Table 2.

Management recommendations for hepatic adverse events.

Diarrhea or Colitis Grade (CTCAE version 5.0)	Laboratory testing*	Imaging	Endoscopy	Initial Treatment	Management of first line treatment failure
1	Increase frequency of liver testing (ALT, AST, ALKP. TBILI, DILI] to weekly or twice weekly	None recommended	Obtain history of alcohol exposure, new medications, and herbal supplement use	Stop potentially hepatotoxic concomitant medications and supplements, advise against alcohol use	N/A
2	Twice weekly liver testing Hepatitis A IgM and IgG, Hepatitis B core antibody, surface antibody, surface antigen; Hepatitis C antibody; EBV and CMV serologies (IgM/IgG) ANA, ASMA, AMA, iron, TIBC, ferritin Consider ceruloplasmin and A1AT	Right upper quadrant ultrasound with vascular flow measurement Consider MRCP and or EUS if predominantly ALKP/TBILI elevation Consider cross sectional Imaging for patients with abdominal malignancies or with hepatic etastases hepatic metastases	History as for grade 1 Consider liver biopsy	0.5 – 1 mg/kg daily prednisone or prednisone equivalent Hold immunotherapy until resolution to grade 1 or less	Liver biopsy if not already obtained Start secondary immune suppression with one of the following: Azathioprine 1–2 mg/kg daily, mycophenolate mofitll 500–1000 mg BID, tacrolimus (goal level 8–10 ng/ mL or lower if early response
3	As for grade 2 with daily or every other day liver tests	As for grade 2	History as for grade 1 Liver biopsy to confirm diagnosis	0.5 – 2 mg/kg BID prednisone or prednisone equivalent Discontinus immunotherapy	Start secondary immune suppression with one of the following: Azathioprine 1–2 mg/kg daily, mycophenolate mofitil 500–1000 mg BID, tacrolimus (goal level 8–10 ng/ mL or lower if early response Triple therapy may be considered in refractory cases
4	As for grade 2 with daily liver tests Check acetaminophen level	As for grade 2	As for grade 3	0.5 – 2 mg/kg BID prednisone or prednisone equivalent Consider hospitalization for IV steroids and close monitoring Discontinus immunotherapy	Start secondary immune suppression with one of the following: Azathioprine 1–2 mg/kg daily, mycophenolate mofitll 500–1000 mg BID, tacrolimus (goal level 8–10 ng/ mL or lower if early response Triple therapy may be considered in refractory cases Antithymocyte globulin may be considered in rapidly progressing hepatitis

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALKP: alkaline phosphatase; TBILI: total bilirubin; DBILI: direct bilirubin; IgM: immunoglobulin M; IgG: immunoglobulin G; Epstein-Barr Virus (EBV); cytomegalovirus (CMV); ANA: antinuclear antibody; ASMA: anti-smooth muscle antibody; AMA: anti-mitochondrial antibody; TIBC: total iron binding capacity; A1AT: alpha-1 anti-trypsin; MRCP: magnetic resonance cholangiopancreatography; EUS: endoscopic ultrasound.