Assessment and Investigations:

• Review medications: e.g. statins, antibiotics, alcohol history and alternative medicines (herbs)
• Perform liver screen: – Hepatitis A/B/C serology – Hepatitis E PCR – Anti-ANA/SMA/LKM/SLA/LP/LCI – Iron studies
• Consider imaging for metastases/portal trombosis

Management:

• Symptoms Grade I, ALT or AST > ULN – 3x ULN, Bilirubin normal (or unchanged to baseline)
  Management escalation pathway
  • Continue ICPI
  • If bilirubin is increasing or in case of doubt: postpone 1 week:
  • Assessment:
    • if hereafter it remains stable or lowers: ICPI can be restarted
    • if hereafter it becomes grade II either for AST, ALT or bilirubin: perform serology and imagery to exclude other causes

• Symptoms Grade II, ALT or AST 3 – 5x ULN, Bilirubin < 3x ULN
  Management escalation pathway
  • Withhold ICPI treatment until normalisation of ALT/AST to grade I
  • If rising ALT/AST when re-checked wait until normalisation unless grade III or bilirubin increases: start methylprednisolone 1mg/kg (https://www.ncbi.nlm.nih.gov/pubmed/29427729)
  • Assessment:
    • Re-check LFTs/INR/albumin every 3 days
    • Review medications, e.g. statins, antibiotics and alcohol history
    • Perform liver screen: – Hepatitis A/B/C serology – Hepatitis E PCR – Anti-ANA/SMA/LKM/SLA/LP/LCI – Iron studie
    • Consider imaging for metastases/portal trombosis

    
    

• Symptoms Grade III, ALT or AST 5 – 20x ULN, Bilirubin > 3x ULN
  Management escalation pathway
  • Suspend ICPI
  • If ALT/AST < 10 x ULN and normal bilirubin/INR/albumin: wait and see (https://www.ncbi.nlm.nih.gov/pubmed/29427729)
  • If bilirubin > 3ULN or if patient was treated with anti-CTLA4/anti-PD(L)1 treatment: oral prednisolone 1 mg/kg
  • Low threshold to admit if clinical concern (hypoglycaemia, increasing bilirubin, lowering INR or albumin) treat intravenously: i.v. (methyl)prednisolone 2 mg/kg
  • Assessment:
    • Daily LFTs/INR/albumin
    • Perform US with Doppler with liver biopsy if no bleeding diathesis (should be discussed with specialised anatomopathologist)
    • If refractory after 3 days to corticoids or bleeding diathesis: consult hepatologist

    
    

• Symptoms Grade IV,  ALT or AST > 20x ULN, Bilirubin >10x ULN
  Management escalation pathway
  • Suspend ICPI
  • If bilirubin < 3ULN: oral prednisolone 1 mg/kg
  • If bilirubin > 3ULN or one of the following hypoglycaemia, increasing bilirubin, lowering INR or albumin: admit patient treat intravenously: i.v. (methyl)prednisolone 2 mg/kg
  • Assessment:
    • Daily LFTs/INR/albumin
    • Perform US with Doppler with liver biopsy if no bleeding diasthesis (should be discussed with specialised anatomopathologist)
    • If refractory after 3 days to corticoids or bleeding diasthesis: consult hepatologist
  • Worsening despite steroids:

    – If on oral change to i.v. (methyl)prednisolone

    – If on i.v. add MMF 500-1000 mg b.d. after discussion with hepatologist

• Grade II: once Grade I, wean over 2 weeks; re-escalate if worsening; treatment may be resumed once prednisolone < 10 mg
• Grade III/ IV: once improved to Grade II, can change to oral prednisolone and wean over 4 weeks
• Only resume ICPI if steroids are fully tapered; ideally this is discussed at a multidisciplinary meeting

• If on oral change to i.v. (methyl)prednisolone
  • If on i.v. add MMF 500-1000 mg b.d.
    • If worse on MMF, consider addition of tacrolimus

• A case report has described the use of anti-thymocyte globulin in steroid + MMF-refractory fulminant hepatitis