Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure
Delia Blaya,
Elisa Pose,
Mar Coll,
Juan José Lozano,
Isabel Graupera,
Robert Schierwagen,
Christian Jansen,
Pedro Castro,
Sara Fernandez,
Julia Sidorova,
Mariuca Vasa-Nicotera,
Elsa Solà,
Joan Caballería,
Jonel Trebicka,
Pere Ginès,
Pau Sancho-Bru
Affiliations
Delia Blaya
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
Elisa Pose
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Mar Coll
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Juan José Lozano
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
Isabel Graupera
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Robert Schierwagen
Goethe University Clinic, Frankfurt, Germany
Christian Jansen
University Clinic Bonn, Bonn, Germany
Pedro Castro
Medical Intensive Care Unit, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
Sara Fernandez
Medical Intensive Care Unit, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
Julia Sidorova
Instituto de Tecnología del Conocimiento (ITC). Campus de Somosaguas, Universidad Complutense de Madrid (UCM), Spain
Mariuca Vasa-Nicotera
Goethe University Clinic, Frankfurt, Germany
Elsa Solà
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Joan Caballería
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Jonel Trebicka
Goethe University Clinic, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Institute for Bioengineering of Catalonia, Barcelona, Spain; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Internal Medicine I, University Clinic Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. Tel.: +34 93 227 14 11; Fax: +34 93 227 14 19
Pere Ginès
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain
Pau Sancho-Bru
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Corresponding authors. Addresses: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Rosselló, 149-153, third floor, 08036, Barcelona, Spain. Tel.: +34 93 227 54 00 ext. 3371.
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.