Dissociating hepatocellular necrosis from hepatic encephalopathy: a murine acetaminophen model to identify second-hit drivers of acute liver failure
- 1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
Abstract
Acetaminophen (i.e. paracetamol; APAP) overdose is the most common cause of acute liver injury in the United States, yet outcomes range from recovery to acute liver failure (ALF), defined by coagulopathy and hepatic encephalopathy (HE). Clinical decision-making is difficult because routine indices of hepatocellular injury (e.g. ALT/AST) do not reliably predict which patients will recover versus progress to ALF. This underscores the need to define mechanisms that drive progression to ALF and to discover biomarkers that better predict clinical trajectory. A major barrier is the lack of an experimentally tractable model in which severe hepatocellular injury is comparable, but neurological outcome diverges—a defining feature of human APAP toxicity. To address this, we established APAP dosing conditions in mice that produce similar peak liver injury yet distinct clinical courses. Mice treated with 300mg/kg or 500mg/kg APAP exhibited comparable increases in ALT and hepatic necrosis. In contrast, only 500mg/kg APAP caused robust neurological dysfunction consistent with HE, including impaired reflex integrity and motor coordination, accompanied by cerebral edema and reduced cerebral blood flow. Hyperammonemia is widely implicated in HE, but ammonia levels do not always track with HE severity in patients, suggesting additional cooperating factors. Consistent with this clinical discordance, blood ammonia increased to a similar extent in both dosing groups despite clear divergence in neurological impairment. Together, these findings establish a patient-relevant platform that dissociates hepatocellular necrosis (and hyperammonemia) from HE, enabling identification of mediators that drive neurovascular dysfunction and the transition from severe liver injury to ALF.
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BibTeX
@article{strickland2026dissociating,
title = {{Dissociating hepatocellular necrosis from hepatic encephalopathy: a murine acetaminophen model to identify second-hit drivers of acute liver failure}},
author = {Jenna Strickland and Yining Jin and Cheryl E. Rockwell and Anne M. Dorrance and Bryan L. Copple},
journal = {Toxicology mechanisms and methods},
year = {2026},
month = jun,
doi = {10.1080/15376516.2026.2686724},
url = {https://europepmc.org/article/PMC/PMC13718725},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Dissociating hepatocellular necrosis from hepatic encephalopathy: a murine acetaminophen model to identify second-hit drivers of acute liver failure
AU - Jenna Strickland
AU - Yining Jin
AU - Cheryl E. Rockwell
AU - Anne M. Dorrance
AU - Bryan L. Copple
PY - 2026
DA - 2026/06/17
JO - Toxicology mechanisms and methods
DO - 10.1080/15376516.2026.2686724
UR - https://europepmc.org/article/PMC/PMC13718725
AB - Acetaminophen (i.e. paracetamol; APAP) overdose is the most common cause of acute liver injury in the United States, yet outcomes range from recovery to acute liver failure (ALF), defined by coagulopathy and hepatic encephalopathy (HE). Clinical decision-making is difficult because routine indices of hepatocellular injury (e.g. ALT/AST) do not reliably predict which patients will recover versus progress to ALF. This underscores the need to define mechanisms that drive progression to ALF and to discover biomarkers that better predict clinical trajectory. A major barrier is the lack of an experimentally tractable model in which severe hepatocellular injury is comparable, but neurological outcome diverges—a defining feature of human APAP toxicity. To address this, we established APAP dosing conditions in mice that produce similar peak liver injury yet distinct clinical courses. Mice treated with 300mg/kg or 500mg/kg APAP exhibited comparable increases in ALT and hepatic necrosis. In contrast, only 500mg/kg APAP caused robust neurological dysfunction consistent with HE, including impaired reflex integrity and motor coordination, accompanied by cerebral edema and reduced cerebral blood flow. Hyperammonemia is widely implicated in HE, but ammonia levels do not always track with HE severity in patients, suggesting additional cooperating factors. Consistent with this clinical discordance, blood ammonia increased to a similar extent in both dosing groups despite clear divergence in neurological impairment. Together, these findings establish a patient-relevant platform that dissociates hepatocellular necrosis (and hyperammonemia) from HE, enabling identification of mediators that drive neurovascular dysfunction and the transition from severe liver injury to ALF.
SN - 1537-6516
SN - 1537-6524
ER -