Tirzepatide-Associated Severe Hepatocellular Injury: A Case Report and Diagnostic Considerations.

Background/Objectives: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is increasingly used for glycemic control and weight reduction and has a generally favorable hepatic safety profile. However, rare cases of clinically significant drug-induced liver injury have been reported. We report a case of severe hepatocellular injury during tirzepatide therapy and compare it with previously reported cases. Case Presentation: A 36-year-old man developed gastrointestinal symptoms, dark urine, and severe hepatocellular injury approximately 5 weeks after starting tirzepatide for weight reduction, shortly after dose escalation from 2.5 mg to 5 mg weekly and amid rapid weight loss of approximately 10 kg. Extensive evaluation excluded viral, autoimmune, metabolic, biliary, and structural causes, with no competing medication or supplement exposure identified. Tirzepatide was discontinued, and clinical and biochemical status improved rapidly. The Roussel Uclaf Causality Assessment Method (RUCAM) score was 7, indicating probable drug-induced liver injury. Discussion: Previously reported cases demonstrate heterogeneous biochemical patterns and severity, ranging from mild hepatocellular injury to mixed or cholestatic presentations and acute liver failure requiring transplantation. The mechanism remains uncertain. An idiosyncratic drug reaction is the most plausible explanation, while rapid weight loss, dose escalation, and hepatic steatosis may represent susceptibility modifiers rather than established causes. Conclusions: Tirzepatide-associated liver injury appears rare but can be clinically severe. Clinicians should remain alert to the possibility of drug-induced liver injury when unexplained hepatic symptoms or liver biochemical abnormalities arise during treatment.