Department of Basic (Bio-)Medical Sciences, Liver Cell Biology Research Group, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
Department of Gastroenterology and Hepatology, University Hospital Brussels (UZ Brussel), B-1090 Brussels, Belgium.
Cells. 2019 Aug 29;8(9):1003. doi: 10.3390/cells8091003.
The current diagnosis of early-stage liver fibrosis often relies on a serological or imaging-based evaluation of the stage of fibrosis, sometimes followed by an invasive liver biopsy procedure. Novel non-invasive experimental diagnostic tools are often based on markers of hepatocyte damage, or changes in liver stiffness and architecture, which are late-stage characteristics of fibrosis progression, making them unsuitable for the diagnosis of early-stage liver fibrosis. miRNAs control hepatic stellate cell (HSC) activation and are proposed as relevant diagnostic markers. We investigated the possibility of circulating miRNAs, which we found to be dysregulated upon HSC activation, to mark the presence of significant liver fibrosis (F ≥ 2) in patients with chronic alcohol abuse, chronic viral infection (HBV/HCV), and non-alcoholic fatty liver disease (NAFLD). miRNA-profiling identified miRNA-451a, miRNA-142-5p, Let-7f-5p, and miRNA-378a-3p to be significantly dysregulated upon in vitro HSC activation, and to be highly enriched in their extracellular vesicles, suggesting their potential use as biomarkers. Analysis of the plasma of patients with significant liver fibrosis (F ≥ 2) and no or mild fibrosis (F = 0-1), using miRNA-122-5p and miRNA-29a-3p as positive control, found miRNA-451a, miRNA-142-5p, and Let-7f-5p, but not miRNA-378a-3p, able to distinguish between the two patient populations. Using logistic regression analysis, combining all five dysregulated circulating miRNAs, we created the miRFIB-score with a predictive value superior to the clinical scores Fibrosis-4 (Fib-4), aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and AST to platelet ratio index (APRI). The combination of the miRFIB-score with circulating PDGFRβ-levels further increased the predictive capacity for the diagnosis of significant liver fibrosis. The miRFIB- and miRFIB-scores are accurate tools for the diagnosis of significant liver fibrosis in a heterogeneous patient population.
目前早期肝纤维化的诊断通常依赖于对纤维化阶段的血清学或影像学评估，有时还需要进行侵入性肝活检。新型非侵入性实验诊断工具通常基于肝细胞损伤标志物或肝硬度和结构变化，这些都是纤维化进展的晚期特征，因此不适合早期肝纤维化的诊断。miRNA 可控制肝星状细胞 (HSC) 的激活，并被提议作为相关的诊断标志物。我们研究了循环 miRNA 的可能性，发现其在 HSC 激活时会失调，可用于标记慢性酒精滥用、慢性病毒感染 (HBV/HCV) 和非酒精性脂肪性肝病 (NAFLD) 患者中存在显著的肝纤维化 (F≥2)。miRNA 谱分析发现，miRNA-451a、miRNA-142-5p、Let-7f-5p 和 miRNA-378a-3p 在体外 HSC 激活时显著失调，并且高度富集于其细胞外囊泡中，提示它们具有作为生物标志物的潜力。使用 miRNA-122-5p 和 miRNA-29a-3p 作为阳性对照，分析具有显著肝纤维化 (F≥2) 和无或轻度纤维化 (F=0-1) 的患者的血浆，发现 miRNA-451a、miRNA-142-5p 和 Let-7f-5p 但不是 miRNA-378a-3p 能够区分这两种患者人群。使用逻辑回归分析，结合所有五个失调的循环 miRNA，我们创建了 miRFIB 评分，其预测价值优于临床评分 Fibrosis-4 (Fib-4)、天门冬氨酸氨基转移酶/丙氨酸氨基转移酶 (AST/ALT) 比值和天冬氨酸氨基转移酶/血小板比值指数 (APRI)。miRFIB 评分与循环 PDGFRβ 水平的结合进一步提高了诊断显著肝纤维化的能力。miRFIB 和 miRFIB 评分是诊断异质患者人群中显著肝纤维化的准确工具。
