Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury

Abstract

IntroductionHepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity.MethodsHere we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents.ResultsWe find that a major feature of these cases is biliary injury, including a unique case of vanishing bile duct syndrome, and that such toxicity was poorly responsive to long-term immunosuppression (corticosteroids and mycophenolate mofetil). Any potential benefits of long-term immunosuppression in these cases were outweighed by therapy-related complications.DiscussionWe discuss potential aetiologies and risk factors for immune-mediated biliary toxicity in the context of the limited literature in this field, and provide guidance for the investigation and supportive management of affected patients.

Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation?

“…Hepatocellular injury secondary to immune checkpoint inhibitors (eg, ipilimumab and nivolumab) are not usually accompanied by positive autoantibodies, yet they respond to corticosteroids and have other features of autoimmunity. (19)(20)(21)(22)(23)(24)(25) Similar findings can be found with infliximab and adalimumab. (26,27) With ipilimumab-induced hepatitis, when a course of corticosteroids has failed, additional immunosuppression may be required with, eg, antithymocyte globulin or mycophenolate mofetil (MMF).…”

Antiprogrammed Cell Death‐1 Immunotherapy‐Related Secondary Sclerosing Cholangitis

“…Cholangitic liver diseases have also been reported, although rare. (2) These cases include avelumab (3) and nivolumab (4,5) related cholangitis, which present similar images ( Fig. 1) and patterns of CD8-positive T-cell infiltration into the bile duct ( Fig.…”

“…However, further studies are necessary to establish the optimal management of patients with this immunotherapy-related SSC. (2,4) These findings suggest that the possibility of SSC should be considered when administering immune checkpoint inhibitors to patients.…”

“…2B) as in our case, which resulted in immune-related cholangitis and a cholestatic pattern of liver injury. (1)(2)(3)(4)(5) Inflammation and destruction of the bile duct can result in SSC and lead to chronic cholestasis. (3,4) This study reports on a patient with pembrolizumab-induced SSC.…”

Secondary sclerosing cholangitis with hemobilia induced by pembrolizumab: Case report and review of published work

“…Among irAEs, cholangitis is rare and its clinicopathological features and management remain unclear. There are some reports about nivolumab‐related cholangitis that describe its imaging and clinicopathological features . Ogawa et al .…”