Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes

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.

Comparison of Clinical Features between Immune-Related Sclerosing Cholangitis and Hepatitis

“…Anti-CTLA-4 inhibitors might modulate the Treg signaling pathway, inducing irHepatitis with endotheliitis. While PD-1/L-1 inhibitors causes in ammation with a high rate of CD8 + /CD4 + cells, which is a pathological feature of immune-related adverse event in the hepatobiliary system [24]. The CD8 + cells associate with sclerosing cholangitis by producing interferon gamma [25].…”

A case of large-cell lung carcinoma successfully treated with pembrolizumab but complicated with cholangitis

“…To our knowledge, 10 cases of pembrolizumab-related cholangitis have been reported in the English literature ( Table 1 ) [ [16] , [17] , [18] , [19] , [20] , [21] , [22] ]. The underlying malignancies were melanoma/NSCLC/mesothelioma/bladder cancer in 2/5/1/2 cases, respectively.…”

Pembrolizumab‐induced secondary sclerosing cholangitis in a non‐small cell lung cancer patient

“…However, they can cause irAEs . Cholangitis is a rare irAE and four cases of pembrolizumab‐induced SSC in NSCLC patients have been reported .…”

“…Anti‐PD‐1 antibody‐related cholangitis was mainly reported in NSCLC patients receiving nivolumab (Table ) . Nivolumab‐related cholangitis was characterized by (1) extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) increase in the biliary enzymes ALP and GGT relative to the hepatic enzymes AST and ALT; (4) absence of the serum immunological markers ANA, AMA, anti‐smooth muscle antibody, and IgG4; (5) CD8 + T cell infiltration in the portal area by liver biopsy; and (6) a moderate‐to‐poor response to steroid therapy .…”