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Matteo Bellia, Mariangela Greco, Monia Lunghi, Riccardo Moia, Gianluca Gaidano, Andrea Patriarca Department of Translational Medicine, Division of Hematology, Universita’ del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, 28100, ItalyCorrespondence: Matteo Bellia, Department of Translational Medicine, Division of Hematology, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Via Solaroli 17, Novara, 28100, Italy, Tel +39-346-5988355, Email matteo.bellia@uniupo.itBackground: Jaundice and hyperbilirubinemia are common clinical problems characterized by the presence of bile pigments in the blood and their deposition in body tissues. This clinical condition can be associated with a broad spectrum of potential benign and malignant causes, including hepatic inflammation, biliary obstruction, impaired bilirubin conjugation and bilirubin overproduction Therefore, the hyperbilirubinemia diagnostic work-up sometimes can be highly challenging and its therapeutic management can require a multidisciplinary approach.Case Report: We report on a unique case of life-threatening jaundice and hepatic failure in a 20-year-old female who presented to the emergency room with complaints of fever, constant left abdominal pain and generalized profuse fatigue. A complete and detailed medical history, multiple tests for various infection, radiologic investigations and histological tests were performed in order to clarify the etiology of that rapidly progressive clinical condition. Based on the results, the patient jaundice was caused by an Epstein-Barr virus (EBV) infection and secondary cold agglutinin syndrome. Given the rare and complex diagnosis, multiple clinical specialists were asked to carry out the best patient management.Conclusion: This rare case highlights how challenging the differential diagnosis and treatment of hyperbilirubinemia can be, presenting a unique case of life-threatening multifactorial hepatic failure treated successfully with rituximab.Keywords: jaundice, Epstein-Barr virus infection, secondary cold agglutinin syndrome, rituximab

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