James L Weemhoff1, Benjamin L Woolbright1, Rosalind E Jenkins2, Mitchell R McGill1, Matthew R Sharpe3, Jody C Olson3, Daniel J Antoine2, Steven C Curry4,5, Hartmut Jaeschke1. 1. Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA. 2. MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 3. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA. 4. Department of Medical Toxicology, Banner -University Medical Center Phoenix, Phoenix, AZ, USA. 5. Department of Medicine, and the Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ, USA.
Abstract
BACKGROUND & AIMS: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis. METHODS: Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients. RESULTS: At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points. CONCLUSIONS: The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.
BACKGROUND & AIMS: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis. METHODS: Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients. RESULTS: At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points. CONCLUSIONS: The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.
Authors: Benjamin L Woolbright; Kenneth Dorko; Daniel J Antoine; Joanna I Clarke; Parviz Gholami; Feng Li; Sean C Kumer; Timothy M Schmitt; Jameson Forster; Fang Fan; Rosalind E Jenkins; B Kevin Park; Bruno Hagenbuch; Mojtaba Olyaee; Hartmut Jaeschke Journal: Toxicol Appl Pharmacol Date: 2015-01-28 Impact factor: 4.219
Authors: C David Williams; Mary Lynn Bajt; Matthew R Sharpe; Mitchell R McGill; Anwar Farhood; Hartmut Jaeschke Journal: Toxicol Appl Pharmacol Date: 2014-01-15 Impact factor: 4.219
Authors: Jeanine Ward; Chitra Kanchagar; Isana Veksler-Lublinsky; Rosalind C Lee; Mitchell R McGill; Hartmut Jaeschke; Steven C Curry; Victor R Ambros Journal: Proc Natl Acad Sci U S A Date: 2014-08-04 Impact factor: 11.205
Authors: G Wetzel; B Relja; A Klarner; D Henrich; N Dehne; B Brühne; M Lehnert; I Marzi Journal: Mediators Inflamm Date: 2014-06-01 Impact factor: 4.711
Authors: Venkat R Pannala; Kalyan C Vinnakota; Kristopher D Rawls; Shanea K Estes; Tracy P O'Brien; Richard L Printz; Jason A Papin; Jaques Reifman; Masakazu Shiota; Jamey D Young; Anders Wallqvist Journal: Toxicol Appl Pharmacol Date: 2019-04-08 Impact factor: 4.219
Authors: Steven C Curry; Angela Padilla-Jones; Anne-Michelle Ruha; Ayrn D O'Connor; A Min Kang; Diana G Wilkins; Hartmut Jaeschke; Kelly Wilhelms; Richard D Gerkin Journal: J Med Toxicol Date: 2019-04-12