An Uncommon Presentation of Selpercatinib (Retevmo)-Induced Severe Transaminitis: A Biopsy-Proven Case Report

Selpercatinib (Retevmo) is a selective rearranged during transfection (RET) kinase inhibitor approved for RET-altered malignancies, including thyroid carcinoma. Hepatic enzyme elevations have been reported; however, biopsy-proven drug-induced liver injury (DILI) associated with selpercatinib is uncommon. We report a case of a 59-year-old woman with recurrent papillary thyroid carcinoma who developed progressive gastrointestinal symptoms followed by severe hepatocellular transaminitis approximately four weeks after initiating selpercatinib (160 mg twice daily). Laboratory evaluation demonstrated marked aminotransferase elevation (aspartate aminotransferase: 525 U/L and alanine aminotransferase: 639 U/L) with mild hyperbilirubinemia (total bilirubin: 2.1 mg/dL), and aminotransferases peaked above 800 U/L during hospitalization. Comprehensive workup for alternative etiologies, including viral hepatitis and autoimmune hepatitis (negative antinuclear antibody and smooth muscle antibody with normal immunoglobulin levels), was unrevealing, and abdominal imaging showed no acute abnormalities. Liver biopsy demonstrated sparse portal lymphocytic inflammation with intact bile ducts and prominent centrilobular (zone 3) hepatocellular necrosis accompanied by macrophages and eosinophils, consistent with DILI. Selpercatinib was discontinued, resulting in progressive biochemical improvement with aminotransferases declining to <100 U/L within approximately four months. Given oncologic necessity, selpercatinib was reintroduced at a reduced dose (40 mg daily) without recurrence of severe transaminitis. This case highlights that selpercatinib can cause clinically significant hepatocellular DILI and underscores the diagnostic value of liver biopsy in distinguishing DILI from autoimmune hepatitis, particularly when considering safe dose modification and rechallenge.