Abstract
Background: 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. Methods: 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). Results: 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. Conclusions: The miRFIB- and miRFIBp-scores are accurate tools for the diagnosis of significant liver fibrosis in a heterogeneous patient population.
Highlights
Liver fibrosis and subsequent cirrhosis result in over one million deaths per year worldwide, making it the eleventh most common cause of death in adults [1]
As hepatic stellate cell (HSC) activation is an early event of liver fibrosis initiation and progression, we hypothesized that HSC-derived circulating miRNAs could be suitable markers for early stage liver fibrosis
These results suggest the potential use of these circulating miRNAs, without the need to distinguish between miRNAs packaged into extracellular vesicles or bound toproteins, as markers for HSC activation and fibrosis progression
Summary
Liver fibrosis and subsequent cirrhosis result in over one million deaths per year worldwide, making it the eleventh most common cause of death in adults [1]. The three most important causes for the development of liver fibrosis are chronic alcohol abuse, chronic infection with the hepatitis B (HBV) or C (HCV) virus, and metabolic syndrome, which can result in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [2]. This activation process is marked by an excessive production and deposition of extracellular matrix [3]. 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. 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)
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