Skin toxicity – Grade 2-4
May 11, 2025Hepatitis – Grade 2
May 11, 2025Hepatitis
Definitions
- Immune-mediated hepatitis should be suspected if liver function tests become elevated between 4 weeks after the initiation of immunotherapy and up to 12 months after the last dose.
- Clinical presentation: mucocutaneous jaundice, nausea and/or vomiting, right upper quadrant pain, loss of appetite, fatigue, dark urine, and spontaneous bleeding or bruising, or bleeding/bruising occurring without significant trauma.
- Severe acute hepatitis is defined by hepatic cytolysis associated with a PT <50%, without any alteration in consciousness.
- Fulminant acute hepatitis is defined by a PT or factor V <50% and the onset of hepatic encephalopathy within 2 weeks after the onset of jaundice
- Subfulminant acute hepatitis is defined by a PT or factor V <50% and the onset of hepatic encephalopathy between 2 weeks and 3 months after the onset of jaundice
- Risk Factors for Hepatotoxicity :
- Pre-existing chronic liver disease
- Hepatic malignancies
- High-dose anti-PD-(L)1 therapy
- Concomitant use of hepatotoxic drugs (statins, paracetamol/acetaminophen, etc.)
- Underlying autoimmune liver disease
Anamnesis
-
Review medications: e.g. statins, antibiotics, alcohol history and alternative medicines (herbs)
Blood sample
- Hepatitis A/B/C, CMV and EBV serologies
- Consider:
- Hepatitis E PCR
- Anti-ANA/SMA/LKM/SLA/LP/LCI
- Iron state
Imagery
- Exclude metastases, biliary lesions and portal thrombosis (US or CT)
- If a cholestatic pattern is present, consider MRCP (magnetic resonance cholangiopancreatography).
R ratio
-
The immune-mediated hepatotoxicity profile is defined by the ratio between serum ALT and ALP levels, normalized to their respective ULN
- R ratio = (ALT / ALT ULN) / (ALP / ALP ULN)
- R ratio :
- ≥ 5 : Hepatocellular pattern
- 2-5 : mixte profile
- ≤ 2 : cholestatic
Grade 1
-
ALT <3x ULN
-
Total bilirubin <1.5x ULN
Grade 2
-
ALT or AST 3 – 5x ULN
-
Total bilirubin 1.5-3x ULN
Grade 3
- ALT or AST 5 – 20x ULN
-
Total bilirubin 3-10x ULN
Grade 4
- ALT >20x ULN
- Total bilirubin >10x ULN
Rechallenge
- We suggest permanent discontinuation of ICIs in the event of grade 3–4 toxicity
- ICI rechallenge may be considered once liver test values have returned to grade 1 at least
- Consider prophylactic treatment with ursodeoxycholic acid (UDCA) when rechallenging with the same agent, after liver toxicity has returned to grade 1, in patients with a cholestatic pattern
- Consider switching ICI class: from anti-CTLA-4 to anti-PD-(L)1 (rechallenge with an anti-CTLA-4 antibody in a patient who has previously experienced anti-PD-1-induced hepatotoxicity has been associated with the development of fulminant hepatitis, the reverse does not appear to be true)