S5671 A Rare Case of Tirzepatide Induced Cholestatic Hepatitis

Introduction: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus and weight management. It has demonstrated favorable cardiometabolic and renal outcomes, along with an overall favorable safety profile. We report a rare case of severe cholestatic hepatitis induced by tirzepatide. Case Description/Methods: A 57-year-old woman with a history of uterine cancer, status post total abdominal hysterectomy in 2009 (without chemotherapy or radiation), DM-2, started on tirzepatide 3 months ago presented with a one-week history of progressive jaundice and abdominal pain localized to the left lower quadrant, radiating across the lower abdomen. She also reported fatigue, poor appetite for the past 2 weeks, and intermittent nausea without vomiting. She denied fever, urinary symptoms, diarrhea, constipation, hematemesis, or melena. There was no prior history of liver disease or alcohol use. She had a small bowel obstruction 2 years earlier that resolved without intervention. On presentation, vitals were stable, physical exam was notable for jaundice without any stigmata of liver disease. Labs showed WBC 12 K/µL, total bilirubin 15.6 mg/dL (direct 8.2 mg/dL), alkaline phosphatase 141, gamma-glutamyl transferase 715 U/L, alanine aminotransferase 791 U/L, aspartate aminotransferase 337 U/L, and CRP 13.5 mg/L. Hepatitis panel, and lipase were negative. Computed tomography abdomen and right upper quadrant ultrasound showed hepatomegaly, marked gallbladder wall thickening, and no biliary ductal dilation. MRCP demonstrated no biliary obstruction. Cultures did not grow any pathogen. Tirzepatide was discontinued, leading to improvement in liver enzymes. Discussion: Tirzepatide, widely used for type 2 diabetes and obesity, provides metabolic benefits including improved adipose function, lipid metabolism, blood pressure, and cardiovascular outcomes, with a favorable safety profile. Post hoc analyses also suggest potential improvements in NASH-related biomarkers in diabetic patients. A meta-analysis of 9 randomized controlled trials investigating tirzepatide’s safety found no association with pancreatitis, cholelithiasis, cholecystitis, or other biliary disorders, However, there was a statistically significant increase in the composite risk of gallbladder or biliary disease compared to placebo or basal insulin, but not GLP-1 receptor agonists. These findings underscore the need for further research and warrant clinical vigilance for potential hepatobiliary adverse events in patients receiving tirzepatide.