Serum N-terminal DDR1: A Novel Diagnostic Marker of Liver Fibrosis Severity.
Serum N-terminal DDR1: A Novel Diagnostic Marker of Liver Fibrosis Severity.
复制标题
血清 N 端 DDR1：肝纤维化严重程度的新型诊断标志物
DOI：
10.14218/jcth.2021.00024
复制
发表时间：
2021-10-28
影响因子：
3.6
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang Y;Liang H;Zhuo Z;Fan P;Chen Y;Zhang Z;Zhang W
背景与目的：在肝纤维化的发展过程中，盘状结构域受体1(discoidin domain rector1，DDR1)的表达普遍上调，并经历胶原诱导的胞外结构域(N-末端)的脱落。本研究旨在评价N-末端DDR1作为肝纤维化诊断生物标志物的临床应用价值。方法对2019年2月至2020年6月298例肝纤维化患者的肝细胞株、肝纤维化模型及临床资料进行分析。将临床数据分为检验队列和验证队列，评价血清N-末端DDR1的诊断性能。结果在肝细胞系模型中，I型胶原刺激的N-末端DDR1的脱落呈时间和剂量依赖性。在小鼠肝纤维化模型中，I型胶原沉积和血清N-末端DDR1水平同时增加。临床数据表明，血清N-末端DDR1水平作为肝纤维化和肝硬变的准确生物标志物具有显著的诊断能力。以N-DDR_1/白蛋白比值检测肝纤维化组织学分期F-≥-2、F-≥-3、F-4的曲线下面积分别为0.790、0.802、0.879、0.865，以肝活检为参照，以肝硬变为标准，诊断准确率进一步提高。以55.6作为临界值，诊断肝硬变的灵敏度、特异度、阳性预测值和阴性预测值分别为82.7%、76.6%、67.4%和88.3%。结论血清N-末端DDR1是一种新的肝纤维化诊断指标。
Background and Aims The expression of discoidin domain receptor 1 (DDR1) is commonly up-regulated and undergoes collagen-induced ectodomain (N-terminal) shedding during the progression of liver fibrosis. This study aimed to evaluate the clinical utility of N-terminal DDR1 as a diagnostic biomarker for liver fibrosis. Methods N-terminal DDR1 shedding was evaluated using cell lines, liver fibrosis mouse models, clinical data of 298 patients collected from February 2019 to June 2020. The clinical data were divided into test and validation cohorts to evaluate the diagnostic performance of serum N-terminal DDR1. Results Time- and dosage-dependent N-terminal DDR1 shedding stimulated by collagen I was observed in a hepatocyte cell line model. The type I collagen deposition and serum N-terminal DDR1 levels concurrently increased in the development of liver fibrosis in mouse models. Clinical data demonstrated a significant diagnostic power of serum N-terminal DDR1 levels as an accurate biomarker of liver fibrosis and cirrhosis. The diagnostic performance was further increased when applying N-DDR1/albumin ratio, achieving area under the curve of 0.790, 0.802, 0.879, and 0.865 for detecting histological fibrosis stages F ≥2, F ≥3, F 4 with liver biopsy as a reference method, and cirrhosis according to imaging techniques, respectively. With a cut-off of 55.6, a sensitivity, specificity, positive predictive value, and negative predictive value of 82.7%,76.6%, 67.4%, and 88.3% were achieved for the detection of cirrhosis. Conclusions Serum N-terminal DDR1 appears to be a novel diagnostic marker for liver fibrosis.