Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
J Hepatol. 2017 Jun;66(6):1214-1222. doi: 10.1016/j.jhep.2017.01.019. Epub 2017 Feb 2.
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).
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).
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®) test and Mayo risk score proved to be stronger predictors of transplant-free survival.
Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.
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.
原发性硬化性胆管炎缺乏预后生物标志物，这阻碍了患者的治疗和治疗的发展。我们旨在鉴定原发性硬化性胆管炎（PSC）疾病严重程度和预后的新型蛋白生物标志物。
使用针对 63 种蛋白的珠基阵列，我们对挪威内镜逆行胰胆管造影胆汁样本的衍生队列（55 例 PSC，20 例疾病对照）和芬兰验证队列（34 例 PSC，10 例疾病对照）进行了蛋白谱分析。在来自两个挪威 PSC 队列的血清中测量了选定的鉴定蛋白（n=167[1992-2006]和 n=138[2008-2012]）、炎症性肠病（n=96）和健康对照者（n=100）。
在胆汁衍生队列中，PSC 患者与对照组之间有 14 种蛋白的水平不同（p<0.05）；所有蛋白在验证队列中均得到确认。在胆汁衍生队列中，24 种蛋白在 PSC 患者中与轻度相比严重胆管造影变化（改良阿姆斯特丹标准）之间有显著差异（p<0.05）；这在验证队列中得到了 18 种蛋白的复制。白细胞介素（IL）-8、基质金属蛋白酶（MMP）9/脂钙素（LCN）2 复合物、S100A8/9、S100A12 和色氨酸羟化酶（TPH）2 在胆汁中与 PSC 诊断和胆管造影变化程度均相关。根据血清中 IL-8 的三分位数分层 PSC 患者，不仅 MMP9/LCN2 和 S100A12，而且在血清衍生和验证队列中均能很好地区分无移植生存。此外，IL-8 在两个血清组的多变量分析中与无移植生存相关，独立于年龄和疾病持续时间，表明其对 PSC 进展有独立影响。然而，增强的肝纤维化（ELF®）检测和 Mayo 风险评分被证明是无移植生存的更强预测因子。
基于胆汁蛋白检测，我们已经鉴定出新型胆汁和血清生物标志物，可作为 PSC 严重程度和预后的指标。
原发性硬化性胆管炎缺乏预后生物标志物，这阻碍了患者的治疗和治疗的发展。我们已经鉴定出包括钙卫蛋白和 IL-8 在内的炎症蛋白，它们是原发性硬化性胆管炎患者胆汁和血清中疾病严重程度和预后的重要指标。
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