Aged Abcb4-/- mice upon acute sublethal chemical insult recapitulate features of acute-on-chronic liver failure in patients

Acute-on-chronic liver failure (ACLF) is a recently recognized fraction of liver patient's entity. ACLF is characterized by decompensated cirrhosis and multi-organ failure with poor outcome (mortality rate 30 – 40%). Some patients recover without transplantation, if minimal organ functions are maintained for one week what so called “golden window”. Several histological features were described to characterize ACLF entity e.g. submassive cellular necrosis and ductular reactions upon severe chronic liver disease. Understanding of underlying mechanisms that control the pathologic decision in ACLF patients, e.g. further organ deterioration or recovery is hampered by lacking a suitable animal model. Therefore, 75 weeks old Abcb4-/- mice were treated with a sublethal dose of carbon tetrachloride (CCl4; 3.2 g/kg) intraperitoneally. Subsequently, survival rate, liver necrosis, cirrhosis and regeneration were investigated in a time-resolved manner and compared with ACLF patients. Surprisingly, survival analysis revealed that some mice died during the first 24h after CCl4, however, the mice survived if able to pass this period. Histologically, massive hepatic necrosis was recorded at days 1 and 2 after the CCl4 hit that recovered at day 4. Proliferation index was measured by Ki-67+ nuclear staining illustrating massive positivity at days 2 and 4 in surviving mice. Hepatocyte-cholangiocyte cell plasticity was investigated by CK19 immunostaining indicating that numerous CK19+ cells occur immediately after the acute insult. Molecular phenotyping of mouse livers and comparative transcriptomics analyses are currently ongoing. In conclusion, administration of a high dose of CCl4 to genetically induced cirrhotic livers induces a phenotype that recapitulates some features of ACLF patients comprising a golden window, cirrhosis, ductular reaction, submassive hepatic necrosis and parenchymal cell plasticity.