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Histologic patterns of liver injury induced by anti-PD-1 therapy
Dongwei Zhang1,2, John Hart3, Xianzhong Ding4
1Department of Pathology, Immunology and Laboratory of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Background:
Nivolumab and pembrolizumab-two monoclonal antibodies that block human programmed cell death-1 (PD-1)-have been successfully used to treat patients with multiple advanced malignancies. The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied and the aim of this study was to explore them.
Methods:
Eight patients with advanced malignancies who were treated with either nivolumab or pembrolizumab were identified from five institutions. These patients had no history of underlying liver disease and a viral hepatitis panel was negative in all patients.
Results:
Seven of eight patients exhibited mild to moderate gastrointestinal symptoms such as abdominal pain, fatigue, nausea, vomiting, and jaundice after anti-PD-1 treatment. Significant elevations in liver-chemistry tests were detected in all patients. Six cases (6/8) demonstrated an acute lobular hepatitis pattern of histologic injury. The remaining two cases showed different histologic patterns of injury: steatohepatitis with mild cholestasis (1/8) and pure acute cholestatic injury (1/8). No case showed typical features of autoimmune hepatitis. The liver function recovered in all eight cases after cessation of anti-PD-1 agents and with immunosuppressive therapy.
Conclusions:
Our study suggests that screening patients for abnormal liver-function tests prior to anti-PD-1 therapy as well as periodic monitoring of liver-function tests are necessary to prevent severe liver injury. Rather than causing classical autoimmune hepatitis, PD-1 inhibitors appear to produce an immune-mediated nonspecific acute hepatitis. Drug cessation, without steroid therapy, may therefore be sufficient in some patients.
Insights
Programmed cell death-1 (PD-1) inhibitors like nivolumab and pembrolizumab can cause liver injury. This study found PD-1 inhibitors induce nonspecific acute hepatitis, not autoimmune hepatitis, necessitating liver function monitoring during treatment.
Area of Science:
- Oncology
- Immunology
- Hepatology
Background:
- Nivolumab and pembrolizumab are monoclonal antibodies targeting programmed cell death-1 (PD-1).
- These agents are used in treating various advanced cancers.
- Histologic patterns of PD-1 inhibitor-induced liver toxicity are not well-characterized.
Purpose of the Study:
- To investigate the histologic patterns of liver injury associated with anti-PD-1 therapy.
- To understand the spectrum of hepatic toxicity from PD-1 inhibitors.
Main Methods:
- Retrospective review of eight patients with advanced malignancies treated with nivolumab or pembrolizumab.
- Exclusion of patients with pre-existing liver disease or viral hepatitis.
- Histopathologic examination of liver biopsies.
Main Results:
- Seven of eight patients developed mild to moderate gastrointestinal symptoms and elevated liver enzymes.
- The predominant histologic pattern was acute lobular hepatitis (6/8 cases).
- Other patterns included steatohepatitis with cholestasis (1/8) and pure acute cholestatic injury (1/8); no cases showed autoimmune hepatitis features.
Conclusions:
- PD-1 inhibitors can cause immune-mediated nonspecific acute hepatitis, distinct from autoimmune hepatitis.
- Monitoring liver function tests before and during anti-PD-1 therapy is crucial.
- Discontinuation of the drug may be sufficient for recovery, potentially without steroid use.
