Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers
Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers
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DOI：
10.1371/journal.pone.0167001
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发表时间：
2016-11-18
期刊：
影响因子：
3.7
通讯作者：
Powell, Elizabeth E.
中科院分区：
文献类型：
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作者：
Irvine, Katharine M.;Wockner, Leesa F.;Powell, Elizabeth E.
背景和目的迫切需要肝纤维化的非侵入性标记物，特别是在非专科环境中使用。本研究的目的是确定新的晚期纤维化的血清生物标志物。方法我们对70名患者(35名无纤维化，35名肝硬变)的120项血清分析包括细胞因子、趋化因子和蛋白酶进行了无偏筛选，并选择了44项候选生物标志物，随后在432名血清HA、PIIINP和TIMP1已知的混合病因队列中进行了测定(包括有效的增强肝纤维化(ELF)试验)。除确定疾病活动性和脂肪性肝炎的生物标志物外，采用多变量Logistic回归模型建立预测晚期或显著纤维化的模型(METAVIR>；=F3和>；=F2)。结果17种分析物在非晚期纤维化患者和晚期纤维化患者之间有显著差异，其中最显著的是透明质酸(HA)和基质金属蛋白酶(MMP7)(p=2.9E-41和p=1.0E-26)。预测晚期纤维化的最佳模型为HA、MMP7、MMP1、甲胎蛋白(AFP)和AST/血小板比率指数(APRI)。与仅包含HA、PIIINP和TIMP1的模型(ELF)相比，我们展示了更高的诊断准确性(AUROC=0.938)(AUROC=0.898，p
Background and AimsNon-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.MethodsWe performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR >= F3 and >= F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis.ResultsSeventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy ( AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone ( ELF) ( AUROC = 0.898, p