S5965 Diagnostic Dilemma: Overlap Syndrome in the Young—Antimitochondrial Antibodies Meet NAFLD

Introduction: Anti-mitochondrial antibodies (AMAs) are present in ∼90%–95% of diagnosed primary biliary cholangitis (PBC) cases. However, they have also been observed in Metabolic dysfunction-associated steatotic liver disease (MASLD). This overlap suggests a potential autoimmune component complicating the clinical picture. We present a case of a young, obese male with AMA-positive MASLD who underwent liver biopsy for further evaluation. Case Description/Methods: A 27-year-old obese male (body mass index 40) with hypertension and prior robotic cholecystectomy for symptomatic cholelithiasis presented with persistently elevated liver enzymes (alanine aminotransferase 67, aspartate aminotransferase 72), proteinuria (albumin/creatinine: 101, 50, 301), and thrombocytosis. He had no alcohol use for over a year, negative viral serologies, and a normal alkaline phosphatase. Lipid profile showed LDL (147 mg/dL), with normal triglycerides. Hemoglobin A1C was 5.5%. Autoimmune/metabolic workup, including ANA, SMA, LKM, ceruloplasmin, and alpha-1 antitrypsin, were negative. However, anti-mitochondrial (M2) antibody was strongly positive (54.2 and 37.6; normal <20). Other comorbidities included vertigo, tendonitis, and sciatica. Family history notable for glioblastoma in a young relative. Medications included lisinopril, Flonase, azelastine, meclizine, and dicyclomine. He underwent FibroScan at BMI 36 after an 80 lbs weight loss with semaglutide, which showed mild steatosis (2.3 kPa, CAP 247; F0–F1). A transjugular liver biopsy revealed moderate portal histiocytosis without bile duct injury or granulomas, consistent with MASLD. AMA positivity raised concern for possible autoimmune cholangiopathy overlap, warranting surveillance. Lifestyle modifications were advised and the patient was transitioned to tirzepatide from semaglutide for continued hepatic and weight-loss benefit. Hepatitis A/B vaccination and black coffee were also recommended. Discussion: This case highlights the diagnostic challenge of AMA positivity in a young, obese patient with MASLD, proteinuria, and prior cholecystectomy, despite no cholestatic picture. Though once thought rare (<2%), Tsuneyama et al. found AMA in 48% of biopsy-proven MASLD cases, suggesting a stronger autoimmune link. AMA positivity, proteinuria, and cholestatic features may indicate advanced disease and serve as diagnostic/prognostic markers for MASH. Emerging therapies include tirzepatide (a GIP/GLP-1 agonist) for weight and fat reduction, and resmetirom, the first FDA-approved treatment for MASH with fibrosis (F2–F3).