Immune checkpoint inhibitor-related hepatotoxicity: A review

Table 3 Comparison of common grading systems for inhibitor-related hepatotoxicity

	Grade
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
CTCAE[87]	(1) Asymptomatic; (2) AST or ALT > 1-3 × more than ULN; and (3) T. Bil > 1-1.5 × more than ULN	(1) Asymptomatic; (2) AST or ALT > 3-5 × more than ULN; and (3) T. Bil > 1.5-3 × more than ULN	(1) Symptomatic liver dysfunction; (2) Fibrosis on biopsy; (3) Compensated cirrhosis; (4) Reactivation of chronic hepatitis; (5) AST or ALT > 5-20 × more than ULN; and (6) T. Bil > 3-10 × more than ULN	(1) Decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma); (2) AST or ALT > 20 × more than ULN; and (3) T. Bil > 10 × more than ULN	Death due to hepatotoxicity
DILIN[73]	(1) Elevations in serum ALT and/or ALP levels; (2) T. Bil < 2.5 ULN; (3) INR < 1.5; and (4) Present with or without symptoms (fatigue, asthenia, nausea, anorexia, RUQ pain, jaundice, pruritus, rashes, or weight loss)	(1) Elevated serum ALT and/or ALP; (2) T. Bil ≥ 2.5 ULN or INR ≥ 1.5; and (3) Symptoms may become aggravated	(1) Elevated serum ALT and/or ALP; (2) T. Bil ≥ 5 ULN ± INR ≥ 1.5; (3) Symptoms are further aggravated; (4) Indication for hospitalization; and (5) No evidence of hepatic encephalopathy	(1) Coagulation abnormality indicated by INR ≥ 1.5; (2) Signs of hepatic encephalopathy; (3) T. Bil ≥ 10 ULN or daily elevation ≥ 1.0 mg/dL in 26 wk after the DILI onset; and (4) Ascites and DILI-related dysfunction of another organ	(1) Death due to DILI; and (2) Or need to receive liver transplantation for survival

ALT: Alanine Aminotransferase; AST: Aspartate aminotransferase; CTCAE: Common terminology criteria for adverse events; DILI: Drug induced liver injury; DILIN: Drug-induced Liver Injury Network; ICH: Immune checkpoint inhibitor-induced hepatoxicity; INR: International normalized ratio; RUQ: Right upper quadrant; T. Bil: Total bilirubin; ULN: Upper limit of normal.