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.

• Klíčová slova
• Decompensated cirrhosis, Fibrosis, Hepatocyte nuclear factor, Interleukin, Mass spectrometry,
• MeSH
• apolipoprotein A-I MeSH
• biologické markery MeSH
• fibróza MeSH
• hepatocelulární karcinom * MeSH
• jaterní cirhóza MeSH
• krevní proteiny MeSH
• lidé MeSH
• nádory jater * MeSH
• prognóza MeSH
• proteomika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• apolipoprotein A-I MeSH
• biologické markery MeSH
• krevní proteiny MeSH

BACKGROUND: Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients. METHODS: Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response. RESULTS: Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline. CONCLUSION: Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.

• Klíčová slova
• Chenodeoxycholic acid, Farnesoid X receptor, Fibroblast growth factor 19, Primary sclerosing cholangitis,
• MeSH
• aplikace orální MeSH
• cholestenony krev   MeSH
• dospělí MeSH
• fibroblastové růstové faktory krev   metabolismus   MeSH
• játra metabolismus   MeSH
• klinické protokoly MeSH
• kyselina chenodeoxycholová aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• purgativa aplikace a dávkování   MeSH
• senioři MeSH
• sklerozující cholangitida krev   farmakoterapie   metabolismus   MeSH
• střevní sliznice metabolismus   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7 alpha-hydroxy-4-cholesten-3-one MeSH Prohlížeč
• cholestenony MeSH
• FGF19 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• kyselina chenodeoxycholová MeSH
• purgativa MeSH