Research Article: Nivolumab-Induced Autoimmune-Like Cholestatic Hepatitis in a Liver Transplant Recipient

Date Published: July 14, 2020

Publisher: Wolters Kluwer

Author(s): Chimaobi Anugwom, Thomas Leventhal.


Cancer treatment has taken giant strides in recent years with the advent of immunotherapy, including checkpoint inhibitors. The use of these medications in liver transplant recipients has been debated, and the added effect of previous hepatitis C infection on the immune system in this setting, is poorly understood. We present a case of cholestatic hepatitis after the treatment of recurrent hepatocellular carcinoma with nivolumab in the post-transplant period. Understanding the pathophysiology is relevant to improving the management of this type of liver injury and expanding our knowledge of programmed death-1 inhibitors in liver transplant recipients.

Partial Text

The treatment of cancer has taken giant strides in recent years with the advent of immunotherapy.1 The checkpoint inhibitors have been approved for the treatment of metastatic melanoma, nonsmall cell lung cancer, and hepatocellular carcinoma (HCC).2 Nivolumab—a PD-1 (programmed death-1) inhibitor, has demonstrated significant survival benefit but has been associated with a myriad of immune-related toxicities. We present a case of cholestatic hepatitis after nivolumab treatment of recurrent HCC in a patient with a history of hepatitis C virus (HCV) cirrhosis.

A 62-year-old man presented with a medical history of alcohol use disorder and chronic hepatitis C infection, with resultant cirrhosis that was further complicated by the development of HCC approximately 2 years before liver transplantation. His malignancy was detected through routine screening ultrasounds, and his serum alpha-feto protein was noted to be only mildly elevated during his disease course and most times within the normal range. He underwent deceased donor liver transplantation approximately 5 years before presentation, was cured of chronic hepatitis C using direct-acting antivirals (DAAs), and was on stable tacrolimus immunosuppressive monotherapy with excellent allograft function. After the removal of the explant, large tumor burden was noted, with microvascular and macrovascular invasion, but no adenopathy or evidence of extrahepatic spread. His Risk Estimation of Tumor Recurrence After Transplant score at the time of transplant was 5, suggesting >75% risk of recurrence. Given his high risk, he was checked every 3–6 months post-transplant period. Approximately 1 year after transplant, he was found to have a nodule in his right upper lung lobe and underwent resection, which demonstrated metastatic HCC. He developed further pulmonary nodules, and an endoscopic ultrasound-guided biopsy of a nodule in the left lower lung demonstrated poorly differentiated nonsmall cell lung cancer. Immunohistochemistry for this biopsy demonstrated “no programmed death ligand-1 expression.” Approximately 1 month after discovering this neoplasm, a mass on his abdominal wall was biopsied and demonstrated poorly differentiated nonsmall cell carcinoma.

Nivolumab, a PD-1 inhibitor, has been approved by the Food and Drug Administration for treatment of nonsmall cell lung cancer, melanoma, renal cell carcinoma, and HCC based on trials highlighting the survival benefits and low rates of toxicity.2–5 Tumor cells escape immune surveillance by expressing the PD-1 ligand that binds to the PD-1 receptor on immune cells. This serves as a checkpoint of T-cell-mediated cell death.6 Hence, by targeting this PD-1/programmed death ligand-1 interaction, nivolumab—a human anti-PD-1 monoclonal antibody, can turn on T-cell-mediated antitumor effect.7 As expected, increasing the activity of the immune system results in a host of inflammatory adverse effects. These have been postulated to be immune-related and can affect the gastrointestinal tract, skin, cardiopulmonary system, and the liver.8

Author contributions: C. Anugwom wrote the manuscript. T. Leventhal revised the manuscript for intellectual content and is the article guarantor.




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