Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis
Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis
复制标题
DOI：
10.1016/j.jhep.2017.01.019
复制
发表时间：
2017-06-01
影响因子：
25.7
通讯作者：
Lund-Johansen, Fridtjof
中科院分区：
文献类型：
--
作者：
Vesterhus, Mette;Holm, Anders;Lund-Johansen, Fridtjof
背景与目的：原发性硬化性胆管炎缺乏预后生物标志物，阻碍了患者的护理和治疗的发展。我们的目的是确定新的蛋白质生物标志物的疾病的严重程度和预后原发性硬化性胆管炎（PSC）。方法：使用珠为基础的阵列靶向63种蛋白质，我们描绘了挪威内镜逆行胆管造影术胆汁样本（55 PSC，20疾病对照）和芬兰验证面板（34 PSC，10疾病对照）的衍生面板。在来自两个挪威PSC组群的血清中测量选定的鉴定的蛋白质结果：在胆汁衍生物组中，PSC患者和对照组中有14种蛋白质的水平存在差异（p < 0.05）;所有结果均在验证组中得到证实。胆汁衍生组中的24种蛋白质在具有轻度与重度胆管造影变化的PSC患者之间显著（p < 0.05）不同（修改的阿姆斯特丹标准）;这在验证组中的18种蛋白质中重复。胆汁中的白细胞介素（IL）-8、基质金属肽酶（MMP）9/脂质运载蛋白（LCN）2复合物、S100 A8/9、S100 A12和色氨酸羟化酶（TPH）2与PSC诊断和胆管造影改变的分级相关。根据血清IL-8而不是MMP 9/LCN 2和S100 A12的三分位数对PSC患者进行分层，在血清衍生和验证队列中提供了对无移植存活的极好区分。此外，在多变量分析中，IL-8与两组血清中的无移植存活率相关，与年龄和疾病持续时间无关，表明对PSC进展有独立影响。然而，增强型肝纤维化（ELF（R））试验和马约风险评分被证明是更强的预测无移植survival.Conclusions：基于胆汁蛋白的测定，我们已经确定了新的胆汁和血清生物标志物作为PSC严重程度和预后的指标。我们已经确定了炎症蛋白，包括钙卫蛋白和IL-8作为疾病严重程度和预后的重要指标，从原发性硬化性胆管炎患者的胆汁和血清。(C)2017年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC).Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992-2006] and n = 138 [2008-2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100).Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p < 0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p < 0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF (R)) test and Mayo risk score proved to be stronger predictors of transplant-free survival.Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.Lay summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.