Asian Journal of Medicine and Health

Introduction: Immune checkpoint inhibitor hepatitis (ICIH) occurs in 0-30% of patients receiving PD-L1 and CTLA-4 inhibitors, while checkpoint inhibitor pneumonitis (CIP) affects 2-19% of patients. ICIH typically presents as steroid-responsive hepatocellular injury. Cholestatic and mixed patterns are rare and are more frequently steroid-refractory, requiring second-line immunosuppression. Concurrent ICIH and checkpoint inhibitor pneumonitis in a single patient is exceptionally rare. The combination of ICIs with other immunosuppressants may magnify hepatotoxicity and pneumonitis through overlapping immune dysregulation. Ursodiol shows promise for cholestatic drug-induced liver injury because of its choleretic, hepatoprotective, and immunomodulatory mechanisms, but it remains poorly studied in ICIH. We present a case of steroid-refractory cholestatic ICIH with concurrent recurrent pneumonitis that was associated with a marked biochemical response to ursodiol.

Case Presentation: A 63-year-old male with metastatic non-small cell lung carcinoma (NSCLC), initially diagnosed in 2017, developed recurrence in 2023. He received eight cycles of carboplatin/paclitaxel followed by pembrolizumab/osimertinib combination therapy. He presented with dyspnoea and was found to have a subsegmental pulmonary embolism, with diffuse bilateral ground-glass opacities on CT. Bronchoalveolar lavage (BAL) confirmed CIP. Simultaneously, cholestatic transaminitis developed (AST 166 U/L, ALT 168 U/L, ALP 336 U/L). The autoimmune workup was negative, and viral testing showed resolved hepatitis B. Despite high-dose corticosteroids for pneumonitis, liver enzymes progressively worsened over seven days, peaking at AST 388 U/L, ALT 410 U/L, ALP 337 U/L, and total bilirubin 3.4 mg/dL. Liver biopsy showed hepatitis and moderate portal inflammation consistent with ICIH. Pembrolizumab was permanently discontinued, but osimertinib was continued with high-dose corticosteroids. Because of steroid-refractory disease, mycophenolate mofetil (MMF) 500 mg twice daily was added, with an initial partial response. However, the patient developed rebound transaminitis (ALP 405 U/L, AST 227 U/L). He had recurrent episodes of severe pneumonitis that required escalating corticosteroid doses; therefore, MMF and osimertinib were held because of worsening infection risk and recurrent pneumonitis. Ursodiol 500 mg daily was initiated as adjunctive therapy for the cholestatic pattern. Liver function tests showed marked improvement on ursodiol monotherapy. Liver function tests had nearly normalised within three weeks of therapy: AST 19 U/L (95% reduction from peak), ALT 24 U/L (94% reduction), and ALP 147 U/L (56% reduction).

Discussion: This case highlights synergistic drug toxicities and therapeutic challenges in managing overlapping immune-related adverse events. The concurrent use of pembrolizumab and osimertinib may amplify both hepatotoxicity and pneumonitis compared with monotherapy, requiring enhanced surveillance. Only 10-15% of ICIH cases fail corticosteroid therapy, and cholestatic-pattern ICIH is generally more treatment-refractory than hepatocellular patterns. Managing concurrent refractory hepatitis and pneumonitis limits conventional treatment options. Ursodiol has been proposed to have choleretic effects, hepatocyte membrane-stabilising activity, anti-apoptotic properties, and immunomodulatory effects through decreased MHC class I expression. Increased MHC class I expression has been reported in cholestatic-pattern injury. The patient's detailed longitudinal clinical course, including laboratory trends and therapeutic modifications, is provided in Supplementary Appendix 1.

Conclusions: This case illustrates the potential risk of severe, overlapping immune-related adverse events with combination ICI-TKI therapy and the particular challenge of cholestatic-pattern ICIH. Most notably, ursodiol was associated with substantial biochemical improvement as salvage therapy in steroid- and MMF-refractory disease, suggesting that it may warrant consideration early in cholestatic ICIH, particularly when infection risk precludes conventional immunosuppression. This case adds to the limited literature supporting the role of ursodiol and highlights the need for prospective trials. Clinicians should remain aware of the synergistic toxicities of immunotherapy and consider alternative therapeutic approaches for refractory cases.