Laboratory and Clinical Profile of Alcohol-Induced Liver Fibrosis in a Transgenic Porcine Model

Liver disease affects ten percent of the world’s population, and estimates show that this yearly incidence is growing each year. Liver fibrosis is a key point in the progression of alcohol liver disease, as it represents the point at which liver damage is no longer reversible and treatment algorithms shift towards more expensive treatment aimed at controlling symptoms of liver damage rather than reversing liver damage. Additionally, fibrosis progresses to cirrhosis, which in turn progresses to hepatocellular carcinoma. Alcohol liver disease is responsible for approximately ninety percent of hepatocellular carcinoma cases, an expensive disease to treat with an uncomfortable quality of life for patients. Therefore, a large animal model of alcohol-induced liver fibrosis is key in research development of clinically relevant medical and interventional treatments for end-stage liver disease and also for hepatocellular carcinoma. This study aims to create a large animal model of liver fibrosis in the oncopig model. The oncopig is a transgenic swine with heterozygous KRAS and TP53 mutations that are present in over fifty percent of gastric cancers, which will be key in creating a hepatocellular carcinoma model. Fibrosis induction procedure was performed in two experimental cohorts of five oncopigs, one serially monitored for eight weeks after fibrosis induction and an extended cohort serially monitored for twenty weeks after fibrosis induction. Both experimental cohorts were compared to the control group in three main areas: clinical exam including neurological assessment, serological biomarkers, and histological assessment for fibrosis and inflammation. Statistical analysis for continuous variables was done using a twotailed t-test, and for categorical variables was done using one-way ANOVA. Fibrosis induction procedure was successful in all ten animals, with peak fibrosis of F3 reached at two to three weeks, but not persistent at twenty weeks. There were no significant differences in neurological assessment or serological biomarkers. This study shows that fibrosis induction procedure is successful in inducing fibrosis at two to three weeks postinduction, indicating a regeneration and resolution of fibrosis and inflammation. This is analogous to the natural disease course of alcohol liver disease in humans, which only develops after chronic misuse of alcohol, equating to contrasting periods of ethanol intoxication and liver damage reversal until liver damage reaches liver fibrosis. This is an important step in creating a persistent large animal model of liver fibrosis in a transgenic swine with utility in translational studies for medical and interventional treatment.