Acute liver failure is a devastating consequence of hepatotoxic liver injury that can lead to the development of
hepatic encephalopathy. There is no consensus on the best model to represent these syndromes in mice, and therefore the aim of this study was to classify hepatic and neurological consequences of
azoxymethane- and
thioacetamide-induced liver injury.
Azoxymethane-treated mice were euthanized at time points representing absence of minor and significant stages of neurological decline.
Thioacetamide-treated mice had tissue collected at up to 3 days following daily
injections. Liver histology, serum chemistry,
bile acids, and
cytokine levels were measured. Reflexes, grip strength measurement, and
ataxia were calculated for all groups. Brain
ammonia,
bile acid levels,
cerebral edema, and
neuroinflammation were measured. Finally, in vitro and in vivo assessments of blood-brain barrier function were performed. Serum
transaminases and liver histology demonstrate that both models generated hepatotoxic liver injury. Serum proinflammatory
cytokine levels were significantly elevated in both models.
Azoxymethane-treated mice had progressive neurological deficits, while
thioacetamide-treated mice had inconsistent neurological deficits.
Bile acids and
cerebral edema were increased to a higher degree in
azoxymethane-treated mice, while cerebral
ammonia and
neuroinflammation were greater in
thioacetamide-treated mice. Blood-brain barrier permeability exists in both models but was likely not due to direct toxicity of
azoxymethane or
thioacetamide on brain endothelial cells. In conclusion, both models generate acute liver injury and
hepatic encephalopathy, but the requirement of a single injection and the more consistent neurological decline make
azoxymethane treatment a better model for
acute liver failure with
hepatic encephalopathy.