From the Guidelines
Immune checkpoint inhibitor (ICI) hepatitis should be managed based on severity, with grade 1 requiring monitoring, grade 2 requiring temporary withholding of ICI therapy and initiation of prednisone 0.5-1 mg/kg/day, and grade 3-4 requiring permanent discontinuation of ICI therapy and initiation of prednisone 1-2 mg/kg/day. The diagnosis of ICI-induced hepatitis is based on liver chemistry tests, including AST/ALT and total bilirubin levels, and clinical symptoms such as liver toxicity 1.
Management of ICI Hepatitis
- For patients with grade 1 hepatitis (AST/ALT 1–3 the upper limit of normal [ULN] or total bilirubin 1–1.5 ULN), more frequent monitoring of liver chemistries with once or twice weekly blood draws is suggested, with or without a delay in ICI dosing 1.
- For patients with probable or confirmed grade 2 ICI hepatitis (AST/ALT >3–5 ULN or total bilirubin >1.5–3 ULN), holding ICI treatment is suggested, and consultation with a gastroenterologist or hepatologist with expertise in the management of ICI hepatitis should be considered 1.
- For patients with clinical symptoms of liver toxicity, prednisone 0.5–1.0 mg/kg/d or equivalent may be administered, and ICI may be resumed if and when the patient recovers to grade 1 hepatitis with a steroid dose of 10 mg of prednisone or equivalent daily 1.
Treatment of ICI Hepatitis
- Systemic glucocorticoids represent the primary treatment for patients whose liver chemistries do not resolve spontaneously and/or require a delay in ICI dosing 1.
- For patients with probable or confirmed grade 3 ICI hepatitis (AST/ALT >5–20 ULN or total bilirubin >3–10 ULN), ICI therapy should be discontinued and urgent consultation with a gastroenterologist/hepatologist is appropriate 1.
- Glucocorticoids are generally initiated at a dose of 1–2 mg/kg methylprednisolone or equivalent with a planned 4- to 6-week taper, although these doses were empirically determined and have not been rigorously examined 1.
- Second-line immunomodulators, such as azathioprine, mycophenolate mofetil, or tacrolimus, may be considered in patients who do not respond to glucocorticoids within 3–5 days, or who have hepatitis flare during steroid taper 1.
Monitoring and Follow-up
- Regular liver function monitoring (every 1-2 weeks during early treatment) is essential for early detection, as many patients are asymptomatic until advanced liver injury occurs 1.
- In patients who resume ICI treatment after resolution of ICI hepatitis, it is recommended to monitor liver tests at least weekly for the first 2 months and every 2 weeks for the 3rd month 1.
From the Research
Diagnosis of ICI-Induced Hepatitis
- ICI-induced hepatitis is a diagnosis of exclusion, made after other etiologies are excluded based on medical history, laboratory evaluation, and imaging and histological findings 2
- Liver biopsy may help identify the exact cause of hepatitis, especially when it is difficult to determine whether the hepatitis is caused by ICIs or chemotherapy 3
- Diagnostic testing such as viral serologies, liver ultrasound, cross-sectional imaging, and liver biopsy may help in the diagnosis of immune-related hepatitis in select patients 4
Treatment of ICI-Induced Hepatitis
- ICI-induced hepatitis might require discontinuation of ICI and/or treatment with immunosuppressants 2
- When drug-induced hepatitis is suspected, clinicians should actively perform liver biopsy to confirm the diagnosis, so that an appropriate therapeutic regimen can be administered 3
- Most patients with immune-related hepatitis respond to corticosteroids, but a substantial fraction require treatment with a secondary immunosuppressive agent 4
- Severe immune-related hepatitis is best managed by a multi-disciplinary team that includes a hepatologist 4
- In some cases, triple concurrent immunosuppression with prednisolone, mycofenolate mofetil, and tacrolimus may be required to resolve liver toxicity 5
- The management of irAEs is based on the temporary or permanent discontinuation of the ICI and (for grade ≥ 2 events) the administration of steroids 6