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Z Gastroenterol 2005; 43(9): 1051-1059
DOI: 10.1055/s-2005-858281
Übersicht

© Karl Demeter Verlag im Georg Thieme Verlag KG Stuttgart · New York

Ursodeoxycholic Acid in the Therapy for Primary Biliary Cirrhosis: Effects on Progression and Prognosis

Ursodeoxycholsäure zur Therapie der primär biliären Zirrhose - Ihr Einfluss auf Krankheitsverlauf und PrognoseU. Leuschner1 , M.-P Manns2 , R. Eisebitt3
  • 1Medizinische Klinik der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany
  • 2Medizinische Hochschule Hannover, Abt. für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
  • 3ClinResearch, Institut für Monitoring, Data Management, Biometry and Medical Writing, Köln, Germany
Further Information

Publication History

manuscript received: 16.2.2005

manuscript accepted: 19.4.2005

Publication Date:
02 September 2005 (online)

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Zusammenfassung

Ein Einfluss von UDC auf die Endpunkte Tod oder transplantationsfreies Überleben kann in klinischen Studien nur dann nachgewiesen werden, wenn die UDC-Therapie in den Frühstadien I, allenfalls noch II, begonnen und bis in die Stadien III/IV, besser IV, fortgesetzt wird. Der Grund hierfür liegt in der Beobachtung, dass in den Stadien I/II kein Patient eine derart progressive Krankheit hat, dass sie zur Transplantation oder zum Tode führt, und dass ein messbarer Einfluss von UDC auf die Fibrose- und Zirrhosestadien III/IV (wie auch für Medikamente bei anderen Leberkrankheiten) zunehmend geringer und schließlich nicht mehr nachweisbar wird. Es muss daher schon in der Entzündungsphase I (allenfalls in der entzündlich-progressiven Phase II) mit der Behandlung begonnen und nach jahrelanger Dauertherapie der Ausgang ermittelt werden. Hierfür sind sehr große, wahrscheinlich nicht erreichbare Patientenkollektive erforderlich. Aus ethischen Gründen bleibt außerdem problematisch, ob man über einen derart langen Zeitraum die Hälfte der Patienten nur mit Plazebo behandeln darf. - Da diese Argumente weder in zwei hier zitierten Metaanalysen noch in irgendwelchen anderen Studien berücksichtigt wurden, lassen sie eine Aussage über die Lebenserwartung unter UDC-Therapie nicht zu. Andererseits lässt sich heute mithilfe international akzeptierter prognostischer Variablen und mit mathematischen Modellen, deren Einschränkungen sehr wohl bekannt sind und berücksichtigt werden müssen, der Krankheitsverlauf für unbehandelte und behandelte Patienten mit hinreichend großer Genauigkeit ermitteln und die Überlebenszeit (transplantatfreies Überleben und Tod) berechnen. Da UDC die wichtigsten Prognosemarker der PBC, wie z.B. Serumbilirubin, Piecemeal-Nekrosen, histologische Progression, Aszites und Ödeme, und offenbar auch die Scores für Pruritus und Lethargie (Fatigue), signifikant positiv beeinflusst, lässt sich nicht nur eine Abnahme der Transplantationsinzidenz nachweisen, sondern auch eine Lebensverlängerung berechnen.

Abstract

The effects in clinical studies of UDCA on the endpoints “death” or “pre-transplantation survival” can only be shown when UDCA therapy is started in an early disease phase, preferably in stage I but no later than stage II, and is then continued into stages III/IV, or preferably stage IV. The reasons for this lie in the observation that, in stages I/II, no patient suffers from progressive disease that irrevocably leads to death or transplantation, while a measurable effect of UDCA, as is true for other drugs and other hepatic diseases, continues to dwindle and finally disappears as patients progress through the fibrotic and cirrhotic stages III and IV. Hence, administration of UDCA must begin in the phase of progressive inflammation (stages I and II) and the outcome documented after many years of long-term therapy. This requires very large, probably unattainable, patient collectives. Whether it is justified to administer placebo to one-half of these patients over such an extended period of time represents a profound ethical dilemma. Because these arguments were not considered in the two meta-analyses cited above or in any other study, they do not allow a definitive statement on the life expectancy of patients on UDCA therapy. On the other hand, it is possible using generally accepted, independent prognostic variables and mathematical models, whose limitations are well-known and must be considered, to predict with a high degree of accuracy the disease course of treated and untreated patients and calculate their life expectancy and/or pre-transplantation survival. Because UDCA exerts a significant positive effect on the most important prognostic markers for PBC, such as serum bilirubin, piecemeal necroses, histological disease progression, ascites and edema, and apparently the scores for pruritus and fatigue, this permits us to demonstrate not only a decrease in the incidence of transplantation but also to calculate a prolongation in life expectancy.

Schlüsselwörter

Primär biliäre Zirrhose - Ursodeoxycholsäure - Therapieergebnisse - Überlebensrate

Key words

Primary biliary cirrhosis - ursodeoxycholic acid - therapy results - survival

References

  • 1 Leuschner U, Fischer H, Kurtz W. et al . Ursodeoxycholic acid in primary biliary cirrhosis: Results of a controlled double-blind trial.  Gastroenterology. 1989;  97 1268-1274
    PubMedGoogle Scholar
  • 2 Poupon R E, Balkau B, Eschwège E. et al . The UDCA-PBC-Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis.  N Engl J Med. 1991;  324 1548-1554
    PubMedGoogle Scholar
  • 3 Combes B, Carithers R L, Maddrey W C. et al . A randomised double-blind placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis.  Hepatology. 1995;  22 759-766
    CrossrefPubMedGoogle Scholar
  • 4 Czaya A J. Autoimmune liver disease.  Curr Opin Gastroenterol. 1999;  15 240-248
    CrossrefPubMedGoogle Scholar
  • 5 Kim W R, Lindor K D, Locke G R. et al . Epidemiology and natural history of primary biliary cirrhosis in a U.S. community.  Gastroenterology. 2000;  119 1631-1636
    CrossrefPubMedGoogle Scholar
  • 6 Kingham J G, Parker D R. The association between primary biliary cirrhosis in coeliac disease: a study of relative prevalence.  Gut. 1998;  42 120-122
    CrossrefPubMedGoogle Scholar
  • 7 Howel D, Fischbacher C, Bhopal R. et al . An exploratory population based case-control study of primary biliary cirrhosis.  Hepatology. 2000;  31 1055-1060
    CrossrefPubMedGoogle Scholar
  • 8 Prince M I, James O FW. The epidemiology of primary biliary cirrhosis.  Clin Liver Dis. 2003;  7 795-819
    CrossrefPubMedGoogle Scholar
  • 9 Scheuer P J. Ludwig-Symposium on biliary disorders - part 2. Pathologic features and evaluation of primary biliary cirrhosis and primary sclerosing cholangitis.  Mayo Clin Proc. 1998;  73 179-183
    PubMedGoogle Scholar
  • 10 Christensen E, Neuberger J, Crowe J. et al . Benefical effect of azathioprine and prediction of progression in primary biliary cirrhosis. Trial results of an international trial.  Gastroenterology. 1985;  89 1085-1091
    PubMedGoogle Scholar
  • 11 Dickson E R, Grambsch P M, Fleming T R. et al . Prognosis in primary biliary cirrhosis: Model for decision making.  Hepatology. 1989;  10 1-7
    PubMedGoogle Scholar
  • 12 Rydning A, Schrumpf E, Abdelnoor M. et al . Factor of prognostic importance in primary biliary cirrhosis.  Scand J Gastroenterol. 1990;  25 119-126
    PubMedGoogle Scholar
  • 13 Christensen E. Prognostic modelling in primary biliary cirrhosis. West End Studios Eastbourne BN, UK.  1999;  93-99
    PubMedGoogle Scholar
  • 14 Murtaugh P A, Dickson E R, van Dam G M. et al . Primary biliary cirrhosis: Prediction of short-term survival based on repeated patient visits.  Hepatology. 1994;  20 126-134
    CrossrefPubMedGoogle Scholar
  • 15 Grambsch P M, Dickson E R, Kaplan M. et al . Extramural cross validation of the Mayo primary biliary cirrhosis survival model establishes its generalizability.  Hepatology. 1989;  10 846-850
    PubMedGoogle Scholar
  • 16 Klion F M, Fabry T L, Palmer M. et al . Prediction of survival of patients with primary biliary cirrhosis. Examination of the Mayo Clinic model on a group of patients with known end point.  Gastroenterology. 1992;  102 310-313
    PubMedGoogle Scholar
  • 17 Christensen E, Altman D G, Neuberger J. et al . Updating prognosis in primary biliary cirrhosis using a time-dependent Cox regression model.  Gastroenterology. 1993;  105 1865-1876
    PubMedGoogle Scholar
  • 18 Kim W R, Wiesner R H, Poterucha J J. et al . Adaption of the Mayo primary biliary cirrhosis natural history model for application in liver transplant candidates.  Liver Transpl. 2000;  6 489-494
    CrossrefPubMedGoogle Scholar
  • 19 Christensen E. Prognostic models including the Child-Pugh, MELD and Mayo Risk scores - where are we and where should we go?.  J Hepatol. 2004;  41 344-350
    CrossrefPubMedGoogle Scholar
  • 20 Christensen E, Schlichting P, Andersen P K. et al . Updating prognosis and therapeutic effect evaluation in cirrhosis using Cox’s multiple regression model for time dependent variables.  Scand J Gastroenterol. 1986;  21 163-174
    PubMedGoogle Scholar
  • 21 Jensen D M. Cholestasis.  Clinics in Liver Disease. 1999;  3 529-570
    CrossrefPubMedGoogle Scholar
  • 22 Angulo P, Lindor K D, Therneau T M. et al . Utilization of the Mayo risk score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid.  Liver. 1999;  19 115-121
    CrossrefPubMedGoogle Scholar
  • 23 Lindor K D, Therneau T M, Jorgensen R A. et al . Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis.  Gastroenterology. 1996;  110 1515-1518
    PubMedGoogle Scholar
  • 24 Emond M, Carithers R L Jr, Luketi V A. et al . Does ursodeoxycholic acid improve survival in patients with primary biliary cirrhosis? Comparison of outcome in the U.S. multicenter trial to expected survival using the Mayo clinic prognosis model.  Hepatology. 1996;  24 168A
    PubMedGoogle Scholar
  • 25 Markus B H, Dickson E R, Grambsch P M. et al . Efficacy of liver transplantation in patients with primary biliary cirrhosis.  N Engl J Med. 1989;  320 1709-1713
    CrossrefPubMedGoogle Scholar
  • 26 Corpechot C, Carrat F, Poupon R. et al . Primary biliary cirrhosis: Incidence and predictive factors of cirrhosis development in ursodiol treated patients.  Gastroenterology. 2002;  122 652-658
    CrossrefPubMedGoogle Scholar
  • 27 Locke I II GR, Therneau T M, Ludwig J. et al . Time course of histological progression in primary biliary cirrhosis.  Hepatology. 1998;  23 52-56
    PubMedGoogle Scholar
  • 28 Roll J, Boyer J L, Barry D L. et al . The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis.  N Eng J Med. 1983;  308 1-7
    PubMedGoogle Scholar
  • 29 Goudie B M, Burt A D, MacFarlane G J. et al . Risk factors and prognosis in primary biliary cirrhosis.  Am J Gastroenterol. 1989;  84 713-716 (erratum in Am J Gastroenterol 1989; 84: 1474)
    PubMedGoogle Scholar
  • 30 Angulo P. Primary biliary cirrhosis and primary sclerosing cholangitis.  Clinics in Liver Disease. 1999;  3 529-571
    CrossrefPubMedGoogle Scholar
  • 31 Pasha T M, Dickson E R. Survival algorithms and outcome analysis in primary biliary cirrhosis.  Seminars in Liver Disease. 1997;  17 147-158
    PubMedGoogle Scholar
  • 32 Parés A, Rodés J. Natural history of primary biliary cirrhosis.  Clinics in Liver Disease. 2003;  7 779-794
    CrossrefPubMedGoogle Scholar
  • 33 Felix R, Schuster S. A new method for the measurement of itch and response to treatment.  Br J Dermatol. 1975;  93 303-312
    PubMedGoogle Scholar
  • 34 Bergasa N V. Pruritus and fatigue in primary biliary cirrhosis.  Clinics in Liver Disease. 2003;  7 879-900
    CrossrefPubMedGoogle Scholar
  • 35 Goldblatt J, Taylor P J, Lipman T. et al . The true impact of fatigue in primary biliary cirrhosis: a population study.  Gastroenterology. 2002;  122 1235-1241
    PubMedGoogle Scholar
  • 36 Cauch-Dudek K, Abbey S, Stewart D E. et al . Fatigue in primary biliary cirrhosis.  Gut. 1998;  43 705-710
    CrossrefPubMedGoogle Scholar
  • 37 Kilmurry M R, Heathcote E J, Cauch-Dudek K. et al . Is the Mayo model for predicting survival useful after the introduction of ursodeoxycholic acid treatment for primary biliary cirrhosis?.  Hepatology. 1996;  23 1148-1153
    PubMedGoogle Scholar
  • 38 Christensen E, Crowe J, Doniach D. et al . Clinical pattern and course of disease in primary biliary cirrhosis based on the analysis of 236 patients.  Gastroenterology. 1980;  236 46-78
    PubMedGoogle Scholar
  • 39 Mahl T, Shockcor W, Boyer J L. Primary biliary cirrhosis. Survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years.  J Hepatol. 1994;  20 707-713
    CrossrefPubMedGoogle Scholar
  • 40 Springer J, Cauch-Dudek K, O’Rourke K. et al . Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis.  Am J Gastroenterol. 1999;  94 47-53
    CrossrefPubMedGoogle Scholar
  • 41 Prince M, Chetwynd A, Newman W. et al . Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years.  Gastroenterology. 2002;  1044 51-123
    PubMedGoogle Scholar
  • 42 Parés A, Bruguera M, Rodés J. Cirrosis biliar. Evaluación clínica y criterios de valor pronóstico.  Gastroenterol Hepatol. 1981;  4 76-81
    PubMedGoogle Scholar
  • 43 Shapiro J M, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis.  Gut. 1979;  20 137-140
    PubMedGoogle Scholar
  • 44 Perez Tamayo R. Cirrhosis of the liver: a reversible disease?.  Pathol Annu. 1979;  14 183-213
    PubMedGoogle Scholar
  • 45 Wanless I R, Nakashima E, Sherman M. Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis.  Arch Pathol Lab Med. 2000;  124 1599-1607
    PubMedGoogle Scholar
  • 46 Poynard T, McHutchison J, Manns M. et al . Impact of pegylated interferon alpha-2 b and ribavirin on liver fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2002;  122 1303-1313
    CrossrefPubMedGoogle Scholar
  • 47 Desmet V J, Roskams T. Cirrhosis reversal: a duel between dogma and myth.  J Hepatol. 2004;  40 860-867
    CrossrefPubMedGoogle Scholar
  • 48 Sobesky R, Mathurin P, Charlotte F. Modeling the impact of interferon alpha treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view.  Gastroenterology. 1999;  116 378-386
    PubMedGoogle Scholar
  • 49 Schaffner F, Popper H. Capillarization of hepatic sinusoids in man.  Gastroenterology. 1963;  44 239-242
    PubMedGoogle Scholar
  • 50 Wanless I R, Wong F, Blendis L M. et al . Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.  Hepatology. 1995;  21 1238-1247
    CrossrefPubMedGoogle Scholar
  • 51 Varin F, Huet P M. Hepatic microcirculation in the perfused cirrhotic rat liver.  J Clin Invest. 1985;  76 1904-1912
    PubMedGoogle Scholar
  • 52 Gaudio E, Pannarale L, Onori P. et al . A scanning electron microscopic study of liver microcirculation disarrangement in experimental rat cirrhosis.  Hepatology. 1993;  17 477-485
    CrossrefPubMedGoogle Scholar
  • 53 Corpechot C, Carrat F, Poupon R. et al . Primary biliary cirrhosis: Incidence and predictive factors of cirrhosis development in ursodiol-treated patients.  Gastroenterology. 2002;  122 652-658
    CrossrefPubMedGoogle Scholar
  • 54 Goulis J, Leandro G, Burrough A K. Randomised controlled trials of ursodeoxycholic acid therapy for primary biliary cirrhosis: a meta-analysis.  The Lancet. 1999;  354 1053-1060
    CrossrefPubMedGoogle Scholar
  • 55 Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis.  Cochrane Database Syst Rev. 2002;  1 CD 000 551
    PubMedGoogle Scholar
  • 56 Papatheodoridis G V, Hadziyannis E S, Deutsch M. et al . Ursodeoxycholic acid (UDCA) in primary biliary cirrhosis. Trial results of a 12-year prospective randomized, controlled trial.  Amer J Gastroenterol. 2002;  32 561-566
    PubMedGoogle Scholar
  • 57 Parés A, Caballeria L, Rodés J. et al . Long-term effects of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis: Results of a double-blind controlled multicentric trial.  J Hepatol. 2000;  32 561-566
    CrossrefPubMedGoogle Scholar
  • 58 Combes B, Luketik V A, Peters M G. et al . Prolonged follow-up of patients in the U.S. multicenter trial ursodeoxycholic acid for primary biliary cirrhosis.  Am J Gastroenterol. 2004;  99 264-298
    CrossrefPubMedGoogle Scholar
  • 59 Poupon R E. Ursodeoxycholic acid for primary biliary cirrhosis: Lessons from the past - issues for the future.  J Hepatol. 2000;  32 685-688
    CrossrefPubMedGoogle Scholar
  • 60 Ludwig J, Dickson E R, McDonald G S. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).  Virchows Arch, A (Pathol Anat). 1978;  379 103-112
    PubMedGoogle Scholar
  • 61 Williams C N, Al Kuawi B, Blanchard W. Bioavailability of four ursodeoxycholic acid preparations.  Aliment Pharmacol Ther. 2000;  14 1133-1139
    CrossrefPubMedGoogle Scholar
  • 62 Schiffman M L, Kaplan G D, Brinkmann V. et al . Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program.  Ann Intern Med. 1995;  122 899-905
    PubMedGoogle Scholar
  • 63 Kjaegard L L, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomised trials in meta-analyses.  Ann Int Med. 2001;  135 982-989
    PubMedGoogle Scholar
  • 64 Schulz K F, Chalmers I, Hayes R. et al . Empirical evidence of bias. Dimensions of methodological quality associates with estimates of treatment of controlled trials.  JAMA. 1995;  273 408-412
    CrossrefPubMedGoogle Scholar
  • 65 Corpechot C, Carrat F, Bonnaud A M. et al . The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.  Hepatology. 2000;  32 1196-1199
    CrossrefPubMedGoogle Scholar
  • 66 Parés A, Caballeria L, Bruguera M. et al . Factors influencing histological progression of early primary biliary cirrhosis. Effect of ursodeoxycholic acid.  J Hepatol. 2001;  34 (Suppl 1) 189-190
    PubMedGoogle Scholar
  • 67 Parés A, Caballeria L, Rodés J. Long-term ursodeoxycholic acid treatment delays progression of mild primary biliary cirrhosis.  J Hepatol. 2001;  34 (Suppl 1) 187-188
    PubMedGoogle Scholar
  • 68 Poupon R E, Lindor K D, Cauch-Dudek K. et al . Combined analysis of randomised controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.  Gastroenterology. 1997;  113 884-890
    CrossrefPubMedGoogle Scholar
  • 69 Poupon R, Corpechot C, Carrat F. et al .Primary biliary cirrhosis: Long-term therapy with ursodeoxycholic acid. Leuschner U, Broomé U, Stiehl A Cholestatic liver diseases. Therapeutic options and perspectives Kluwer, Dordrecht, Boston, London; 2004: 171-178
    Google Scholar
  • 70 Corpechot C, Carrat F, Bahr A. et al . The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.  Gastroenterology. 2005;  128 297-303
    CrossrefPubMedGoogle Scholar

Prof. Dr. Ulrich Leuschner

Medizinische Universitätsklinik, Johann Wolfgang Goethe Universität

Theodor-Stern-Kai 7

D-60590 Frankfurt am Main

Phone: ++ 49/69/59 72/53

Fax: ++ 49/69/56 01/6 69

Email: U.Leuschner@em.uni-Frankfurt.de

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