Published online Apr 27, 2014. doi: 10.4254/wjh.v6.i4.243
Revised: January 17, 2014
Accepted: February 16, 2014
Published online: April 27, 2014
AIM: To propose an alternative model of hepatic encephalopathy (HE) in mice, resembling the human features of the disease.
METHODS: Mice received two consecutive intraperitoneal injections of thioacetamide (TAA) at low dosage (300 mg/kg). Liver injury was assessed by serum transaminase levels (ALT) and liver histology (hematoxylin and eosin). Neutrophil infiltration was estimated by confocal liver intravital microscopy. Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time. Hemodynamic parameters were measured through tail cuff. Ammonia levels were quantified in serum and brain samples. Electroencephalography (EEG) and psychomotor activity score were performed to show brain function. Brain edema was evaluated using magnetic resonance imaging.
RESULTS: Mice submitted to the TAA regime developed massive liver injury, as shown by elevation of serum ALT levels and a high degree of liver necrosis. An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury. This led to mice mortality and weight loss, which was associated with severe coagulopathy. Furthermore, TAA-treated mice presented with increased serum and cerebral levels of ammonia, in parallel with alterations in EEG spectrum and discrete brain edema, as shown by magnetic resonance imaging. In agreement with this, neuropsychomotor abnormalities ensued 36 h after TAA, fulfilling several HE features observed in humans. In this context of liver injury and neurological dysfunction, we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome.
CONCLUSION: In summary, we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans, which may provide new insights for treatment.
Core tip: The study of hepatic encephalopathy is crucial for development of new therapies but has been dampened by the absence of murine models resembling the disease in patients. We showed that sequential thioacetamide injections cause extensive liver injury in mice, leading to increased ammonia levels, electroencephalography alterations and brain edema. In line with this, mice presented with poor psychomotor activity and survival rate. Liver injury and brain function impairment by thioacetamide resulted in systemic alterations such as coagulopathy, hemodynamic instability and lung inflammation, consistent with multiple organ failure. Therefore, this alternative model may provide tools for new therapeutic insights for hepatic encephalopathy.