Asparaginase-induced hepatotoxicity: rapid development of cholestasis and hepatic steatosis.

Abstract

BACKGROUND:

L-Asparaginase is a bacterial enzyme used in the treatment of acute lymphoblastic leukemia. In the ongoing U.S. Drug-Induced Liver Injury Network (DILIN) prospective study, standard and pegylated asparaginase were the most frequent cause of liver injury with jaundice among anti-cancer agents (8 of 40: 20%). The unique features of this hepatotoxicity are described.

METHODS:

Eight cases from 5 DILIN centers were reviewed for clinical course, laboratory values, imaging, and histopathology.

RESULTS:

Seven females, aged 29-59 years, and one 8-year-old boy, all with leukemia, developed jaundice within 9-21 days (median 15 days) of starting asparaginase or pegaspargase, during the first (n = 6) or second (n = 2) cycle. Prominent symptoms were jaundice (n = 8), fatigue (6), abdominal pain (6) but rarely pruritus (1). Initial median ALT level was 284 U/L (range 83-1076), Alk P 159 U/L (64-452), and bilirubin 4.4 mg/dL (3.7-8.4). Bilirubin levels rose thereafter in all patients to median peak of 17.5 mg/dL (11.7-25.7), INR rose to 1.1-1.7 and serum albumin fell to 1.5-2.6 g/dL. Hepatic imaging revealed fatty liver in all patients. Liver biopsy showed steatosis but minimal hepatocyte necrosis. One patient restarted on pegaspargase re-developed less severe injury.

CONCLUSION:

Asparaginase is a common cause of antineoplastic-induced liver injury with jaundice, typically with short latency, marked steatosis, and prolonged jaundice, which can lead to delays in antileukemic therapy. The cause of injury is likely direct inhibition of hepatic protein synthesis caused by asparagine depletion.

• Authors: Natasha Kamal, Christopher Koh, Niharika Samala, Robert J Fontana, Andrew Stolz, Francisco Durazo, Paul H Hayashi, Elizabeth Phillips, Tongrong Wang, Jay H Hoofnagle, Drug-Induced Liver Injury Network
• Journal: Hepatology international (Hepatol Int) Vol. 13 Issue 5 Pg. 641-648 (Sep 2019) ISSN: 1936-0541 [Electronic] United States
• PMID: 31392570 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Polyethylene Glycols
• pegaspargase
• Asparaginase
• Bilirubin

Topics

• Adult
• Antineoplastic Agents (therapeutic use, toxicity)
• Asparaginase (therapeutic use, toxicity)
• Bilirubin (blood)
• Chemical and Drug Induced Liver Injury (etiology)
• Cholestasis (chemically induced)
• Fatty Liver (chemically induced)
• Female
• Humans
• Liver (drug effects, pathology)
• Male
• Middle Aged
• Polyethylene Glycols (therapeutic use, toxicity)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)