Preclinical Models of Acute Liver Failure

Acute liver failure (ALF) is a rare and often heterogeneous presentation of severe liver dysfunction in a patient with otherwise no pre-existing liver disease. Various factors can cause acute liver injury, and most factors are caused by drug-induced liver toxicity. Animal models are important for the study of such rare diseases, both for understanding the pathophysiology and for the development of potential treatments. Broadly, artificially-induced preclinical ALF models can be grouped into surgical, pharmacological, or immunogenic approaches.

Surgical Models

Some surgical models, such as portocaval anastomosis (PCA) with hepatic artery ligation and partial hepatectomy with ischemia or portacaval shunt, seek to create a generalized model of ALF, whereas other surgical models are aimed at specific causes of ALF.

• An-hepatic models. An-hepatic models have been described in rats, rabbits, dogs, and pigs. Both single and multi-stage procedures have been reported. While an-hepatic models produce the purest form of liver failure in some sense, they lack a direct clinical correlation.
• Partial hepatectomy. An alternative to total hepatectomy is major liver resection models, which generally range from 70% to 95% resection of the liver mass. This has been reported in mice, rats, rabbits, pigs, and baboons.
• Portocaval anastomosis & hepatic artery ligation. Another commonly used surgical model involved PCA plus hepatic artery ligation. PCA may be done at the same time as arterial ligation or separately. This has been described in rats, rabbits, dogs, and pigs.

Pharmacological Models

• Acetaminophen. Acetaminophen (APAP) is a commonly used pharmacological model. APAP toxicity models have been described in mice, rabbits, dogs, and pigs. It can be administered intravenously (IV), intraperitoneally (IP), subcutaneously (SC), or orally (PO).
• D-galactosamine. D-galactosamine (d-Gal) is another commonly used pharmacological agent for inducing ALF in animal models. D-Gal characteristic results in diffuse rather than zonal necrosis seen with most hepatotoxic drugs.
• Carbon tetrachloride. Though more commonly used in chronic models of hepatic fibrosis, carbon tetrachloride (CCl₄) can be given in a single large dose to induce acute injury. Hepatic fibrosis is achieved by administering multiple small doses.
• Thioacetamide. Thioacetamide is an organosulfur compound, which, like CCl₄, can be used in both acute and chronic models of liver injury.
• Azoxymethane. Azoxymethane is a compound that has been widely used in animal models of colorectal cancer, where it induces tumor formation via DNA alkylation.
• Creative Bioarray provides various pharmacological models of acute liver injury, including models induced by carbon tetrachloride (CCl₄), acetaminophen (APAP), thioacetamide (TAA), D-Galactosamine (D-GalN), lipopolysaccharide (LPS).

Immunogenic Models

• Concanavalin A. Concanavalin A (ConA) initiates immune-mediated liver injury and has been used specifically to model autoimmune hepatitis. ConA for the induction of ALF is well described in mice, though not well characterized in other animal models.
• Fas antibody. The Fas receptor is a member of the TNF receptor family with a death domain that can assemble a death-inducing signaling complex to induce caspase activation and apoptosis. Fas ligand FasL or its antibody Jo2 is often used in research to induce liver injury models.
• Viral models of ALF. In addition to the variety of models that may be created using recombinant genetic techniques on the virus and/or host, there are several species-specific viruses associated with fatal hepatitis in wild-type animals, such as murine hepatitis virus (MHV) strain 3, rabbit hemorrhagic disease virus (RHDV), and others.
• Creative Bioarray provides various immunogenic models of acute liver injury, including models induced by carbon concanavalin A (ConA) or Fas Ab.

Reference

1. Hefler J, et al. (2021). "Preclinical models of acute liver failure: a comprehensive review." PeerJ. 9, e12579.