Nielsen Mette Juul, Leeming Diana Julie, Goodman Zachary, Friedman Scott, Frederiksen Peder, Rasmussen Daniel Guldager Kring, Vig Pamela, Seyedkazemi Star, Fischer Laurent, Torstenson Richard, Karsdal Morten Asser, Lefebvre Eric, Sanyal Arun J, Ratziu Vlad
Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
J Hepatol. 2021 Dec;75(6):1292-1300. doi: 10.1016/j.jhep.2021.08.016. Epub 2021 Aug 27.
BACKGROUND & AIMS: The development of accurate non-invasive tests to detect and measure the extent of fibrosis and disease activity in patients with non-alcoholic steatohepatitis (NASH) - the progressive phenotype of non-alcoholic fatty liver disease (NAFLD) - is of great clinical importance. Herein, we aimed to validate the performance of PRO-C3 and ADAPT for the detection of moderate/severe fibrosis within the CENTAUR screening population.
PRO-C3 was assessed in plasma from the screening population of the phase IIb CENTAUR study (NCT02217475) in adults with NASH and liver fibrosis. The relation between PRO-C3 and histologic features of NASH was evaluated, as well as the demographics of patients with high and low levels of PRO-C3. The diagnostic ability of PRO-C3, as a standalone marker or incorporated into ADAPT, to identify patients with F≥2 and NASH was estimated using receiver-operating characteristic analysis and logistic regression models.
A total of 517 individuals with matched biopsy and PRO-C3 measurements were included. Patients with PRO-C3 levels ≥20.2 ng/ml showed increased levels of insulin, HOMA-IR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and platelet count compared to patients with low PRO-C3 (p <0.05). PRO-C3 increased stepwise with increasing liver fibrosis, lobular inflammation, hepatocyte ballooning, steatosis, and NAFLD activity score (p <0.05), and could distinguish between NAFL and NASH (p <0.0001). PRO-C3 was independently associated with fibrosis and NASH when adjusted for clinical confounders. ADAPT outperformed Fibrosis-4, AST-to-platelet ratio index, and AST/ALT ratio as a predictor of advanced fibrosis and NASH (p <0.001).
PRO-C3 was associated with NAFLD activity score and fibrosis. ADAPT outperformed other non-invasive scores for detecting NASH. These data support the use of PRO-C3 and ADAPT as diagnostic tools to identify patients with NASH eligible for inclusion in clinical trials.
NCT02217475 LAY SUMMARY: PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis. Its performance for the detection of disease activity and fibrosis is improved when it is incorporated into the ADAPT score. Herein, we showed that ADAPT was better at selecting patients with non-alcoholic steatohepatitis for inclusion in clinical trials than other non-invasive scores.
开发准确的非侵入性检测方法以检测和测量非酒精性脂肪性肝炎（NASH）患者（非酒精性脂肪性肝病（NAFLD）的进展型表型）的纤维化程度和疾病活动度具有重要的临床意义。在此，我们旨在验证PRO-C3和ADAPT在CENTAUR筛查人群中检测中度/重度纤维化的性能。
在CENTAUR IIb期研究（NCT02217475）的成人NASH和肝纤维化筛查人群的血浆中评估PRO-C3。评估PRO-C3与NASH组织学特征之间的关系，以及PRO-C3水平高低患者的人口统计学特征。使用受试者工作特征分析和逻辑回归模型估计PRO-C3作为独立标志物或纳入ADAPT中识别F≥2和NASH患者的诊断能力。
共纳入517例活检和PRO-C3测量值匹配的个体。与PRO-C3水平低的患者相比，PRO-C3水平≥20.2 ng/ml的患者胰岛素、HOMA-IR、丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶和血小板计数水平升高（p<0.05）。PRO-C3随着肝纤维化、小叶炎症、肝细胞气球样变、脂肪变性和NAFLD活动评分的增加而逐步升高（p<0.05），并且可以区分NAFL和NASH（p<0.0001）。校正临床混杂因素后，PRO-C3与纤维化和NASH独立相关。作为晚期纤维化和NASH的预测指标，ADAPT的表现优于Fibrosis-4、AST与血小板比值指数和AST/ALT比值（p<0.001）。
PRO-C3与NAFLD活动评分和纤维化相关。在检测NASH方面，ADAPT的表现优于其他非侵入性评分。这些数据支持将PRO-C3和ADAPT用作诊断工具，以识别有资格纳入临床试验的NASH患者。
NCT02217475 总结：PRO-C3是一种与肝病活动和纤维化相关的血清生物标志物。当将其纳入ADAPT评分时，其检测疾病活动和纤维化的性能会得到改善。在此，我们表明，与其他非侵入性评分相比，ADAPT在选择非酒精性脂肪性肝炎患者纳入临床试验方面表现更好。
