背景:原发性硬化性胆管炎(PSC)的疾病严重程度和预后需要新的无创预测因子。这项研究评估了细胞外基质重塑标志物诊断纤维化分期和预测PSC相关纤维化进展和临床事件的能力。
方法:肝脏组织学和胶原蛋白形成的血清标志物(III型胶原蛋白的前肽[Pro-C3],IV型胶原蛋白的前肽,V型胶原蛋白的前肽),胶原降解(III型胶原基质金属蛋白酶降解产物和IV型胶原基质金属蛋白酶降解产物),和纤维化(增强的肝纤维化[ELF]评分及其成分[金属蛋白酶-1,III型前胶原,透明质酸])在纳入一项评估辛妥珠单抗(NCT01672853)的研究中纳入的PSC患者从基线到第96周的样本中进行了评估。通过逻辑回归和AUROC评估晚期纤维化(Ishak3-6期)和肝硬化(Ishak5-6期)的诊断性能。通过AUROC和Wilcoxon秩和检验评估PSC相关临床事件和纤维化进展的预后表现。
结果:在234名患者中,51%有晚期纤维化和11%的肝硬化在基线。基线Pro-C3和ELF评分及其组成部分为区分晚期纤维化(AUROC0.73-0.78)和肝硬化(AUROC0.73-0.81)提供了中等诊断能力。基线Pro-C3,ELF评分,和III型前胶原为PSC相关临床事件提供了中度预后(AUROC0.70-0.71).在基线无肝硬化的患者中,至第96周,进展至肝硬化的患者中,Pro-C3和ELF评分的中位数变化高于未进展至肝硬化的患者(均p<0.001).
结论:Pro-C3与纤维化分期相关,和Pro-C3和ELF评分提供了晚期纤维化和肝硬化的区分以及预测的PSC相关事件和纤维化进展。结果支持Pro-C3和ELF评分在PSC中用于分期和作为预后标志物的临床实用性。
BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events.
METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test.
RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001).
CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.