Yoh Zen1,2, Yen-Ying Chen3,4, Yung-Ming Jeng5, Hung-Wen Tsai6, Matthew M Yeh7,8. 1. Institute of Liver Studies, King's College Hospital and King's College London, London, UK. 2. Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan. 3. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 4. School of Medicine, National Yang-Ming University, Taipei, Taiwan. 5. Department of Pathology, National Taiwan University, Taipei, Taiwan. 6. Department of Pathology, National Cheng-Kung University, Tainan, Taiwan. 7. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. 8. Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Abstract
AIMS: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab. METHODS AND RESULTS: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+ /CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis. CONCLUSIONS: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.
AIMS: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab. METHODS AND RESULTS: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+ /CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis. CONCLUSIONS:Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.