Immune checkpoint inhibitor-related hepatotoxicity: A review

Table 2 Differential diagnosis and suggested investigations

System	Differential diagnosis	Investigations
Drug-induced liver injury	(1) Other co-administered anti-cancer drugs; (2) Alcohol related liver disease; and (3) Acetaminophen toxicity	Medication history
Tumor-related	Metastatic disease	Abdominal imaging with ultrasound, CT or MRCP
Infectious	(1) Sepsis; (2) Acute HAV infection; (3) Acute HBV or flare of chronic HBV; (4) Chronic HCV; (5) Acute HEV; (6) Acute CMV or reactivation; and (7) Acute EBV	(1) Septic screen as appropriate; (2) Anti-HAV (IgM); (3) HBsAg, Anti-HBc IgG, IgM, ± HBV DNA; (4) Anti-HCV ± HCV RNA; (5) Anti-HEV (IgM); (6) CMV IgM and IgG ± CMV DNA; and (7) EBV IgM and IgG
Biliary disease	(1) Cholecystitis; (2) Cholangitis; and (3) Pancreatitis	(1) Abdominal imaging; and (2) Serum lipase
Autoimmune	Autoimmune hepatitis1	ANA, Anti-SMA, Anti-LKM1, serum IgG levels
Musculoskeletal	(1) Myositis (potentially an irAEs); and (2) Rhabdomyolysis	Serum CK
Metabolic	Underlying NASH	(1) Metabolic risk factors; and (2) Abdominal imaging for hepatic steatosis
Vascular	(1) Portal-vein/hepatic vein thrombosis; and (2) Ischemic hepatitis	Abdominal imaging and clinical history

¹Although anti-nuclear antibodies is frequently positive at low-titres in IC (< 1:80), specific auto-antibodies seen in autoimmune hepatitis are usually negative.

ANA: Anti-nuclear antibodies; Anti-HBc: Anti-Hepatitis B core antibody; anti-LKM1: Anti-liver-kidney microsomal 1 antibody; Anti-SMA: Anti-smooth muscle antibody; CK: Creatine kinase; CMV: Cytomegalovirus; CT: Computed tomography; EBV: Epstein-Barr virus; HAV: Hepatitis A virus; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; irAEs: Immune-related adverse events; MRCP: Magnetic resonance cholangiopancreatography; NASH: Non-alcoholic steatohepatitis.