Work up of suspected checkpoint inhibitor related autoimmune hepatitis

Baseline testing: viral hepatitis serologies, transaminase levels (ALT and AST) and bilirubin should be tested prior to starting therapy with checkpoint inhibitors. Viral hepatitis serology include Hepatitis-B virus (HBV) surface Antigen (HBsAg), Hepatitis-B core antibody (HBcAb) and Hepatitis C virus (HCV) antibody. A positive HBsAg or HBcAb serology should prompt checking HBV DNA and a positive HCV antibody should be followed by HCV RNA levels. Clinicians should obtain hepatology consultation for all patients with positive viral serology to consider viral hepatitis treatment either prior to, or concurrently with, checkpoint inhibitors. The decision to treat viral hepatitis will depend on the viral load, liver enzymes, and underlying liver condition. An ‘HBcAb positive/HBV DNA negative’ panel suggests prior exposure to HBV and although the rate of potential HBV reactivation is low, it should be considered as the patient undergoes therapy.

Monitoring on therapy: clinicians should have a low threshold to work up suspected drug related hepatotoxicity to differentiate checkpoint inhibitor-induced immune related toxicity from other causes of hepatocyte damage. These include the effect of concurrent or prior treatments, underlying malignancy, infection or inflammation. In patients with known HBV or HCV infection, isolated increases in transaminases, particularly ALT, could be from activation of the immune system leading to increased immune response to HCV or HBV and subsequent decrease in viral load. There has been concern that immune modulation from checkpoint inhibitors could lead to an increase in viral replication.

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Transaminase (ALT and AST) and bilirubin levels should be checked prior to each dose of therapy. An increase of ALT or AST of more than 2 times the upper limit of normal (ULN) should prompt work up of hepatotoxicity (Figure 1). Medication reconciliation including evaluation for alternative therapy/herbal medications should be performed and hepatotoxic drugs discontinued. Workup should include basic viral hepatitis serologies (HAV, HBV, and HCV) depending on baseline serologies and immune status. Additional workup should include antinuclear antibodies (ANA), smooth muscle antibody (SMA), Epstein Barr virus (EBV) IgM, cytomegalovirus (CMV) PCR depending on the clinical context and possible preexisting liver dysfunction.

(To view a larger version of Figure 1, click here.)