ICI-related hepatitis

ICI hepatitis · immune-mediated hepatitis · checkpoint-inhibitor hepatitis

ICI-related hepatitis is a relatively common immune-related adverse event affecting 2-10% of patients on anti-PD-1 monotherapy and 10-30% on combination ICI. Typically presents 6-14 weeks after ICI start as asymptomatic transaminase rise (hepatocellular pattern) or, less commonly, mixed / cholestatic pattern. Grade 3-4 (ALT/AST >5× ULN or >20× ULN) requires ICI hold ± systemic corticosteroids. ESMO and ASCO guidelines underpin a structured management framework with mycophenolate as second-line and infliximab specifically avoided (rare paradoxical hepatotoxicity).

CurrentLast reviewed 16 May 2026

Epidemiology

Incidence:
- Anti-PD-1 monotherapy: 2-10% (any grade); G3+ ~1-2%.
- Anti-CTLA-4 monotherapy (ipilimumab): 5-10%.
- Combination (ipilimumab + nivolumab): 10-30%; G3+ 10-15%.
Onset: typically 6-14 weeks; rare delayed onset months after ICI cessation.
Risk factors: combination ICI, pre-existing autoimmune liver disease, prior hepatitis B/C (usually safe with monitoring).

Clinical features

Usually asymptomatic transaminitis discovered on routine bloods.
Symptomatic cases: fatigue, anorexia, nausea, abdominal discomfort, jaundice (rare).
Hepatocellular pattern (ALT / AST > ALP) commonest; mixed and cholestatic also occur.
Acute liver failure rare but reported (especially with combination ICI).

CTCAE grading

Grade	ALT / AST	Bilirubin	Action
G1	<3× ULN	<1.5× ULN	Continue ICI; weekly monitoring.
G2	3-5× ULN	1.5-3× ULN	Hold ICI; weekly monitoring; consider prednisolone 0.5-1 mg/kg if persists.
G3	5-20× ULN	3-10× ULN	Hold ICI; prednisolone 1-2 mg/kg; admit; daily monitoring.
G4	>20× ULN	>10× ULN	Permanently discontinue ICI; IV methylprednisolone 2 mg/kg; admit / HDU.

Workup

Exclude alternative causes:
- Viral hepatitis (HBV, HCV, HEV, CMV, EBV) PCR / serology.
- Drug-induced liver injury (paracetamol, antibiotics, antifungals).
- Autoimmune liver disease: ANA, AMA, ASMA, anti-LKM, IgG.
- Liver metastasis (imaging — USS, MRI, CT).
- Biliary obstruction.
- Alcohol, NAFLD.
USS abdomen ± MRI / MRCP for cholestatic pattern.
Hepatology consultation for G3+.
Liver biopsy reserved for refractory / atypical / diagnostic uncertainty cases — typically not required.

Management

G1: continue ICI; weekly monitoring.
G2: hold ICI; if no resolution in 1-2 weeks → prednisolone 0.5-1 mg/kg/day; restart ICI when ≤G1.
G3:
- Hold ICI.
- Prednisolone 1-2 mg/kg/day with taper over 4-6 weeks.
- Hepatology consultation.
- If no improvement in 3-5 days → mycophenolate mofetil 500-1000 mg BD as second-line.
G4:
- Permanently discontinue ICI.
- IV methylprednisolone 2 mg/kg/day.
- Admit; hepatology / ICU as required.
- MMF as second-line if no response in 3-5 days.
- Consider tacrolimus.
AVOID infliximab — rare paradoxical hepatotoxicity reported in ICI hepatitis; use mycophenolate, tacrolimus or anti-thymocyte globulin instead.
Vedolizumab — emerging option (limited data).
Steroid taper over weeks; PPI gastric protection, calcium / vitamin D, infection screening as standard.
ICI rechallenge: case-by-case after G1-G2; permanently discontinue after G3-G4 with severe disease.

References

Haanen J et al. ESMO Clinical Practice Guideline for immune-related adverse events. Ann Oncol. 2022;33:1217-1238.

Schneider BJ et al. ASCO clinical practice guideline update: management of immune-related adverse events. J Clin Oncol. 2021;39:4073-4126.

Reynolds K et al. Immune-related hepatotoxicity from anti-PD-1/PD-L1 therapy: a comprehensive review. JHEP Reports. 2022;4:100460.

De Martin E et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181-1190.

British Society of Gastroenterology. UK practice guidelines on the management of ICI-related hepatitis. London: BSG; 2023.