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

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

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