Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Liver Int. 2016 Dec;36(12):1867-1875. doi: 10.1111/liv.13110. Epub 2016 Apr 4.
Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold.
We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics.
A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3×ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3×ULN at T1.
ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC.
原发性硬化性胆管炎（PSC）是一种缓慢进展的肝脏疾病。迫切需要可靠的生物标志物来预测结局，以作为临床试验中的替代终点和/或分层因素。血清碱性磷酸酶（ALP）的降低已被提议作为 PSC 的预后替代标志物。本研究旨在评估诊断时（T0）、1 年后（T1）的 ALP 以及两个时间点之间的百分比变化是否具有预后价值，并确定最佳阈值。
我们回顾性地收集了纳入大型 PSC 队列的患者在 T0 和 T1 时的 ALP 水平。分析了 T0、T1 时的 ALP 以及百分比变化与联合终点（PSC 相关死亡、肝移植）的相关性。使用 C 统计量确定预测价值。
共纳入 366 例患者，其中 66 例（18%）达到终点：26 例（7%）PSC 相关死亡，40 例（11%）肝移植。在 T0 和 T1 时，84%的患者使用了熊去氧胆酸。T0 和 T1 时的 ALP 水平与达到终点的风险呈正相关，直至接近正常值上限（xULN）的 2.5 倍。T0 和 T1 之间 ALP 的较大下降降低了事件发生率。发现了一系列（0.5-3×ULN）具有相似 C 统计量的阈值。在该队列中，T1 时的最佳阈值为 1.3×ULN。
ALP 可用于区分预后良好和预后不良的 PSC 患者。这些发现表明 ALP 可用作 PSC 临床试验中的分层因素，并可能作为替代终点。
