Park, Byoung Uk

Metabolic dysfunction-associated steatohepatitis (MASH) is a global health care burden. Appropriate large animal models mimicking the main MASH characteristics of steatosis, inflammation, and hepatocyte damage alongside progression of fibrosis are imperative for robust preclinical studies, especially in the field of hepatobiliary surgery. The present study aimed to characterize a novel model of steatohepatitis in fumarylacetoacetate hydroxylase-deficient ( FAH -/- ) pigs. FAH -/- pigs were generated using a CRISPR/Cas9 system. The animals received a choline-deficient, L-amino acid-defined high-fat diet and subtherapeutic doses of nitisinone and were followed for 3 months. Liver biopsies were obtained at baseline and every month during treatment. Steatosis, inflammation, and fibrosis were assessed by conventional histological scoring systems and by an artificial intelligence (AI) model. Serum liver parameters were analyzed every 2 weeks. Steatosis increased significantly throughout the study, with severe steatosis observed as early as 2 months into treatment. The inflammation score was increased in all animals after 3 months of treatment, whereas the AI-based CD45+ cell count showed region-specific trends in the portal and lobular areas. Collagen content and the corresponding fibrosis stage showed an increase over the 3-month period; however, the difference was not significant. Serum liver parameters did not show any relevant elevations during the study. In summary, we successfully developed and characterized a novel model of steatohepatitis in the FAH -/- pig within 3 months. Further studies with prolonged observation time and/or cycling of nitisinone administration are needed to evaluate whether progressive fibrosis and cirrhosis could be achieved with this model.

ABSTRACT The use of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has markedly increased for the treatment of weight loss and management of diabetes mellitus. Gastrointestinal adverse effects of GLP-1/GIP agonist therapy, including nausea, vomiting, and constipation, are common. We report a case of colonic ischemia in a 62-year-old woman which developed in association with the use of tirzepatide for weight loss. This report highlights a potential risk relationship between GLP-1/GIP agonist therapy and colonic ischemia and identifies risk factors that should be considered before prescribing tirzepatide.

ABSTRACT We present the cast of a 74-year-old woman with a remote history of recurrent localized breast cancer who presented with nonspecific gastrointestinal symptoms who was subsequently found to have metastatic breast cancer in the transverse colon. Nonspecific gastrointestinal complaints can be the first sign of cancer recurrence in these patients. Providers should maintain a high index of suspicion for disease recurrence when evaluating cancer survivors.