Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: An autopsy case report

Our plain-English summary of Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: An autopsy case report, by K. Arai, M. Matsuda, H. Nakayasu, et al (Clinical Case Reports, 2021).

The study

• Authors: K. Arai, M. Matsuda, H. Nakayasu, S. Meguro, T. Kurokami, A. Kubota, T. Iwasaki, M. Suzuki, S. Kawaguchi, T. Iwashita
• Journal: Clinical Case Reports
• Published: 2021;9(12):e05174
• Type of article: Case report
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

This is the first autopsy report of hepatotoxicity from nivolumab immunotherapy for malignant mesothelioma. The increase in levels of biliary enzymes and randomly distributed endothelial damage were steroid-refractory, but second-line option was abandoned because of cachexia. Further discussions are needed regarding the customized management of immune-related toxicities.

© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.

In plain English

This case report from Shizuoka General Hospital, Japan, described a 76-year-old man with biphasic malignant mesothelioma, found on biopsy of the left parietal pleura. The article did not report whether he had been exposed to asbestos. After 67 months of chemotherapy, with the cancer spread to several organs, he began the immunotherapy drug nivolumab, 240 mg intravenously every 2 weeks. On the 15th day after his second course, his liver enzymes rose sharply, and nivolumab was stopped. A liver biopsy showed acute hepatitis, with infiltrating lymphocytes mainly CD3+ and CD8+ T cells. Transaminases fell but never returned to normal. Biliary enzymes (alkaline phosphatase and gamma-glutamyl transpeptidase) stayed high despite oral prednisolone and then 78 days of methylprednisolone. A second-line drug, mycophenolate mofetil, was not given because of cachexia and infection risk. He died of advanced cachexia about 5.5 months after starting nivolumab. At autopsy, the liver damage was randomly scattered: necrosis, vein inflammation and bile duct injury. The authors concluded that this uneven distribution was the most characteristic finding of nivolumab-induced liver injury.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case report with autopsy (single patient), including liver biopsy and autopsy pathology
• Who was studied: One 76-year-old man at Shizuoka General Hospital, Japan, with biphasic malignant mesothelioma diagnosed on parietal pleural biopsy (left pleura); dates of care not given
• Exposure: Nivolumab monotherapy (240 mg/body intravenously every 2 weeks), given after 67 months of chemotherapy and radiation. No asbestos exposure history is reported.
• Main results:
  • On the 15th day after the start of the second nivolumab course, the patient's liver enzymes rose rapidly. Alkaline phosphatase reached 2721 U/L (normal range 38 to 113 U/L). Total bilirubin stayed within the normal range.
  • After nivolumab was stopped, the patient's transaminases fell to grade 2 or 1. Biliary enzymes, which had reached grade 4, persisted at grade 3.
  • Methylprednisolone was given until just before death, for 78 days (total 1672 mg), after earlier oral prednisolone. Biliary enzymes persisted at grades 2 or 3, and transaminases improved but did not normalize.
  • The liver biopsy, taken on day 47 after the first nivolumab course, showed acute lobular hepatitis. Infiltrating lymphocytes were mainly CD3+ and CD8+ T cells.
  • The second-line drug mycophenolate mofetil was not given because the patient developed cachexia and had a high risk of infection.
  • The patient died of advanced cachexia about 5.5 months after starting nivolumab, and an autopsy was performed.
  • At autopsy, the active liver changes were randomly distributed and uneven. They included confluent necrosis, endothelialitis of the portal vein branches and chronic cholangitis with necrosis.
  • At autopsy, the tumor had spread extensively in the patient's peritoneum and other organs, with minimal therapeutic effect. No notable immune-related adverse events were found in organs other than the liver.
• The authors' conclusion: The authors concluded that the uneven, random distribution of lesions was the most characteristic finding of nivolumab-induced liver injury. They also concluded that endothelial damage followed by ischemic or necrotic lesions makes this injury refractory to treatment.
• Limitations the authors state:
  • The examination focused only on the liver.
  • The authors could not properly interpret why transaminases fell while scattered necrosis persisted.
  • Because of the patient's long chemotherapy and poor general condition, it is not clear that all liver lesions were caused by nivolumab.
  • The report shares the intrinsic limitations of a single case report.

Topics

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Mesothelioma, Autopsy, Immunotherapy, Cachexia.

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