Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes
Journal
Histopathology
Journal Volume
76
Journal Issue
3
Pages
470-480
Date Issued
2020
Author(s)
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, K?pffer 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. ? 2019 John Wiley & Sons Ltd
Subjects
atezolizumab; cholangitis; hepatitis; liver biopsy; pembrolizumab
SDGs
Other Subjects
antinuclear antibody; atezolizumab; immunoglobulin G; ipilimumab; nivolumab; pembrolizumab; prednisolone; antineoplastic agent; atezolizumab; monoclonal antibody; pembrolizumab; abdominal pain; adult; advanced cancer; aged; antibody detection; antibody titer; Article; autoimmune hepatitis; autoimmune hypophysitis; bile duct disease; CD4 CD8 ratio; cell aggregation; cell death; cell hyperplasia; cell infiltration; cholestasis; clinical article; clinical feature; colon cancer; drug substitution; drug withdrawal; eosinophil; fatigue; female; fever; hepatitis; hepatobiliary disease; hepatobiliary system; histology; human; human tissue; immunoglobulin blood level; immunohistochemistry; jaundice; Kupffer cell; liver biopsy; liver function; liver injury; loss of appetite; malaise; male; melanoma; merkel cell carcinoma; non small cell lung cancer; pancreatitis; priority journal; rash; sclerosing cholangitis; side effect; steroid therapy; transitional cell carcinoma; vomiting; weakness; biopsy; cholangitis; cohort analysis; digestive system disease; drug effect; hepatitis; liver; liver disease; middle aged; pathology; toxic hepatitis; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholangitis; Cohort Studies; Digestive System Diseases; Female; Hepatitis; Humans; Immunohistochemistry; Liver; Liver Diseases; Male; Middle Aged
Publisher
Blackwell Publishing Ltd
Type
journal article