New Rat Model of Cholestatic Liver Cirrhosis Developing Acute-on-Chronic-Liver failure

Introduction Acute-on-chronic liver failure (ACLF) has a dramatic 28-day mortality. Several precipitating events, such as severe alcoholic injury, bacterial translocation and infections lead via multiple organ dysfunction and failure to acute decompensation (AD) and ACLF. Validated animal models for ACLF are needed for therapeutic treatments.

Methods Bile duct ligation (BDL) induced cholestatic liver cirrhosis. Alcohol injury was mimicked by ethanol binge drinking (6g/kg). Repetitive lipopolysaccharide (LPS) injections were implemented as bacterial translocation models. Finally, transnasal stool inocculation (TNI) and cecal ligation and puncture (CLP) were used to induce pneumonia and peritonitis. Organ dysfunctions and failures were assessed using histology, invasive pressure measurements, blood biochemistry and gene/protein expression and categorized by adapted CLIF-SOFA score.

Results All precipitants induced ACLF as defined by CLIF-SOFA score with liver, coagulation and circulatory failure. Liver failure was assessed by stainings, gene expression levels and measurement of blood parameters, while coagulation failure was defined by a significant increase in International Normalized Ratio (INR). Circulatory failure was confirmed by a decrease in mean arterial pressure and reduced organ perfusion. Renal failure was induced in the models of Binge and CLP, based on gene expression levels and blood parameters. Cerebral failure was induced only by CLP, as investigated by neurological tests. Respiratory failure could be induced only in 10–20% of the animals across the models.

Conclusion In the cholestatic liver cirrhosis model, alcoholic injury, bacterial translocations and infections induce consistent liver, coagulation and circulatory failures. Alcoholic injury and CLP are the most severe precipitants in this setting.

Publication History

Article published online:
26 January 2022