{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:06:10Z","timestamp":1753891570926,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48\u2009h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at T<jats:sub>baseline<\/jats:sub>, T<jats:sub>24<\/jats:sub>, and upon reaching the endpoint (T<jats:sub>end<\/jats:sub>). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All ALF animals (<jats:italic>n<\/jats:italic>\u2009=\u20094) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T<jats:sub>24h<\/jats:sub> and T<jats:sub>end<\/jats:sub>, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1363979","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T04:49:49Z","timestamp":1711601389000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure"],"prefix":"10.3389","volume":"11","author":[{"given":"Philipp","family":"Felgendreff","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed M.","family":"Hosseiniasl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Felgendreff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce P.","family":"Amiot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Minshew","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boyukkhanim","family":"Ahmadzada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvana","family":"Wilken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Arribas Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott L.","family":"Nyberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey N.","family":"Cook","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1002\/hep.22177","article-title":"Acute liver failure: summary of a workshop","volume":"47","author":"Lee","year":"2007","journal-title":"Hepatology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/S0140-6736(19)31894-X","article-title":"Acute liver failure","volume":"394","author":"Stravitz","year":"2019","journal-title":"Lancet"},{"key":"ref3","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-13761-2_30","article-title":"Intensive Care Management of Severe Acute Liver Failure","volume-title":"Annual update in intensive care and emergency medicine 2015","author":"Warrillow","year":"2015"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3238\/arztebl.2020.0043","article-title":"The epidemiology of acute liver failure","volume":"117","author":"Weiler","year":"2020","journal-title":"Dtsch Arztebl Int"},{"key":"ref5","first-page":"665","article-title":"Complications of acute liver failure","volume":"10","author":"Munoz","year":"2014","journal-title":"Gastroenterol Hepatol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s12028-008-9123-6","article-title":"Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and management","volume":"9","author":"Wendon","year":"2008","journal-title":"Neurocrit Care"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"9240","DOI":"10.3748\/wjg.v19.i48.9240","article-title":"Pathophysiology of cerebral oedema in acute liver failure","volume":"19","author":"Scott","year":"2013","journal-title":"World J Gastroenterol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1002\/hep.510290309","article-title":"Cerebral herniation in patients with acute E liver failure is correlated with arterial ammonia concentration","volume":"29","author":"Clemmesen","year":"1999","journal-title":"Hepatology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1002\/hep.21838","article-title":"Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure","volume":"46","author":"Bernal","year":"2007","journal-title":"Hepatology"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41582-021-00616-3","article-title":"Blood GFAP as an emerging biomarker in brain and spinal cord disorders","volume":"18","author":"Abdelhak","year":"2022","journal-title":"Nat Rev Neurol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1007\/s00134-007-0678-z","article-title":"Neuromonitoring in the intensive care unit. 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Intracranial pressure and cerebral blood flow monitoring","volume":"33","author":"Bhatia","year":"2007","journal-title":"Intensive Care Med"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.12998\/wjcc.v7.i13.1535","article-title":"Intracranial pressure monitoring: gold standard and recent innovations","volume":"7","author":"Nag","year":"2019","journal-title":"World J Clin Cases"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s12028-009-9193-0","article-title":"Hemorrhagic complications of ventriculostomy placement: a meta-analysis","volume":"10","author":"Binz","year":"2009","journal-title":"Neurocrit Care"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1002\/lt.20625","article-title":"Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy","volume":"11","author":"Vaquero","year":"2005","journal-title":"Liver 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disease","volume":"26","author":"Kril","year":"1997","journal-title":"Hepatology"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1002\/lt.21436","article-title":"Glial fibrillary acidic protein as an early marker of hepatic stellate cell activation in chronic and posttransplant recurrent hepatitis C","volume":"14","author":"Carotti","year":"2008","journal-title":"Liver Transpl"},{"volume-title":"Acute Liver Failure","year":"2023","author":"Shah","key":"ref32"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1002\/glia.1104","article-title":"Glial cell influence on the human blood-brain barrier","volume":"36","author":"Prat","year":"2001","journal-title":"Glia"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1002\/(SICI)1098-1136(199804)22:4<390::AID-GLIA8>3.0.CO;2-7","article-title":"Impaired induction of blood-brain barrier properties in aortic endothelial cells by astrocytes from GFAP-deficient 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