Abstract
It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immune-related liver damage. We should focus on the programmed cell death-receptor-1 (PD-1) antibody and non-small cell lung cancer (NSCLC) to analyze the characteristics of hepatitis related to iCIs and find factors that could be useful biomarkers for the diagnosis. A single-center retrospective study of 252 NSCLC patients who received PD-1 antibody (nivolumab or pembrolizumab). Some of the biochemical markers and immunological markers were analyzed during PD-1-antibody treatment with or without ALT elevation. Histopathological features were reviewed by a single expert of hepatic pathology focusing on the following features: fibrosis, portal inflammation, lobular inflammation, lobular necrosis. The formation of macro- and micro-granulomas was also evaluated. The frequency of liver damage induced by nivolumab including grade 1 to 4 (ALT) was 41.9% (78/186 patients). The positive rate of anti-nuclear antibody in the nivolumab group with iCIs-related hepatitis was significantly higher than that in the nivolumab group without iCIs-related hepatitis (p = 0.00112). Granulomatous changes were significantly increased in patients with iCIs-related hepatitis compared with DILI and AIH patients (p < 0.05). The ratios of inflammatory cells CD4/CD8, and CD138/CD3 in ICIs-related hepatitis were significantly lower than those in AIH or DILI patients (p < 0.05). We demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis in the NSCLC with anti-PD-1 therapy.
Highlights
It has been reported that various kinds of immune checkpoint inhibitors could induce immunerelated liver damage
Most patients with immune checkpoint inhibitors (iCIs)-related liver damage revealed the phenotype of hepatocyte injury
It is difficult to confirm the representative phenotypes of liver damage induced by iCI treatment since various kinds of iCIs and the origins of the tumor could affect the pathogenesis of iCIs-related liver damage
Summary
It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immunerelated liver damage. In addition to the histopathology of iCIs-related hepatitis, we should consider possible biomarkers that might predict hepatitis after using iCIs. It has been reported that auto-immune disorders such as paraneoplastic syndromes could be potential biomarkers for predicting immune-related liver injury induced by treatment with iCIs8. Immune-related liver diseases such as auto-immune hepatitis (AIH) and primary biliary cholangitis (PBC) could be exacerbated by using iCIs. an analysis of potential biomarkers to predict the onset of AIH or PBC such as anti-nuclear antibody (ANA) and anti-mitochondria antibody (AMA) might be useful for preventing liver injury induced by iCIs. Some groups including ours have reported that preexisting antibodies and rheumatoid factor were common among patients who developed irAEs1,9. We tried to identify possible biomarkers to detect iCIs-related hepatitis induced by PD-1 antibody in lung cancer patients by analyzing the histopathology of liver and serum markers
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