S5864 Weight Loss or Liver Loss? Cholestatic Injury Following Semaglutide and Supplement Use: A Diagnostic Dilemma

Introduction: Drug-induced liver injury (DILI) is a diagnostic challenge, especially with increased use of over-the-counter supplements and, glucagon-like peptide-1 (GLP-1) receptor agonists. Nattokinase and serrapeptase, marketed for cardiovascular and anti-inflammatory benefits, are not FDA-regulated and lack hepatotoxicity data. Semaglutide (Wegovy) is widely used for obesity, with minimal evidence linking it to liver injury. We present a case of cholestatic liver injury temporally associated with both agents. Case Description/Methods: A 55-year-old man with obesity (baseline 232 lbs) and moderate alcohol use (previously 3×/week, reduced to 2–3×/month after March) had been on semaglutide since September 2024. In March 2025, he began taking a supplement containing nattokinase and serrapeptase. Four days later, he developed jaundice, dark urine, pale stools, pruritus, nausea, and RUQ discomfort. Labs showed elevated total bilirubin (3.0 mg/dL), alanine aminotransferase (ALT) 263 U/L, and alkaline phosphatase (ALP) 170 U/L. Hepatitis panel was negative; abdominal ultrasound revealed cholelithiasis without ductal dilation. Both semaglutide and the supplement were discontinued. Workup including autoimmune, metabolic, and celiac serologies was unremarkable; ferritin was mildly elevated (464 ng/mL). Liver tests initially improved, but later rebounded with persistent pruritus and mild jaundice. As of May, total bilirubin remained elevated at 1.8 mg/dL, direct bilirubin at 1.0 mg/dL, ALT 117 U/L, and ALP 177 U/L. Prior LFTs in 2023 were normal. Discussion: The timing of symptoms appearing 4 days after starting nattokinase/serrapeptase, suggests a temporal relationship. The clinical course and exclusion of other causes support a likely DILI, with a cholestatic or mixed pattern. While semaglutide has not been widely associated with hepatotoxicity, its role cannot be excluded, especially given the rebound in liver enzymes post-discontinuation. This case highlights the importance of detailed supplement and medication histories in unexplained liver injury. Given the expanding use of GLP-1 agonists and unregulated supplements, clinicians must remain alert to emerging hepatotoxic risks.