Hepatology and Gastroenterology Section, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, St Mary's Hospital Campus, London, UK.
Am J Gastroenterol. 2011 Sep;106(9):1711-7. doi: 10.1038/ajg.2011.187. Epub 2011 Jun 14.
Accurate differentiation between benign and malignant causes of biliary obstruction remains challenging and reliable biomarkers are urgently needed. Bile is a potential source of such biomarkers. Our aim was to apply a proteomic approach to identify a potential biomarker in bile that differentiates between malignant and benign disease, and to assess its diagnostic accuracy. Neutrophil gelatinase-associated lipocalin (NGAL) is multi-functional protein, released from activated neutrophils, with roles in inflammation, immune function, and carcinogenesis. It has not previously been described in bile.
Bile, urine, and serum were collected prospectively from 38 patients undergoing endoscopic retrograde cholangiopancreatography ("discovery" cohort); 22 had benign and 16 had malignant pancreatobiliary disease. Initially, label-free proteomics and immunoblotting were performed in samples from a subset of these patients. Enzyme-linked immunosorbent assay was then performed for NGAL as a potential biomarker on all samples in this cohort. The diagnostic performance of biliary NGAL was then validated in a second, independent group ("validation" cohort) of 21 patients with pancreatobiliary disease (benign n=14, malignant n=7).
NGAL levels were significantly raised in bile from the malignant disease group, compared with bile from the benign disease group in the discovery cohort (median 1,556 vs. 480 ng/ml, P=0.007). Biliary NGAL levels had a receiver operating characteristic area under curve of 0.76, sensitivity 94%, specificity 55%, positive predictive value 60%, and negative predictive value 92% for distinguishing malignant from benign causes. Biliary NGAL was independent of serum biochemistry and carbohydrate antigen 19-9 (CA 19-9) in differentiating between underlying benign and malignant disease. No significant differences in serum and urine NGAL levels were found between benign and malignant disease. Combining biliary NGAL and serum CA 19-9 improved diagnostic accuracy for malignancy (sensitivity 85%, specificity 82%, positive predictive value 79%, and negative predictive value 87%). The diagnostic accuracy of biliary NGAL was confirmed in the second independent validation cohort.
NGAL in bile is a novel potential biomarker to help distinguish benign from malignant biliary obstruction.
准确区分胆道阻塞的良性和恶性原因仍然具有挑战性，因此迫切需要可靠的生物标志物。胆汁是此类生物标志物的潜在来源。我们的目的是应用蛋白质组学方法来鉴定胆汁中区分良恶性疾病的潜在生物标志物，并评估其诊断准确性。中性粒细胞明胶酶相关脂质运载蛋白（NGAL）是一种多功能蛋白，从活化的中性粒细胞中释放出来，在炎症、免疫功能和癌变中发挥作用。它以前尚未在胆汁中描述过。
前瞻性收集 38 例接受内镜逆行胰胆管造影术（“发现”队列）的患者的胆汁、尿液和血清；22 例为良性疾病，16 例为恶性胰胆管疾病。最初，在这些患者的一部分样本中进行无标记蛋白质组学和免疫印迹分析。然后对所有样本进行酶联免疫吸附试验以检测 NGAL 作为潜在的生物标志物。然后在第二个独立的胰胆管疾病患者（良性疾病 14 例，恶性疾病 7 例）（“验证”队列）中验证胆汁 NGAL 的诊断性能。
与良性疾病组相比，恶性疾病组胆汁中的 NGAL 水平显着升高（发现队列中中位数分别为 1556 与 480ng/ml，P=0.007）。胆汁 NGAL 的受试者工作特征曲线下面积为 0.76，区分良恶性病因的敏感性为 94%，特异性为 55%，阳性预测值为 60%，阴性预测值为 92%。在区分潜在的良性和恶性疾病时，胆汁 NGAL 独立于血清生化和碳水化合物抗原 19-9（CA 19-9）。在良性和恶性疾病之间未发现血清和尿液 NGAL 水平有显着差异。结合胆汁 NGAL 和血清 CA 19-9 可提高恶性肿瘤的诊断准确性（敏感性 85%，特异性 82%，阳性预测值 79%，阴性预测值 87%）。在第二个独立的验证队列中证实了胆汁 NGAL 的诊断准确性。
胆汁中的 NGAL 是一种新的潜在生物标志物，可帮助区分良性和恶性胆道阻塞。
