Bioanalytical Services, Celerion, Lincoln, NE, United States of America.
Scientific Affairs, Celerion, Tempe, AZ, United States of America.
PLoS One. 2019 Jul 10;14(7):e0217263. doi: 10.1371/journal.pone.0217263. eCollection 2019.
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that can lead to cirrhosis, liver transplant, and even hepatocellular carcinoma. While liver biopsy remains the reference standard for disease diagnosis, analytical and clinical development of non-invasive soluble biomarkers of NASH are of great importance to advance the field. To this end, we performed analytical and clinical validation on a series of pro-inflammatory cytokines and chemokines implicated hepatic inflammation; IL-6, CRP, TNFα, MCP-1, MIP-1β, eotaxin, VCAM-1. Biomarker assays were validated for accuracy and precision. Clinical performance was evaluated in a random sample of 52 patients with biopsy-proven NAFLD/NASH. Patients were categorized into three groups according to their fibrosis stage; advanced (F3-F4), mild (F1-2) and no (F0) fibrosis. Serum IL-6 was increased in patients with advanced fibrosis (2.71 pg/mL; 1.26 pg/mL; 1.39 pg/mL p<0.01) compared to patients with mild or no fibrosis respectively. While, there was no significant difference noted in CRP, TNFα, MCP-1, MIP-1β, eotaxin among the three groups, VCAM-1 levels were increased by 55% (p<0.01) and 40% (p<0.05) in the advanced cohort compared to the mild and no fibrosis groups respectively. VCAM-1 also displayed good clinical performance as a biomarker of advanced fibrosis with an area under the receiver operating curve of 0.87. The VCAM-1 assay demonstrated robust accuracy and precision, and VCAM-1 outperformed IL-6, CRP, TNFα, and the chemokines MCP-1, MIP-1β, and eotaxin as a biomarker of advanced fibrosis in NASH. Addition of biomarkers such as IL-6 and VCAM-1 to panels may yield increased sensitivity and specificity for staging of NASH.
非酒精性脂肪性肝炎（NASH）是一种慢性肝病，可导致肝硬化、肝移植，甚至肝细胞癌。虽然肝活检仍然是疾病诊断的参考标准，但 NASH 非侵入性可溶性生物标志物的分析和临床开发对于推动该领域的发展非常重要。为此，我们对一系列与肝炎症有关的促炎细胞因子和趋化因子进行了分析和临床验证；IL-6、CRP、TNFα、MCP-1、MIP-1β、嗜酸性粒细胞趋化因子、VCAM-1。对生物标志物检测进行了准确性和精密度验证。在 52 名经活检证实的 NAFLD/NASH 患者的随机样本中评估了临床性能。根据纤维化阶段，患者分为三组；晚期（F3-F4）、轻度（F1-2）和无（F0）纤维化。与轻度或无纤维化患者相比，晚期纤维化患者的血清 IL-6 增加（2.71pg/mL；1.26pg/mL；1.39pg/mL p<0.01）。然而，CRP、TNFα、MCP-1、MIP-1β、嗜酸性粒细胞趋化因子在三组之间没有显著差异，与轻度和无纤维化组相比，VCAM-1 水平分别增加了 55%（p<0.01）和 40%（p<0.05）。VCAM-1 作为晚期纤维化的生物标志物也具有良好的临床性能，ROC 曲线下面积为 0.87。该 VCAM-1 检测方法具有良好的准确性和精密度，并且在 NASH 中作为晚期纤维化的生物标志物，其性能优于 IL-6、CRP、TNFα 和趋化因子 MCP-1、MIP-1β 和嗜酸性粒细胞趋化因子。将 IL-6 和 VCAM-1 等生物标志物添加到面板中可能会提高 NASH 分期的灵敏度和特异性。
