S3277 Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis Presenting With Cholestatic Hepatitis: A Case Report

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of excessive immune activation, triggered by genetic defects or external triggers such as infections and malignancies. Hallmarks include fever, cytopenias, hyperferritinemia, and hepatosplenomegaly. Epstein-Barr virus (EBV) is a key infectious driver, causing rapid disease progression and high mortality. Cholestasis in HLH is rare and may mimic obstructive hepatitis, often delaying diagnosis. We present a case of EBV-HLH with a cholestatic presentation, emphasizing HLH in the differential of unexplained jaundice and systemic inflammation. Case Description/Methods: A 56-year-old man with no known medical history presented with fatigue, rash, nausea, vomiting, diarrhea, and progressive jaundice after eating spoiled food prior to symptom onset. He had no recent travel or drug use. Labs showed acute kidney injury (Cr ∼11), metabolic acidosis, and mixed-pattern liver injury (AST/ALT 300–400s, total bilirubin 10 mg/dL, elevated ALP and GGT). INR peaked at 2.37 without hepatic encephalopathy (MELD 39). Imaging revealed no biliary obstruction. Workup was negative for autoimmune or metabolic etiology except for high EBV viral load. Ferritin >10,000 ng/mL, elevated sIL-2R, and hemophagocytosis on marrow and liver biopsy with acute hepatitis with marked cholestasis and rare hemophagocytic cells confirmed EBV-HLH. He improved with dexamethasone and supportive care. Discussion: Adult-onset HLH often poses a diagnostic challenge due to nonspecific symptoms that overlap with other inflammatory or infectious diseases. While the HLH-2004 criteria remain widely used, they may lack sensitivity in cases with atypical hepatic presentations involving cholestasis. Our patient presented with marked jaundice, direct hyperbilirubinemia, and cholestatic liver enzyme elevation, initially raising concern for biliary obstruction or viral hepatitis. However, imaging and routine serologies were negative. The presence of EBV viremia, pancytopenia, hyperferritinemia, and hemophagocytosis on liver biopsy confirmed EBV-HLH. Few cases in the literature describe EBV-HLH mimicking obstructive jaundice, underscoring the diagnostic challenge when liver dysfunction dominates the clinical picture. Broader awareness is needed to identify HLH in adults with unexplained cholestasis and systemic inflammation.