage III, 20% stage IV) were similar in the UDCA and the placebo group. Most interestingly, there was no significant difference in histologic progression between the two treatment groups when all patients (histologic stages I–IV) were included. In contrast, a trend to a lower progression rate was found in the non-cirrhotic patients (stages I–III) of the UDCA group and a significantly (P<0.03) lower progression rate in the patients of the UDCA group having histologic stages I–II. The benefit of UDCA was mainly due to a higher percentage of patients with ‘no change’ of histologic stage rather than to an improvement of histology. One is disappointed not to find statistically significant differences in terms of progression of the degree of fibrosis, portal inflammation, and bile duct paucity between the UDCA and the placebo group not only in the whole group (histologic stages I–IV) but also in the subgroups, but this may result from too small numbers of patients in the subgroups. Only a significant delay in the progression of periportal necroinflammatory lesions (P=0.03) and an improvement in the degree of ductular proliferation (P<0.02) was found under UCDA treatment in the whole group of patients. What do we learn from these findings? First, UDCA has little, if any effect on the progression of the disease in the late stages (stages III and IV) of PBC. Second, once extensive fibrosis or cirrhosis is present, the major targets of UDCA therapy namely the small interlobular bile ducts have largely vanished. Protection of the biliary epithelium of small interlobular bile ducts against toxic effects of hydrophobic bile acids appears to be one of the major mechanism of action of UDCA. Third, and most importantly, if treatment is initiated early, the progression of the disease may be delayed. In the light of the findings of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] the results of a recent randomized, controlled trial of Papatheodoridis and colleagues [[15]Papatheodoridis G.V. Hadziyannis E.S. Deutsch M. Hadziyannis S.J. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial.Am J Gastroenterol. 2002; 97: 2063-2070Crossref PubMed Google Scholar] can be better understood. This trial has a long follow up (7.3±3 years) but a relatively small number of patients (n=86) and the rather serious limitation that it is not placebo controlled. It compared UDCA treatment (12–15 mg/kg per day) against no treatment and did not detect an effect of UDCA on the development of liver decompensation or on liver death or transplantation. It must, however, be recognized that, because of the relatively small number of patients, a difference of less than 30% between the UDCA and the no treatment group could not be excluded. In the 86 patients who were randomized to receive UDCA or no treatment, a liver biopsy was performed before entry into the study or within the previous 12 months and the histological lesions were classified according to the Ludwig criteria. In the UDCA group 9.3% of the patients had histologic stage I, 25.6% stage II, 25.6% stage III and 39.5% stage IV. The respective figures in the group of patients receiving no treatment were 11.6, 25.6, 32.6 and 30.2%. It is important to note that more than 25% of the treated patients had extensive fibrosis and nearly 40% had cirrhosis at baseline. Follow-up liver biopsies were performed in 82% of patients with histologic stages I–III after a medium time interval of 5.0 years (range: 2.0–10.1) in the UDCA group and 5.1 years (range: 1.8–10.3) in the no treatment group. According to the findings of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] one would not expect to see a slowing of histologic progression of the disease by UDCA in this subgroup with a large proportion of stage III patients. Exactly, this was the case. The study did not find an effect of UDCA on histologic progression of the disease. To detect a beneficial effect of UDCA in patients with stages I–II, the number of patients in the trial of Papatheodoridis et al. [[15]Papatheodoridis G.V. Hadziyannis E.S. Deutsch M. Hadziyannis S.J. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial.Am J Gastroenterol. 2002; 97: 2063-2070Crossref PubMed Google Scholar]obviously is to small for a valid statistical analysis. The study of Poupon and colleagues [[14]Poupon R.E. Lindor K.D. Parés A. Chazouillères O. Poupon R. Heathcote E.J. Combined analysis of the effects of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.J Hepatol. 2003; 39: 12-16Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar] in the present issue of the Journal is important because it confirms previous reports [8Angulo P. Batts K.P. Therneau T.M. Jorgensen R.A. Dickson E.R. Lindor K.D. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.Hepatology. 1999; 29: 644-647Crossref PubMed Scopus (178) Google Scholar, 9Pares A. Caballeria L. Rodes J. Bruguera M. Rodrigo L. Garcia-Plaza A. et al.Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.J Hepatol. 2000; 32: 561-566Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 10Corpechot C. Carrat F. Bonnand A.M. Poupon R.E. Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.Hepatology. 2000; 32: 1196-1199Crossref PubMed Scopus (246) Google Scholar] that UDCA can delay the progression of PBC from early stages of the disease to severe fibrosis or cirrhosis. It reminds us that, to reach this goal, we should start UDCA treatment of our patients with PBC early.