S5809 A Triple Threat to the Liver: Coexisting MASH, Autoimmune Hepatitis, and Alpha-1 Antitrypsin Deficiency in a Single Patient

Introduction: Chronic liver disease can stem from metabolic, autoimmune, genetic, infectious, or toxin-induced etiologies. As the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) continues to rise, the likelihood of encountering overlap syndromes involving multiple etiologies is increasing. We present a rare case of triple-pathology liver disease involving MASH, autoimmune hepatitis (AIH), and alpha-1 antitrypsin (AAT) deficiency. Case Description/Methods: A 52-year-old woman with a history of newly diagnosed Hashimoto’s thyroiditis and hyperlipidemia presented with 6 months of asymptomatic transaminitis. Labs revealed an alkaline phosphatase of 238 IU/L, aspartate aminotransferase 72 IU/L, and alanine aminotransferase 91 IU/L. Liver ultrasound showed hepatomegaly (18 cm) and hepatic steatosis. Given her autoimmune background, additional testing was performed. ANA was positive at 1:1280; other autoimmune markers including AMA, ASMA, LKM1 and immunoglobulin levels were unremarkable. Viral hepatitis panel was negative. AAT levels were low 83 mg/dL with MZ phenotype. Fibroscan indicated F0–F1 fibrosis with a CAP of 334 dB/m consistent with severe steatosis. As the clinical picture remained unclear, a liver biopsy was performed with histology demonstrating F2 fibrosis, active steatohepatitis, PAS-positive diastase-resistant globules confirming AAT deficiency, and prominent interface hepatitis with plasma cells, consistent with AIH. The patient was diagnosed with overlapping MASH, AIH, and AAT deficiency. She was treated with prednisone 40 mg daily for 10 weeks with 5 mg taper weekly and azathioprine 50 mg daily that was titrated to 75 mg daily. Serial hepatic panels showed biochemical improvement, though mild transaminitis persisted. Discussion: This case underscores the clinical complexity and diagnostic challenge of overlapping liver pathologies. Coexisting MASH, AIH, and AAT deficiency is extremely rare and has not been previously reported. Overlapping liver diseases confer higher risk for progression to cirrhosis and worse outcomes compared to isolated liver conditions. Clinicians should maintain a high index of suspicion for multiple concurrent liver diseases in patients with unexplained or persistent liver enzyme abnormalities, especially in the context of metabolic syndrome and autoimmune conditions. Liver biopsy remains critical when noninvasive testing is inconclusive. Identifying and addressing all contributing etiologies is essential for guiding treatment and improving prognosis.