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Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure

Authors: Blaya, Delia; Pose, Elisa; Coll, Mar; Lozano, Juan José; Graupera, Isabel; Schierwagen, Robert; Jansen, Christian; +9 Authors

Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure

Abstract

Background & Aims MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF). Methods Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16). Results miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs (i.e. miR-146a-5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs. Conclusions This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility. Lay summary Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes.

Highlights • Circulating miRNAs are dysregulated with cirrhosis progression and in patients with ACLF. • Patient decompensation is associated with important changes in the levels of circulating miRNAs. • A total of 11 circulating miRNAs were identified as associated with organ failure and 7 with poor outcome. • The miRNAs most dysregulated during cirrhosis progression were miR-146a, miR-26a, and miR-191. • miR-146a was dysregulated in PBMCs of patients with decompensated cirrhosis vs. compensated cirrhosis.

Graphical abstract

Country
Denmark
Subjects by Vocabulary

Microsoft Academic Graph classification: Cirrhosis Disease Chronic liver disease Gastroenterology Liver disease Model for End-Stage Liver Disease medicine.medical_specialty Encephalopathy Internal medicine medicine Decompensation business.industry medicine.disease Circulating MicroRNA business

Library of Congress Subject Headings: lcsh:RC799-869 lcsh:Diseases of the digestive system. Gastroenterology

Keywords

AST, aspartate aminotransferase, RC799-869, FoxO, forkhead box O, Non-coding RNAs, Immunology and Allergy, TGF, transforming growth factor, LDH, lactate dehydrogenase, Chronic liver disease, Gastroenterology, Diseases of the digestive system. Gastroenterology, Liver decompensation, Research Article, NASH, non-alcoholic steatohepatitis, CXCL10, C-X-C motif chemokine ligand 10, MELD, model for end-stage liver disease, ALT, alanine aminotransferase, TIPS, transjugular intrahepatic portosystemic shunt, Internal Medicine, EF CLIF, European Foundation for the Study of Chronic Liver Failure, INR, International Normalised Ratio, PBMCs, peripheral blood mononuclear cells, PCA, principal component analysis, Hepatology, ACLF, acute-on-chronic liver failure, qPCR, quantitative PCR, MAPK, mitogen-activated protein kinase, Biomarkers

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    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    14
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    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
14
Top 10%
Average
Top 10%
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