BACKGROUND AND AIM: Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing. METHODS: Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis. Unsupervised hierarchical clustering was performed with Perseus software and R. Ingenuity pathway analysis (IPA) suggested upstream regulators that were validated in liver tissues. The behavior and prognostic usefulness of selected biomarkers was investigated in 61 controls and 285 subjects with decompensated cirrhosis. RESULTS: Proteomics uncovered 65 and 16 hepatocellular serum proteins that are significantly downregulated or upregulated in patients with cirrhosis vs. controls. Hierarchical clustering revealed two main clusters and six sub-clusters. IPA identified HNF4α and IL-6 as the two major upstream regulators that were confirmed by hepatic gene expression analyses. Among pseudocholinesterase, transferrin, transthyretin, albumin, and apolipoprotein AI (Apo-AI), Apo-AI was the best predictor of 90-days transplant-free survival (AUROC 0.678; p = 0.0001) and remained an independent predictor in multivariable Cox independently of the presence of acute-on-chronic liver failure. CONCLUSION: Our study reveals cirrhosis-associated changes in hepatocellular serum proteins and underlying transcription factors. Serum apolipoprotein AI may constitute a useful prognostic adjunct in patients with decompensated cirrhosis.

4th Department of Internal Medicine 1st Faculty of Medicine General University Hospital Prague Charles University Prague Czech Republic

Department of Internal Medicine 3 and IZKF Gastroenterology Metabolic Diseases and Intensive Care University Hospital Aachen Pauwelsstraße 30 52074 Aachen Germany

Department of Internal Medicine 4 Jena University Hospital Friedrich Schiller University Jena Germany

Department of Medicine and Infectious Diseases Faculty of Veterinary Medicine University of Sadat 12 City Sadat City Egypt

Department of Molecular Systems Biology Helmholtz Centre for Environmental Research Leipzig Germany

Department of Science and Technology Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine Guangxi Zhuang Autonomous Region Nanning 530011 China

Department of Surgical Oncology Fujian Provincial Hospital Fuzhou China

Faculty of Life Sciences Institute of Biochemistry University of Leipzig Leipzig Germany

German Centre for Integrative Biodiversity Research Halle Jena Leipzig Leipzig Germany

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine General University Hospital Prague Charles University Prague Czech Republic

Proteomics Facility Interdisciplinary Center for Clinical Research University Hospital RWTH Aachen Germany

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Serum proteomics of adults with acute liver failure provides mechanistic insights and attractive prognostic biomarkers