Late hepatotoxicity after treatment for childhood cancer

Table 1 Grading of hepatotoxicity by the common terminology criteria of adverse events v5

Parameter/CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Alanine aminotransferase increased	> ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 3.0-5.0 × ULN ALT and/or AST > ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Alkaline phosphatase increased	> ULN - 2.5 × ULN if baseline was normal; 2.0-2.5 × baseline if baseline was abnormal	> 2.5-5.0 × ULN if baseline was normal; > 2.5-5.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Aspartate aminotransferase increased	> ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 3.0-5.0 × ULN if baseline was normal; > 3.0-5.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Blood bilirubin increased	> ULN - 1.5 × ULN if baseline was normal; > 1.0-1.5 × baseline if baseline was abnormal	> 1.5-3.0 × ULN if baseline was normal; > 1.5-3.0 × baseline if baseline was abnormal	> 3.0-10.0 × ULN if baseline was normal; > 3.0-10.0 × baseline if baseline was abnormal	> 10.0 × ULN if baseline was normal; > 10.0 × baseline if baseline was abnormal
Hepatic failure	–	–	Asterixis; mild encephalopathy; drug-induced liver injury; limiting self care ADL	Life-threatening consequences; moderate to severe encephalopathy; coma	Death
Hepatic necrosis				Life-threatening consequences; urgent invasive intervention indicated	Death

ADL: Activities of daily living; CTCAE: Common terminology criteria of adverse events; ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 2 Potential late hepatic adverse effects of childhood cancer therapy

Type of cancer treatment	Potential hepatic late effects	Recommended evaluation
Thiopurines	Hepatosplenomegaly, fibrosis	ALT, AST, GGT, ALP, bilirubin, platelets
Methotrexate	Uncommon, possible fibrosis and cirrhosis	ALT, AST, GGT, ALP, bilirubin
Dactinomycin	Uncommon, possible elevations in LFTs	ALT, AST, GGT, ALP, bilirubin
Busulfan	Persistent LFTs elevation, cholestasis, hepatic fibrosis, SOS	ALT, AST, GGT, ALP, bilirubin
Oxaliplatin and cisplatin	LFTs elevation, SOS	ALT, AST, GGT, ALP, bilirubin
Docetaxel	Hepatitis/steatohepatitis, transient LFTs elevation	ALT, AST, GGT, ALP, bilirubin
Etoposide	Uncommon, possible hepatitis/steatohepatitis	ALT, AST, GGT, ALP, bilirubin
	Cholestatic injury
Azathioprine	Hepatic fibrosis	ALT, AST, GGT, ALP, bilirubin
Cytarabine	SOS	ALT, AST, GGT, ALP, bilirubin
Cyclophosphamide and ifosfamide	Persistent LFTs elevation	ALT, AST, GGT, ALP, bilirubin
Anthracyclines	Uncommon	ALT, AST, GGT, ALP, bilirubin
Radiation exposing liver/biliary tract	Hepatic fibrosis/cirrhosis; focal nodular hyperplasia; cholelithiasis	ALT, AST, GGT, ALP, bilirubin, prothrombin time, screen for viral hepatitis; ultrasonography
Hematopoietic stem cell transplantation	Hepatic dysfunction; hepatic fibrosis/cirrhosis; iron overload	ALT, AST, GGT, ALP, bilirubin, prothrombin time, screen for viral hepatitis; ferritin

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; SOS: Sinusoidal obstruction syndrome; LFTs: Liver function tests.