Elsevier

Journal of Hepatology

Volume 55, Issue 6, December 2011, Pages 1361-1367
Journal of Hepatology

Research Article
Early primary biliary cirrhosis: Biochemical response to treatment and prediction of long-term outcome

https://doi.org/10.1016/j.jhep.2011.02.031Get rights and content

Background & Aims

The 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.

Methods

The efficiency of several combinations of serum bilirubin, alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcome was assessed after 1 year of UDCA in 165 patients with early-stage PBC followed up for an average 7 years. The Barcelona, Paris, Rotterdam, and Toronto criteria were also assessed.

Results

The most accurate discrimination of the patients according to the multiple endpoints was given by the following criteria: ALP and AST ⩽1.5× upper limit of normal, with a normal bilirubin level. Responders and non-responders were equally distributed, while all adverse events were observed in non-responders (p <0.001). These criteria remained valid when early PBC was defined by both normal bilirubin and albumin concentrations at baseline.

Conclusions

This study defines the best efficient biochemical response to UDCA that identifies patients with early PBC at very low risk of long-term development of liver failure or cirrhosis.

Introduction

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic disease associated with the development of cirrhosis and liver failure that may justify liver transplantation. Ursodeoxycholic acid (UDCA) is currently the only drug approved specifically for the treatment of PBC [1], [2]. UDCA improves liver biochemistry, delays histological progression, as well as the development of portal hypertension and its complications [3], [4], [5], [6]. However, the transplant-free survival of patients treated with UDCA remains lower than that of an age and sex-matched population [7], [8], [9] indicating that new therapeutic options are warranted. To evaluate efficacy of new treatments, surrogate end-points of disease progression are required [10]. Observational studies in PBC have shown that the biochemical response to UDCA correlates with the long-term outcome [11], [12], [13], [14] and thus could have a role in clinical practice and future therapeutic trials by identifying the patients with a poor prognosis. Different definitions of the biochemical response as a surrogate marker of survival without transplantation have been proposed and currently the so-called Paris criteria have been recognized as the most relevant [10]. However, since most patients are nowadays diagnosed and treated at an early stage, traditional hard end-points, such as the occurrence of death or liver transplantation, are no longer thought to be realistic [10]. Accordingly, more extended end-points and stringent criteria in homogeneous cohorts of patients are required to define clinically relevant criteria of biochemical response in early PBC.

The aim of the present study was, therefore, to determine in patients with initially early histological stage of PBC the best biochemical criteria of response to UDCA able to predict the absence of adverse outcome, as defined not only by liver-related death, liver transplantation, or referral to a transplant unit, but also by complications of cirrhosis or histological evidence of cirrhosis development during follow-up.

Section snippets

Patient population

All the patients included in the study had serologically and histologically proven early-stage PBC, were treated with UDCA at the daily dose of 13–15 mg/kg of body weight and had documented biochemical analyses (that is: serum bilirubin and albumin concentrations; serum activities of alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)) before and after 1 year of treatment with UDCA. The histological stage was

Descriptive data

Among a cohort of 292 patients with PBC, whose long-term outcome was described previously [13], a total of 165 patients (94% females; age, 51 ± 12 years) complied with the inclusion criteria. The biochemical characteristics of the patients at baseline and after 1 year of UDCA therapy are shown in Table 1. After 1 year of UDCA treatment, the serum activities of ALP, GGT, AST, and ALT were decreased by about 50% (p <0.0001) and the serum concentration of total bilirubin by 30% (p <0.01), as compared to

Discussion

The identification of PBC patients with a poor long-term prognosis among those treated with UDCA at the daily dose of 13–15 mg/kg is an important issue in clinical practice as well as in the design of trials aimed at assessing new therapeutic approaches. Serum bilirubin, albumin, and prothrombin time are the traditional independent predictors of survival in patients with advanced PBC. These variables are now of less utility since most patients are diagnosed at an early stage and treated with

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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