Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model

Without transplantation, similar to 50-90% of all patients with fulminant h epatic failure (FHF) die. This poor outcome is due in part to the absence o f an appropriate animal model, which would allow for a greater understandin g of the pathophysiology of this syndrome. Given the reports of liver injur y in humans and livestock fed cycad palm nuts on the island of Guam, we hyp othesized that the active ingredient azoxymethane (AOM) could cause FHF. We therefore evaluated AOM in C57BL/6J mice. Histologically, we observed micr ovesicular steatosis 2 h, sinusoidal dilatation 4 h, and centrilobular necr osis 20 h after AOM administration, and transmission electron microscopy sh owed that this agent causes mitochondrial injury. FHF was associated with a ll four stages of encephalopathy, as well as by a prodromal period of decre ased eating and drinking lasting similar to 15 h before the development of stage I encephalopathy (i.e., loss of scatter reflex). Late encephalopathy was associated with increased arterial ammonia, decreased serum glucose, an d evidence of brain edema (astrocyte swelling). We show that AOM-induced FH F is highly reproducible, without evidence of lot-to-lot variability, and i s dose dependent. These findings therefore suggest that AOM is an excellent agent for the study of FHF, as well as indicate that Guamanian FHF may be due to AOM found in unwashed cycad palm nuts.