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Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes
Author(s) -
Zen Yoh,
Chen YenYing,
Jeng YungMing,
Tsai HungWen,
Yeh Matthew M
Publication year - 2020
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.14000
Subject(s) - medicine , pembrolizumab , primary sclerosing cholangitis , autoimmune hepatitis , gastroenterology , cholestasis , hepatitis , liver biopsy , pathology , liver injury , biopsy , immunotherapy , cancer , disease
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.