Imaging: ultrasound or CT scan imaging can evaluate progression of hepatic metastasis and possible biliary obstruction. Hyperprogressive disease where in accelerated progression in an otherwise slowly progressive disease occurs after starting checkpoint inhibitors has been observed in up to 9% of patients on anti-PD-1/PD-L1 drugs and should be considered in the differential (20).

Biopsy: liver biopsy can help differentiate between various etiologies of hepatocyte damage. Individual patient circumstances, including the results of laboratory and imaging findings listed above, can drive the decision of when to proceed with a biopsy. Early tissue biopsy can help differentiate between various etiologies of hepatitis but there is significant overlap between features of autoimmune hepatitis and checkpoint inhibitor related injury. The treatment of suspected immune related hepatitis should not be delayed for tissue confirmation and it should be recognized that these may mask features of immune related injury.

Liver biopsy should be strongly considered in patients with negative viral hepatitis serologies who have persistent grade 2 hepatotoxicity despite 3–4 days of adequate steroid therapy, and in patients with grade 3 and 4 toxicity. Clinicians should tailor their testing to balance the risk and cost of biopsy with additional yield of clinically relevant information.

Treatment

Treatment with checkpoint inhibitors should be interrupted for AST/ALT elevations between 2 and 5 times ULN, and permanently discontinued for elevations greater than 5 times ULN (1,21,22).

Prompt treatment of suspected checkpoint-inhibitor related immune hepatotoxicity is critical to ensure patient safety. Patients with elevation between 5–10 times ULN of AST/ALT and negative viral serology, should start treatment with oral prednisone 1–2 mg/kg/day PO and monitored with frequent blood testing. Treatment with IV methylprednisolone 2–3 mg/kg/day should be considered if there is no improvement in 3–5 days. Treatment with Mycophenylate mofetil can be added after 3–5 days of maximal steroid treatment if no improvement is seen.

Patients with (I) continually rising AST/ALT levels despite adequate oral prednisone therapy, or (II) those that increase to >10× ULN (with or without bilirubin elevation >5× ULN) should be admitted to the inpatient setting. IV Methylprednisolone 4 mg/kg/day should be started emergently, a Hepatology consult should be obtained and a liver biopsy considered. LFTs should be monitored daily until AST/ALT falls to <8× ULN. Mycophenylate mofetil 1 g twice daily should be started if the LFT’s don’t respond to IV corticosteroids after 2 days. Refractory immune related toxicity that does not responded to IV steroids and Mycophenylate has been reported to respond to antithymocyte globulin therapy (23). Of note, Infliximab, which is usually used in severe autoimmune adverse reactions, should be avoided in autoimmune hepatitis as it is hepatotoxic.

A slow taper of the steroid dose over no less than 4 weeks can be started once hepatitis begins to improve. Pneumocystis carinii prophylaxis should be considered for patients receiving prednisone equivalent of 20 mg or more daily for 4 weeks or more (24). Of note, hepatitis can recur even after discontinuation of checkpoint inhibitors and some patients require repeated courses of steroids.

Restarting checkpoint inhibitors: The decision to restart checkpoint inhibitor after an episode of suspected treatment related hepatotoxicity depends on the degree of hepatocyte damage and duration of toxicity. Restarting checkpoint inhibitor therapy is not recommended for patients (I) with peak AST/ALT elevation of >5× ULN, (II) whose levels do not improve to grade 1/baseline, and (III) who show signs of liver decompensation such as increasing INR. For patients with peak elevation between 2 and 5× ULN, restarting checkpoint inhibitors can be considered if levels return to baseline/grade 1 and individual package insert guidelines should be followed.