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

K. Remih, FM. Hufnagel, AS. Karl, V. Durkalski-Mauldin, WM. Lee, CJ. Karvellas, Z. Su, JA. Rule, P. Tomanová, L. Krieg, I. Karkossa, K. Schubert, M. von Bergen, F. Tacke, S. Luckhardt, N. Ziegler, A. Kannt, B. Engel, R. Taubert, RJ. Fontana, P....

. 2025 ; 7 (5) : 101338. [pub] 20250130

Status neindexováno Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25014449

BACKGROUND & AIMS: Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers. METHODS: Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts. They were analyzed using untargeted proteomics with mass spectroscopy and a serum cytokine profiling and compared with 30 healthy controls. The primary clinical outcome was 21-day transplant-free survival. Single-cell RNAseq data mapped biomarkers to cells of origin; functional enrichment analysis provided mechanistic insights. Novel prognostic scores were compared with the model for end-stage liver disease and ALFSG prognostic index scores. RESULTS: In the discovery cohort, 117 proteins differed between patients with ALF and healthy controls. There were 167 proteins associated with APAP-related ALF, with the majority being hepatocyte-derived. Three hepatocellular proteins (ALDOB, CAT, and PIGR) robustly and reproducibly discriminated APAP from non-APAP cases (AUROCs ∼0.9). In the discovery cohort, 37 proteins were related to 21-day outcome. The key processes associated with survival were acute-phase response and hepatocyte nuclear factor 1α signaling. SERPINA1 and LRG1 were the best individual discriminators of 21-day transplant-free survival in both cohorts. Two models of blood-based proteomic biomarkers outperformed the model for end-stage liver disease and ALFSG prognostic index and were reproduced in the validation cohort (AUROCs 0.83-0.86) for 21-day transplant-free survival. CONCLUSIONS: Proteomics and cytokine profiling identified new, reproducible biomarkers associated with APAP etiology and 21-day outcome. These biomarkers may improve prognostication and understanding of the etiopathogenesis of ALF but need to be independently validated. IMPACT AND IMPLICATIONS: Acute liver failure (ALF) is a sudden, and severe condition associated with high fatality. More sensitive and specific prognostic scores are urgently needed to facilitate decision-making regarding liver transplantation in patients with ALF. Our proteomic analysis uncovered marked differences between acetaminophen and non-acetaminophen-related ALF. The identification of routinely measurable biomarkers that are associated with 21-day transplant-free survival and the derivation of novel prognostic scores may facilitate clinical management as well as decisions for/against liver transplantation. Further studies are needed to quantify less abundant proteins. Although we used two cohorts, our findings still need to be independently and prospectively validated.

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$a BACKGROUND & AIMS: Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers. METHODS: Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts. They were analyzed using untargeted proteomics with mass spectroscopy and a serum cytokine profiling and compared with 30 healthy controls. The primary clinical outcome was 21-day transplant-free survival. Single-cell RNAseq data mapped biomarkers to cells of origin; functional enrichment analysis provided mechanistic insights. Novel prognostic scores were compared with the model for end-stage liver disease and ALFSG prognostic index scores. RESULTS: In the discovery cohort, 117 proteins differed between patients with ALF and healthy controls. There were 167 proteins associated with APAP-related ALF, with the majority being hepatocyte-derived. Three hepatocellular proteins (ALDOB, CAT, and PIGR) robustly and reproducibly discriminated APAP from non-APAP cases (AUROCs ∼0.9). In the discovery cohort, 37 proteins were related to 21-day outcome. The key processes associated with survival were acute-phase response and hepatocyte nuclear factor 1α signaling. SERPINA1 and LRG1 were the best individual discriminators of 21-day transplant-free survival in both cohorts. Two models of blood-based proteomic biomarkers outperformed the model for end-stage liver disease and ALFSG prognostic index and were reproduced in the validation cohort (AUROCs 0.83-0.86) for 21-day transplant-free survival. CONCLUSIONS: Proteomics and cytokine profiling identified new, reproducible biomarkers associated with APAP etiology and 21-day outcome. These biomarkers may improve prognostication and understanding of the etiopathogenesis of ALF but need to be independently validated. IMPACT AND IMPLICATIONS: Acute liver failure (ALF) is a sudden, and severe condition associated with high fatality. More sensitive and specific prognostic scores are urgently needed to facilitate decision-making regarding liver transplantation in patients with ALF. Our proteomic analysis uncovered marked differences between acetaminophen and non-acetaminophen-related ALF. The identification of routinely measurable biomarkers that are associated with 21-day transplant-free survival and the derivation of novel prognostic scores may facilitate clinical management as well as decisions for/against liver transplantation. Further studies are needed to quantify less abundant proteins. Although we used two cohorts, our findings still need to be independently and prospectively validated.
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$a Karl, Anna Sophie $u Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
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$a Durkalski-Mauldin, Valerie $u Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
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$a Lee, William Martens $u Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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$a Karvellas, Constantine J $u Department of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada
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$a Su, Zemin $u Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
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$a Rule, Jody A $u Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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$a Tomanová, Petra $u Department of Econometrics, Prague University of Economics and Business, Prague, Czechia
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$a Krieg, Laura $u Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
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$a Karkossa, Isabel $u Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
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$a Schubert, Kristin $u Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
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$a von Bergen, Martin $u Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
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$a Tacke, Frank $u Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
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$a Luckhardt, Sonja $u Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
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$a Ziegler, Nicole $u Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
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$a Kannt, Aimo $u Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany $u Goethe University, Institute of Clinical Pharmacology, Frankfurt am Main, Germany
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$a Engel, Bastian $u Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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$a Taubert, Richard $u Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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$a Fontana, Robert John $u Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
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$a Strnad, Pavel $u Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
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