Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
Hepatol Commun. 2024 Jun 3;8(6). doi: 10.1097/HC9.0000000000000448. eCollection 2024 Jun 1.
There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events.
We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy.
Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events.
Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.
需要新的非侵入性标志物来对代谢相关脂肪性肝病（MASLD）患者进行分层，以确定发生肝脏相关事件（包括肝癌和肝功能失代偿）的高危患者。本研究通过对细胞外囊泡（EVs）中的蛋白质进行蛋白质组学分析，以确定新的生物标志物，这些标志物随纤维化进展而变化，并能预测肝脏相关事件的发生。
我们分析了 50 例 MASLD 患者的血清 EVs，这些患者通过活检评估了纤维化程度，并鉴定了与晚期纤维化相关的改变的蛋白质。对另一组 463 例 MASLD 患者进行了进一步评估，这些患者进行了活检。
通过对血清 EVs 的蛋白质组学分析，鉴定出 8 种候选蛋白质。其中，纤维调蛋白-3、纤维调蛋白-1 和ficolin-1 的血清水平与其 EV 水平相关。此外，血清纤维调蛋白-3和纤维调蛋白-1水平随纤维化进展而显著变化。在另一组接受活检的患者中，我们发现，晚期纤维化患者的血清纤维调蛋白-3浓度显著升高，但血清纤维调蛋白-1浓度无显著差异。多变量 Cox 比例风险分析显示，较高的纤维化-4（FIB-4）指数和较高的血清纤维调蛋白-3浓度是肝脏相关事件的独立危险因素。当根据 AUROCs 的 Youden 指数将血清纤维调蛋白-3浓度的截断值设定为 6.0μg/ml 时，高血清纤维调蛋白-3浓度的患者发生肝脏相关事件的频率显著高于其他患者。使用另一组 226 例临床诊断为 MASLD 的患者进行验证，证实了高血清纤维调蛋白-3水平与肝脏相关事件的发生频率增加有关。
血清纤维调蛋白-3被鉴定为预测 MASLD 患者肝脏相关事件的生物标志物。
