Hepatobiliary and Pancreatic Adverse Events

Abstract

The expanded approval of immune checkpoint inhibitors (ICIs) for the treatment of multiple cancer types has offered patients more opportunities in treatment selection and survival.

Hepatotoxicity is a well-recognized immune-related adverse event (irAE) associated with treatment with ICI. It is considered a type of drug-induced liver injury (DILI). Depending on the specific ICI and whether the patient receives single- or dual-drug therapy, the incidence of hepatotoxicity in general could be as high as 30%. As more patients receive treatment with ICI, more cases of hepatotoxicity are expected to occur. Clinicians must exercise close pharmacovigilance to recognize liver-related irAEs early.

ICI-mediated hepatobiliary toxicity (or “IMH”) generally presents as asymptomatic elevations of alanine transaminase and aspartate transaminase, with or without alkaline phosphatase elevation. Some patients may present with jaundice, fever, or malaise. Rarely, it may cause liver failure and death. The diagnosis of IMH is made after careful exclusion of other causes of acute hepatitis based on medical history, laboratory evaluation, imaging, and liver histological findings. In clinically significant cases of IMH, the management involves discontinuation of ICI followed by close monitoring and the initiation of immunosuppression. Current society guidelines, which are not based on robust evidence, specify treatment recommendations depending on the grade of liver injury, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. However, our clinical experience suggests possible alternatives, including lower corticosteroid dosing with adjunct therapies. Whereas current guidelines endorse permanent cessation of future ICI treatment in patients diagnosed with grades 3–4 IMH, published clinical experience suggests potential for flexibility when assessing for candidacy of resuming ICI.

Because histologic bile duct injury has been observed in cases ascribed to IMH, ICI-mediated cholangiopathic disease probably exists on a spectrum within IMH. Even extrahepatic bile duct involvement has been observed. This phenotype warrants special considerations in treatment and surveillance.

ICI-related cholecystitis has been rarely reported in the literature. Management follows current standards of care for typical cases of cholecystitis. No relationship with ICI-mediated cholangiopathic disease has been observed.

Assessing for and managing ICI-associated pancreatic injury remain challenging to the clinician. Many cases of asymptomatic serum lipase elevation are detected on routine labs without clinical signs or symptoms of typical acute pancreatitis. However, symptomatic patients should be initially managed like traditional cases of acute pancreatitis requiring hospitalization for evaluation and inpatient management.